Silbergleit Study Analysis

Introduction

While intravenous (IV) lorazepam is typically used in hospitals to treat seizures, paramedics increasingly use intramuscular (IM) midazolam in seizure patients on the way to the hospital due to its faster and more reliable administration. The Silbergleit, et al. study comparing the effectiveness of IV lorazepam to that of IM midazolam in prehospital seizure patients contributes to evidence-based decision-making by determining whether the administration of IM midazolam is at least as effective as the administration of IV lorazepam prior to arriving at the hospital. The study’s findings that the IM treatment is indeed at least if not more effective than the IV treatment in prehospital seizure patients provide support for the use of the IM treatment among paramedics.

In the decision analysis for this trial, the primary outcome was defined as the absence of seizures upon arrival at the emergency department of the hospital without the need for rescue therapy. Secondary outcomes included recurrent seizures and the time it took between administration of the treatment and cessation of the seizures. The study medication was given to subjects whose convulsions persisted for at least five minutes and who were still convulsing once the paramedics had arrived. As seizures were absent without rescue therapy in 73.4% of the patients who received the IM treatment vs 63.4% who received the IV treatment, the IM treatment was judged at least as effective as the IV treatment. An additional benefit of the IM midazolam treatment is that midazolam is more when not refrigerated than is the lorazepam that is used for the IV treatment.

Study Strengths

The Silbergleit et al. study was a double-blind, randomized, noninferiority trial that also served as a pragmatic trial since it studied typical practice (IM treatment among paramedics) on typical patients (prehospital seizure patients). The randomization of the trial provides high internal validity and minimizes confounding effects, meaning the relationship between the treatment and the outcomes can confidently be interpreted as a cause and effect relationship. As a pragmatic trial, the study also provides high external validity, meaning the results in the sample population can be generalized to the study population. These characteristics were the major strengths of the study and helped meet the goal of comparative effectiveness research (CER), which is to “improve decisions that affect medical care at the levels of both policy and the individual” (Sox & Goodman, 2012). This study meets each of the key elements of CER: it compares two active treatments head-to-head, it studies patients typical in day-to-day practice, and it focuses on evidence-based practices to inform the care of patients.

Study Limitations

The greatest weakness of the study is that, although this is a pragmatic trial, a few of the methods used in the study were different from the typical medical practice. While the doses of midazolam and lorazepam used in this trial are consistent with the most effective doses for the treatment of the type of seizure treated in this study, the doses in the study were higher than the ones used by many EMS systems and emergency physicians (Silbergleit, et al., 2012). Additionally, an autoinjector was used in the intramuscular treatment rather than conventional intramuscular injections. Moreover, the administration of the IV treatment was slightly more delayed in the study than it would be outside of the study because the IM treatment was always administered before the IV treatment. Each of these alterations from what would occur in a real-world situation decreases the external validity of the study to some extent. Furthermore, as patients in real-world situations seek alternative treatments such as CBD oil, the interferences of the IM with that daily dosage could greatly alter results.

The study can be improved by aligning more of the methods used with those used in day-to-day practice, thereby increasing the external validity of the study. For instance, the doses of midazolam and lorazepam could be lowered to levels typically used by EMS systems and emergency physicians. In addition, conventional injections could be used for the IM treatments. Furthermore, the administration of both the IV treatment and the IM treatment could begin at the same time, perhaps with two paramedics administering the treatments. These changes would provide greater insight into what the effects of the treatments would be in the study population because the actions taken in the study would be more in line with the actions that would be taken outside of the study.

Conclusion

Despite some limitations, the Silbergleit et al. study provides evidence to support the use of IM midazolam in prehospital seizure patients. The randomization in the trial minimizes confounding concerns and maximizes internal validity, and the pragmatic nature of the trial provides for high external validity. However, the external validity could be further improved upon by aligning the methods used in the study more closely with what takes place in day-to-day medical practice.

References

Silbergleit, R., Durkalski, V., Lowenstein, D., Conwit, R., Pancioli, A., Palesch, Y., & Barsan, W. (2012). Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus. New England Journal of Medicine, 591-600.

Sox, H. C., & Goodman, S. N. (2012). The Methods of Comparative Effectiveness Research. Annual Review of Public Health, 425-445.