Episode 48- "Status Underdosingus": Part 3: Refractory status epilepticus

Hello and welcome to Episode 48 of ER-Rx. Last week in Part 2 of our Mini Grand Rounds series, we discussed second-line, urgent treatment of status epilepticus (SE). This week in Part 3, and the last part of our status series, we discuss the treatment of refractory status epilepticus (RSE).

RSE is defined as a failure to break the seizure after both first and second-line agents have been given. Up to 35-45% of patients in status can develop refractory status. Why does RSE happen? One reason is due to “receptor trafficking” which can occur during prolonged seizures. What happens here is that inhibitory GABA receptors become internalized, and excitatory AMPA and NMDA receptors become over-expressed, leading to increased sensitivity to excitatory neurotransmitters. Going back to Part 1 of the series, this is another reason why we give large benzo doses up front- we want to catch the benzodiazepine receptors prior to them being internalized.

After failure of the second-line agent, our options are to repeat a bolus of the second-line agent already given or to immediately initiate additional agents – the latter being more preferred. This is because no data suggests that watchful waiting is safer than proceeding with more aggressive treatment if a patient fails urgent control therapy. Most will recommend immediate intubation with continuous infusions of anti-epileptic drugs (AEDs) along with continuous EEG monitoring. As a little side note if you do decide to intubate- consider using propofol, midazolam, or ketamine as your induction agents during RSI, since they have anti-epileptic activity, and consider avoiding succinylcholine as your paralytic given the risk of hyperkalemia with prolonged seizures.

Continuous infusions of midazolam, propofol, ketamine, or pentobarbital are some of the most commonly used and highly recommended agents for patients in RSE. These agents are titrated to burst suppression or electrographic evidence of seizure cessation and are then titrated off over at least 24 hours once the seizure has broken.

Midazolam is dosed at 0.05-2 mg/kg/hour, with 0.1-0.2 mg/kg boluses as needed. Note the much higher dosing we use in the setting of status, compared to when this agent is used for sedation in the ICUs (typically dosed at 0.02-0.1 mg/kg/hour).
Propofol is dosed at 30-200 mcg/kg/min, with 1 mg/kg boluses as needed. Once again, the dosing range is much higher than we would normally see for sedation (10-80 mcg/kg/min). Both of these agents can cause hypotension, and it may be necessary to add on a vasopressor to maintain blood pressure.
The use of ketamine is also growing given more recent supporting efficacy and the fact that it has a better side effect profile than the other agents- including a much lower risk of hypotension. The use of ketamine makes intuitive sense based on the “receptor trafficking” phenomenon and the fact that this agent hits the up-regulated excitatory NMDA receptors. In this setting, we use 0.5-7 mg/kg/hour- again much higher than normal doses.
And lastly, another option is pentobarbital. This is usually only used if the other agents have failed due to its very high risk of hypotension, pneumonia, thromboembolism, cardiac depression, and paralytic ileus.

Overall, as in the urgent phase, there is no preferred agent. There is also no defined seizure duration or number of trials of seizure control after which care is considered futile. Some reports have shown that patients can be treated for RSE for weeks to months after which full recovery can still occur. It’s important to remember that you will continue the second-line, urgent therapy agent you started and will titrate to therapeutic, or slightly supra-therapeutic levels of these agents. It may also be necessary to add on additional agents including urgent-phase agents not already given, or things such as lamotrigine, topiramate, lacosamide (Vimpat), or clobazam (Onfi)- among others.

This phase of therapy is very pharmacist heavy, and I’d recommend leaving detailed progress notes or sign-outs that include all of the agents and doses the patient has received. I’d also include dates and times of drug levels and start and stop times of continuous infusions. This can help the team keep track of what was already given and why certain things were changed, discontinued, or dose-adjusted.

In conclusion of this three-part series, remember that in the emergent phase, we use IV lorazepam at 0.1 mg/kg or IM midazolam at 0.2 mg/kg. Both agents and routes are safe and effective, and based on numerous clinical trials and recommendations from experts, these doses lead to less intubation than giving lower, inadequate doses. In the urgent phase, we use agents like phenytoin at 20 mg/kg, valproate sodium at 40 mg/kg, and levetiracetam at 60 mg/kg- with levetiracetam being the safest agent and the one that we can mix up at bedside and give over the shortest period of time. For RSE, we use high dose continuous infusions along with continuing agents given in the urgent phase in addition to a wide variety of AEDs which will be chosen based off of patient history, availability, and provider preference. 

As always, thank you so much for your time. If you have anything to add to the SE series, please feel free to reach out to us on errxpodcast.com, or on our Instagram page: “errxpodcast.”