Episode 47- “Status Underdosingus”: Part 2: Urgent therapy

Hello and welcome to Episode 47 of ER-Rx. Last week in Part 1 of our Mini Grand Rounds series, we discussed first-line, emergent treatment of status epilepticus (SE) with benzodiazepine agents, and how these agents are frequently and unnecessarily underdosed. This week in Part 2 of the series, we discuss second-line, urgent therapy.

Remember that anti-epileptic drugs (AEDs) are required after a benzodiazepine has been given even if the seizure was terminated. Our goals here are to rapidly attain therapeutic maintenance levels of these agents for those who have responded to emergent therapy with a benzodiazepine or to terminate SE in those who have failed emergent therapy.

In this phase, we use agents that focus on mechanisms other than GABA receptors. The most highly recommended agents in clinical guidelines are IV phenytoin/fosphenytoin, valproate sodium, or levetiracetam. Just like in the emergent phase, these agents come with specific doses that should be committed to memory. Phenytoin is dosed at 20 mg/kg IV (with an additional 5-10 mg/kg dose after 10 minutes if needed). Being a class I anti-arrhythmic, this agent comes a Black Box Warning related to risks of arrhythmias and hypotension with rapid infusion, and IV loading doses require EKG monitoring due to these risks.

Valproate sodium is given at a dose of 20-40 mg/kg IV (with an additional 20 mg/kg dose given after 10 minutes if needed). In the setting of SE, we prefer the higher, 40 mg/kg dose. This agent comes with a risk of hyperammonemia, pancreatitis, thrombocytopenia, and hepatotoxicity.

Levetiracetam is given at a dose of 40-60 mg/kg. Again, we prefer the higher, 60 mg/kg dose in the setting of SE. Unlike the other agents, this one has less serious side effects and can be given as an IVP at certain doses.

Choosing between these agents occurs on a case-by-case basis, and unfortunately there is little data directly comparing the efficacy of these agents in head-to-head trials. In 2019, the ESETT trial was published in the NEJM to address this issue. This was a highly anticipated trial that set out to determine which of these three agents works best as second-line therapy for SE. They used the higher dosing range of each agent, with phenytoin given at 20 mg/kg (with a max dose of 1500 mg), valproate sodium given at 40 mg/kg (with a max dose of 3000 mg), and levetiracetam given at 60 mg/kg (with a max dose of 4500 mg). They found no difference in efficacy between the three agents, which were about 45-47% effective.

Although this may seem like a negative study, it is still practice changing. If we know all of the agents have similar efficacy, why not use the safest one? I think this study will lead to a decreased use of phenytoin and valproate sodium given their side effect profile, toxicities, and required monitoring. Conversely, I hope that this study leads to more levetiracetam use and at higher doses, given its lack of side effects and the fact that it can be safely given at very rapid rates. At my site, vials of levetiracetam are available in the ER Pyxis machines and we allow IVP for doses up to 1500 mg. For doses greater than 1500 mg, we mix the dose in 50 mL of NS and administer it over 15 minutes. For more info on this process, check out Episode 2.

Unfortunately, even these second-line agents are routinely under-dosed. In a paper published out of Mayo, the authors found 80% of patients received an inadequate dose of these second-line agents.

You may be asking, what is the big deal? Does this really matter? You may think that I’m just a dose-obsessed pharmacist. Well, that’s true. But we have data showing that under-dosing patients in SE is harmful.

Factors associated with poor outcomes include the underlying etiology of the seizure, older age, and duration of the seizure- which are all intuitive. But one of the overlooked factors predicting poor outcomes is insufficient drug therapy. This includes giving an insufficient dose, using the wrong route of administration, having prolonged delays between treatments, and not following a guideline/protocol aimed at treating SE. In patients with adequate therapy, the mortality rate may be as low as 8%, while it may be as high as 45% in those given insufficient drug therapy. In addition, adherence to a treatment protocol was associated with better seizure control and shorter ICU and hospital length of stay.

In 2010, Aranda and colleagues published a study in Epilepsia that looked at management of GCSE. They found that adequate first-line treatment resulted in patients being about 8 times (7.7) more likely (95% CI 3.1-19.3) to achieve seizure cessation (with a 74% vs 29% efficacy rate (P <0.0001)). Adequate second-line treatment resulted in patients being about 5 times (4.7) more likely (95% CI 3.1-17.8) to have seizure cessation (with an 83% vs 50% efficacy rate, (P = 0.002)). They also found that adherence to a protocol was associated with a decreased rate of RSE (P = 0.01). And here’s the final kicker: patients who had treatment in accordance with a protocol were 3.8 times more likely to avoid intubation during SE management.

In conclusion, I think it’s a good idea to commit the doses of phenytoin, valproate sodium, and levetiracetam to memory, and to avoid under-dosing these agents. In the long run, I think we will be using much more levetiracetam than the other agents given its safety and ease of administration. Consider educating on these points at your own institution, along with creating a SE treatment protocol or guideline- both of which will help improve patient outcomes.

As always, thank you so much for your time. Please tune in next week as we discuss the management of RSE.