Episode 94: Mastering seizure pharmacology with Tom Bleck

We explore the vagaries and nitty-gritty of drugs for seizure termination, including benzos and ASMs, with the great Tom Bleck, MD MCCM FNCS, neurointensivist, professor, and founding member of the Neurocritical Care Society.

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Takeaway lessons

In the RAMPART study, IM midazolam (10 mg) achieved faster seizure control than IV lorazepam (4 mg), with most of the difference accounted for by the time needed to start the line. So if there’s no IV, use IM midazolam.
If there is an IV, there is no data on superiority of any benzo over any other. This makes it appealing to use lorazepam, simply because we have the most data surrounding its use. But use whatever.
It is often hard to truly know the timeline since seizures began, other than those already on EEG monitoring. Probably in many published populations, non-benzo-responders may have been patients who were already seizing for some time. As soon as seizures begin, benzo-sensitive gaba A receptors immediately begin to be replaced by benzo-insensitive receptors (a phenomenon not seen when benzos are used for other applications).
Most seizures, even in the ICU, end in about 90 seconds. If you don’t witness the onset, you should probably plan to treat it. If you do, you should prepare to treat, but wait five minutes to see if it stops, our current cutoff for status epilepticus—most will stop before then. The caveat is that it’s not impossible some of these people who appear to stop convulsing have simply become non-convulsive… this generally takes longer (30+ minutes), but in critically ill patients all bets are off.
Meaningful respiratory dysfunction from benzos for seizures is vanishingly rare. Most patients who get intubated due to benzo-related sedation do so out of clinician preference, not true need. Consider a side-lying rescue position to maintain the airway, or an oral or nasal airway.
The VA Cooperative trial used a lorazepam dose of 0.1 mg/kg, one time, no cap. Most of the current guidelines now suggest giving a 4 mg dose, then repeating if necessary. If this still leaves you under 0.1 mg/kg, a third dose to finish it out is reasonable. Giving more than 0.1 mg/kg is probably not more effective. Six minutes between doses is sometimes recommended, but most would go closer to 4-5 minutes at most.
The goal is cessation of convulsions, or of any other clinical signs of seizure (twitches, eye deviation, etc). Ideally, the patient would then wake up promptly, but this is a rarity, especially in the ICU. This then leaves the question of whether the patient is still seizing, merely non-convulsively. This needs an EEG to answer, but the risk to the brain once convulsions cease is probably less, so you can probably wait for the EEG (rather than giving more empiric doses of benzos).
If not rousing, however, you should probably treat with an anti-seizure medication, unless rapid access to EEG can prove lack of ongoing seizure. The three studied in the ESETT trial were: levetiracetam 60 mg/kg, valproate at 40 mg/kg, or fosphenytoin at 20 mg/kg, all of which had about 40% response rate. This was used in patients still convulsing at the time, but efficacy can probably be extrapolated to non-convulsive patients (or prevention of the next seizure in delicate patients). The study was not powered to look at subgroups, and all three seemed equally effective.
Levetiracetam is most popular by dint of its ease of use, especially now that it’s available by IV push, and there are very few times it would be the wrong choice in this context. (Even in renal failure, the same load can be used; maintenance will simply be lower/less frequent.) For long-term use, it does sometimes cause behavioral problems, but that is not an acute issue.
60 mg/kg is probably the right dose in most patients. Possibly less is effective in some cases, but it doesn’t seem to have toxicity at this dose, and higher doses probably reach adequate brain levels faster.
There is now some question whether introducing ketamine after the failure of the first benzo dose may decrease the chance of proceeding to require general anesthesia. This will be studied more in the upcoming KESETT trial.
When to intubate and induce general anethesia? For Tom, only if they’re still convulsing (after benzo + ASM), or proven to still be seizing by EEG. But it’s an open question. Rapid EEG devices are a great tool here. If there is absolutely no access to EEG, you should consider transfer to a center that has it, probably within an hour or so if not waking.
There may be some role for inducing “procedural sedation” with propofol without intubating, which will terminate seizures in some cases. But this is a challenge for most non-anesthesiologists.
Most induction meds for intubation have some anti-seizure effect, including etomidate, so there’s not much reason to use an unusual drug here. However, do use some kind of sedative, even if they’re already obtunded (please don’t merely paralyze).
If paralyzing with rocuronium (not a bad idea, due to the risk of hyperkalemia in some of these patients), consider reversing it after, if you plan to use clinical markers to monitor their status.
Once intubated, high dose benzo (usually midazolam) or propofol? No data on this, but benzos tend to cause more problems, such as long weans due to metabolites. Most ICU folks are more comfortable with high dose propofol.
If using midaz, use a loading dose of 0.2 mg/kg (loading propofol is probably not necessary though it was done in some trials), then start an infusion of 0.2 mg/kg/hr. As tachyphylaxis sets in fast, you may need to frequently increase the dose afterwards (hourly or so), tough to do without an EEG; propofol may be a better choice without continuous EEG.
Tom would empirically use about 80 mcg/kg/min propofol if hemodynamically tolerated, if EEG was unavailable.
Ketamine as an adjunct to general anesthesia has useful hemodynamic properties (e.g. added to propofol to combat hypotension), but also seems to have an effective anti-seizure effect on its own. It’s less clear about using it as monotherapy. For effective seizure therapy, go for a completely dissociative dose (e.g. 5 mg/kg).
Not all epileptiform activity on EEG needs to be treated by escalating therapy. This is pertinent to the rapid EEG devices that try to report seizure via algorithm, as they’ll generally alert for anything seizure-like, whereas not all of these truly need treatment.
Usually with propofol, barbituates, or inhalational anesthesia, the initial goal is burst suppression with 10 second suppression between bursts. (Even this may only control about 1/3 of patients, who may need complete flatline.) If using midazolam or ketamine, however, you may never achieve burst suppression (only around 1/5 ever will), yet you may still achieve seizure control.
Frequency of monitoring of continuous EEG depends somewhat on the situation, eg is the patient still trying to achieve seizure control/suppression or have they reached a fairly steady state. Note: an occasional self-terminating seizure (e.g. one a day) may not mean a patient is failing weaning, as an occasional seizure in the outpatient setting is not exactly an emergency.
Levetiracetam has been dosed as high as 6 g per day, which is usually tolerated, although behavioral problems are common. Adding additional agents is usually better than megadoses, but Tom prefers to add them one by one if seizures prove refractory; adding multiple agents at one makes it hard to pinpoint the cause of drug reactions. Clobazam is favored by some to help wean anesthesia.
Tom would most often use valproate as a second line. A single dose is safe even in pregnant women (pregnancy was not screened in ESETT, though it wouldn’t be continued in known pregnancy). Fosphenytoin is still reasonable, though has more complications, and was the most associated with intubation in ESETT.
Lacosamide is often underdosed; it’s best loaded with 10-13 mg/kg, monitoring the PR interval.
Phenobarbital is a good drug, especially in difficult to control patients, but start with an aggressive general anesthetic dose: 20 mg/kg load, usually hitting a serum level ~20 (then taper), and may need to go to 100-150 mg/kg to allow weaning of general anesthesia. Some patients will even wake up on these doses once they adapt. Halflife is around 120 hours, so if you make a change, give a load or expect to wait for steady state; pentobarbital is faster, but its cost has been exorbitantly raised, so if you use it, maybe load, then switch to phenobarb.
In new onset refractory status (NORSE), adding therapies fairly early like anakinra or tocilizumab (as they often have ample IL-1 or IL-6) can be wise. Treat vitamin deficiencies; vit D deficiency may be a marker that supplementation is beneficial. A ketogenic die can be tried fairly early, though it’s a lot of work for the dieticians and pharmacists to eliminate carbohydrates from meds (eg dextrose); the target beta-hydroxybutyrate level is not clear. Ganaxolone probably has little role now.
In general, partial/focal seizures probably do not need to be treated as aggressively as generalized seizures. There is likely a spectrum, based heavily on the extensiveness of seizure; complex partial seizures (focal with altered awareness) that persist past 10 minutes or so should probably be treated. Most would not intubate/induce general anesthesia for these, but would treat with ASMs, and benzos may not be needed. Absence status seems to cause no damage regardless of duration, though they can be terminated by benzos, and ethosuximide can be used.
If focal seizures arise from a foci such as intracranial hemorrhage, it’s usually worth using an ASM to try and prevent generalization, but understand that sometimes the focal seizures can’t be suppressed. (And if there’s a foci like a tumor, remove it—it will help.) Vagal nerve stimulators or direct brain stimulation may help with focal seizures too, and maybe transcranial current stimulation, all areas of research.
Don’t despair. About 35% of patients with super refractory status will return to their baseline. (35% will also die, but that’s not bad odds.)

Episode 94: Mastering seizure pharmacology with Tom Bleck

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