The authors of this report from the US note that many emergency medical services (EMS) systems have started to use intramuscular (IM) midazolam rather than an intravenous (IV) agent, largely because the former route is faster and is consistently achievable. This is despite the lack of clinical-trial data regarding the efficacy and safety of IM midazolam. They note that although IV lorazepam is the preferred treatment for patients with seizures in the emergency department, it is rarely used by paramedics in the pre-hospital setting because of the potential difficulty with IV administration, as well as the short shelf-life of lorazepam when it is not refrigerated, thus there is a need for a practical alternative that is at least as safe and effective as IV lorazepam.
The Rapid Anticonvulsant Medications Prior to Arrival Trial (RAMPART) is a non-inferiority study involving 79 hospitals and more than 4000 paramedics, which examined whether IM midazolam is as effective as IV lorazepam, with a similar degree of safety, for terminating status epilepticus seizures before arrival at the hospital
The study involved 893 children and adults in status epilepticus treated by paramedics whose convulsions had persisted for more than 5 minutes and who were still convulsing after paramedics arrived. They were given the study medication by either IM autoinjector or IV infusion. The primary outcome was absence of seizures at the time of arrival in the emergency department without the need for rescue therapy. Secondary outcomes included endotracheal intubation, recurrent seizures, and timing of treatment relative to the cessation of convulsive seizures. This trial tested the hypothesis that IM midazolam was non-inferior to IV lorazepam by a margin of 10%.
The following findings were reported:
• At the time of arrival in the emergency department, seizures were absent without rescue therapy in 329 of 448 subjects (73.4%) in the IM midazolam group and in 282 of 445 (63.4%) in the IV lorazepam group (absolute difference, 10%; 95% CI, 4.0 to 16.1; p < 0.001 for both non-inferiority and superiority).
• The two treatment groups were similar with respect to need for endotracheal intubation (14.1% with IM midazolam and 14.4% with IV lorazepam) and recurrence of seizures (11.4% and 10.6%, respectively).
• Among subjects whose seizures ceased before arrival in the emergency department, the median times to active treatment were 1.2 minutes in the IM midazolam group and 4.8 minutes in the IV lorazepam group, with corresponding median times from active treatment to cessation of convulsions of 3.3 minutes and 1.6 minutes.
• Adverse-event rates were similar in the two groups.
The researchers concluded that IM midazolam is non-inferior to IV lorazepam in stopping seizures before arrival in the emergency department in patients with status epilepticus treated by paramedics. Intramuscular midazolam was also found to be as safe as IV lorazepam. They suggest from these findings that IM administration of midazolam by EMS is a practical, safe, and effective alternative to the IV route for treating prolonged convulsive seizures in the prehospital setting.
An accompanying editorial discuses the treatment of status, the study findings and future developments, such as use of nasal or buccal benzodiazepines, what the next step should be when first-line treatment fails, and seizure anticipation or warning systems under development that may allow abortive treatment, perhaps in an automated manner, even before clinical seizure activity occurs. It concludes that “as soon as a practical intramuscular autoinjector for midazolam becomes widely available, the findings in this study should lead to a systematic change in the way patients in status epilepticus are treated en route to the hospital.”