Assessment of clinical effectiveness

This chapter reports the evidence for the clinical effectiveness of treatments for status epilepticus in pre-hospital and ED settings.

Systematic review methods

The systematic review was conducted in accordance with the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for reporting systematic reviews and meta-analyses.54,55 The methods for this assessment were pre-specified in a research protocol (PROSPERO registration CRD42020201953) (www.crd.york.ac.uk/prospero/display_record.php?RecordID=201953; accessed 4 August 2020).

Identification of studies (search strategy and information sources-dates)

A sensitive search strategy to identify all relevant literature, using database index terms and text words, was developed by an information specialist. The search encompassed the facets of status epilepticus, all benzodiazepines and antiepileptics in addition to named drugs, and the pre-hospital setting. The results were limited to RCTs in accordance with the review protocol. There were no date or language restrictions. The electronic databases searched included MEDLINE, EMBASE and PsycInfo^® (all via the Ovid interface), and EBSCOhost, CINAHL and Cochrane CENTRAL. The searches were carried out in July 2020. The complete search strategies are reported in Appendix 1.

Inclusion and exclusion criteria

Types of studies

Evidence was considered from parallel-group RCTs and cluster RCTs assessing pharmacological interventions for the first-line treatment of convulsive status epilepticus in adults. Studies were included regardless of their publication status or language of publication. The following types of reports were excluded:

• crossover trials
• single-armed studies and observational studies
• narrative reviews, editorials and opinions
• case reports
• conference abstracts for which a full publication or further methodological information could not be found
• non-English-language reports for which a translation could not be organised.

Types of participants

Eligible participants for this assessment were:

• adults (aged ≥ 16 years) with convulsive status epilepticus attended out of hospital by non-medical staff (e.g. caregiver)
• adults (aged ≥ 16 years) with convulsive status epilepticus attended out of hospital by paramedics
• adults (aged ≥ 16 years) experiencing convulsive status epileptics out of hospital who are attended (receive their first-line treatment) at arrival at the ED.

We did not restrict eligibility of participants to a specific definition of status epilepticus. Traditionally, status epilepticus was defined as a seizure lasting ≥ 30 minutes, but more recent definitions indicate ≥ 5 minutes of either continuous seizure activity or repetitive seizures with no recovery of consciousness in between.3,7 It was anticipated that some studies may enrol participants with a metabolic cause of status epilepticus, for example hypoglycaemia or severe sodium or potassium imbalances. Some such metabolic disorders need to be corrected slowly (e.g. hyponatraemia or hypernatraemia) but the use of anticonvulsants is still appropriate to stop the seizure, while correcting the underlying metabolic disorder. Therefore, studies with a mixed population of patients with a known epilepsy syndrome and patients with a reversible metabolic cause of seizures were deemed eligible for inclusion. Studies recruiting a mix of other eligible and ineligible participants (e.g. studies including both children and adults) were deemed suitable for inclusion, providing that demographic and outcome data were reported separately for the group of interest or the proportion of ineligible participants was < 10% of the study participants. Studies that focused exclusively on children and young adults or on patients with non-convulsive status epilepticus were excluded.

Types of interventions

The interventions considered were any benzodiazepine offered as first-line treatment for the treatment of convulsive status epilepticus in adults administered either on site by paramedics or non-medical staff before or during transfer of patient to the ED or on arrival at the ED by ED staff.

Newer antiepileptic drugs (AEDs) including levetiracetam, sodium valproate and phenytoin, so far as they were used as first-line treatment in the pre-hospital setting or at arrival at the ED, were also considered. Pharmacological treatments were considered regardless of whether they were used as monotherapy or combination therapy and regardless of their routes of administration [i.e. i.v., i.m., intranasal, buccal, rectal or oromucosal administration].

Any second-line treatment of convulsive status epilepticus was excluded, as were antiepileptic drugs and anticonvulsants used in hospital or intensive care units (ICUs). We considered first-line treatment as any immediate pharmacological treatment that could be repeated once, and second-line treatment as any subsequent pharmacological treatment that involved the use of another class of drug, such as an anticonvulsant. Studies with a focus on in-hospital or second-line treatments of status epilepticus were excluded.

Types of comparators

The comparators considered included placebo or any of the active treatments eligible for this review. Comparisons of two or more active treatments or two or more treatment protocols of the same active treatment (e.g. different doses, dose frequencies or routes of administration) were eligible for inclusion.

Types of outcomes

The following primary outcomes were considered:

• seizure cessation, measured in terms of –
  • the number of people with cessation of seizure activity within 5–15 minutes of study drug administration (or any designated period of time as specified by trial investigators)
  • the time to seizure cessation from the time of study drug administration
• recurrence of seizure, measured in terms of –
  • the number of people with recurrence of seizures within a designated period (probably 12 hours)
  • the time from seizure cessation to recurrence
• adverse events (AEs) –
  • respiratory depression
  • 30-day mortality.

Secondary outcomes considered were:

• need for additional drugs to stop seizure (within 12 hours)
• need for hospital admission
• length of stay in ICU
• 6-month mortality
• return to baseline function (3–6 months)
• health-related quality of life (e.g. psychosocial sequelae, depression, anxiety)
• number of people requiring an emergency call out (among those attended out of hospital by non-medical staff).

Data extraction strategy

Two review authors (MC and MI) independently screened all citations identified by the search strategies. Full-text versions of potentially relevant articles were retrieved and independently assessed for eligibility by the same two reviewers. Disagreements were resolved by discussion or consultation with a third review author (MB, LA or CC). A data extraction spreadsheet was developed for the purpose of this assessment, piloted and amended as necessary. Two review authors (MC and MI) independently extracted information from each study on study characteristics, participant characteristics, flow of participants through the study, details of intervention/comparators, specified outcomes, potential confounding factors, funding and declarations of interest by study investigators. Disagreements were resolved by discussion.

Critical appraisal strategy

The risk of bias of included RCTs was assessed independently by two review authors (MC and MI) using a revised Cochrane Risk of Bias tool for randomised trials (RoB 2).56 Disagreements were resolved by discussion. For the purposes of the risk-of-bias assessments only, we categorised the specified outcomes into two categories, with advice from the review team’s clinical expert (CC): subjective (i.e. requiring judgement by the observer) or objective (i.e. not requiring judgement by the observer). It was decided to split the subjective outcome ‘respiratory depression’ to include the specified objective outcome ‘respiratory depression requiring ventilation’ to take account of the objective nature of the ventilation component. The outcomes were categorised as follows:

• subjective outcomes –
  • seizure cessation
  • recurrence of seizure
  • respiratory depression (all related outcomes with the exception of respiratory depression requiring ventilation)
  • return to baseline neurological function
  • quality of life.
• objective outcomes –
  • mortality
  • need for additional treatment
  • need for hospital admission
  • length of stay in ICU
  • number of people requiring an emergency call out
  • respiratory depression requiring ventilation.

Methods of data synthesis

Random-effects meta-analyses and subgroup analyses had been specified in the protocol but were not carried out owing to the limited number of identified studies and their heterogeneity in terms of treatment comparisons and reported outcomes. The results of each included study were tabulated and summarised narratively for each outcome.

Results of the evidence synthesis

Quantity of the evidence (studies included and excluded)

The literature searches identified 191 records, and 46 additional records were identified in the study brief for a total of 237 retrieved records. After deduplication, 113 records were screened for relevance. Of these, 73 were considered potentially relevant and selected for full-text assessment. Eight articles could not be obtained because of COVID-19 pandemic restrictions. The search also identified one ongoing study. Of the 64 articles retrieved and assessed in depth, 13 articles relating to four studies met the inclusion criteria, while 51 articles were not deemed suitable for inclusion.

A PRISMA flow diagram detailing the process of study selection is presented in Figure 1. Appendices 2–4 provide the bibliographic details of the included, excluded and ongoing studies, respectively.

FIGURE 1 The PRISMA flow diagram of selected studies. Reproduced with permission from Cruickshank et al.60 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure. (Figure not reproduced here; see the original article.)

Study characteristics

The study characteristics of the four included RCTs22,57–59 (total number of participants 1345, of whom 1234 were adults) are detailed in Appendix 5 and are summarised in Table 1. All four trials were published in full. Three trials enrolled only adults22,57,59 and one trial included a mixed population of adults (89%) and children (11%).58 Each trial reported a different treatment comparison. The trial by Alldredge et al.,22 with a total of 205 participants, was the only three-arm trial and compared 2 mg of i.v. lorazepam with 5 mg of i.v. diazepam and i.v. placebo; the trial by Navarro et al.,57 with a total of 203 participants, compared 2.5 g of i.v. levetiracetam plus 1 mg of clonazepam with i.v. placebo plus 1 mg of clonazepam; the trial by Silbergleit et al.,58 with a total of 893 participants, of whom 782 were adults, compared 10 mg of i.m. midazolam with 4 mg of i.v. lorazepam; and the remaining trial, by Shaner et al.,59 with a total of 44 participants, assessed 100 mg/minute i.v. phenobarbital plus 40 mg/minute optional phenytoin compared with 2 mg/minute i.v. diazepam plus 40 mg/minute phenytoin.

Three trials involved the administration of study drugs by paramedics22,57,58 and one study was based in an emergency room setting.59

Three trials were conducted in the USA22,58,59 and one trial was conducted in France.57 Shaner et al.,59 recruited participants from a single centre, whereas the other three trials were multicentre: one physician-based hospital and nine destination hospitals;22 13 emergency medical centres and 26 hospital departments;57 and 4314 paramedics, 33 emergency medical centres and 79 receiving hospitals.58

Participant characteristics

The eligible population in the trial by Silbergleit et al.,58 known in the literature as the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART), consisted of adults and children with body weight of at least 13 kg. Via personal correspondence with the principal investigator (Professor Robert Silbergleit, Department of Emergency Medicine, University of Michigan, MI, USA), it was established that 116 participants were aged < 16 years and that a publicly accessible data set of participant-level data was available. This data set was obtained, and relevant data for participants aged ≥ 16 years were extracted. Despite there being a comprehensive data dictionary alongside the data, it was not always possible to identify which variables were pertinent for the relevant outcomes. Therefore, only primary outcomes that were considered to be of clear origin in the data set are reported in this assessment.

Table 2 presents a summary of the characteristics of participants included in the four trials and Appendix 6 presents full details of participants’ characteristics.

The mean age was reported in all four trials and ranged from 55 years57 to 66 years22 in the active treatment arms and from 43.8 years59 to 71 years22 in the control arms. All four trials also reported the sex of participants and all involved more males than females, with around two-thirds of study populations tending to be male.

With regard to the discharge diagnosis, two trials distinguished between status epilepticus and non-epileptic psychogenic events or spells. Navarro et al.57 reported a final diagnosis of status epilepticus for 97.1% of participants in the levetiracetam plus clonazepam group and 94.1% of participants in the placebo plus clonazepam group and a diagnosis of a non-epileptic psychogenic event for 2.9% and 5.9% of participants in each treatment group, respectively. For each treatment group (midazolam group and lorazepam group), Silbergleit et al.58 reported a diagnosis of status epilepticus for 90% of participants, a diagnosis of a non-epileptic spell for 7% of participants and an undetermined diagnosis for 3% of participants. Shaner et al.59 reported 55.6% and 50% participants with focal features in the phenobarbital and placebo groups, respectively.

Two trials reported time from onset of status epilepticus to drug administration. Alldredge et al.22 reported means of 34 [standard deviation (SD) 17.8] minutes, 31.3 (SD 14.5) minutes and 46.7 (SD 38.8) minutes for the lorazepam, diazepam and placebo groups, respectively. Navarro et al.57 reported a median of 58 (range 15–135) minutes for the levetiracetam plus clonazepam group and a median of 60 (range 20–258) minutes for the placebo plus clonazepam group.

With respect to the total dose of active drug administered (see Appendix 6), Alldredge et al.22 reported the number of injections received by the study participants [lorazepam arm, 34 participants received one injection (2 mg) and 32 received two injections (4 mg); diazepam arm, 34 participants received one injection (2 mg) and 32 received two injections (4 mg); placebo arm, 29 participants received one injection and 42 received two injections]. Shaner et al.59 reported a range of 5–23 mg/kg phenobarbital administered in the phenobarbital plus optional phenytoin arm. In addition, seven participants in this group received phenytoin in doses ranging from 6 to 23 mg/kg. The remaining two trials did not report the total dose of study drug.57,58

All four included trials reported causes of status epilepticus (see Appendix 6). A subtherapeutic level of AEDs was the most common cause in three trials,22,58,59 while lesion was reported as the most frequent cause of status epilepticus in the Navarro et al. trial.57 Other commonly reported causes were alcohol abuse22,57 or withdrawal,59 infections22,57,59 and metabolic factors.22,57,59

None of the included trials reported the patients’ previous history of status epilepticus. The proportion of participants with a history of seizures ranged from 54.6% to 66.2% in the treatment arms of the Alldredge et al. trial22 and from 61% to 78% in the treatment arms of the Shaner et al. trial.59 The proportion of participants with a history of epilepsy ranged from 59% to 70%57 in the treatment arms of the Navarro et al. trial57 and from 65% to 66% in the Silbergleit et al. trial.58 None of the trials reported presence of known difficult-to-treat epilepsy, or functional dependence status at baseline.

All characteristics reported in the publications by Silbergleit et al.58 (i.e. RAMPART) were comparable to those extracted for the adult population from the data set received by the trial investigators.58

Risk-of-bias assessment of included studies

Each risk-of-bias domain was assessed separately for objective outcomes and for subjective outcomes for each of the four included trials. Therefore, a total of eight risk-of-bias assessments are reported. Figure 2 presents the summary of the risk-of-bias assessments for all included trials. Risk-of-bias assessments of individual trials are presented in Figure 3.

FIGURE 2 Summary of risk of bias of all included trials. (Figure not reproduced here; see the original article.)

FIGURE 3 Risk-of-bias assessments of individual trials apart from Shaner et al.,59 which was judged to be at a high risk of bias (due to the high risk-of-bias assessment of measurement of subjective outcomes). All other trials were considered to have a low risk of bias.22,57,58 CLZ, clonazepam; DIZ, diazepam; LEV, levetiracetam; LOR, lorazepam; MDZ, midazolam; PBO, placebo; PHB, phenobarbital; PHT, phenytoin. Reproduced with permission from Cruickshank et al.60 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure. (Figure not reproduced here; see the original article.)

For the ‘randomisation process’ domain, three trials were judged to be at a low risk of bias,22,57,58 but in the Shaner et al.59 trial there was insufficient information on which to make a definitive judgement.

Regarding the ‘deviations from intended interventions’ domain, three trials were properly blinded and judged to be at a low risk of bias;22,57,58 the trial by Shaner et al.59 was described as ‘non-blinded’, indicating that those delivering the intervention would have been aware of the allocated intervention. Nevertheless, it was considered unlikely that participants would have been aware of the intervention received because of the nature of the clinical condition (i.e. status epilepticus). There was insufficient information on which to make a judgement regarding deviations from the intended intervention due to the experimental context. The combination of these factors led to a judgement of ‘some concerns’ for this trial.59

All four trials were judged to be at a low risk of bias for ‘missing outcome data’ because of the low withdrawal/discontinuation rates, which were balanced across treatment groups.22,57–59

The ‘measurement of the outcome’ domain was judged to be at a low risk of bias for three trials for both objective and subjective outcomes.22,57,58 As the Shaner et al.59 trial was not blinded, the measurement of the subjective outcomes was judged to be at a high risk of bias, but objective outcomes were less likely to be affected by this bias and, therefore, were judged to be at a low risk of bias.

For the Shaner et al.59 trial, there was insufficient information on which to make a robust judgement about the ‘selection of the reported result’. There was no evidence of selective reporting in the remaining three trials, which were considered to be at a low risk of bias for this domain.22,57,58

Overall, three trials were assessed to be at a low risk of bias for both the subjective and the objective outcomes.22,57,58 The trial by Shaner et al.,59 which was published in 1988 and was not blinded, was assessed as being at a high risk of bias for subjective outcomes and with some concerns for objective outcomes.

Results of the individual studies and synthesis: primary outcomes

A summary of the primary clinical outcomes reported in the four included trials is presented in Table 3. Full details of these outcomes, including outcome definitions, are presented in Appendices 7 and 8.

All four included trials reported the number of people with cessation of seizure activity, albeit the definitions of the outcome varied across studies. Two trials22,58 defined the outcome as termination of seizures before arrival at the ED, with one of these also specifying that no rescue therapy was needed.58 These two trials both involved i.v. administration of lorazepam in either the intervention group22 or the control group,58 with the proportion of participants in the lorazepam groups with seizure cessation being similar (59.1% and 63.4%, respectively). The trial by Alldredge et al.22 showed that, compared with placebo, both 2 mg of i.v. lorazepam and 5 mg of i.v. diazepam were effective in terminating the episodes of status epilepticus (the proportions of participants with seizure cessation were 59.1%, 42.0% and 21.1%, in the lorazepam, diazepam and placebo groups, respectively).22 In RAMPART, by Silbergleit et al.,58 assessing 10 mg of i.m. midazolam versus 4 mg of i.v. lorazepam, the proportion of adults achieving seizure cessation at the time of arrival in the hospital ED was similar between intervention groups (73.9% and 62.4% in the i.m. midazolam and i.v. lorazepam groups, respectively) and akin to those reported for the overall mixed population (73.4% and 63.4% in the i.m. midazolam and i.v. lorazepam groups, respectively).58

The remaining two trials specified that seizures had to stop within either 15 minutes57 or 10 minutes59 from onset of treatment. In general, the proportion of participants with seizure cessation was similar across these trials and across treatment groups: 73.2% of participants in the 2.5 g of i.v. levetiracetam plus 1 mg of clonazepam group and 83.8% of participants in the i.v. placebo plus 1 mg of clonazepam group of the Navarro et al. trial,57 and 72.2% of participants in the 100 mg/minute i.v. phenobarbital plus 40 mg/minute phenytoin group in the Shaner et al.59 trial. The exception was the 2 mg/minute i.v. diazepam plus 40 mg/minute phenytoin control group in the Shaner et al.59 trial, which reported only 33.3% of participants with seizure cessation.

All four trials reported time to seizure cessation from administration of study drug using broadly similar definitions. The median time for i.v. administration ranged from 1.6 (i.v. lorazepam group)58 to 15 minutes (i.v. diazepam plus phenytoin group).59 The Navarro et al.57 trial reported administration times of up to 50 minutes. For time to seizure cessation, Alldredge et al.22 reported a HR of 2.94 [95% confidence interval (CI) 1.41 to 5.88] for the lorazepam versus the placebo comparison and a HR of 1.54 (95% CI 0.85 to 2.77) for the lorazepam versus the diazepam comparison.

Two trials reported the number of participants with recurrence of seizures. Navarro et al.57 reported that 10.4% of the i.v. levetiracetam plus clonazepam group and 19.1% of the placebo plus clonazepam group experienced seizure recurrence during their hospital stay, whereas Silbergleit et al.58 reported that 11.4% of participants in the i.m. midazolam group and 10.6% of participants in the i.v. lorazepam group experienced recurrence of seizures within 12 hours of arrival at the ED.

None of the four included trials reported time from seizure cessation to recurrence. Silbergleit et al.58 reported that the mean time of seizure recurrence since ED arrival for the adult population was 4.3 (SD 9.4) minutes in the i.m. midazolam group (n = 53) and 4.5 (SD 13.6) minutes in the i.v. lorazepam group (n = 50).

Table 4 presents a summary of the primary safety outcomes reported by the four trials. Full details of these outcomes, including outcome definitions, are presented in Appendix 9.

Respiratory depression was reported in three of the four trials, with varying definitions across trials.22,57,58 Silbergleit et al.58 reported ‘respiratory depression’ as a serious adverse event (SAE) in 6.4% of total enrolments in the i.m. midazolam group and 10% in the i.v. lorazepam group. Alldredge et al.22 reported ‘change in respiratory status requiring ventilation assistance by bag–valve–mask or an attempt at ventilation’ in 10.6% of the i.v. lorazepam group, 8.8% of the i.v. diazepam group and 15.5% of the placebo group. Navarro et al.57 reported several outcomes relating to respiratory depression; these included ‘prehospital health failures: respiratory’ in 10.3% of the i.v. levetiracetam plus clonazepam group and 4.5% of the placebo plus clonazepam groups and ‘need for prehospital assistance: respiratory’ in 42.6% of the i.v. levetiracetam plus clonazepam group and 34.8% of the placebo plus clonazepam group. In addition, a small number of participants was reported to experience ‘respiratory, thoracic and mediastinal’ AEs or SAEs [i.e. hypoxia (SAE), acidosis respiratory (AE), hypoxaemia (AE), respiratory distress (AE), respiratory failure (AE)], with a maximum of two participants (2.9%) in any category.57

The protocol for this assessment specified 30-day mortality as a primary outcome and 6-month mortality as a secondary outcome. However, none of the included studies reported mortality at these specified time points. Two trials22,57 reported the proportion of participants who died between enrolment and discharge from hospital.22,61 The differences in mortality rates among treatment groups in each individual trial were not significant. In the trial by Alldredge et al.,22 mortality rates ranged from 4.4% to 7.6% in the i.v. diazepam and i.v. lorazepam group, respectively, whereas the proportion of deaths in the placebo group was 15.5%.22 In the Navarro et al.57 trial, the proportion of people who died was 4.5% in the levetiracetam plus clonazepam group and 6.2% in the placebo plus clonazepam group.57 Silbergleit et al.58 reported similar mortality rates among adults treated with i.m. midazolam and those treated with i.v. lorazepam (2.8% vs. 2%, respectively).

Results of the individual studies and synthesis: secondary outcomes

A summary of the secondary outcomes reported in the four included studies is presented in Table 5. Full details of these outcomes, including outcome definitions, are presented in Appendix 10.

The need for additional drugs to stop a seizure within 12 hours was specified in the protocol for this assessment. None of the studies reporting this outcome specified a 12-hour limit, so relevant outcomes are reported here as defined by the trials’ investigators. Outcome definitions varied across studies.

Navarro et al.57 reported that similar numbers of participants in the levetiracetam plus clonazepam group and in the placebo plus clonazepam groups required a second clonazepam injection after 5 minutes (41.8% and 43.1%, respectively) and an injection of antiepileptic drugs after 15 minutes (28.4% and 23.1%, respectively).57 In the trial by Shaner et al.,59 anaesthesia was needed in one participant (5.6%) who received i.v. diazepam plus phenytoin but in none of those treated with i.v. phenobarbital plus phenytoin. RAMPART, by Silbergleit et al.,58 reported the number of participants who required rescue therapy and the number who were still having seizures on arrival at the ED.22 The proportion of participants who received rescue therapy and whose seizures were terminated was 10.5% in the i.m. midazolam group and 12.8% in the i.v. lorazepam group; the proportion of those who received rescue therapy and whose seizures were not terminated was 4.9% in the i.m. midazolam group and 9.4% in the i.v. lorazepam group; the proportion of participants whose seizures were not terminated but did not receive rescue therapy was 11.2% in the i.m. midazolam group and 14.4 in the i.v. lorazepam group. In general, those in the i.m. midazolam group were less likely to have seizures at arrival at the ED than those in the i.v. lorazepam group (proportion of participants without seizures: 83.9% vs. 76.2% in the i.m. and i.v. groups, respectively).

Two trials reported the numbers of participants who were admitted to hospital. Alldredge et al.22 reported that a higher proportion of participants were admitted to ICU (56.9% in the i.v. lorazepam arm, 47.8% in the i.v. diazepam arm and 63.4% in the placebo arm) than to a hospital ward (29.2%, 26.9%, 23.9%, respectively). In the Silbergleit et al.58 trial, more participants were admitted to a hospital ward (57.6% in the i.m. midazolam group and 65.6% in the i.v. lorazepam group) than to ICU (28.6% and 36.2%, respectively).

Navarro et al.57 reported that, in each treatment group, the median length of stay in ICU was 3 days, whereas Silbergleit et al.58 reported a mean of 5.7 days for the i.m. midazolam group and of 4.1 days for the i.v. lorazepam group.

None of the identified trials reported 6-month mortality, health-related quality of life or the number of people requiring an emergency call-out.

Summary of clinical effectiveness

Findings from four included trials showed that the benzodiazepines were effective for the pre-hospital treatment of status epilepticus in adults, albeit the definitions of status epilepticus and outcome measures varied across trials. In particular, more of the participants receiving either 2 mg of i.v. lorazepam or 5 mg of i.v. diazepam had no seizures at arrival to the ED than those treated with placebo. A dose of 10 mg of i.m. midazolam was as effective as 4 mg of i.v. lorazepam in controlling status epilepticus. Of some note is that participants treated with i.m. midazolam had a higher rate of discharge from the hospital ED than those treated with i.v. lorazepam. Across the trials, levels of seizure recurrence was generally low, as was the number of AEs in terms of respiratory depression and mortality.