The lead article in today's New England Journal of Medicine is a randomized, double-blinded trial of IM midazolam (Versed) vs. IV lorazepam for the prehospital treatment of status epilepticus. I don't know how many paramedics read this blog, but ER docs, hospitalists and neurologists will need to be familiar with RAMPART (Rapid Anticonvulsant Medication Prior to Arrival Trial), so let's review it.
The study was designed to see if IM midazolam is noninferior to the current standard of care, IV lorazepam. While lorazepam has been shown to be an effective initial treatment for status, it's not always easy to get IV access, especially while a patient is actively seizing. Lorazepam also has to be refrigerated, unlike midazolam.
Adult or pediatric patients who had been continuously convulsing for 5 minutes, or those with intermittent seizures without regaining consciousness for 5 minutes, were eligible for the study. Patients with certain acute precipitants of seizures, such as cardiac arrest, were excluded. The paramedics tore open a study box, which activated a voice recorder. The box contained an intramuscular auto-injector and a preloaded intravenous syringe. One contained the active drug, while the other contained placebo. The paramedics were instructed to give the IM medication first, then establish venous access and give the IV medication next. During this time, EMS personnel verbally recorded when they gave the medication, and when the seizure stopped.
The primary outcome was the cessation of seizures before arrival to the ED, without the need for rescue medication. Even though the study was powered for non-inferiority, IM midazolam ended up being superior to IV lorazepam: 73% in the midazolam group stopped seizing, compared to 63% of the lorazepam group. The absolute risk reduction was 10%, with a respectable number needed to treat of 10. There were no differences in the secondary outcomes of intubation or seizure recurrence.
RAMPART was randomized, double-blinded, intention-to-treat, with excellent follow-up (it's hard to lose an unconscious patient in an ambulance). My only beef is that it seemed designed to give IM midazolam an edge: the paramedics were instructed to give the IM drug before the IV one. The trial could have randomized the order of medication given. And indeed, the mean time to delivery of active treatment was significantly shorter in the IM group (1.2 minutes) than the IV group (4.8 minutes). On the flip side, once the medication actually got into the patient, lorazepam was faster in terminating the seizure (1.6 minutes) than midazolam (3.3 minutes).
So is midazolam superior to lorazepam in the treatment of status, or is giving an IM medication just faster and thus superior to starting an IV? We may never know. The authors of this paper appropriately titled it "Intramuscular versus Intravenous Therapy..." instead of "Midazolam Is Superior to Lorazepam...." Note that this study isn't applicable to patients who already have an IV. If a hospital inpatient goes into status, it makes sense to give IV instead of IM treatment because of its faster onset.
Next post: RAMPART was extremely well-designed. But was it ethical?