The Future of Prehospital Treatment of Convulsive Status Epilepticus
Abstract & Commentary
By Padmaja Kandula, MD, Assistant Professor of Neurology and Neuroscience, Comprehensive Epilepsy Center, Weill Cornell Medical College. Dr. Kandula reports no financial relationships relevant to this field of study.
Synopsis: Early cessation of prehospital seizures via an intramuscular injection of midazolam was at least noninferior, if not superior, to traditional intravenous lorazepam.
Source: Silbergleit R, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. New Engl J Med 2012;366:591-600.
Since the initial 1998 landmark veteran's administration (VA) study, intravenous benzodiazepines have been first-line treatment for status epilepticus (SE). However, the VA cooperative study, like many others to follow, only studies an intravenous route of administration of acute abortive agents. Over time, the medical community became increasingly aware that untreated prolonged convulsive SE has the potential to become refractory. Out of these clinical observations, the operational definition of SE has grown to include seizure activity of 5 minutes or greater duration. This timely article by Silbergleit et al is the first large-scale, randomized, blinded study to compare the traditional intravenous vs intramuscular route of benzodiazepine administration for prehospital seizure cessation.
The Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) involved 79 centers nationwide and a total of 448 subjects assigned to active treatment with intramuscular midazolam and 445 assigned to active treatment with intravenous lorazepam. Patients met criteria for inclusion if convulsive seizures of longer than 5 minutes in duration were noted. Both patients and emergency medical personnel were blinded and randomized to treatment via the use of investigational autoinjectors and prefilled syringes with either 10 mg intramuscular midazolam followed by intravenous placebo, or intramuscular placebo followed by 4 mg of intravenous lorazepam. A time-stamped voice recorder in the prefilled study kit allowed paramedics to record orally when intramuscular treatment was administered, when intravenous access was gained, when intravenous study drug was administered, and when convulsions clinically stopped. Rescue therapy, as dictated by local paramedic protocol, was used for patients who were still convulsing 10 minutes after the last study medication was administered or if convulsions resumed after transient cessation.
The primary outcome of this study was clinical seizure cessation without the need for rescue therapy before emergency room arrival. In particular, the authors' primary aim was to demonstrate noninferiority of intramuscular midazolam vs intravenous lorazepam in prehospital treatment of convulsive seizures. Secondary outcome measures included time from study box opening to seizure cessation, time from initiation of study drug to termination of seizures, frequency and duration of hospitalization to the intensive care unit, frequency of endotracheal intubation, and seizure recurrence.
Seizures were successfully aborted in 73.4% and 63.4% in the intramuscular vs intravenous treatment groups respectively. The median time to active treatment in the intramuscular group was 1.2 minutes vs 4.8 minutes in the intravenous group. However, the actual onset of action (termination of seizures) was more immediate in the intravenous group vs the intramuscular group (1.6 vs 3.3 minutes). The secondary endpoints of frequency of intubation, recurrent seizures, and duration and frequency of hospitalization were similar in both treatment groups.
Results of the study not only showed that intramuscular midazolam was noninferior to intravenous lorazepam in terminating seizures, but that intramuscular administration of midazolam was more rapidly accomplished. In a setting where brain recovery is time dependent, intramuscular midazolam presents a novel method of achieving seizure cessation even before emergency room assessment. The logistical ease of intramuscular delivery in a convulsing individual and lack of need for refrigeration of midazolam are also attractive and useful properties in an abortive agent. Currently, the only alternative to oral administration for acute abortive treatment in the home setting is rectal diazepam. In an actively convulsing patient, particularly in an adult, rectal delivery presents a great challenge to effective and timely administration of the drug.
The future of effective status cessation is largely dependent on early treatment. So, perhaps the timely treatment of seizures actually lies in the hands of the very first responders, which may include family and non-medical bystanders. By exploring alternative routes of home-based drug administration, such as buccal and nasal midazolam in current development, it is possible that prolonged hospitalization and increased mortality associated with convulsive SE may become a relic of the past.