Intramuscular versus Intravenous

Benzodiazepines for Prehospital Treatment of

Status Epilepticus
Lawrence J. Hirsch, M.D.

N Engl J Med 2012; 366:659-660February 16, 2012

Acute seizures account for 1% of adult and 2% of pediatric emergency department visits, at an
annual cost of $1 billion (in U.S. dollars).1 When seizures are prolonged or repetitive without
recovery between episodes, the condition is termed status epilepticus, and it occurs in
approximately 6% of visits to the emergency department for seizures. The cost for inpatient care
of patients in status epilepticus has been estimated to be $4 billion (in U.S. dollars) annually.2
Although the term prolonged was previously used to refer to seizures lasting 30 minutes or
longer, this interval has been shortened to 5 to 10 minutes in recent studies. This change occurred
for several reasons. First, almost all convulsive seizures in adults cease in less than 5 minutes
without treatment; seizures lasting longer than this are more likely to be self-sustained and to
require intervention.3,4 Second, the longer seizures persist, the harder they are to terminate
pharmacologically.5 Third, outcome tends to correlate with seizure duration even after one
controls for other factors. Mortality among patients who present in status epilepticus is 15 to
22%; among those who survive, functional ability will decline in 25% of cases.6

A little more than half the cases of epilepsy have an acute, symptomatic cause (e.g., acute brain
injury, metabolic dysfunction, or ethanol withdrawal).7 About 25% of patients in status
epilepticus will not respond to initial treatments. After convulsive movements cease, seizure
activity will continue to appear on electroencephalography over the subsequent 24 hours in 48%
of patients.8 Thus, if patients do not wake up shortly after their convulsive movements cease,
nonconvulsive seizures should be considered, and an electroencephalogram should be obtained
as soon as possible.7
The first-line treatment for convulsive status epilepticus is a benzodiazepine, typically
intravenous lorazepam, a choice based largely on the results of the 1998 Veterans Affairs
Cooperative Status Epilepticus Study.9 In 2001, a landmark study on prehospital treatment of
status epilepticus was published in which patients were randomly assigned to treatment with
lorazepam, diazepam, or placebo administered intravenously while they were en route to the
hospital.10 Successful termination was much more common in the two groups that received
benzodiazepines (59% with lorazepam, 43% with diazepam, and 21% with placebo). Since
respiratory distress was twice as common in the group given placebo as in either of the groups
given a benzodiazepine, the best way to avoid the need for intubation is to stop seizure activity.

In this issue of the Journal, Silbergleit et al. present the results of the RAMPART (Rapid
Anticonvulsant Medications Prior to Arrival Trial).11 This study involved 79 hospitals and more
than 4000 paramedics, as well as the use of intramuscular autoinjectors and automatic time-
stamped voice recorders, and the subjects were excepted from informed consent. Ultimately, 893
subjects with convulsive seizures lasting longer than 5 minutes were randomly assigned to either
intravenous lorazepam plus intramuscular placebo or intravenous placebo plus intramuscular
midazolam. Success was defined as cessation of clinical seizure activity and lack of additional
rescue medication before arrival in the emergency department. The goal was to show
noninferiority of intramuscular midazolam.

Results showed that intramuscular midazolam not only was noninferior but was superior to
intravenous lorazepam, with successful termination of seizures in 73.4% subjects in the
intramuscular-midazolam group versus 63.4% in the intravenous-lorazepam group (P<0.001 for
both noninferiority and superiority). This difference was due to the more rapid administration of
the intramuscular medication (1.2 minutes, vs. 4.8 minutes with the intravenous route). This
more rapid administration outweighed the faster cessation of seizures with intravenous
administration once it was given (1.6 minutes, vs. 3.3 minutes with the intramuscular route). In
those for whom seizures ceased prior to arrival in the emergency department, the overall median
time to cessation of convulsions was not significantly shorter in the intramuscular-midazolam
group (about 5 minutes, vs. 7 minutes with the intravenous route). Intubation was required in
14% of both groups, and other adverse events were also similar. The rate of hospitalization was
lower in the intramuscular-midazolam group, as compared with the intravenous-lorazepam group
(57.6%, vs. 65.6%; relative risk, 0.88).

Other trials have shown a more rapid response with nonintravenous administration of
benzodiazepines than with intravenous administration. In a small trial of children with prolonged
motor seizures, cessation was achieved more quickly with intramuscular midazolam than with
intravenous diazepam (8 minutes vs. 11 minutes, P=0.047).12 Multiple studies have shown that
nasal or buccal midazolam stops seizures faster than rectal or intravenous diazepam13 and is
absorbed faster than intramuscular midazolam.13-15 However, there may be issues with reliable
and consistent delivery or absorption with the buccal and nasal routes, as compared with the
intramuscular route. For this reason the intramuscular route was chosen for RAMPART, in
addition to paramedics' familiarity with the use of intramuscular medication.

What's next in this field? Home treatment with nasal or buccal benzodiazepines will soon be
widely available and may help prevent status epilepticus and visits to the emergency department
for patients who are at risk for prolonged or repetitive seizures (clusters). A comparison
between the intramuscular and nasal or buccal routes for administering midazolam is needed, as
is more research to determine the next step when first-line treatment fails, including the possible
usefulness of combinations of medications and neuroprotective agents. Finally, seizure
anticipation or warning systems are under development that may allow abortive treatment
perhaps in an automated manner even before clinical seizure activity occurs. Thus, the future
of care for seizure emergencies is quite bright. The study reported by Silbergleit and colleagues
is an important step in this direction. 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.

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