Discussion
Statement of principal findings
Clinical effectiveness
The purpose of this assessment was to systematically review the current evidence on the effects of the use of benzodiazepines and other antiepileptic drugs for the treatment of adults with convulsive status epilepticus in the pre-hospital setting. We included evidence from four published RCTs (total number of participants 1345, of whom 1234 were adults) comparing i.v. lorazepam with i.v. diazepam and i.v. placebo; i.m. midazolam with i.v. lorazepam; i.v. levetiracetam plus i.v. clonazepam with i.v. placebo plus i.v. clonazepam; and i.v. phenobarbital plus i.v. phenytoin with i.v. diazepam plus i.v. phenytoin. 22,57,58 We considered the following primary outcomes: proportion of people with termination of seizure activity, time to seizure cessation from the time of study drug administration, recurrence of seizure, and AEs (respiratory depression and mortality). We considered the following secondary outcomes: need for additional drugs to stop seizure (within 12 hours), need for hospital admission, length of stay in ICU, return to baseline function, health-related quality of life and number of people requiring an emergency call-out. Not all trials provided data for the assessment of the prespecified primary and secondary outcomes. Differences across the four trials in terms of treatment comparisons and definitions of outcome measures precluded the possibility of combining findings in a meta-analysis. Three trials were at a low risk of bias22,57,58 and the remaining trial, published in 1988, was at a high risk of bias.59
On the whole, the evidence from the four identified trials indicates that i.v. and i.m. benzodiazepines administered by paramedics or ED personnel are safe and effective for the pre-hospital treatment of convulsive status epilepticus in adults.
In particular, evidence from Alldredge et al.’s22 trial assessing i.v. administration of lorazepam, diazepam and placebo indicates that the proportion of adults with termination of seizure is higher in the lorazepam group and in the diazepam group than in the placebo group, but with no significant differences between the two benzodiazepine groups.22 Evidence from RAMPART by Silbergleit et al.58 shows a higher rate of seizure cessation and of discharge from the ED among people treated with i.m. midazolam than among those treated with i.v. lorazepam.
Furthermore, evidence from Navarro et al.’s57 trial shows that the addition of the AED levetiracetam to the benzodiazepine clonazepam is safe for the treatment of adults with status epilepticus but does not result in a higher rate of seizure cessation.
Median time to seizure cessation from administration of i.v. medications ranged from 1.6 minutes (i.v. lorazepam) to 15 minutes (i.v. diazepam plus phenytoin) across trials. In the trial by Silbergleit et al.58 that assessed i.v. lorazepam versus i.m. midazolam, the reported median time from drug administration to termination of seizure was shorter with i.v. lorazepam (1.6 minutes vs. 3.3 minutes). However, this does not take into account the time from paramedic arrival to drug administration, which was longer in the i.v. group than in the i.m. group (4.8 minutes vs. 1.2 minutes, respectively), reflecting the longer time needed to establish i.v. access. Thus, there was little difference in total time from paramedic arrival to seizure termination in the two benzodiazepine groups.58
The frequency of cardiorespiratory complications and the need for respiratory assistance were generally low across trials, with no significant differences between treatment arms of individual trials. Recurrent seizures, need for additional drugs to stop seizures, need for hospital admission and length of stay in ICU were also similar between treatment arms of the individual trials that assessed these outcomes.
It is worth noting that, despite the beneficial outcomes associated with the use of benzodiazepines in the pre-hospital setting, a proportion of people who received the active treatment were still experiencing seizures at the time of arrival to the ED (from 16% to 67% of people across trials).
Overall, our results are in line with current clinical recommendations. There is a general agreement that benzodiazepines should be used for the initial treatment of status epilepticus.4,24,65 The 2016 evidence-based guideline of the American Epilepsy Society,24 for example, recommends the administration of a benzodiazepine (specifically i.m. midazolam, i.v. lorazepam or i.v. diazepam) as the initial therapy of choice.
Cost-effectiveness
Despite comprehensive literature searches, we identified only one economic evaluation of first-line treatments for status epilepticus that matched our predefined inclusion criteria. The findings of this economic evaluation indicate that there is potential for good pre-hospital care to improve outcomes and significantly reduce the burden of hospital resource use.
Strength and limitations of the assessment
This assessment was conducted in accordance with current methodological standards, and its methods were prespecified in a peer-reviewed research protocol (PROSPERO registration CRD42020201953) (www.crd.york.ac.uk/prospero/display_record.php?RecordID=201953; accessed 4 August 2020). In particular, we conducted comprehensive literature searches of major electronic databases and relevant websites and used transparent methods for data selection and extraction.
There are, however, some limitations to take into consideration when interpreting the findings of this assessment:
- We identified only a limited number of trials for the pre-hospital treatment of convulsive status epilepticus in the adult population.
- The included studies differed in terms of treatment comparisons and choice and definition of outcome measures. This hampered the possibility of conducting any meaningful meta-analysis.
- None of the included trials was conducted in the UK, with three of the four included trials conducted in the USA.
- Only one study the met the inclusion criteria for economic evaluation, and the study in question was limited by its reliance on retrospective observational data from a small number of cases, and a narrow focus on treatment acquisition costs in the relation to outcomes.
Uncertainties from the assessment
Clinical effectiveness
In the pre-hospital setting, the optimal pharmacological treatment for adults with convulsive status epilepticus or prolonged seizures is still unclear. The trials identified for this assessment focused exclusively on i.m. or i.v. treatment that needed to be given by paramedics.
Current NICE clinical guidance on the diagnosis and management of epilepsies recommends buccal midazolam as first-line pre-hospital treatment in children, young people and adults with prolonged or repeated seizures in the community and rectal diazepam as an alternative option or when buccal midazolam is not available.25 These have the advantage that they can be given immediately by trained caregivers in those at risk, rather than waiting for paramedics to attend. Administration of rectal diazepam requires, however, the removal of clothes and adequate positioning of the patient66 and may be regarded as a less practicable and socially acceptable option for adult patients than benzodiazepines administered via the mouth or nose. In children, buccal and intranasal midazolam have been reported to have similar efficacy for the early treatment of status epilepticus and the use of midazolam by non-i.v. routes has been proposed as a favourable alternative to diazepam.66,67 Nevertheless, in the adult population, we have not identified any RCTs assessing the use of buccal midazolam or rectal diazepam, or indeed intranasal midazolam, which, even though unlicensed, can also be used in clinical practice. Although it would not be acceptable to perform placebo-controlled trials of such interventions, given the recognised effectiveness of benzodiazepines in stopping prolonged seizures, head-to-head randomised clinical trials, which compare different routes of benzodiazepines administration, would be particularly useful to inform clinical practice. Comparisons of interest include rectal diazepam versus nasal or buccal midazolam administered by trained caregivers in people with known epilepsy at high risk of status epilepticus; i.m. midazolam versus buccal midazolam versus intranasal midazolam administered by paramedics; and i.v. lorazepam versus i.m. midazolam administered by paramedics, which could also include patients in whom caregiver administration of rectal, buccal or nasal benzodiazepines had failed to stop the seizure. Observational studies using existing routinely collected data may provide some information on effectiveness and safety of acute rescue therapy (whatever route of administration) versus no rescue therapy, but they are more susceptible to methodological bias.
The doses of the benzodiazepines used in the identified studies were effective, but it is unclear whether other doses may have similar or different efficacy and safety.
The level of training paramedics should receive to recognise status epilepticus and treat people in the community setting is unknown. Similarly, the acceptability and ease of administration of different pharmacological treatments in the pre-hospital setting have not been properly evaluated but rather reported anecdotally.
Cost-effectiveness
Overall, there is a lack of robust data from which to draw firm conclusions on the cost-effectiveness of first-line treatments of status epilepticus, suggesting that further research is required. While no firm conclusions can be drawn from the available studies, cost-of-illness studies do suggest that the duration of the status epilepticus episode is a key determinant of the length of hospitalisation and the management cost, with the analysis also showing a clear relationship between duration of episode and time to treatment. This suggests that there is potential for more effective first-line treatments that can reduce the time to seizure control, to deliver significant cost-savings that can offset increases in the initial treatment cost.
Conclusions
Implications for health care
Both 2 mg of i.v. lorazepam and 5 mg of i.v. diazepam administered by paramedics are more effective than placebo for the pre-hospital treatment of convulsive status epilepticus in adults; 10 mg of i.m. midazolam is non-inferior to 4 mg of i.v. lorazepam in the pre-hospital setting. The addition of levetiracetam to clonazepam does not offer clear advantages over clonazepam alone.
Recommendations for research
Harmonisation of outcome measures would be useful to facilitate future clinical research.
Identification of the optimal pre-hospital pharmacological treatment of adults with status epilepticus requires further RCTs assessing different benzodiazepines (and potentially other anticonvulsant medications) as well as their route of administration and acceptability.
This assessment indicates that large well-designed clinical trials are needed to assess the use of i.v. lorazepam versus i.v. diazepam and to confirm the efficacy and safety of i.m. midazolam compared with i.v. lorazepam. In the pre-hospital setting, i.m. midazolam may have the advantage of a rapid and easy administration, which counterbalances the faster effect of i.v. medications.
Given the current clinical recommendations about the use of benzodiazepines, which can be administered rectally or via the mouth by caregivers in the pre-hospital setting, and the absence of evidence in the adult population, direct head-to-head trials comparing buccal midazolam and rectal diazepam are required to establish their efficacy, safety and acceptability.
It is also necessary to establish which midazolam formulation is the best option for the first-line treatment of adults with convulsive status epilepticus. Future clinical trials comparing i.m. midazolam versus buccal midazolam and versus intranasal midazolam would provide useful information to inform the pre-hospital management of patients, especially when i.v. access is not feasible. Further trials aiming to conclusively establish whether or not i.m. midazolam is more effective than i.v. lorazepam, as suggested by the single trial in the review, would be helpful.
Future clinical studies could also aim to establish optimal doses of benzodiazepines used as first-line treatments in the pre-hospital setting.
It would be important to improve adherence to clinical guidelines on the use of currently available benzodiazepines in the pre-hospital setting. For example, a recent large trial of second-line hospital-based treatment of status epilepticus in the USA found that only 57% of patients had received benzodiazepines before arrival at the hospital and 7% breached the protocol by not receiving a predefined minimally adequate benzodiazepine dose.44
As there is still a proportion of patients who do not respond to treatment, further research aiming to understand the underlying pathophysiology of treatment response would be useful to inform future treatment development.
High-quality economic evaluations are required to determine the value for money of different treatments for convulsive status epilepticus and their modes of administration. It would be useful if future economic evaluations could capture the full cost of managing the convulsive episode up to the time of discharge from hospital. In cases where higher-cost first-line treatments are not fully offset by subsequent management cost savings, it may be necessary to model the impact of improved short-term outcomes on longer-term health-related quality of life and future resources use.