By: Jamie Prashek, PharmD, PGY1 Pharmacy Resident, University of Missouri Health Care
Status epilepticus broadly refers to a seizure with prolonged activity; historically this was defined as a duration of at least 30 minutes.1-3 Lowenstein et al. further specified this definition as convulsive seizures with at least five minutes of continuous seizure activity or intermittent seizures without recovery of consciousness in-between.4,5 Current recommendation is for prompt initiation of treatment once activity has reached five-minutes.2 A delay in initiation increases the chance for prolonged activity and risk for neuronal injury. Morbidity and mortality increases as seizure time lengthens, with seizures lasting greater than 30 minutes having an increased risk for worse outcomes.2,5-7
Approximately 150,000 individuals develop epilepsy yearly, with 15% experiencing status epilepticus at some point.8 Since “time is brain”, status epilepticus is a medical emergency with immediate and effective treatment being imperative. Benzodiazepines have historically been the agents of choice as first line options.1,3 However, the exact agent, dose, and route of administration has been up for debate. Different routes of administration include intravenous (IV), intramuscular (IM), rectal, buccal, and intranasal. In addition, another question is which second line treatment agent is appropriate when status epilepticus is refractory to benzodiazepine treatment. The following will review key literature and guidelines to outline recommended and effective treatment in those with status epilepticus.
In 2016, the American Epilepsy Society released a guideline recommending treatment for convulsive status epilepticus in both children and adults.3 As mentioned previously benzodiazepines remain the initial treatment of choice, however, with various benzodiazepines and routes of administration, it is imperative to consider the feasibility of administration when making a selection. Intravenous benzodiazepines have been widely used, but obtaining access during active convulsions is not always feasible and another route must be available. Two pivotal studies discussed below, have helped to guide treatment with benzodiazepines.
The pre-hospital treatment for status epilepticus (PHTSE) study was a randomized, double blind, placebo controlled trial evaluating the safety of intravenous benzodiazepines by emergency medical service (EMS) providers.9,10 Study intervention included 2mg IV lorazepam, 5mg IV diazepam, or placebo, with the allowance of a one-time repeated dose if necessary. The primary outcome was cessation of status epilepticus prior to arrival to the emergency department (ED). Termination of status was evident in 59.1% in those who received IV lorazepam, 42.6% who received IV diazepam, and 21.1% who received placebo (p=0.001).
Silbergleit et al. compared the use of IM midazolam to IV lorazepam for pre-hospital treatment in those with active status epilepticus.11 The rapid anticonvulsant medication prior to arrival trial (RAMPART) was a randomized, double blind, non-inferiority trial designed to find an alternate efficacious agent.11 Treatment was as follows, patients weighing 40 kg or more received 10 mg IM midazolam followed by IV placebo, or they received IM placebo followed by 4 mg IV lorazepam. With dose adjustments for those between 13 to 40 kg, active drug doses at 5 mg IM midazolam and 2 mg IV lorazepam. The primary outcome of cessation of convulsions prior to ED arrival was evident in 73% of the IM midazolam group compared to 63.4% in the IV lorazepam group (p<0.001).11 Importance for this study was to provide EMS providers an alternative agent to IV lorazepam that was comparable in safety and efficacy. Limitations for IV lorazepam included the potential difficulty in obtaining IV access, along with the limited shelf life of unrefrigerated lorazepam solution.12
At the time of the 2016 guidelines, a gap in evidence existed for deciding the best secondary agent when status is refractory to benzodiazepine therapy. Chamberlain et al. with the established status epilepticus treatment trial (ESETT) set out to answer this exact question. ESETT was a double blind, randomized, Bayesian response trial comparing levetiracetam, fosphenytoin, and valproate in those after adequate benzodiazepine administration.13 Treatment randomization was in a 1:1:1 ratio with levetiracetam 60 mg/kg (max of 4500 mg), fosphenytoin 20 mg PE/kg (max of 1500 mg PE), or valproate 40 mg/kg (maximum 3000 mg) infused over 10 minutes. The primary outcome was for cessation of clinical seizures and improved responsiveness at 60 minutes without the need for additional anti-seizure medications or endotracheal intubation. Across the different age groups efficacy was evident in roughly half of the patients treated with each agent. Although, the ESETT did not answer the question of which agent is preferred, it does give more reassurance that utilizing levetiracetam, fosphenytoin, or valproate should be effective if dosed accurately.
The 2016 guidelines developed a treatment algorithm helping providers decide what agent is ideal at specific time intervals. See Figure 1 for a modified algorithm and Table 1 for treatment agents and dosing. IV lorazepam dosed at 4 mg is an ideal first line agent. In those without IV access IM midazolam is an appropriate alternative agent. After treatment with benzodiazepines, a plan for immediate treatment with a second phase agent is just as important, with appropriate choices including levetiracetam, fosphenytoin, and valproate.