Intranasal midazolam as first-line inhospital treatment for status epilepticus: a pharmaco-EEG cohort study

Abstract

Objective: We sought to evaluate the efficacy and tolerability of intranasal midazolam (in-MDZ) as first-line inhospital therapy in patients with status epilepticus (SE) during continuous EEG recording.

Methods: Data on medical history, etiology and semiology of SE, anticonvulsive medication usage, efficacy and safety of in-MDZ were retrospectively reviewed between 2015 and 2018. Time to end of SE regarding the administration of in-MDZ and ß-band effects were analyzed on EEG and with frequency analysis.

Results: In total, 42 patients (mean age: 52.7 ± 22.7 years; 23 females) were treated with a median dose of 5 mg of in-MDZ (range: 2.5-15 mg, mean: 6.4 mg, SD: 2.6) for SE. The majority of the patients suffered from nonconvulsive SE (n = 24; 55.8%). In total, 24 (57.1%) patients were responders, as SE stopped following the administration of in-MDZ without any other drugs being given. On average, SE ceased on EEG at 05:05 (minutes:seconds) after the application of in-MDZ (median: 04:56; range: 00:29-14:53; SD:03:13). Frequency analysis showed an increased ß-band on EEG after the application of in-MDZ at 04:07 on average (median: 03:50; range: 02:20-05:40; SD: 01:09). Adverse events were recorded in six patients (14.3%), with nasal irritations present in five (11.9%) and prolonged sedation occurring in one (2.6%) patient.

Conclusions: This pharmaco-EEG-based study showed that in-MDZ is effective and well-tolerated for the acute treatment of SE. EEG and clinical effects of in-MDZ administration occurred within 04:07 and 5:05 on average. Intranasal midazolam appears to be an easily applicable and rapidly effective alternative to buccal or intramuscular application as first-line treatment if an intravenous route is not available.

Figure 1

Kaplan–Meier graph showing the time from in‐MDZ application to the cessation of SE in patients rated as responders and nonresponders to in‐MDZ. In three cases rated as nonresponders, other anticonvulsants such as lorazepam, brivaracetam, or lacosamide were given prior to the end of SE.

Figure 2

Beta‐band power increase in one example subject that had the least amount of noise. Beta‐band power increase is visible within a narrow band (18–25 Hz), starting 4 min after in‐MDZ application.

Figure 3

(A) Quantification of the signal increase over the whole frequency band (1‐30) Hz. For this, we calculated the relative change ([time_after MDZ – time_before MDZ]/ time_before MDZ) and plotted this relative change. The average increase in beta‐band power was 15.7%, the maximum increase was found at 21Hz at 18.3%. (B) Quantification of the beta‐band increase over time. The beta‐band power increase starts at 4.5 min after in‐MDZ application. It then stays on a plateau for about 3 min (until 7.5 min after in‐MDZ application) and diminishes back to baseline.