This double-blind, randomized trial showed that prehospital treatment with intramuscular midazolam was at least as effective as intravenous lorazepam in subjects in status epilepticus (P<0.001 for noninferiority and for superiority). Establishing intravenous access in patients who are having seizures in the prehospital environment can be challenging and time-consuming. Since intramuscular treatments can be given more quickly and reliably than intravenous treatments and have noninferior efficacy, our data support the use of the former route of administration by EMS personnel.
The use by EMS systems of intramuscular midazolam for status epilepticus has been increasing because small studies have indicated its efficacy and because this drug is rapidly absorbed intra-muscularly. According to a meta-analysis of small trials, the use of nonintravenous midazolam in the hospital setting compared favorably with intravenous diazepam in the emergency treatment of status epilepticus.8
Furthermore, unlike lorazepam, midazolam does not have the problem of poor stability when not refrigerated. Midazolam can be administered by other nonintravenous routes as well, but the intramuscular route is more consistently effective than the intranasal or buccal routes because the drug cannot be blown or spat out by the convulsing patient.
In this noninferiority study, we used lorazepam as an active control. Inclusion of a placebo group would have been unethical, since PHTSE showed unambiguously that benzodiazepines are superior to no treatment in subjects in status epilepticus in the prehospital setting. The clinically important question is whether intramuscular midazolam works well enough for patients in status epilepticus to routinely forgo the intravenous route in order to improve the ease and speed of treatment administered by EMS personnel. The active control drug, the noninferiority margin, the trial setting, and the analysis plan were carefully chosen to avoid the known potential pitfalls and limitations of noninferiority studies.7
The doses of midazolam and lorazepam used in this trial are consistent with the most effective doses for the treatment of status epilepticus that are reported in the literature.9,10
Although these initial doses are higher than the ones used by many EMS systems and emergency physicians, they are the same as those approved for this indication and are in line with those used by epileptologists. Use of an autoinjector maximized the speed and ease of intramuscular delivery (with a nominal latency period of about 20 seconds for opening the autoinjector and administering the medication) and reduced delays in initiating intravenous access.
The relationships among benzodiazepine dose, respiratory depression, and subsequent need for endotracheal intubation are poorly characterized, but higher doses of benzodiazepines may actually reduce the number of airway interventions. Our data are consistent with the finding that endotracheal intubation is more commonly a sequela of continued seizures than it is an adverse effect of sedation from benzodiazepines.11
With regard to the mechanism of drug action, our temporal data are consistent with what would be expected: the intramuscular route delivers the medication more rapidly after the paramedics’ arrival at the scene than the intravenous route, but its onset of action is more rapid after intravenous administration than after intramuscular administration. The time saved by using the intramuscular route appears to more than offset the delay in the drug’s onset of action. It is interesting to speculate that a difference of just a few minutes with the earlier administration in the intramuscular group may have been enough to drive the slight superiority of the intramuscular route with respect to outcome. However, it is also possible that the difference in outcome between the two treatment groups reflects differences in the efficacy of the agents used rather than in the route of administration. Because this is a pragmatic clinical trial designed to inform EMS clinical practice rather than to elucidate mechanism, the effect of agent and route cannot be meaningfully separated in analyzing these data. Similarly, an autoinjector was used in this study to optimize the speed and efficiency of intramuscular delivery, but it is not possible to determine the importance of using this tool for intramuscular injections, as compared with conventional intramuscular injections.
Our data are consistent with a finding of statistical superiority of intramuscular midazolam. Regardless of whether it is noninferior or superior, this trial supports the clinical decision to use the more pragmatic intramuscular approach in the prehospital treatment of status epilepticus.
In conclusion, intramuscular midazolam is noninferior to intravenous lorazepam in stopping seizures before arrival in the emergency department in patients with status epilepticus treated by paramedics. Intramuscular midazolam is also as safe as intravenous lorazepam. The group of subjects treated with intramuscular midazolam had a higher rate of discharge from the emergency department than the group treated with intravenous lorazepam and had similar or lower rates of recurrent seizures and endotracheal intubation. The intramuscular administration of midazolam by EMS is a practical, safe, and effective alternative to the intravenous route for treating prolonged convulsive seizures in the prehospital setting.