Neurology/original research
Real-World Midazolam Use and Outcomes With Out-of-Hospital Treatment of Status Epilepticus in the United States

https://doi.org/10.1016/j.annemergmed.2022.05.024Get rights and content

Study objective

Guidelines recommend 10-mg intramuscular midazolam as the first-line treatment option for status epilepticus. However, in real-world practice, it is frequently administered intranasally or intravenously and is dosed lower. Therefore, we used conventional and instrumental variable approaches to examine the effectiveness of midazolam in a national out-of-hospital cohort.

Methods

This retrospective cohort study of adults with status epilepticus used the ESO Data Collaborative research dataset (January 1, 2019, to December 31, 2019). The exposures were the route and dose of midazolam. We performed hierarchical logistic regression and 2-stage least squares regression using agency treatment patterns as an instrument to examine our outcomes, rescue therapy, and ventilatory support.

Results

There were 7,634 out-of-hospital encounters from 657 EMS agencies. Midazolam was administered intranasally in 20%, intravenously in 46%, and intramuscularly in 35% of the encounters. Compared with intramuscular administration, intranasal midazolam increased (risk difference [RD], 6.5%; 95% confidence interval [CI], 2.4% to 10.5%) and intravenous midazolam decreased (RD, −11.1%; 95% CI, −14.7% to −7.5%) the risk of rescue therapy. The differences in ventilatory support were not statistically significant (intranasal RD, −1.5%; 95% CI, −3.2% to 0.3%; intravenous RD, −0.3%; 95% CI, −1.9% to 1.2%). Higher doses were associated with a lower risk of rescue therapy (RD, −2.6%; 95% CI, −3.3% to −1.9%) and increased ventilatory support (RD, 0.4%; 95% CI, 0.1% to 0.7%). The instrumental variable analysis yielded similar results, except that dose was not associated with ventilatory support.

Conclusion

The route and dose of midazolam affect clinical outcomes. Compared with intramuscular administration, intranasal administration may be less effective and intravenous administration more effective in terminating status epilepticus, although the differences between these and previous results may reflect the nature of real-world data as opposed to randomized data.

Introduction

Generalized, convulsive status epilepticus is a neurologic emergency that relies on out-of-hospital EMS providers to administer first-line treatment when the status epileticus develops outside the hospital, making our out-of-hospital system critical for ensuring that patients are appropriately treated. Guidelines recommend midazolam as a single 10-mg intramuscular injection by out-of-hospital or hospital providers because its administration is simple and fast and there is high-quality (level A) evidence demonstrating its efficacy; however, intranasal midazolam is an alternative with level B evidence, and intravenous midazolam has not been mentioned.1, 2, 3, 4 However, outside of research settings, in the “real-world,” midazolam is frequently administered intranasally or intravenously and delivered at doses lower than those recommended.5, 6, 7

Evidence from single-EMS-agency cohort studies has suggested that both lower midazolam dosing and intranasal administration lead to less effective seizure termination.5,6 However, these studies are limited by the scope of their study population and because the providers may have altered the dose of midazolam administered based on the perceived severity of illness, leading to potential confounding, which previous cohort studies have been unable to address.8

In the absence of head-to-head randomized clinical trials, observational data that can account for confounding and reflect a broad population of patients with generalized, convulsive status epilepticus have the greatest potential to provide valid estimates of the effectiveness of different combinations of midazolam dose and route. The objective of this cohort study was to leverage a large national research database of EMS electronic health records to examine the association among out-of-hospital midazolam administration, seizure termination, and respiratory failure before arrival at the hospital using conventional regression and instrumental variable approaches.9, 10, 11

Section snippets

Study Design and Data Source

We conducted a retrospective cohort study of adults with status epilepticus encountered in the out-of-hospital setting and treated with midazolam to identify the real-world effect of differing midazolam doses and routes on the risk of recurrent seizures and respiratory failure. We used the ESO Data Collaborative public-use research dataset.9 ESO is a provider of out-of-hospital electronic medical record software in the United States. The data elements in the electronic medical records include

Study Population

There were 7,634 out-of-hospital encounters for status epilepticus treated with midazolam across 657 EMS agencies. The EMS agencies were located in all 9 Census Bureau-designated divisions, and 110 (16.7%) were located in rural settings. The mean age of the patients was 46 years (SD 18), and 3,752 (49.5%) were women (Table 1). Treatment with midazolam matched the expert guideline recommendations (10-mg intramuscular injection) in 4.1% (310) of the encounters. Rescue therapy was administered in

Limitations

There are important limitations to mention. First, the cohort was derived from all EMS agencies that use ESO for their out-of-hospital electronic medical records, but the cohort was not sampled or weighted to be nationally representative. Although we cannot consider this a population-based cohort, the agencies provided data from every out-of-hospital encounter, they were geographically distributed across all Census Bureau divisions, and they included care in both urban and rural settings, all

Discussion

In this large cohort study of adults with status epilepticus who were administered midazolam in the out-of-hospital setting, we found that the route of administration and dose both affected the clinical outcomes and that the patients rarely received treatment that matched the midazolam dose and route recommended by the guidelines. Our findings suggest that the intranasal administration of midazolam is less effective and the intravenous administration of midazolam more effective in terminating

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There are more references available in the full text version of this article.

Please see page 320 for the Editor’s Capsule Summary of this article.

Supervising editor: Jane H. Brice, MD, MPH. Specific detailed information about possible conflict of interest for individual editors is available at https://www.annemergmed.com/editors.

Author contributions: ELG, JFB, and TBN performed the concept, design, and statistical analysis of the article. ELG drafted the article. All authors acquired, analyzed, or interpreted the data and performed critical revisions of the manuscript for important intellectual content. ELG had full access to all the data in the study and takes responsibility for the paper as a whole

All authors attest to meeting the four ICMJE.org authorship criteria: (1) Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND (2) Drafting the work or revising it critically for important intellectual content; AND (3) Final approval of the version to be published; AND (4) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (seewww.icmje.org). Dr. Guterman received funding from the National Institute of Neurological Disorders and Stroke (1K23NS116128-01), National Institute on Aging (5R01AG056715), American Academy of Neurology. She has received personal compensation from Marinus Pharmaceuticals, Inc., JAMA Neurology, and Remo Health, which are unrelated the submitted work. Dr. Crowe received personal compensation as an employee of ESO, Inc. Dr. Lowenstein received funding from the National Institute of Neurological Disorders and Stroke (U01NS088034), the Office of The Director, National Institutes of Health (U54 OD020351), and the Human Epilepsy Project. Dr. Josephson received personal compensation from JAMA Neurology and Continuum Audio, which are unrelated to the submitted work. Dr. Betjemann received personal compensation from Marinus Pharmaceuticals, Inc., which is unrelated the submitted work. Dr. Burke received funding from the National Institute on Minority Health and Health Disparities (5R01MD008879-05) and the National Institute on Aging (5R01AG059733-02).

Presented as a poster at the National Association of EMS Physicians Annual Meeting, San Diego, CA, January 13, 2022.

Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number K23NS116128 and the American Academic of Neurology under the Practice Based Research Scholarship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the American Academic of Neurology.

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