Anyone who has ever been challenged to start an IV in a patient having a seizure knows why depending upon intravenous lorazepam to terminate status epilepticus is not ideal. Terminating a seizure as quickly as possible is imperative, as the longer a patient seizes, the more difficult it becomes to terminate with pharmacotherapy. The knowledge that the longer the patient seizes, the worse the clinical outcomes, only makes those seconds struggling to gain access seem more interminable.
Intravenous lorazepam has demonstrated clinical efficacy for seizing patients in the Emergency Room. However, paramedics, treating patients in the field, often reach for intramuscular midazolam instead. Though this immediate delivery of treatment likely feels more effective than watching a patient seize as you fumble with an IV, in the absence of clinical trials, the question has remained: does intramuscular midazolam actually do the trick?
In today’s issue of NEJM, the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) investigators provide data to suggest that, indeed, intramuscular midazolam is as safe and effective as IV lorazepam for pre-hospital treatment of patients in status. This non-inferiority trial included 79 hospitals and over 4000 paramedics. 893 patients in status were randomized to either IV lorazepam or intramuscular midazolam. Status was defined as convulsions lasting longer than five minutes, and still occurring upon EMS arrival. Both adults and children over 13 kg were included. The study was designed to be double-blind, double-dummy, meaning all patients either received either intravenous lorazepam plus intramuscular placebo, or intravenous placebo plus intramuscular midazolam. IM injection was made simple by using an auto-injector. The primary outcome was termination of the seizure prior to arrival to the Emergency Department, without the requirement for additional therapy. The results?
Intramuscular midazolam was clearly non-inferior, successfully terminating seizures in 73% of patients, as compared to a 63% termination rate in the lorazepam group. Notably, among those in the intravenous medication group who were still seizing upon ED arrival, 31 (of 445) never received the medication because of difficulty placing an IV. This was compared to 5 in the intramuscular group who did not receive medication due to malfunction of the auto-injector.
Secondary outcomes, including the need for endotracheal intubation, recurrent seizures, and safety endpoints, midazolam was also non-inferior. Though lengths of stay did not differ between the two groups for those who were eventually admitted, more patients who had received midazolam were actually discharged from the ED, (42% in the midazolam group versus 34% in the lorazepam group). Adverse events did not differ between the two groups.
Though it is at this juncture where one usually points out the study’s limitations, and suggests the opportunities for future investigation, these data are really quite definitive: intramuscular midazolam is at least as good as IV lorazepam for prehospital treatment of patients in status. Wondering how to effectively deliver therapy to seizing patients in the field may not be what keeps you up at night, but for those who face this challenging task daily, this trial is a game changer.
For more on this topic, see the editorial by Lawrence Hirsch, M.D., from Yale University School of Medicine.