Not that long ago, it was still considered ethical in prehospital research to compare benzodiazepines with placebo for seizure control. Fortunately, it was irrefutably demonstrated that benzodiazepine administration by prehospital providers was not only safe but also terminated status epilepticus more effectively than sugar water. (N Engl J Med 2001;345:631.)
Patients who received benzodiazepines in that study had a significantly higher chance of resolved seizure activity by ED arrival: lorazepam (59.1%), diazepam (42.6%), and placebo (21.2%).
The Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) published in the Feb. 16 New England Journal of Medicine once again sheds light on prehospital management of status epilepticus, this time giving IM benzodiazepines a fair shake.
Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus
Silbergleit R, et al
N Engl J Med
Adult and pediatric patients were included in the RAMPART trial if they met the criteria for status epilepticus according to reliable witness account, meaning continuous convulsive activity for longer than five minutes or intermittent convulsive activity for longer than five minutes without return of consciousness. Patients were enrolled only if actively seizing upon paramedic arrival. Notable study exclusions included prisoners, pregnant women, and patients with seizures presumptively caused by trauma, hypoglycemia, bradycardia, or cardiac arrest.
Meticulous steps were taken in the design of this double-blinded protocol to ensure accuracy and minimize bias. After candidates were stabilized, an instrumented medication box was opened that automatically activated a voice recorder that time stamped all interventions. All patients received two injections: an IM shot using an auto-injector and then an IV push once access was established.
Patients were randomized to receive either midazolam 10 mg IM followed by placebo IV or placebo IM followed by lorazepam 4 mg IV. Patients less than 40 kg were similarly randomized, but received each intervention at half the dose.
The primary outcome measure was termination of seizure activity prior to ED arrival. Secondary outcome measures included the time from opening the study medication box to seizure termination and the frequency of hospitalization, intubation, and seizure recurrence. A total of 893 subjects were enrolled over a 19-month period.
The RAMPART trial showed that patients with status epilepticus are more likely to be seizure-free upon arrival to the ED when treated with IM midazolam (74.3%) vs. IV lorazepam (63.4%; p<0.001, 95% CI [4.0 to 16.1].) Frequency of recurrent seizures and intubation was similar in each group. Rate of hospitalization seemed to favor the IM group (58.0%) over the IV group (67.6%), but this was a secondary outcome.
The intravenous route, when already available, is clearly a preferred route for anticonvulsant administration in the seizing ED patient. But emergency physicians arriving at the bedside usually have a saline lock readily available or multiple people dedicated to establishing one rapidly. Unfortunately, paramedics arriving at the scene of a patient in status don't have that luxury.
The RAMPART trial showed seizures resolved much more quickly after IV intervention (1.6 minutes) than after IM intervention (3.3 minutes). This benefit, however, was lost after taking into account the significant time necessary to establish IV access. Comparing the overall time from when the study box was opened to the termination of the seizure, median seizure time in the IM group was almost two minutes shorter: 4.5 minutes in the IM group and 6.4 minutes in the IV group.
Ninety-nine percent (443/448) of patients randomized to IM benzodiazepines received an intervention prior to ED arrival. IM auto-injector malfunction in this group was a rare event, occurring only five times. On the other hand, 9.4 percent (42/448) of patients randomized to IV benzodiazepines never received prehospital intervention because of failed IV access.
Attempting IV access in actively seizing patients also puts paramedics at risk for needle stick, and might contribute to transportation delay, something RAMPART wasn't designed to measure. Proving IM benzodiazepines are as effective as IV benzodiazepines in this scenario should stir up discussion on prehospital protocols for these patients because deferring attempts at IV access could result in shorter transport times to definitive care.
This study also may have ramifications on managing status epilepticus in the ED if IV access is lost or unobtainable. Although the intraosseous route might be considered in these circumstances, IO access may be unsafe or difficult to secure in the actively seizing patient.
Don't get shaken up if an increasing number of patients being treated for status epilepticus arrive at your doors after receiving only an IM intervention. Instead, acknowledge the excellent care they received, and give your paramedics their props because there is good science behind this practice. Your patient likely suffered a shorter seizure burden and probably got to you sooner. He is also less likely to be trembling when you greet him and more likely to shake your hand when you send him home.
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Dr. Lovato is an associate professor at the David Geffen School of Medicine at UCLA, the ED director of clinical practice at Olive View-UCLA Medical Center, and the co-chair for the Emergency Medicine Best Practices Committee for the Los Angeles County Department of Health Services.
* Read an abstract of the New England Journal of Medicine article at http://bit.ly/IMseizure.
* Read all of Dr. Lovato's past columns in the EM-News.com archive.
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