All right. So, hi, everyone. Welcome to San Francisco. So, my name's Nicole Davis. I'm the neuro ICU clinical pharmacist at Mount Sinai. And I'm going to end the talk today about talking about some of our third and fourth phase options for status epilepticus, and then how do drug interactions come into play. So, all of the talks before me, you've noticed that there's been a lot of data, lots of RCTs, big numbers. Well, guess what? When it comes to this phase, we don't have that. We have a few well-done trials, so you think of RAMPART, you think of the VA study, you think of ESSIT, you know well-done trials like about the initial management of status. But once we get to this phase three, you kind of have to lean on expert opinion and what makes sense mechanistically, what makes sense logically when we manage these patients. Okay. So, when it comes to status epilepticus, obviously, it is associated with lots of badness, right? You have increased morbidity, increased mortality. You worry about things like rhabdomyolysis, raised ICPs, but what we should also be considering and worrying about is increased pharmacoresistance. So I'm sure everyone's kind of heard of the when you're getting increased pharmacoresistance. What that means is you're having an internalization of your GABA receptors and an externalization of your glutamate receptors, all right, so sometimes we may say like your NMDA receptors. So what can we give these patients to try to optimize what's happening pathophysiologically? So when we turn to the guidelines, now there's two sets of guidelines, the American Epilepsy Society and the Neurocritical Care Society. So they really turn to a lot of evidence to guide the first few phases of status epilepticus. So everyone knows when you come in with status epilepticus, you get a big dose of benzos and you have to get a robust dose of either levotracetam, phenytoin, or valproic acid. So really it's kind of dealer's choice for which ASM that you want to give. But when we progress to that third phase, so the American Epilepsy Society says the 40 to 60 minute phase of just this patient's management, there's no clear evidence to guide this phase. And they're completely right. Really we only have lots of retrospective data, maybe a few very tiny RCTs to kind of guide this level of evidence. So let's kind of work through mechanistically what makes sense. So before we get started, we're going to go and eliminate two drugs that we're not going to really discuss today. Thiopental hasn't been available in the United States since around 2010, though it is still available in some other countries. And then lorazepam isn't really used that frequently to manage status epilepticus, unless there's like some kind of massive shortage going on. But it has propylene glycol, so it's going to be an issue whenever we're giving it to patients. So we have three anesthetic drugs that we'll talk about first. So these will be kind of our big three players initially. So focusing on midazolam first. So midazolam is our classic benzo agent, so this is the agent that I'll prefer to use in my practice initially. So it's a hemodynamically neutral agent, and it will really focus on hitting those GABA receptors while the patient still has them externalized. So as we talked about, as the progression of status continues, you get some internalization of those GABA receptors. So your GABA agents are going to become less effective over time. So when that happens, you do have to increase your dose of midazolam to try to overcome this. So what is really nice about midazolam is the sky's kind of the limit when it comes to dosing. So there is evidence that does indicate up to 2.9 mgs per kg per hour can be used in these patients. So if you think about in like a 100 kilo patient, it's almost 300 milligrams of midazolam an hour, which is a crazy amount. But we do have evidence to support that practice. So shifting gears a little bit to propofol. So propofol also a nice agent and has mostly GABA activity, but then it does have a little bit of anti-NMDA. So that could be helpful. The unfortunate part of propofol is it does seem to have more side effects initially as compared to midazolam. So it is a hemodynamic suppressant. So when you start using those really big doses, you may actually need to start some vasoactive agents. And then of course, everyone I'm sure is well aware that the higher your doses of propofol, the longer you give it to patients, propofol-related infusion syndrome does become a significant concern. The dosing is there for you. So in my practice, I've never actually ever been able to reach 200 mgs per kg per minute in these patients, usually because the side effects just become too much. So now I want to kind of talk about ketamine. So ketamine is one of my favorite agents to use in status epilepticus. Now ketamine has not made it into any of the guidelines, though I know some of the guidelines are kind of being re-looked at and re-evaluated, and I'm sure that ketamine will make it into the next iteration of guidelines. But ketamine is an anti-NMDA. So it makes sense. You have all your RGABA agents. Now we have a nice anti-NMDA agent. So it makes sense. Like as status progresses, maybe the ketamine will become more effective. So ketamine is hemodynamically neutral, at least initially. As time goes on and as your patient depletes their endogenous supply of catecholamines, ketamine can then actually act as a negative inotrope. So this could manifest later on in your patient's course. And then for the dosing for ketamine, there is evidence to suggest that you can go up to 15 mg per kick per hour. So for ketamine and status epilepticus, this indication, you'll see the highest doses of ketamine. So we don't use doses like this for really anything else. So if you're going to start using doses like this, really loop in your pharmacy team and your pharmacy operations team, because you're going to quickly burn through your hospital's ketamine supply doing this. So those are the agents individually. But really what the question should be is, what agent should we start when? Should we combine them? Is it better? Give one agent. Oh, the patient's still seizing. Let's start a different agent and DC the initial agent. Or do we combine them? So what I want to first talk about is combining midazolam and propofol. So this is probably the most common combination that we used to see. Maybe not so much anymore. But it made sense, because these are both primary GABA agents. And then everyone's probably pretty familiar with using them for sedation. So there was some level of comfort to use them then for status. You know what to expect with these agents. The only limitation that I think about with these two agents is, again, they're both GABA. So theoretically, as the patient progresses, they may become less effective. So then for midazolam and ketamine, so at least at my hospital, this is the combination that we'll lean on most frequently. So it makes sense. We have a nice GABA agent. We have a nice anti-NMDA agent. And they're both hemodynamically neutral. So the patient should do pretty well. Unfortunately, there are several case reports out there now. And I've also seen this in my own practice. As time goes on and as you increase the doses of both of these agents, patients will develop a metabolic acidosis, as well as some hemodynamic instability. So unfortunately, if these do start to manifest in your patient, you may need to back off on both of these drips sooner than you would intend to. So then finally, the combination that I've seen the least amount of evidence for, again, when I'm saying evidence, I'm talking about retrospective case series, but propofol and ketamine. Again, I think this combination makes perfect sense. With propofol being a hemodynamic suppressant, maybe giving some ketamine might actually alleviate some of the suppression that comes from the propofol. But again, I do think when you think mechanistically, this combination does make sense. Okay, so those are kind of the pharmacologic aspects to these agents. So let's kind of talk about what evidence is there to support them. So whenever you have a patient that you're going to start an anesthetic drip in, what your practice should be is you bolus the drip, and then you increase your infusion. Patient continues to seize, re-bolus, increase the infusion. And that's consistent for both midazolam, propofol, and ketamine. So there was a study in 2014 looking at high-dose versus low-dose midazolam. So low-dose was 0.2 mg per kick per hour, high-dose being anything above 0.4 mg per kick per hour. With the higher doses of midazolam, they actually found that there is less chance of seizure recurrence, maybe this improvement in mortality. But unfortunately, it can be associated with longer lengths of stays. And then that higher dose of midazolam was also associated with hypotension, maybe similar to what you would see with propofol. So there was a small RCT. This was in India in 2018, comparing patients who came in with status epilepticus, and they received either midazolam or they received propofol. In terms of seizure suppression, it was actually the same between the two groups, same incidence of mortality, but the propofol group had a shorter hospital length of stay. So we would kind of expect that, because as you give higher doses of midazolam for longer periods of time, patients will accumulate that midazolam. And then if you throw in renal failure into it, then those patients will be asleep for days and days, right? So kind of what we would expect to see. But I think right now, with what evidence that we do have, I think using either midazolam or propofol is appropriate. So it's kind of whatever your institution, whatever your practice is, whatever you're comfortable with. So for ketamine, so this is kind of in the one to 24-hour phase of management for status. So if you look at all of the case reports for ketamine, it seems like it's very effective. And it does, at least from what I've seen anecdotally, patients do respond really well when you start a ketamine drip. So something that I think is kind of cool to do, especially when you have bedside EEG, is you can give a bolus of ketamine. If the EEG responds, if the EEG looks better, that can be your impotence to actually start a drip. So a lot of these cases that are available, they show you can get seizure control pretty quickly. But unfortunately, there is a risk of metabolic acidosis as time progresses, and especially in combination with midazolam. The other part of ketamine that I did want to mention is there have been some animal studies that have indicated that it shows improvement in inflammation. So patients who have status epilepticus with an etiology like encephalitis, maybe ketamine may be even extra beneficial in those patients. Again, this is just animal data and kind of theorizing its mechanism. All right, so let's talk about the rest of the course. So once you've exhausted your midazolam, your propofol, your ketamine, whatever combination you chose to use, this is where I think it gets very patient-specific as to what you start next. So one option that we do have, and this was an option that's kind of been around for a long time and used to be used a lot more frequently, but now we don't tend to use it as much as pentobarbital. So there was a study that looked at midazolam versus propofol versus pentobarbital, and it showed that pentobarb is highly, highly effective at causing EEG burst suppression. So maybe that could be helpful in your patients. But unfortunately, what it's also associated with is lots of significant adverse effects. So while you can achieve burst suppression very quickly and very easily with pentobarb, unfortunately, it does come at the risk of significant hypotension, ileus, decreased body temperatures, so lots of adverse effects to the patient. We also have inhaled anesthetics. So inhaled anesthetics like isoflurane and desflurane, they show lots of GABAergic activity as well as anti-NMDA activity. So it makes sense, and they're actually pretty effective at controlling seizures. Unfortunately, with inhaled anesthetics, they are associated with hypotension, though there was one case report that I came across that it actually allowed the patient's pentobarb drip to be weaned, so it improved their hemodynamics. But then these inhaled anesthetics are also associated with a pretty high rate of seizure recurrence when you wean them. So it may be good to control the patient initially and then give your background ASM some time to kick in. But unfortunately, this is not a long-term management strategy by any means. There's also a lot of logistical challenges with these inhaled anesthetics, so you really have to loop in your OR colleagues and your respiratory therapist to be able to have the machines at bedside to give these medications. And then for the last, this is more of a non-pharmacologic option, but the last option that I'm going to talk about is the ketogenic diet. So the ketogenic diet has been around for a long time. They actually learned back in the 1970s that, hey, this diet may actually control seizures, so it's mostly used in pediatric populations, but has now been extrapolated and studied in the adult population. So you'll see seizure response rates above 80%. But some of the issues with the ketogenic diet, we can't initiate it in patients who are hemodynamically unstable or have a metabolic acidosis because the ketogenic diet can actually worsen these things. Additionally, if you're using a propofol drip, starting a ketogenic diet probably isn't a great idea because then you're just going to overload the patient with lots of fat intake. So not optimal. So these are for patients who you still can't quite control their seizures. Maybe you don't need anesthetic drips. This is something that we have started in the ICU. So a couple things to think about before you do start this diet. If you've converted all of your ASMs to some type of PO route or if you've used ASMs that only have a PO option, make sure that you don't give them an oral solution. So oral solutions mostly contain sugar alcohols to make them more palatable. So change them to either a crushable tablet or a capsule that can be opened and put down NG tubes. Additionally, you want to make sure any drips that you are giving these patients, don't give them in D5W because if you give them any form of carbohydrate, then it kind of negates the benefit of the ketogenic diet. So I always loop in our unit dietician to help me with this. So it's a really, it's a team approach to starting this diet, but you can use serum beta-hydroxybutyrate to monitor to make sure that your patient does remain in ketosis. So there are a couple other options I'm not going to really focus on, but some other options, there's lots of surgical options that can be beneficial for certain patient types. And then there's vagal nerve stimulators that also have pretty good data and are pretty effective if used in the right patient population. All right. So we kind of talked about all the various drugs that you can initiate for the third phase of status. What I didn't talk about is while you're titrating all of these drips, you're also probably going to be starting multiple ASMs in the background. You're starting them, you're increasing the dose, you're changing the drugs. So when this comes into play, you know, drug-drug interactions does become a pretty significant concern. Now, before I delve into which drug interactions do we actually need to worry about, I do want to do just a brief overview. So we have two types of drug interactions. You have a pharmacokinetic interaction and a pharmacodynamic. So the way that I like to teach this is for pharmacokinetic interactions, it's what your patient's body is going to do to the drug. And then for a pharmacodynamic interaction, this is what the drug will do to your patient's body. So for a lot of our pharmacokinetic interactions, this occurs mostly at the phase of metabolism. So we're talking about like our CYPP450 enzymes. So in a normal patient that doesn't necessarily have any inhibitors or inducers being started, you give the patient active drug. The CYPP450 enzymes do their thing and metabolize the drug, then your patient will excrete inactive drug. Now, in the case of where you start, let's say an inhibitor like diltiazem, for example, this is where you have a decrease in your enzyme activity, right? So you give active drug, you have less enzymes there to metabolize that drug. So therefore, you have less inactive drug to actually excrete. Now, with inhibition, when you start an inhibitor, usually that inhibitive effect takes place pretty quickly. It's a little bit different with induction. So with induction, you have an increase in your P450 enzymes. So you give active drug, there's a lot more enzyme there to metabolize that drug, therefore, you have a lot more inactive drug that you're going to excrete. So your drug concentrations will decrease. So the difference with inhibitors or inducers, though, is that it does actually take some time for this effect to take place. So as inhibitors, the effect takes place pretty quickly. With inducers, it can take one to two weeks for that full effect to be present. And then for pharmacodynamic interactions, so this is kind of what I'm talking about when you have different drugs that compete for the same binding site. So Albumin is a very popular binding site for a lot of our ASMs. So if you're giving two drugs that like the same binding site, then they kind of kick each other off the site. You also have drug interactions, pharmacodynamic interactions, where you get additive side effects. So like one example would be Propofol and Midazolam, when you combine them, obviously you're going to give the patient more sedation. So not necessarily a bad thing, but it's just something to consider. Okay, so to end my talk, I'm going to talk about some of the drug interactions that I do think you need to be aware of as intensivists. So the first one is combining phenytoin and valproic acid. Now I do see this combination a lot, and I'm sure if you have a clinical pharmacist with you that launches them immediately into this whole discussion as to why this is going to be difficult to monitor, why this isn't the best idea, at least for me and my unit, it launches me every single time. But with valproic acid and phenytoin, they compete for the same binding site, right? So it's going to be really difficult to monitor the serum levels, because serum levels are a combination of your bound plus your unbound portion of drug. So when you don't necessarily know what the binding fraction is, it's hard to say exactly how much therapeutic drug you have available. Additionally, phenytoin and valproic acid, they'll induce and they'll inhibit each other, so they really don't play nice at all. My recommendation is to avoid them unless you have very easy access to free levels. At my hospital, unfortunately, they're all send out, so not the easiest thing to monitor. The other reason that I do recommend not giving them together is because phenytoin will induce the production of hepatotoxic and hypoamineemic metabolites of valproic acid. So to me, that's a reason to maybe not give them even outside of just trying to monitor them. Another interaction is phenytoin will induce the metabolism of midazolam. So as we talked about with that GABA internalization, midazolam doses have to increase. So when you combine it with phenytoin, that effect may be even more pronounced, because you'll have to increase the doses of midazolam to get the same effect. So again, not a reason to not give them together, but just something to be aware of. Now, the other big category that I like to focus on is anticoagulants. So with phenytoin and a DOAC, these are drugs that you absolutely cannot give together. So phenytoin will make the concentrations of DOACs subtherapeutic, so it makes patients more prone to clot. So this is a do not use a category X drug interaction, if you want to say. When it comes to warfarin, so warfarin, as we know, warfarin seems to interact with just about everything, right? But even though warfarin has a drug interaction with almost everything, there's almost never like a contraindication. So we have the INR, it's pretty easy to monitor and adjust for different dose changes. So the same idea with phenytoin and valproic acid. So phenytoin will decrease your INRs, valproic acid will increase your INRs. Again, we'll just monitor the INR, make adjustments, but just be aware whenever you start warfarin or you start phenytoin or you start valproic acid or make any dose adjustments, just be a little bit careful. Now, so for the longest time, we kind of always thought valproic acid and DOACs, safe to give together, probably no drug interaction. But there was a recent nested cohort study that looked at patients who were receiving anticoagulants and then patients who received phenytoin, carbamazepine, valproic acid, or levotiracetam. And so for all those patients, so they weren't necessarily receiving them together, but individually. So all of those patients actually had an increased risk of some type of VTE event. Mostly increased risk of stroke, so these patients were getting their DOAC for AFib. Now, we expect that with phenytoin and carbamazepine, but it's kind of surprising to see that with valproic acid and even levotiracetam. So there is some in vitro data now that indicates that valproic acid can increase the activity of P-glycoproteins. So then that would mean they're going to have less DOAC available. And the same in vitro data was seen with levotiracetam. So right now, because of that, it was just a cohort study and then it's just this in vitro data. We're still combining and it's still considered like a category C drug interaction, but it's going to be interesting to see if more data comes out about this and if it is significant. So this is something newish that I learned, so just to make everyone aware that, you know, maybe levotiracetam doesn't play as nice as we thought. So for antibiotics, so if you're going to remember two drug interactions, please remember phenytoin and DOACs and then remember valproic acid and carbapenems, so like meropenem. So when you give valproic acid with carbapenems, the carbapenem will make your valproic acid level essentially zero. It drives it down to negligible concentrations very, very quickly. You cannot give more valproic acid to overcome this. You have to either change your ASM or you have to change your antibiotic, all right? So this is not something like, oh, I'll just monitor the level, it'll be fine. It will not be fine, guys, just please don't do it. With our antiretrovirals, so there's actually a lot of drug interactions with valproic acid and phenytoin. It's very drug specific, but if you see your patient on a regimen that includes cobasistat, take a closer look at it and see if any adjustments do need to be made. All right, and then my last slide to wrap up. So amiodarone will inhibit phenytoin's metabolism via 2C9. So you can get toxic phenytoin levels once amiodarone is initiated. So you could avoid this combination, but it's also appropriate to monitor just to be aware of it. Now phenytoin will induce the metabolism of nemotipine. So that could be a pretty big problem in our Subarac patients, right? Because they need their nemotipine to promote their long-term outcomes. So there's actually been a few studies now that have looked at patients who received seizure prophylaxis with phenytoin. They seem to have maybe worse outcomes. So maybe some of those worse outcomes can actually be explained by this particular drug interaction. And then to wrap up with, so phenytoin will also induce the metabolism of dexamethasone. Usually dexamethasone is only prescribed for short courses, so maybe it's not that big of a deal. But if patients require large doses or prolonged courses, just something to consider if they're also on phenytoin that you may need to increase the dose of the dexamethasone. All right, so just to wrap up with, if you guys walk out of this presentation not remembering anything from my talk, just remember valproic acid and carbapenems and phenytoin and DOACs, please don't do it. All right, thank you so much.

status epilepticus

treatment options

drug interactions

benzodiazepines

antiseizure medications

ketogenic diet