Episode 46- “Status Underdosingus”: Part 1: Emergent therapy

Hello and welcome to Episode 46 of ER-Rx. In this three-part Mini Grand Rounds series, we discuss one of my favorite topics; status epilepticus (SE). In each episode, we’ll focus on a specific phase of SE treatment, focusing on the anti-epileptic drugs (AEDs) used. Plus, we’ll go a little deeper into how and why many of us are under-dosing these agents, and how that can be a major disservice to our patients.

SE is defined as 5 minutes or more of continuous seizure activity or recurrent seizures without recovery between episodes. Approximately 50,000 – 150,000 Americans develop SE each year. Mortality rates are very high. For generalized convulsive SE (which is characterized by rhythmic jerking of the extremities and mental status impairment), mortality ranges anywhere from 19-27%, and non-convulsive SE (which is characterized by seizure activity seen on EEG, without the clinical findings associated with GCSE) has an even higher mortality rate of up to 65%- due in part to the fact that it may be more difficult to diagnose. Patients who develop refractory SE (RSE) have about a 40% mortality rate. RSE is defined as a failure to break the seizure after both first- and second-line agents have been given.

The treatment of SE occurs in a continuum of phases including emergent therapy, urgent therapy, and controlled therapy. Although we break these phases down into specific steps, remember that in practice, these phases can and should happen almost simultaneously.

In this episode, we’ll focus on the initial, emergent phase. In this phase, benzodiazepines, specifically lorazepam and midazolam, are the agents of choice. The Neurocritical Care Society guidelines published in 2012 and the American Epilepsy Society guidelines from 2016 highly recommend these agents. Remember that the doses and routes of these agents are very specific and should be committed to memory. If we have IV access, we prefer using lorazepam at a dose of 0.1 mg/kg (with a max dose of 4 mg), which can be repeated once in 5-10 minutes if the patient is still seizing. Note that all of your patients weighing more than 40 kg should receive the maximum dose of IV lorazepam. Obtaining IV access in a seizing patient is difficult, and that’s why IM midazolam is the preferred agent for patients without IV access. This is one reason that IM midazolam is found in many EMS SE treatment protocols. Here, midazolam is given at a dose of 0.2 mg/kg (with a max dose of 10 mg). Note that any patient weighing more than 50 kg should receive the maximum dose. This should be almost all of your adult patients in SE. Please note that it is preferred to give one adequate full dose rather than to give the total dose broken up into multiple smaller doses. Based on clinical trials, IV lorazepam and IM midazolam should terminate the seizure in about 50-65% of patients. We do have other routes available to us, such as the nasal and buccal routes (using midazolam), or rectal routes (using diazepam), but these routes have not been well studied and won’t be discussed in this episode.

Due to the risks of respiratory depression with benzodiazepines and the fear of intubation, a lot of people are reluctant to use these high benzodiazepine doses. But this perceived higher risk of intubation isn’t based on reality for a couple of reasons. The first reason is that many of your patients will already be intubated or will require intubation due to the seizure or underlying etiology itself. The second reason is that respiratory problems are an important consequence of untreated or under-treated SE in and of itself.

For example, in the famous “Pre-Hospital Trial” published in the NEJM in 2011, the authors found that out-of-hospital complications (which included hypotension, cardiac dysrhythmia, and respiratory intervention) occurred more commonly in patients receiving placebo than those receiving lorazepam or diazepam at these higher doses (~ 22% vs 10%, P=0.08). The most common complication was a change in respiratory status requiring ventilation or intubation, which occurred in 7 patients given lorazepam (2 mg repeated x 1), 6 patients given diazepam (5 mg repeated x 1), and 11 patients given placebo. The author’s concluded that “respiratory complications associated with prolonged seizures may be more pronounced than those caused by IV lorazepam or diazepam…”

Despite this and other studies showing that these so-called high doses of benzodiazepines are safe, we still have major “intubatophobia” (credit to EMCrit for coining that term) and we are drastically under-dosing these agents, both in the pre-hospital and ER settings.

In a letter published in JAMA in 2019, a group of physicians from California looked at EMS SE treatment protocols throughout the state to see how many included adequate, guideline-recommended dosing of benzodiazepines. They found that only 2 out of 33 protocols (6%) used the doses and routes of lorazepam and midazolam discussed previously and recommended in the American Epilepsy Society guidelines. In a more recent study, the authors found that of patients given lorazepam in their ER, only 1.5% were dosed appropriately, with an average dose of < 2 mg. Of those that received their benzodiazepine pre-hospital, none of them received adequate initial benzodiazepine doses.

The reason? Although we can’t be sure, based on studies like this and my personal experiences in the ER setting- it is because providers are so reluctant to give higher doses of benzodiazepines, citing unfounded fears of intubation.

In conclusion, remember that IV lorazepam and IM midazolam are the highest recommended agents for initial, emergent therapy in the setting of SE. Also, we all have to remember that patients in SE require higher doses of benzodiazepines than we are used to giving. But, giving lower doses may actually lead to higher rates of intubation given the inadequate treatment of the seizure itself.

As always, thank you so much for your time. Tune in next week as we discuss second-line, urgent therapy, and the under-dosing of AEDs in that setting as well.