Emerge in EM

E16: Benzodiazepine-refractory status epilepticus

• Mohamed Hagahmed

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In this episode of 'EMERGE in EM,' Dr. Mohamed Hagahmed and ICU doctor Dr. Obi Anozie discuss the critical neurological emergency of benzodiazepine-refractory status epilepticus (BRSE). They explore the pathology behind why BRSE occurs, the necessary aggressive treatment strategies, and second-line agent options including levetiracetam, valproic acid, fosphenytoin, propofol, and ketamine. They emphasize the importance of correct dosing, timely escalation of treatment, and thorough patient examination. The conversation also covers the need for a comprehensive approach to non-convulsive status epilepticus and the practical aspects of pre-hospital and ED management, including the use of paralytic agents like rocuronium over succinylcholine.

Paper reference: Pelletier J, Merriman W, Koyfman A, Long B. Benzodiazepine-refractory status epilepticus: A narrative review. Am J Emerg Med. 2025;81:228-235. doi:10.1016/j.ajem.2025.01.046.

Mohamed:

Hey folks, welcome back to EMERGE in EM. Today we're addressing one of the most time critical neurological emergencies, status epilepticus, and specifically the subset that challenges even experienced clinicians benzodiazepine refractory status Epilepticus or BRSE. This is a scenario where guideline recommended doses of benzodiazepines fail GABAergic pathways downregulate. Excitatory neurotransmission accelerates and ongoing seizure activity begins causing progressive neuronal injury. Joining me is ICU doctor, Dr. Obi Anozie, who is a friend of mine and someone who routinely manages refractory seizures in the ICU and understands the nuanced physiology and treatment escalation required in these cases. And to help guide our discussion, we'll be reviewing the paper, discussing the topic of Benzodiazepine refractory status epilepticus that is published in the American Journal of Emergency Medicine by Jessica Pelletier, etal. So let's dive in. Obi thank you for coming back again to the podcast. Obi just remind our audience where you're from and what do you do.

Obi:

Yeah. Right now I'm currently based in Beaufort, Georgia. I work for Piedmont an intensivist over there. So definitely enjoy doing that. We see all sorts of pathophysiologies. Very interesting. In the off time, you can always find me in the gym. I'm born and raised in Canada. I like the colds even though, it has been pretty cold, but I'm very used to it. I do and appreciate a good four seasons. What else do I like? I like video games.

Mohamed:

Let's discuss a topic that it's considered Bread and butter emergency medicine and critical care, Obi, you work in the ICU, I work in the emergency department. We see these cases all of the time. Obviously in the ICU, the presentation is a little bit different because by then they're either intubated or maybe they're like. On continuous, EEG and whatnot, you're just basically managing them. But the reason why this topic caught my eyes is because benzo refractory, and the common understanding of status epilepticus, that almost all of them respond to benzodiazepine. I was actually shocked by the number that is published in this paper that up to 40% of status epilepticus cases don't respond to benzodiazepine. And I wanna ask you why is that? What is the pathophysiology behind that?

Obi:

Yeah, absolutely. Yeah and to your point, I think that's a startling statistic and I think a lot of that has to do with, time dependency, like, how long they've been seizing. And the fact that the longer a patient seizes, the more it becomes a self-sustaining cycle. Because from a pathophysiological standpoint, you're talking about the inhibitory mediators of the brain, which is GABAergic pathways mediated by GABA receptors that allow, chloride, influx and hyperpolarization of neurons. So if those receptors are becoming internalized and they're not available, then it becomes very difficult to start for the brain to actually inhibit seizures, and they become more and more progressive and self-sustaining.

Mohamed:

So the longer I wait to treat my seizure, the worst is for me to manage it in a more efficient way, meaning that the longer I wait, the harder it becomes to cease seizing. I don't know.

Obi:

There you go. A hundred percent. Yep.

Mohamed:

And like you said, like it really from a neurochemical pathway and all these receptors in your brain, like you said, like those GABAergic receptors almost become reabsorbed, or less of them become more exposed to what you and I use most of the time, which is benzodiazepine.

Obi:

Yeah.

Mohamed:

So I guess now, because this is nice, it's nice to segue to, to later discussion about therapy because now we have to think and maybe pay extra attention to the other receptors. Like you said, the glutaminergic receptor is one of them.

Obi:

Absolutely.

Mohamed:

I know we've been through this before. Definition of a status epilepticus, the 30 minute, magical window of putting your hands in your pocket. Don't do anything until the 30 minute mark before we start doing something. This is old school, right? This is so 1980s. So what is the current definition of status of epilepticus? Man, I just feel old right now. I said 1980s.

Obi:

Yeah, absolutely. Old school. Indeed. And like when you just think about it, how irrational would it be to sit there and watch someone seize for 30 minutes and expect that even if their seizure stopped at the end of 30 minutes. They'll be just perfectly fine. I think that's very irrational to have that train of thought. And I think, from a definition standpoint that's been revised because we've all come to terms with waiting for 30 minutes. Just doesn't make sense. So status epilepticus is really a seizure that is, these are lasting for more than five minutes or multiple seizures back to back without a return to baseline.

Mohamed:

Five minutes. Unable to return the baseline. Let me ask you this. So how many of these seizures actually just recover within a minute? Is it always. Like a priority to just jump to treat them within the first minute of seizing. You know what I mean? I'm just like thinking of that from my standpoint of that person in triage, who seizes, and then the nurse is like rushing to bring them to the trauma bay. Yeah. And it's been like a minute. And majority of these cases what return, correct. Like a

Obi:

The majority of them I, they return and here's the thing, because you and I, we work in different settings right? You work in the emergency room. I work in the ICU, but I also respond to patients on the medical floor. I'll respond to a rapid response that's called overhead, and that usually means there's something happening with a patient on the floors. And if it's related to a seizure, the first thing I'll ask when I get to the bedside is, how long has this been going? Is, has this been going on? Has they, have they been seizing on and off all day? Or if this is the first seizure this patient's had, how long has the seizure, been happening? Because as an ICU doctor, I will feel a little bit more comfortable to give a little bit of wiggle room to see if a patient can start to respond on their own. Because obviously if things are getting worse, you're giving medications and then we're going down a pathway. But if they could potentially break and then we can give them anti-seizure medication, then maybe we can resolve the issue. So I think it's not a bad idea if they haven't been seizing for a long time by the time you encountered them on the first, on your first encounter to give a little wiggle room to see if it responds.

Mohamed:

I agree. I'm in exact same thought processes on that. I don't really jump into giving benzodiazepine like within the first like 30 seconds. I don't do that. I which. The majority of cases is not the case. So I'm gonna bring up a pre-hospital case so let's say this case is about a person, let's say in their fifties, and they seized multiple times by EMS. Actually, when EMS got there on the scene the family member of the patient gave a rescue dose, lorazepam initially just help because of history of epilepsy. So EMS found the patient unresponsive. They did what they had to do and they gave first dose of Midazolam. So the patient got Lorazepam, they gave Midazolam in the us Lorazepam is Ativan. And for those of you who are not in the us, midazolam is Verset. So by the time they actually got to us in the ed, in the emergency department they seized total of three times. At that point, EMS was supporting the patient from a respiratory standpoint with BVM, oxygen, all that stuff. So let me, just go over some of the things that we want to know in the pre-hospital setting, in the acute setting, hyperacute setting before we determine what the next steps are, what's some questions that jump to your mind, Obi about this situation?

Obi:

That's a good, that's a good question. A big question actually. Probably one of the main questions I want to know because you mentioned that they've given Lorazepam, we've given Midazolam. But my, one of my, one of my questions would be, how much was given because, and this is something that you probably are well aware of. We often underdose benzos and I see this on the floors all a lot of times too. One of one of Midazolam two. Midazolam, one of Ativan. Two of Ativan. So I would like to know how much they've been given, what medications are they normally on? Do they have a history of epilepsy? Questions like that.

Mohamed:

Yeah that's a good one. And of course for me for someone who works in EMS, I always ask the other questions like, what is the blood glucose? Is there any history of pregnancy? Obviously this was a male, but if there were a female is a history of pregnancy and we'll talk about some of these causes a little bit here, but these are like the kind of acute things that I can hopefully manage or reverse, but you're right. So dosing. Let's go over dosing because I think this, you said that the 2 of Ativan it's a medical show. Like everybody gets, give two milligrams of

Obi:

Yep. Too much apprehension. Too much apprehension to, to, really go big or

Mohamed:

Exactly what is, what do you think is the fear behind behind giving high doses of benzodiazepine?

Obi:

Probably the biggest fear has gotta be there's two main things that you're gonna watch out for. And there's hemodynamic instability, hypotension and the loss of the airway, respiratory suppression, loss of the airway. And, as nice two physiciaans and you know yourself as a, as an ER physician, I think our comfort level will be a little bit, more, I'm more willing to give a bigger dose because I think it's more important to really stop the seizure. Especially when, when you think about the potential morbidity and potential mortality that ongoing seizure could potentially cause if it's not broken within a certain timeframe. So I'm more willing to see, look, is this gonna work or is it not? And give a big dose. But I think, like on the general floors there yeah, there's that apprehension because of hypotension and potential need for intubation.

Mohamed:

I'll be honest with you, like I don't care about the hypotension.'cause in the pre-hospital setting, we know how to fix it, per epinephrine or norepinephrine drip. But the respiratory suppression for me is interesting because you're right, if I am fearful of giving a high dose of benzodiazepine in this case will be midazolam or Versed. With the reasoning that I'm gonna compromise the respiratory status. You're right, the underlying status, because that patient's already in status epilepticus, that is already a risk factor for a compromising airway, right?

Obi:

True. Yeah, absolutely.

Mohamed:

So I feel and by the way, I'm just saying this because I don't come from a position of righteousness. I come from a position of vulnerability because I tell you I've thought myself whenever I get these consults, I actually thought a little bit and question giving high doses of benzodiazepine myself to be truthfully honest.'cause the problem that I have as an EMS physician is that I have to rely on the paramedics consults. Their story, their assessment to give them the right order. Does that make sense to you?

Obi:

Yeah, that makes sense.

Mohamed:

So if I feel that the story, maybe that doesn't make sense, then I'm. More cautious about giving high doses of benzodiazepine. Let's say for example, maybe the story is consistent with or suspicious for dysrhythmia, and there was no EKG done or obtained, and I was like, maybe we should get an EKG first and see that dysrhythmia, I wouldn't want to give them a high doses of Benzodiazepine. Anyway, what I'm trying to say is that if the story is concerning, sure. Go ahead, go high with the 10 milligrams of intramuscular, midazolam. And here the doses I'll show I'll put this in the show notes for all the adequate doses of all the benzodiazepine. However, you're right, though the respiratory suppression is a concern, but what concerns me more is that if they continue seizing. It's gonna be not only harder for me to control the seizure down the line, but also harder for me to manage that airway. But I'll tell you from pre, from a pre-hospital standpoint, it's tricky because if you're in the back of the truck by yourself as a paramedic, you have no backup, you have no resources. Maybe I would go with a smaller doses to see until you get like the backup that you need to help you with. Airway setup, that kind of stuff. I it's very logistical driven environment. That's what I'm trying to say. Ob, does that make sense?

Obi:

Oh, it makes perfect sense. And I don't get to see that aspect as much because I only work in the setting I work in. But yeah, that makes perfect sense.

Mohamed:

So in Pennsylvania, let me just share with you this, but in Pennsylvania, the protocol that I'm looking at right now, so for the adult dose, the midazolam dose starts at 0.2 mg per kilo. Up to 10 milligrams intramuscularly. And honestly, if you ask a lot of EMS directors, they normally start like depending when the patient's weight, let's say like 70 kilos, they normally start like at five or seven and a half, maybe intramuscular dose initially. And then for the Lorazepam, which most EMS agencies don't carry, is a two milligram, obviously IV io intranasal intramuscular, which is. Very convenient. And diazepam, almost no one carries, but it's 0.2 mg per kilo up to 10 milligram, just like the Versed. for Peds, the dose goes a little bit higher because now Peds we have to be aggressive at treating the seizure because they can actually decompensate very quickly. So

Obi:

They have a higher morbidity

Mohamed:

is like 0.3 mg per kilo for midazolam. But for here, for this article, it says for lorazepam is 0.1 mg per kilo, up to four milligrams, not the two milligrams that you are not familiar with. And then the Midazolam is 10 milligram intramuscularly. Let me ask you just truthfully and complete show of vulnerability here. What do you start your doses with benzodiazepine for your patient who are seizing? Let's say this is a code on the floor.

Obi:

Oh, absolutely. So the way I, and the way what I like to advertise or, advise others is there's what, the dosages say that you should give, but there's also your clinician judgment. There's also what in the patient, what you said too. What have this, what has this patient been getting, is the story consistent? Does that make sense? But I like to also use my own judgment and I'd like to take a look at the patient. A lot of times I if they're frail appearing cachectic, I might start with five milligrams. Like you said, I might start with five milligrams of midazolam. And then repeat it, or, if Midazolam is not available and I have an IV and this is Lorazepam, I'll start with I'll start with four. And then I'll reevaluate the response.

Mohamed:

Okay, that sounds good. Obviously during that time, you and I will ask questions and try to also focus on history and examination too. I remember why they're seizing. In a pre-hospital setting, it gets a little bit trickier. So let's just cover some of the common causes of status epilepticus.

Obi:

Yeah. You mentioned a really easy one. You mentioned a really easy one. And probably the easiest one to diagnose would be like hypoglycemia. I, that's one of the first questions I ask at. At every code or every rapid, any patient that comes in, you'll get a finger stick. If the blood sugar is like 30, then that's something that's easily easily correctable. You wanna look at cardiac arrhythmia two, get an EKG, Brugada syndrome has presented like that. Wolf, Parkinson White, Urine Tox is important to see if patients are on any substances. Space occupying lesions are huge. Like tumors or brain bleeds, infections, abscesses, tuberculosis, meningitis. Are they septic, especially in your elderly patients like a UTI. UTI can essentially present with status epilepticus, and on my recollection, I think I've had actually. In the last few months, patients that have had, maybe somewhat closer to a non convulsive status epilepticus but definitely had raging UTIs to go along with it. Metabolic causes, hypomagnesemia, hypocalcemia, right? Calcium plays a key role. We're talking about glutaminergic transmission. And that's mediated through calcium, so that's huge. Pregnancy, there, there are so many things to think about.

Mohamed:

Yeah, and it's easier for us, you and I in a hospital to try to get some more objective data. In the prehospital is setting, not a lot of resources out there. So like you said. Sugar, diabetes, hypoglycemia hyperglycemia as well. I'm thinking about trauma fall, CVA, strokes I'm thinking about anything that just compromises oxygenation to the brain. Asphyxia things like lung disease, pneumonia, sepsis. You mentioned that as well, and

Obi:

Carbon monoxide would be really

Mohamed:

Oh, yes,

Obi:

Yeah. That be pretty big.

Mohamed:

Anything that compromises oxygen delivery, carbon monoxide for sure will result in seizures. And then the other thing that I keep thinking about, you mentioned also eclampsia in, in any female of childbearing age, you just assume they're eclamptic and unproven otherwise. But also think a lot about, this is the very commonly I would tell you, like maybe ignored fact is alcohol withdrawal,

Obi:

big one.

Mohamed:

it's just like something I don't know about Atlanta, but Pennsylvania, we see this a lot, especially in rural areas, urban area, we see it everywhere basically. And nowadays we're seeing like substance induced seizures mostly stimulants like, methamphetamine, cocaine. But we're also seeing also withdrawal from opioids. We're seeing this huge now epidemic of xylazine overdoses,

Obi:

Yeah.

Mohamed:

and xylazine withdrawal and xylazine, as it's it's an alpha two agonist. So basically acts like, precedex. if you withdraw, I've seen like really bad xylazine withdrawal in the ed, and a lot of times these patients can present with PRES. So posterior reversible encephalopathy syndrome, and you, they have like just seizures and hypertension, severe agitation, nausea, vomiting. A lot of them require like Precedex. Again, we'll talk about the management, but this is the things that I also worry about. Substances electrolytes, trauma, stroke, anything genetic within the pediatric population. So I would also inquire the parents about any genetic predisposition for seizures. And then last but not least, medications,'cause some medications can lower the threshold for seizures, including stuff that you and I give all the time, cephalosporin, Penicillin and.

Obi:

We give that a lot.

Mohamed:

Wellbutrin is the most common, antidepressant, bupropion carbamazepine, which is an anti-seizure, but it can lower the seizure threshold. Phenytoin, S-S-R-I-S-N-R-I. These are antidepressant medication. They can lower seizure threshold. So imagine now someone who is suffering from a psychiatric illness and taking SSRI and SNRI, and then they overdose on something, like cocaine or stimulant or their withdrawal, that's like really bad combination. So

Obi:

over. That's overdrive for them.

Mohamed:

absolutely, this is the thing that I think about when whenever they come to the ed. And one last thing, I just want to bring this up because. It happened to me before is the importance of physical examination. Especially in the pre-hospital setting. In the acute setting in the ED is like a lot of time when they seize these folks at high risk for, traumatic dislocation, like they can actually dislocate the shoulder especially if it's a con convulsive status epilepticus, and I think I told you about this before OB had a case like with a missed right shoulder dislocation, so it's a missed shoulder dislocation. After a prolonged status epilepticus and the staff missed it like for a while. That's like a few days,

Obi:

Yeah.

Mohamed:

crazy to me that this person has been intubated, sedated in the ICU and then missed a shoulder dislocation because again, it's very easy to focus on the management and not really examine them thoroughly. So an important pearl is. Do a thorough examination on every status epilepticus patient who is disoriented, to be honest with you, do a thorough examination on every patient. That's that's, you don't wanna miss anything. Anything you wanna add?

Obi:

That's why at least in the ICU, the nursing staff usually comes extremely handy because the best time to do a physical examination on the patient is right when they come in, because they come in, the nurses help move the patient from bed to bed, and upon moving, they do an extremely thorough physical examination. Oftentimes, they'll come to you with things that, you overlooked and missed yourself. But if you're right there. When the, when a new patient comes in, that's a great opportunity to look for anything. We're talked about sepsis being a a pretty strong driver of status epilepticus and it can be very difficult to locate a source of sepsis in patients. But then you might rotate a patient and miss a stage four a pressure ulcer.

Mohamed:

Absolutely.

Obi:

Which is absolutely infected and absolutely causing sepsis and potentially, driving a patient into status epilepticus. So you just never know. Like you, you can never have a like a, like an anchoring bias or anything like that. You just don't expect anything. Just look and do a look. Be thorough, be detailed, and really use your resources.

Mohamed:

Let's talk about second line agents and I wanna see your choices and your rationale. Why would you choose them?

Obi:

Sure. So for second line agents. Agents there, there're really only, there are three main ones that come to mind. So that's Keppra, otherwise known as Levetiracetam. There's a Depakote or valproic acid. And then there's Fosphenytoin used to be Phenytoin, there was issues with, hypotension and maybe cardiac arrhythmias. And you can also, you can only get phenytoin at a certain rate, so you have to give it really slow. And on the floors you probably have to move a patient from one unit to another just to monitor that patient on Phenytoin. So Fosphenytoin is much safer. So those are really the three that I would use.

Mohamed:

I'm gonna just start a, not even an argument with you,'cause I know you agree with me, but if I'm thinking about second line agents. In my mind automatically I'll be thinking about ketamine.

Obi:

Of course. Great agent.

Mohamed:

ketamine is for a great agent for a lot of things, man. I'm telling you. But by that point,'cause I feel like if I am losing control and I'm like running out of time, ketamine would be my choice for a couple of reasons. First, you talked about those, glutaminergic receptors. That ketamine can have a lovely effect on, right? It's an NMDA antagonist, and then I use ketamine for induction for intubation, right? So it's more hemodynamically stable and can also provide some analgesia induction phase. And then I can use it either as boluses for sedation post intubation in a pre-hospital setting or. I can just use it for maybe a drip, right? A drip in, in, in a ed. But yes, you're right. So I think about those second line agents. The common pitfall that I see all of the time is under dosing levetiracetam or Keppra, is always that one gram that everybody love. I don't know what this was, what's up with this one gram? I don't know. Everybody thinks it's just one gram of Keppra and we're done. They're outta that room.

Obi:

So this is what I, this is what I would say. And just to add to what you're saying if I'm in a situation with a patient in status epilepticus. And they've not responded to my first, dose of benzos. That's when I'm re-dosing, but then I'm adding a second line agent. But definitely in the back of my mind, agents propofol and ketamine are always, they're always there. They're always, you always need to maintain an awareness of that'cause like of what we said, NMDA receptor antagonist. But yeah, it's very easy to un under dose. Especially Keppra's probably one of the most underdosed anti-seizure medications is out there. And what the most common dose is one gram. Okay. Give the benzo, load him with a gram, load him with a gram. I rarely see, maybe once in a while, at least one and a half grams. So it's a severely underdose drug when you really consider, the mg per kg that you're supposed to be administering to the patient. You're supposed to be going up to, you can go up as high as 60 milligrams per kg. So when you think about that, if you're, if the standard dose standard size a patient being 70 kilograms, that amounts to more like closer to four and a half grams of Keppra in a single dose. So we're severely underdosing.

Mohamed:

Absolutely. I talked to a neurointensivist. So I got this neuro intensive for transfer. I used to work in a community hospital and I remember I gave my first dose for the status of epilepticus. And this patient was complicated. It was cancer patient, there was so many issues happening. But I gave 20 mg per kilo. And even after I intubated them, they were just very hard to sedate, and the neurointensivist like asked me like, how much did you give? I was like, yeah. And I was like, I sounded so proud of myself.'cause was like, I gave 20 but per kilo, 20 make per kilo. That's what I give. That's, I'm so good. I'm more than the other people. It was like, whatever, 1500 grams. And she was like, that's not enough. Give some more. So she's you can actually, the second dose be 40 mg per kilo. Up to 60 mg per kilo and the max dose is 4.5 grams, like you said. And levetiracetam is generally well tolerated, right?

Obi:

It's a good second line agent to just automatically have in your back pocket because, Keppra is really associated with few interactions, especially when it comes in patients that we get in the unit or even a pre-hospital setting, you're seeing patients that. You've never met before. A lot of these patients are on a lot of different medications, like polypharmacy is a thing. It's a thing. A lot of patients, just laundry list of medications. So Keppra is good because it has, at least it minimizes interactions with other drugs.

Mohamed:

Yeah. So again probably we have to think twice about giving about Depakote because of, it can cause hepatotoxicity, right? Hepatotoxicity. So maybe consider twice. About giving valproic acid in somebody who has, end stage liver disease or cirrhosis, that kind of stuff. Obviously pregnancy right? Is is highly teratogenic, can cause fetal abnormalities.

Obi:

Yeah. No, that's true. And I think, you might get to this, but I think. The study also showed that levetiracetam valproate, even though I don't think it was very statistically significant number, but there were still fewer intubations in those patients that received it. When you compare it against fosphenytoin, which is still in its right, a good second line agent.

Mohamed:

Very interesting. Any idea why Obi? Why is that,

Obi:

I think it was just, I think it was more of an incidental, I don't think there was anything, they're all three arguably second line agents. I think it was just, and like I said, the number wasn't statistically significant, but I think they did report that. Yeah. They've seen slightly less intubations with Keppra and Valproate.

Mohamed:

Got it. And fosphenytoin mentioned all the properties and why we. I tend to like using it more than Phenytoin. Again, phenytoin and fosphenytoin are both sodium channel blockers, right?

Obi:

Yes. Yeah,

Mohamed:

probably I would not give this agent to someone who just. Took a bunch of TCAs, like a tricyclic antidepressant to overdose, right? Because I would not wanna cause arrhythmias, torsades, and cardiac And also fosphenytoin will cause hypotension too. So again, I don't really care much about hypotension because I know how to fix it. I don't dysrhythmia as well, but I don't want them to die, right? Dude, even though I know how to fix dysrhythmias is, I don't want them to die on me. That's why, I'll be honest with you about phenobarb. I have my mixed feelings on phenobarb. I just jumped to propofol'cause I know what's gonna be happening next if still if things are still not controlled. Do you use phenobarb a lot in the ICU versus propofol versus something else?

Obi:

The majority of the cases I use phenobarbital for don't somewhat related to seizures, but mostly related to, as you mentioned earlier, alcohol withdrawal. But once again we're still talking about that balance between, neuro excitation and neuro inhibition and. I also just like ketamine, I also believe that phenobarbital is a wonderful drug. I think there's even been demonstration that it had a high, it has a higher, propensity to cause seizure cessation, but with a higher risk of, hypotension and intubation compared to other anti-seizure medications. I think it's a great drug, but I don't use it much for seizures at all. I use it more and actually the patients that I've used penal barbital on procedures, they've already been intubated and had airways and things like that. And it was really being added on adjunctively, second line agent. So yeah, I think we're talk, we're in the realm of propofol and ketamine, if I'm giving first and second line agents without success.

Mohamed:

I agree. And this review article actually shows an algorithm of managing these patients. I'll tell you, like the only thing that I disagree with is that. Ketamine is probably like the last what I would do for my algorithm. Cognitively I'll be thinking about ketamine earlier, and like you said, maybe I'll give the first couple doses of benzodiazepine, maybe two doses, three doses. I don't know. It depends on the situation. And then if they're still seizing by minute, five or 10 or even 15. I'm just jumping to ketamine. And then thinking obviously about the other stuff that we just mentioned, second line agents likely I will jump to levetiracetam. And then thinking about intubation by then.

Obi:

No, and I think from a synergistic standpoint combining. A benzodiazepine with with ketamine. It, it makes brilliant sense because then you're basically attacking the seizure from two fronts. On one end you're hitting the GABA pathway, the other end you're hitting the NMDA receptor pathway, the glutaminergic pathway, and causing blockade of them both. One thing that people don't realize about ketamine i, is that ketamine does not caused respiratory suppression. I at least and if it did, you would have to give probably the, just the chunkiest dose ever. From my standpoint, I've given people two mgs per kg of ketamine, and they were dissociated, right? They were dissociated. They it was great. They were sedated and dissociated, but they were still actively Breathing, which makes it just a great agent to use,

Mohamed:

yeah, for that exact reason, I use Ketamine a lot. In, in so many situations, right? In so many cases. My favorite is status asthmaticus, another status, right? Is. Where, I don't want to intubate these folks, I just try to keep the respiratory drive as, as long as possible and ketamine is a perfect choice for that. So I love Ketamine for that exact reason. And like I said, ketamine has also the, the analgesic kind of perspective, the antiepileptic perspective, the sedative perspective. So all these points are really pluses for me. I don't see, I don't see any downsides.

Obi:

And just to add, and just to add, for whoever's listening, especially the part of the audience obviously is pre-hospital, but there's probably a good part of the hospital that is or the audience that is either in the ER or maybe even in the ICU as a nurse RT or provider, at least in my, you know, anecdotal experience. There have been countless patients that I've been able to extubate because of ketamine. Like the only reason why I extubated them is because I put them on ketamine. That's what people don't realize, because I think that it's a drug, it's an agent that gets a bad rap maybe because of the name and and things like that. But you, like you mentioned, status asthmaticus. COPD with impaired expiratory flow. Absolutely amazing. That patient who is refractory to multiple sedatives. And the only thing hindering them from extubation is the fact that you just can't do a spontaneous breathing trial because they break through everything. You try to put'em on Ketamine. Try Ketamine and you said analgesia. One of my most recent experiences where I was able to keep several patients off the ventilator is from splinting, taking breaths, but breathing is shallow. They're developing further alveolar hypoventilation. The work of breathing is going up because lung compliance is going down as lungs are continuing to close up. Put'em on ketamine. They will not feel the pain, and they will take nice, deep breaths and their lungs will open and then you won't intubate them. So I just think that ke ketamine is underutilized in so many scenarios, including status epilepticus and I think it's just one of those things where, you know you, you really have to dive into the pharmacology of the agent to understand why it can be beneficial for patients with such a broad range of presentations.

Mohamed:

I could not agree more, and I would tell you, I wouldn't even add this, just one single point. I'd draw the ketamine over midazolam drip or a benzodiazepine drip. You know that exact reason people are just difficult to extubate and go over become delirious and all these kind of like bad sequela, after they get ICU, I'd rather have that than a benzodiazepine and of course sedation. I also use propofol, like you said. Also add in an analgesic dose as well. Like I can add fentanyl. Either boluses in a pre-hospital setting or fentanyl, drip propane and propofol.'cause propofol is fast on, fast off, again, I don't care about the hypotension'cause I can fix that. But. What's more important to me is to see my patients comfortable and fully capable of getting extubated without experiencing trauma. I think that's the probably one of the things that we don't appreciate in the ED very much, but we sometimes, I would tell you, it's so easy to jump into paralysis. Induction paralysis and then just step away from the patient and just hand the patient to respiratory and then sign'em out to the ICU.

Obi:

Yeah.

Mohamed:

that's probably one of my biggest pet peeves that I see in Ed. We have to take care of the patient from a pain and sedation perspective.

Obi:

I appreciate that, man.

Mohamed:

I got you back, bro. I got you back.

Obi:

I appreciate that.

Mohamed:

All right, so last but not least, I wanna open up a brief kind of conversation about the choice of paralytics. Do you use a different agent for your neuro patient than any other patient? Let's say the one with brain bleed, mass herniation, status epilepticus is like this one versus any other medical patient.

Obi:

That's a good question. And it's more convenient because, the answer could have potentially been different if you, let's say you asked me this question several years ago before they had something called Sugammadex, right? Because, succinylcholine was a favorite of many providers. Why? Because it's rapid. It, it acts rapidly and it comes off rapidly. And rocuronium, you give it and you're stuck with it. But now we have sugammadex and you can reverse it. I, but even before Sugammadex, I could universally say that pretty much 99% of my intubations were done with rocuronium. And I just believe and it's especially in status epilepticus, where, you're coming to the bedside. You don't know what's going on with the patient. They're seizing and they're severely hypoxemic, and airways imminent. You need to, break the seizure, established some hemodynamic stability and then secure and airway. I'm gonna go with rocuronium essentially a hundred percent of the time, especially in a patient that has a potential status epilepticus from a space occupying lesion. You want something that's more non depolarizing because there's a potential, if you give something like succinylcholine, which causes an initial depolarization at the neuromuscular junction, there's a chance of a transient increase in your intracranial pressure, ICP, which could be unfavorable for the patient.

Mohamed:

Yeah, that's interesting'cause I, I read about that and really there is no mortality benefit. Because I try to be open-minded to both sides of the argument. I fully agree with you. I'm a Roc all the way kind of person. I try to optimally manage my status epilepticus patient, knowing that is a cognitive bias once they're paralyzed and with prolonged paralysis that might not see the seizure, but on the different, because that's, again,'cause that seizure. Might be masked by the longer acting rocuronium, but to me, the bias is even my patients that come in by EMS and they're not moving, I am not completely excluding non convulsive status epilepticus, right? So I feel if I am thinking about succinylcholine, just because I can see them seizing within whatever minutes.

Obi:

Yeah.

Mohamed:

they end up seizing again, to me, like that's to me like a flaw in my management. Does that make sense? Because if I know, if I'm aggressive, I'm gonna be aggressive, I'm gonna be like doing all the things. Sure. But by then, let's say they go to CT scan, get a, whatever, a CT head or pan scan or whatever, that few minutes in a CT scan, while me being optimal in management. I don't think that's gonna hinder me from optimally managing them. I'm not sure how to say the best, but I think

Obi:

Yeah.

Mohamed:

That short period of time for the CT scan I, and it's gonna be these patients gonna be sick, so they're gonna go to CT scan sooner than later. I think that just doesn't justify the s choline. I do see both sides of the argument and both sides. Say that, one side say suucinylcholine for that reason, because it's short acting. You can see if they seizing. You can manage it quicker, but to me, I don't think that makes a big difference in their outcome.

Obi:

makes a big difference either because at the end of the day, you know once. You've either established or you, your your high suspicion is telling you that this patient is in status epilepticus from some, could be any cause, potentially even a space occupying lesion. I, me, this is just, as a provider, I would prefer, to shut it down, get them intubated. Give them Roc, and then make sure the sedation is started right away. Get'em to the CT scan and see what I'm looking at. And then get a, get continuous EEG going, tap so that we can really start seeing what's happening in the brain and, really start directing our treatment at it. What you said, that short little window, with succinylcholine I don't know. How much it really does. But me, I think especially knowing and especially and everywhere you go is different. Like you, you might be in a facility where, you know, depending on how busy it is, because I know you guys in the er, you guys get super busy sometimes, and you might have so many different patients that you have to like, stabilize and triage. It gets busy, it gets really busy. So in, in that sense. It, knowing that, like what's the timing on, when, how soon is that patient gonna get the ct right? You give them succinylcholine, right? And the paralytic is worn off pretty quickly, but it's so busy in whatever unit that you're working in, whether it's ICU or whether it's er that there's, there could be, delays in getting, the imaging test, is it not? Then just safer. To at least, be fairly aggressive with your anti-seizure therapy and your sedation, so at least you have a high confidence. If you're waiting for continuous EEG, which you need, or you're waiting for imaging, at least there's a higher chance that you're suppressing seizure activity because you're aggressive.

Mohamed:

I fully agree with you. I guess the bottom line here, it depends on your clinical setting where you work. It depends on your comfort, right? Comfort level, your staffing availability. There's a lot of times you might not have, you might just have one nurse for the entire ED that you work at, if it's a rural community, and also depends on your. Availability to have pharmacy in the ED to help you with those medication dosages.'cause not a lot of us actually know the dosages or know which medication or they don't know how soon can I get that medicine from the pharmacy? And of course, like in some in my, for example, like in my clinical setting. It's so easy to have pharmacy there at bedside with us, and they normally, most of the times, if the patient is crashing or sick, they're usually managing that patient with us that like we were talking to them. And that's like really a privilege that I have at one of our UPMC facilities here. It's really great to have them also on board. So pharmacists definitely do save your life.

Obi:

And they watch your but and they watch your butt

Mohamed:

They always love my big on my back. Man, I make sure our pharmacists are well fed and definitely well cared for every time, every day.

Obi:

I brought a bag of candy in after Halloween. I'm sure they had some of it, so it's.

Mohamed:

love it This has been a great discussion. Thank you. I'm gonna try to summarize the main important points in this discussion. So the big ones that I got from this conversation. Number one, don't underdose benzos, right? Give the full dose for your hospital. Folks, get a thorough history. Don't forget about your examination. Prepare for airway if you're gonna be given those big doses and always talk to your medical command for additional recommendations. The other big point is don't delay escalation in the ED or in the ICU obviously. So always think about those other agents that we just talked about and again, don't underdose them. Then we talked about treating the causes. So again, in the pre-hospital setting, look for trauma, pregnancy, infection, glucose and then make sure that you manage the patient, their seizure as you navigate or investigate the possible causes and obviously correct them. And then the airway is always an issue for us in the ICU as well. Try to be fully prepared ahead of time. In a pre-hospital setting, get your equipment ready, have an algorithm in your mind of how to manage difficult airways. Always monitor for any decompensation, so reassess your patient for the in hospital setting. Ask for help. Ask for backup if needed, and know your choices of induction and paralytic agents.

Obi:

Of course.

Mohamed:

Anything else you wanna add? Anything else that I've.

Obi:

Yeah. Yeah, absolutely. A few things. The algorithmic approach is helpful. Because, status epilepticus is a complicated diagnosis, but the steps, the stepwise fashion, it helps you like the algorithms, they help you progressing from okay, your benzos to your second line agents, to your third line agents. It helps you and obviously be prepared to have to step outside and understand that, during your treatment, patients might also sustain other complications that you may have to just manage. Another thing is. The majority of these patients with status epilepticus, it's gonna be convulsive status, epilepticus that they present with. That 30 minute window is critical because beyond 30 minutes, that's when mortality, morbidity, and mortality really starts to ramp up. So you wanna really get aggressive and try to break that within those 30 minutes. But also I think something that kind of goes overlooked is the amount of patients or the possibility for a patient to go from convulsive status epilepticus to non convulsive status epilepticus. We're used to, when you see, when you hear the term status epilepticus, you automatically default to convulsion, right? So you're thinking about, they're moving, they're seizing, but what about those patients that their seizure breaks, but they remain unresponsive. They don't wake up, so we can't just sit on that because they can also still be a non convulsive status epilepticus. And those patients do worse probably for what, for reasons I just mentioned. It goes unchecked, right? They're a non convulsive, status epilepticus, but because they're not convulsing, the sense of urgency to, diagnose that or get other, diagnostic tests like EEG is maybe not, it doesn't, you don't have that sense of urgency, but in patients that have convulsive status, epilepticus have failed to regain their baseline, do you have to worry about non convulsive status, epilepticus and a continuous EEG or some kind EEG, should be obtained in those patients. So that's that's a, that's another important point that I think deserves to be mentioned.

Mohamed:

So don't be fooled by the lack of convulsions. Always consider a non convulsive status in your diagnosis as well.

Obi:

Yeah.

Mohamed:

I appreciate you bringing in your perspective as well from the ICU. And for our audience, if you found this episode valuable, please share with your colleagues, residents medical students, even a paramedic partner any ICU colleagues neurointensivist because I like to also hear different opinions, right? I want to hear reviews, your experiences, share anything you want with us, maybe a unique paper or something that you've heard about, especially. For those of you who practice globally and internationally. So until then, and I'm gonna try to bring up more topics related to resuscitation critical care. If you think of any cool topics you'd like us to discuss, please send me an email as well. I'm Dr. Mohamed Hagahmed. Stay curious, stay compassionate, and as always, keep pushing the boundaries of emergency medicine and critical care. Ob, I appreciate you, man. Thank you.

Obi:

Thank you.