Background

An efficient, well tolerated, and safe emergency treatment with a rapid onset of action is needed to prevent seizure clusters and to terminate prolonged seizures and status epilepticus.

Objectives

This study aimed to examine the efficacy, tolerability, and safety of intranasal midazolam (in-MDZ) spray in clinical practice.

Methods

In this retrospective, multicenter observational study, we evaluated all patients with peri-ictal application of in-MDZ during video-EEG monitoring at the epilepsy centers in Frankfurt and Marburg between 2 014 and 2017. For every patient, we analyzed the recurrence of any seizure or generalized tonic–clonic seizures after index seizures with and without in-MDZ administration. Treatment-emergent adverse events (TEAEs) were also evaluated.

Results

In-MDZ was used in 243 patients with epilepsy (mean age 35.5 years; range 5–76 years; 46.5% female) for treatment of 459 seizures. A median dose of in-MDZ 5 mg (i.e., two puffs; range 2.5–15 mg) was administered within a median time from EEG seizure onset until in-MDZ application of 1.18 min [interquartile range (IQR) 1.27], while median time from clinical seizure onset until in-MDZ administration was 1.08 min (IQR 1.19). In-MDZ was given within 1 min after EEG seizure onset in 171 seizures. An intraindividual comparison of seizures with and without application of in-MDZ was feasible in 171 patients, demonstrating that in-MDZ reduced the occurrence of any (Cox proportional-hazard model p < 0.001) and generalized tonic–clonic seizure (Cox proportional-hazard model p = 0.0167) over a period of 24 h. The seizure-free timespan was doubled from a median of 5.0 h in controls to a median of 10.67 h after in-MDZ administration. We additionally clustered in-MDZ administrations for the 119 patients who received in-MDZ more than once, comparing them with the index cases without in-MDZ. Even when considering subsequent seizures with in-MDZ administration, a patient receiving in-MDZ is still half as likely to incur another seizure in the upcoming 24 h as compared with when the same patient does not receive in-MDZ (hazard ratio 0.50; 95% CI 0.42–0.60; p < 0.01). In-MDZ was well tolerated without major adverse events. The most common side effects were irritation of the nasal mucosa [37 cases (8.1%)], prolonged sedation [26 cases (5.7%)], and nausea and vomiting [12 cases (2.6%)]. A decline in oxygen saturation was measured after 78 seizures (17%).

Conclusion

We conclude that in-MDZ is a safe and efficient treatment option to prevent short-term recurrence of seizures. In-MDZ can be administered very quickly by trained staff within 1–2 min after seizure onset. No major cardiocirculatory or respiratory adverse events were observed.

中文翻译：

---

视频脑电图监测期间浓缩鼻内咪达唑仑喷雾剂作为癫痫患者紧急药物的功效、耐受性和安全性。

 背景

需要一种有效、耐受性良好、安全且起效迅速的紧急治疗方法，以预防丛集性癫痫发作并终止长期癫痫发作和癫痫持续状态。

 目标

本研究旨在检验鼻内咪达唑仑 (in-MDZ) 喷雾剂在临床实践中的功效、耐受性和安全性。

 方法

在这项回顾性、多中心观察性研究中，我们评估了 2014 年至 2017 年间在法兰克福和马尔堡癫痫中心进行视频脑电图监测期间在发作期应用 in-MDZ 的所有患者。对于每一位患者，我们分析了任何患者的复发情况。在使用或不使用 MDZ 给药的情况下，发作或初次发作后的全身强直阵挛发作。还评估了治疗引起的不良事件（TEAE）。

 结果

In-MDZ 用于 243 名癫痫患者（平均年龄 35.5 岁；范围 5-76 岁；46.5% 女性）治疗 459 次癫痫发作。从 EEG 癫痫发作到使用 in-MDZ 的中位时间为 1.18 分钟，中位剂量为 in-MDZ 5 mg（即两次喷吸；范围 2.5-15 mg）[四分位距 (IQR) 1.27]，而中位剂量为 1.18 分钟。从临床癫痫发作到MDZ内给药的时间为1.08分钟（IQR 1.19）。 171 例癫痫发作中，在 EEG 癫痫发作后 1 分钟内给予 In-MDZ。对 171 名患者应用和不应用 in-MDZ 的癫痫发作进行个体间比较是可行的，证明 in-MDZ 减少了任何癫痫发作（Cox 比例风险模型p < 0.001）和全身强直阵挛癫痫发作（Cox 比例风险模型 p < 0.001）的发生。 24 小时内的危险模型p = 0.0167)。在 MDZ 内给药后，无癫痫发作时间跨度从对照组的中位 5.0 小时增加到中位 10.67 小时。我们还对 119 名多次接受 in-MDZ 治疗的患者进行了聚类，将其与未接受 in-MDZ 的指示病例进行了比较。即使考虑到使用 in-MDZ 给药后的后续癫痫发作，与未接受 in-MDZ 给药的患者相比，接受 in-MDZ 治疗的患者在接下来的 24 小时内再次发生癫痫发作的可能性仍然只有一半（风险比 0.50；95） % CI 0.42–0.60； p < 0.01）。 In-MDZ 的耐受性良好，没有发生重大不良事件。最常见的副作用是鼻粘膜刺激[37例(8.1%)]、长时间镇静[26例(5.7%)]和恶心和呕吐[12例(2.6%)]。 78 次癫痫发作 (17%) 后测量到血氧饱和度下降。

 结论

我们的结论是，in-MDZ 是预防癫痫短期复发的安全有效的治疗选择。 In-MDZ 可以由训练有素的工作人员在癫痫发作后 1-2 分钟内快速施用。没有观察到重大的心脏循环或呼吸系统不良事件。