E12: Medetomidine toxicity and withdrawal

This episode of the EMERGE, join me and Dr. Mike Lynch, an expert in emergency medicine, medical toxicology, and addiction medicine. The discussion delves into the public health emergency of medetomidine-related toxicity and withdrawal. Dr. Lynch shares insights from real cases, emphasizing the clinical red flags and management strategies for medetomidine withdrawal. We discuss the transition from Xylazine to medetomidine in the drug supply, the role of naloxone, and the risks of misidentifying opioid-related cases. Key points include the need for extended observation in the ED, the potential requirement for ICU care, and the effectiveness of dexmedetomidine in managing severe withdrawal symptoms. The episode also highlights the importance of medication for opioid use disorder (MOUD) and the evolving drug supply landscape.

Transcript

0:06

Welcome back to Emerge, the podcast where we explore the cutting edge of emergency medicine, resuscitation, and global health. I'm your host, Dr. Mohamed Hagahmed. Today's episode takes us deep into a public health emergency that is hitting our streets, our hospitals, and our most vulnerable patients, medetomidine-related toxicity and withdrawal. Joining me is Dr. Mike Lynch, an emergency physician, medical toxicologist, and addiction medicine specialist based right here in Pittsburgh. We'll walk through real cases, bust some dangerous myths about naloxone, talk about the clinical red flags of medetomidine withdrawal, and offer practical strategies for EMS and ED clinicians navigating these complex presentations. So let's get into it.

Mike: 0:58

Thanks for having me Mo. It's good to be with you. So I am an emergency physician, medical toxicologist and board certified addiction medicine. So I still work clinically in the emergency department at one of our, city hospitals here in Pittsburgh, UPMC mercy. Our toxicology service does inpatient admissions and consultations at five hospitals, including children's in person, as well as telehealth to another couple dozen hospitals in Pennsylvania. Also, do some work with UPMC Health Plan and run a telemedicine bridge clinic, to help people with opioid use disorder get immediate access to medications.

Mohamed: 1:31

As you know, the reason why I brought you here today is to discuss a specific public health emergency that is impacting our regions and hospitals, and that's medetomidine related toxicity or withdrawal. So we'll talk about all of that stuff and I'd like to start with you, first with a case, if you don't mind.

Mike: 1:52

Yep. Please do.

Mohamed: 1:56

Sadly, we see a lot of these cases lately in our EDs. But this is a prehospital case. So EMS responds to a male in their twenties, unconscious, unresponsive, downtown by an alley. He was found by a bystander who was kind enough to, provide Narcan so intranasal Narcan with no response. When EMS got there, that patient is still unresponsive. Still breathing has a pulse, and they did more Narcan intranasally with, again, minimal response. At that point,they got an IV, so total he got maybe six milligrams of Narcan between the intravenous and the intranasal routes. And information that we received in the hospital that the breathing is actually adequate. And, we noticed that he was hypotensive and bradycardic without ischemic signs on the EKG. So we did our workup in the ed. We kind of observed them for a few hours and everything that came back actually blood wise is normal except for UDS that is positive for fentanyl. But something was off about this situation'cause it was a prolonged period of sedation. So just get us through medetomidine. Why do we need to care about that?

Mike: 3:11

Yeah, absolutely. So medetomidine is a veterinary sedative. So not unlike Xylazine, which we've been talking about for a few years now, has gone increasingly prevalent, over the last year, a little over a year, in Pennsylvania and then elsewhere in the country has been identified. It works as an alpha two agonist. And so what that means, you know, in the periphery, it can cause a little bit of vasoconstriction first, but then as it moves into the brain, it causes deep sedation. You can get miotic or pinpoint pupils, and it basically shuts off your sympathetic system so you can see bradycardia, hypotension, along with that deep sedation. And importantly, it is not an opioid. So while some of the effects can kind of overlap with an opioid, and when used in combination, the effects can be somewhat synergistic. The alpha two agonist will not be reversed by Naloxone, as in the case that you saw.

Mohamed: 4:07

So why is it becoming a problem in our region here in Pennsylvania and beyond? Like why is this an issue and how did that transition happen between Xylazine and medetomidine?

Mike: 4:17

It's a great question. The really true answer is I don't know for sure. But, Xylazine really started, becoming prevalent in southeastern Pennsylvania, in Philadelphia and around that, in 2018. Prior to that, it had been, identified and described in Puerto Rico, in the first half of the two thousands essentially, in particularly in a paper in 2012. And then since 2018, it's spread throughout all of Pennsylvania and really all of the us. With medetomidine, what we know based on drug checking data, which is incomplete, but also with laboratory clinical data, is that xylazine sort of rapidly has declined in prevalence and medetomidine rapidly increased just over the last year. You know, at the beginning of last year in Pennsylvania. We didn't identify medetomidine at all. And nowadays it's present in nearly all of our drug supply. So why that happened, why that sort of switch? Could be because medetomidine is much more potent than Xylazine. It could be that, sources of xylazine became more challenging. Some places including Pennsylvania have scheduled Xylazine, so potentially there was more, attention paid to it. It was harder to get, could be less expensive. There's a lot of economic factors that go into what ends up in the drug supply, so it's hard to know. But I think the idea behind adding an alpha two agonist, in general, is to give it, you know,"legs" meaning when as we transition from heroin and other opioids to primarily fentanyl in our drug supply, the onset of fentanyl is very rapid. And while it can stay in your system the immediate effects start to wear off fairly quickly. So people were noting that they were starting to have withdrawal symptoms fairly quickly. They may be having to use more often. So the thought, and again, we don't know this for sure, is that by adding something that's a sedative. Other than an opioid, ideally if it's inexpensive, could prolong some sedation and potentially ease some of those ups and downs that were being experienced. Now, whether it really does that or not, I don't know, and whether that had anything to do with why those things are there, I don't know that either. Uh, another common reason that anything is mixed in with drugs is that then you may need less of that drug, to, you know, sell the same bag of fentanyl, but include less fentanyl in it, but sell it for the same price. All of those things may be factors.

Mohamed: 6:34

Mike, I remember with Xylazine one thing that scared us, are these dermatologic manifestations or adverse effects, right? Of xylazine, you know, these almost like necrotizing soft tissue infection requiring debridement and surgeries. So are we seeing the same sequelae or manifestations with I. Medetomidine as well.

Mike: 6:53

It seems not. It might be too early to say, and you're right. I mean, Xylazine, I think one of, in addition to some of the immediate effects, which were similar but not as pronounced as we see with medetomidine, the wounds that were associated with its use that could form primarily on the extremities, but maybe anywhere. Not always associated with where people injected, but primarily so it didn't start as infections, but did become necrotic and really could get, quite deep, including bone, exposure and actually even eating through bones. And these terrible wounds that place people at significant risk for infection certainly is disfiguring, and can be very painful. And all those sorts of things. So that, that was really an important public health effect of the Xylazine presence. Potentially even a reason why it became less popular is, nobody really wanted that effect. But, fortunately, I hesitate to say fortunately, but so far, with medetomidine, it seems as though with the increase in prevalence of medetomidine, the overall development of new wounds has not increased or maybe decreased relative to when Xylazine was almost universally present. At least for now, anecdotally, I can't point to any, peer reviewed research. It seems that medetomidine is less likely to be associated with those kinds of wounds, developing.

Mohamed: 8:10

So this is get back to the pre-hospital scenario that we just talked about. So initially bystanders gave Narcan, which I feel it's, it's the right thing to do.

Mike: 8:20

Absolutely.

Mohamed: 8:21

When EMS shows up and they see that exact same patient after Narcan, no response, minimal respirations, maybe they're like now almost close to the apneic side. So they give more narcans, right? This is like the reflex is to give more Narcan. Hey, but my goal of Narcan is what is it to achieve level of, alertness to make them go back home, or what is our goal with that?

Mike: 8:45

Yeah, I mean, the goal of Naloxone is to help people breathe and keep them from dying. The goal of Naloxone has actually never been to wake people up. I think for a long time that was the experience of giving Naloxone. So that became the expectation, is I will give somebody naloxone after oxycodone or heroin or whatever and they will wake up and that's how I will know that it worked. So it's understandable then that's your experience. You expect to see that moving forward, but as we've seen more sedatives, sometimes even benzos mixed in with Fentanyl, that is no longer necessarily the experience where we give Naloxone. And even when we see people start breathing again adequately, they don't wake up the way that we expected. And unfortunately, one of the things that can then happen is people do continue to give more Naloxone because their experience tells them, wait, no, they should be waking up. And that does two things. One, it increases the risk of developing an opioid withdrawal, particularly while you're still sedate, which could be vomiting and aspiration, which is a major risk in any overdose and reversal situation. And the other has generated these unfortunate sort of, untrue claims or concerns of a,"naloxone-resistant opioid" or saying that Naloxone doesn't work, for a specific opioid, which has not been the case, to date.

Mohamed: 10:08

So what are some of the stigma or maybe myth that you have heard? Specifically related to medetomidine and management, either in a hospital or prehospitally.

Mike: 10:20

Yeah, I mean, as far as myth, I think it still follows along with what we just described, which is, that naloxone, because it does not reverse medetomidine, which it does not. Neither did it reverse xylazine or benzos, Naloxone is still working. It is reversing the Fentanyl portion and the part of, an exposure that's likely to lead to somebody dying. The worst adverse effects is still the opioid portion. So if we're able to reverse the opioid regardless of whether they stay sleepy or not, then we'll be going a long way to saving somebody's life. And so still, when bystanders encounter somebody who is not responding at all and to, as best they can tell isn't breathing or isn't breathing well, giving Naloxone is still absolutely the right thing to do. And similarly for our pre-hospital colleagues. When they encounter a patient who doesn't appear to be breathing adequately, as you described, in this case, giving more naloxone is, perfectly appropriate. And what we, what is more difficult and more nuanced, and harder to do, the further away from a hospital that you get, is trying to assess. How their breathing is not just, are they breathing adequately? You know, it's understandable. Bystander, I, I don't think we can reasonably expect most bystanders to truly be able to assess that. And even for pre-hospital providers, it can be challenging. You know, you have things like end tidal and certainly respiratory monitors and pulse oximetry and that all, every one of those tools helps us to recognize and understand. But still in, in the heat of a moment, in an uncomfortable and unfamiliar. Maybe even dangerous kind of situation where you're trying to move fast to save somebody's life. Those are hard things to be able to recognize and assess fully. But that's still what always has been the goal of Naloxone is to make sure that they're breathing. And so I think just reinforcing that, again, with this new sort of development, it's a new development, but an old concept.

Mohamed: 12:15

And I'll tell you, Mike, for me, naloxone is, it's a medication that creates this cognitive block, right? That. Prevents me from thinking like, what else might be happening with this patient in front of me? And I'll tell you, like I've, I've run into, like with QI and some of the pre-hospital cases, a lot of the danger happens when we anchor our thought process on one specific etiology and then just like we refuse to think otherwise, right? So giving more Naloxone or Narcan, everybody knows, just creates this cognitive block that. What else might be missing? Are we missing a trauma? Maybe compartment syndrome. Maybe something else is happening, you know, maybe they're overdosing something else, like you said. Maybe benzodiazepine or infection, sepsis. So these things that we have to consider in our assessment, and specifically these patients, because they're very vulnerable, right? They don't have a strong, social system, right? They don't have, I. Adequate care or primary care follow up, and a lot of them have also chronic conditions, so we have to keep our minds open. So the answer is not high doses of Naloxone, but good thorough assessment and respiratory support. Is there anything else you wanna add to that?

Mike: 13:27

Absolutely. No, I completely agree. Particularly when you get into, there are periods of time where potentially there are more overdoses and so you become, just an auto time, you're like, oh, here comes another overdose. I'm gonna manage it the same. It's easy to do for any of us, whether in the pre-hospital, in the hospital, in the emergency department. It's easy to do that. And anchoring, you're right, is the source of so many, bad outcomes. Potentially preventable bad outcomes. I can tell you that there was a case that I remember very well, and this was from quite a while ago, of somebody who was known to use drugs, who was found unresponsive, was given naloxone and then more naloxone'cause the person wasn't waking up, vomiting, you know, piloerection. So clearly withdrawal turned out to have a subarachnoid hemorrhage from an aneurysm. I mean, we identified in the ED and, and likely we wouldn't have done anything different. Up until that identification. But it's just an example of when things aren't fitting with, you know, that's the other thing that we do is we sometimes try to make that square peg fit the round hole, because I assume it's an overdose. Sometimes we need to treat them a little differently and back up and, and rethink about all the pieces of information, before we make that conclusion.

Mohamed: 14:34

Absolutely. Thank you, Mike, for sharing that tragic case, but it's very important to consider the other differential diagnoses, you know, CNS medetomidinebolic, infectious, musculoskeletal trauma, you know, so this is very wide base of list of differential diagnoses that need to be considered if the initial response, to Naloxone was not appropriate. Now, one thing that came up, and I was asked this question before, is the bradycardia, right? A lot of our overdose patients in the pre-hospital settings, they're not transported on a monitor. And I'm not sure if you noticed this, but because of the current shortage in the EMS workforce, so a lot of these calls end up being transported to us by either an advanced EMT or an EMT. Who just like, you know, they're fine, they're breathing, they're on oxygen. I don't need a monitor. I don't need to put anything else. So does the bradycardia like, kind of imply something bad? Like do they need to be on a monitor on the way to the hospital? Maybe. I guess my question is, does the bradycardia maybe is a, a veal for ischemia or maybe some other cardiac abnormalities?

Mike: 15:40

Typically what we expect from medetomidine or Alpha two agonists will be a sinus bradycardia. So that's a really important and challenging, especially like you said, for sort of an EMT-B or something like that to differentiate a sinus bradycardia versus a heart block. I mean, you know, I've looked at EKGs where sometimes it's hard to tell, that is important to be able to recognize is this heart block or is it sinus? And then is there associated hypotension? Those are probably two of the most important initial questions to answer. Bradycardia, whether sinus or otherwise, can certainly be indicative of lots of things. Could be a beta blocker overdose, who knows? Could be a primary, cardiac pathology, whether electrical or, potentially ischemic. Our experience with medetomidine in particular is that the bradycardia is sinus. It can be associated with hypotension, but isn't always, oftentimes that hypotension is treatable with IV fluids alone. some patients do need vasopressors, which obviously again, in the pre-hospital space, that isn't critical care transport. You're gonna be limited to if you have the ability push-dose epi and things like that. another challenge and nuance is we don't treat sinus bradycardia. Sinus bradycardia with no evidence of decreased perfusion and normal blood pressure doesn't really require any intervention. It needs to be monitored. And all those factors need to be continuously assessed. You know, whether it be on a monitor, a pulse ox, ideally repeated blood pressures, things like that. But just the bradycardia itself doesn't require treatment. In fact, one of the things, this drug, medetomidine, mimics, multiple medications, but one of them is clonidine. And a classic teaching in toxicology is because, as I mentioned before, alpha two agonists can sometimes cause really briefly, initially. Hypertension because of peripheral effects before it moves centrally. And reflex bradycardia will sometimes see people treat that bradycardia despite normal or hypertension and really drive the blood pressure up even more, particularly in somebody who isn't used to it. And so that can lead to its own problem. So again, it just, it's more about, it makes things a more complicated and more things to think about and assess in an already difficult, challenging context.

Mohamed: 17:57

So the main point for our pre-hospital clinicians out there, these patients are sick. They need ALS support, they need a thorough assessment. Respiratory support monitor, EKG, and definitely transport to appropriate facility, which I will get back to also, because this was a question, another question that came up too, Mike, is what hospital should we go to? Obviously in the city that we live in. In Pittsburgh, we have so many big, nice hospitals, right? But let's say out there in the community, let's say, maybe a rural hospital, can they handle these patients? Like do they need to be transported there or maybe considered different destination, for the best management they can get. What are your thoughts on that?

Mike: 18:40

I would suggest that probably the nearest emergency department, is still the right answer.'Cause much of this, especially the initial stabilization. Should be done at any emergency department.

Mohamed: 18:52

Sure.

Mike: 18:53

some patients, particularly if they have other issues, but even if it's just severe medetomidine toxicity or withdrawal, which we'll talk about, will need an ICU, which not all hospitals have. And potentially they could end up needing to be transferred. But I don't think I would initiate a longer initial transport particularly. You know, by maybe an EMT as opposed to a paramedic, where they just have fewer tools available to them, you know, to get to somewhere that may have more capabilities on the backend. I think getting them to an emergency department where airways can be managed if necessary. Vascular access can be obtained if it can't otherwise, which is always challenging in this patient population. Vasopressors can be initiated if needed. Those things can all happen in basically any ED. From there, Certainly some of these patients may then need to be transferred, but I don't think that would be something I would recommend right up front, particularly if it delays transportation times by any significant degree. And the other thing to remember, with medetomidine specifically, and of course you never know for sure, especially in the pre-hospital world exactly what you're dealing with, but if it's fitting that picture, the half-life is right around two and a half, over two and a half hours. So the most severe acute toxicity, often starts resolving over the course of a few hours. So even if they are that sick and unstable at the beginning, they might end up at that moment. They would have to be admitted to an ICU within a few hours. For all those reasons, I think still starting with the local ED is probably the right answer. Understanding that some percentage of these, probably a small percentage overall, would then have to be transferred on the backend.

Mohamed: 20:25

Okay, so they come to the ED and let's say they come to any of our eds that you and I work in, and we do our initial workup, like with this patient. And, we tend to, what we do best is observe them, right? To see, hopefully they can"metabolize to freedom". And I tell you this, in my experience, usually two hours is my threshold. In any overdose, see how they're doing. If they're like able to wake up, interact, eat a sandwich, drink, and I'm not really concerned about anything else, two hours they can go home. But what I'm noticing with these overdoses with medetomidine is that they end up requiring a longer ED observation. So my question to you, when do I consider like early admission?

Mike: 21:04

Yeah, I mean I think a lot of that really has to do with the culture at your individual emergency department. And you and I both practiced in a bunch of different eds and have different approaches where I practice now where we see, you know, among the highest volumes of, overdose kinds of patients in the state. We have a pretty high threshold to admit, meaning we will watch patients for longer than probably some others would. The expectation that they'll probably be able to be discharged. And part of that has to do, and you know, this is outside of what we're talking about here today, but I think on a larger system level is every bed upstairs that I take is another bed that may not be available for the next patient. So if I have somebody in front of me who is on a course that I can reasonably predict, is going to end in a disposition, even if it's a little bit longer than like I would for a chest pain or something else, I might hold onto that person to make sure that the other one who I know is gonna need to go upstairs isn't sitting boarding in my emergency department for a full day because that person who wakes up in six hours is sort of occupying that bed. So that, that's a larger sort of system based kind of consideration. But specifically to this, to our topic today with fentanyl plus medetomidine, is mostly what we're considering, they can and do stay sedate for longer and yeah, I often wouldn't expect them to be fully awake by two hours. So you may be looking at more of like a six hour kind of obs before they're, waking up. But I've seen people go from bradycardic and hypotensive, and even needing pressors to awake, alert and oriented within six hours. I think it would be uncommon outside of other factors and contributors and substances, that it would be much more than eight to 12 hours. It could go that long, potentially, which is very long for an ED stay. But again, it, I think it really depends on the culture, whether you have an OBS unit, how you use that, what your anticipated disposition is, what the boarding capacity is, all of those other things. While it is longer than your"heroin overdose", particularly the one that got Naloxone and you watch for a couple hours, you know they're not gonna sedate and you can discharge after a couple hours. These folks do need to be watched longer.

Mohamed: 23:18

So I got this question from someone in Europe, and he said that we have an antidote there.

Mike: 23:23

Yeah. And I may say it wrong'cause I mostly read it and not said it, Atipame zole, is a veterinary antidote for medetomidine. But, it's not approved for human use in the US. And I think importantly, probably wouldn't recommend using it. So it's perfect when you've given the medication. You know, say a veterinary anesthesiologist, if that's a thing. And you want to reverse it because you're done with the procedure and you want the animal to wake up. That makes sense just like we do in the ORs here. As we've said, the medetomidine. Potentially can contribute to life-threatening toxicity, but generally in and of itself, when the opioid is reversed, isn't something that's gonna be fatal. But, what has been much more severe and much more dangerous has been withdrawal from medetomidine. And so I would be concerned about, it'll, it'd be almost like giving fomepizole, which we typically don't do, for people who are chronically on benzos because we're afraid of putting them into withdrawal. Particularly when we know the acute toxicity is well tolerated, particularly in a hospital setting. I kind of put it in that category where if somebody's been regularly exposed to medetomidine and I abruptly reversed it, I could have a real big and potentially life-threatening problem on my hands. Whereas before it might've just gradually resolved itself, and given me more time to tailor treatments to what I was seeing as opposed to being hit. Boom. Like a bomb, of medetomidine withdrawal out of nowhere. So I, at least that's my opinion. I have, you know, I think there's certainly more to consider about that long term. But right now, the thing that I'm seeing that I'm most concerned about and seems most dangerous to patients is the withdrawal,

Mohamed: 25:02

which is a nice segue to that segment specifically, but I just, first you brought up the analogy of like Flumazenil, right? Flumazenil with, benzo. It's okay. No, of course. But that analogy is very crucial, right? Because again, we do have an antidote for benzodiazepine. We don't use it. I've never used it in my life as a resident or, now as an attending. The important point is to support them through that overdose period, and then, prevent withdrawal symptoms, which is now, the most important thing that you and I see, and the most complicating factor is actually managing these withdrawal symptoms?'cause I'll tell you, I've seen one, I've managed one. It was a shit show. It was a tremendous amount of work, that required multiple medications to ensure sedation. And you mentioned alpha two, agonism withdrawal is very severe. And you mentioned hypertension, the tachycardia, the agitation. So these patients can present like other withdrawal? Like maybe alcohol withdrawal, opioid, withdrawal, right? I mean, is there any, any different presentation that can specifically scream, this is medetomidine withdrawal.

Mike: 26:10

Yeah. You know, I think what you're describing, I is just so typical of my, experience and the experience I hear from everyone else when they start to see it. Which is one that it's a shit show and two, that nothing works. And so I. When you describe it, when you put the words down on paper, tachycardia, hypertension, agitation, tremor, diaphoresis, you're like GABA agonist, withdrawal. Could be a benzo withdrawal, could be an alcohol withdrawal. It could be a Sympathomimetic toxicity. Those, all those words would be used to describe all of them. You'll know it when you see it because those things are all true. But these people just look different. They look like garbage. I mean, they look so terrible. And you feel awful because they just, they're vomiting. The nausea and vomiting, which actually has, some alpha two, specific, reasoning behind it. As well as the tachycardia, the hypertension, the agitation, eventually encephalopathy and delirium, which can be typical of GABA agonist withdrawal. But all of these things are really atypical, other than nausea and vomiting. Opioid withdrawal. So when I've seen it early on, it kind of looks like really bad opioid withdrawal, lot's of nausea, lots of vomiting, lots of stomach cramps, sweating, and again looking terrible, which is, that's true of opioid withdrawal. One of the things that's been a bit atypical is it starts a lot sooner than you would expect opioid withdrawal to that severity to start. So people four to six hours after the last use. We'll be looking like that while people who use opioids only might start having symptoms by four to six hours, but they don't look that bad. In fact, the first person I saw is like it just isn't fitting. Like, are you sure you just used four hours ago? That doesn't make any sense. And then the other factor is then you start treating them with medications. So you try opioids, you try antiemetics, you try benzos and barbs, and you try more and more and nothing works, right? You try ondansetron, you try droperidol and we love droperidol, right?'cause it's supposed to work for everything. It does nothing. It does absolutely nothing. At least in my experience. Prochlorperazine maybe works a bit better. Olanzapine, maybe a little bit, the Benzos and Barbs eventually, maybe you can get them asleep, but they still look terrible. The opioids, maybe it helps a little bit with some of those symptoms, but it doesn't really. And so that, that's, I think it's really hard until you see it, to understand that the description of it doesn't do it justice, with both how bad people look and feel and frankly, as a provider, how helpless you feel in trying to help them feel better, because all the things that you think should work don't.

Mohamed: 28:46

That is absolutely true, and I'm still having chills from that. But let's just get back to the prehospital real quick setting. As you know, agitated, combative patients, can just bring all the challenges, to manage them pre hospitally, and there's so many biases associated with that as well. Like, just don't get me going about the biases based on ethnicity, color, and socioeconomic status. These patients, they're clear, they can see them, they're combative. We use the MCRASS score to measure their, combative state. Plus four is the combative patient that we just cannot get close to. We have to do something now before it gets outta control. So is ketamine a good choice for them?

Mike: 29:26

I think in the undifferentiated, MCRASS plus four patient. Yes. One, I wouldn't expect that probably to be medetomidine withdrawal. People can get agitated and encephalopathic, but it, it is a little, it's usually more hypoactive. hyperactive, agitated, delirious patient, I'd still be more concerned about primarily a stimulant or something else. And in general, as you mentioned, I mean, the point is that's a dangerous place to be for the patient and for anyone else around them. And it needs to be controlled as quickly as possible. And an agent like ketamine, it can do that. Presentation or it's methamphetamine toxicity or some of the other things, or not drug induced. Getting control of the situation, getting the patient in a safer place, with chemical rather than physical restraint to the greatest degree possible is still the right first step. I do think ketamine, there's no harm. There's no. Atypical or odd effect of ketamine on this patient population that would give me pause in using and in fact, it would be something that I would use in the most severe cases if needed.

Mohamed: 30:32

What about benzo? Does the five milligram of intramuscular versed or Midazolam work? Is it enough?

Mike: 30:39

I mean for this, for medetomidine withdrawal, no, it won't really. But for that patient, I mean, I think GABA agonist in general in the super agitated. Possibly, or maybe even probably intoxicated patient. A GABA agonist is almost always a good idea. It may or may not be terribly effective, but it's highly unlikely to be harmful. And it could potentially, you know, whether there's something else going on. GABA agonist withdrawal or stimulant, you prevent seizures, things like that. So no, there's no downside from my perspective, in this population of giving it like you would in any other sort of, very agitated patient population.

Mohamed: 31:16

Are there any, specific pathologies we should definitely be on the lookout for when they come to us in the hospital. Things that are associated with withdrawal symptoms like maybe PRES or some other conditions that we should have to worry about

Mike: 31:28

so PRES has been reported primarily by our colleagues in Philadelphia. They've had a few MRI proven cases of, posterior resolving encephalopathy syndrome or PRES, you know, myocardial injury. We haven't seen sort. Typically the I EKG abnormalities are certainly STEMIs, but we have seen troponin elevations pretty assumed to be demand related up into the thousands. Another really important, thing to look out for is QTc prolongation, so whether from just their general illness, electrolyte abnormalities, acidosis, whatever, it's pretty, been pretty common. You know, it's not always there. But it's been pretty common in a lot of these severe cases that their QTc is fairly prolonged. And where it becomes particularly important is many of the anti-emetics that we would give. Basically everything that I already named also prolongs QTc. So not to say that it can't definitely can't be given, but every single one of them does it. So whether it's ondansetron, prochlorperazine, droperidol, all prolong the QTc to some degree or another. So there's scopolamine patches, which you can try. Not harmful. But that's, I think, an important sort of clinical, like nugget is just to keep an eye out for that. And then we've also seen pretty severe metabolic acidosis, lactates up in the double digits. PH is less than seven. Potassiums in the twos. Lots of metabolic derangements, that can go along with it as well. Whether they're, they're. It's a cause or whether they were just present when, this all progressed, how long it's been going on, hard to know, but all things to look out for. So you're gonna wanna do some basic labs, EKG, intervals once you get them calm enough that you can do it, while you're initiating treatment.

Mohamed: 33:05

And what is your threshold to initiate a Dexmedetomidine drip on them?

Mike: 33:10

Yeah. So yeah, what we have found and what our colleagues in Philadelphia, where they've seen a lot of these as well, and, and prior to us, frankly, what we found that works the best in these situations when they're really tachycardic hypertensive, nothing's working is starting a Dexmedetomidine infusion. Typically, we're giving a bolus dose, so like one mcg per kilo bolus over 10 minutes, and then, starting an infusion, maybe around 0.5 mcg per kilo per hour and titrating up historically, oftentimes the, the max dose will be listed at 1.5. We've pushed through that to two, 2.4 mcg per kilo per hour because patients can tolerate it frankly. But when to pull the trigger, you know, there, I wouldn't say that there are fixed. criteria.'cause like you said, we're learning as we go, you know, it's evolving. For me it really has to do with nothing else is working. So kind of when they fit that picture of their tachycardic, they're hypertensive, they look and feel terrible. And I've given the normal quote unquote, normal medications, which I ideally would include some type of opioid replacement, for opioid withdrawal symptoms and it's just not effective. You know, that includes trying things like oral clonidine or oral Guanfacine, which are oral alpha two agonists. If somebody's vomiting so much that they can't tolerate that, or they take it and it's not working, and they're progressing like that to a point where, you know, you can't put'em on the floor'cause their heart rate's in the 120's and those systolic blood pressures 190. Those are the folks where I start the Dexmedetomidine. Sometimes they're really tachycardic but not so hypertensive or vice versa, or they just really look terrible. Their vitals are a little bit abnormal, but not awful. Nothing else is working. They can't tolerate PO and it's the only thing I can do to calm everything down. So there's, there's a pretty broad range, but I, I've, my threshold to get there has, has gotten much faster, over the last six months or so.

Mohamed: 34:59

And obviously by then, once you pull that trigger, they already automatically go to the ICU, right? So that's something also to consider in case they need to go to a smaller hospital that does not have an ICU and they need to be transferred to a different hospital system

Mike: 35:10

Yeah,

Mohamed: 35:10

sure.

Mike: 35:11

and for those who go into withdrawal about 90% end up in the ICU. So once people go into this. Really pronounced syndrome. It's almost impossible to divert them from the ICU. In cases where we've even tried, they end up on the floor, even in the a withdrawal management unit and after a few hours end up conditioning, or we've seen patients discharged from the emergency department who hours later at a rehab facility or something like that end up getting sent back and end up in the ICU. So it's a major challenge and a major, strain in our health system capacity.

Mohamed: 35:43

For sure. I was not aware of that number. This is a very high number. Okay, well that's good to me to know on my next shift. So the last thing I wanna just, hopefully get your insight on, is that patient, now that we treated in the ed, we're able to kind of discharge safely. Any specific considerations, when discharging them? What are some of the things that we can provide them with? Any resources, Mike, that you, are willing to share with us, in this podcast so people can actually maybe utilize, when caring for these patients?

Mike: 36:14

Well, I mean, I think, most importantly is it's hard to predict who's gonna have the medetomidine withdrawal, et cetera. But what we know for sure in the. vignette that you gave, which is so similar to so many patients that we have seen in one way or another who are using opioids. First and foremost, the thing that's going to have the best, most important impact on their lives is if we can initiate them on medication for opioid use disorder. So whether that's buprenorphine or methadone, them engaged with follow up. If people are on one of those two medications, they're half as likely to die, as if they're not. So that's the most important thing we can do, kind of regardless of what else might be in the drug supply. Nowadays with the alpha two agonists, a couple of things that we have are still developing maybe a formal algorithm or something to publish. But as we watch people a bit longer in the ed, to our point before, not just for resolution of intoxication, but if people come in seeking, substance use treatment or withdrawal management or come in in withdrawal, we watch them a bit longer. By longer, three, four up to six hours just to watch their trend. Are they responding to our medications? Are their vital saying, okay. Are Looking stable or are they gradually getting worse despite what we're doing and we're having to escalate medication? So that's part of it. Is it, it stinks. And, you know, that's not a great use of resources. But at this point, that's what we're kind of stuck doing. And in outpatient settings where they do assessments about where they people should go for substance use treatment, we're recommending that they watch longer. Because while it does progress rapidly, not every patient needs to go to the emergency department just to be watched. That would be a terrible use of resources.'Cause not every patient, even if they've been exposed to medetomidine, has this withdrawal. But. For their, that subset of patients that isn't going to the ICU. And is otherwise leaving the, emergency department, but is still having some symptoms in addition to the anti-emetics. I think really, making sure that there's some access to an alpha two agonist, whether that be clonidine, Guanfacine, one milligram every eight hours around the clock or clonidine, like 0.1, 0.2 milligrams every six hours. You know, either around the clock or as needed. Those are not new treatments for opioid withdrawal management. But historically, if you also started MOUD, they were less important. You know, because they don't treat opioid withdrawal as well. But I think adding those, or considering those, or even doing transdermal clonidine, as another way of delivering some alpha two effect, recognizing that at least a good portion of our patients will have had some degree of regular exposure to alpha two agonists. And the withdrawal, even if it's not putting'em in the ICU, be enough that it, doesn't let them be successful in engaging in treatment

Mohamed: 38:55

that's really awesome. So if you don't mind, Mike, I'm gonna share some of the resources that you have. Let's say if any of our listeners. Work or live in Pennsylvania or maybe near Pittsburgh. I'm gonna share that in show notes. That way they know the regimen per discharge, maybe some of the resources, that are associated with you in a toxicology clinic, maybe some phone numbers. That would be awesome. Is that okay with you?

Mike: 39:15

Yeah, of course.

Mohamed: 39:16

I I learned so much from you today, Mike. It's a great discussion. I think this is an important discussion for all of our colleagues that work in the healthcare system. Pre-hospital physicians, paramedics, EMTs, flight nurses, doctors, nurses. I think this is a great discussion that we should be familiar with this challenging, epidemic. And I know it's gonna an evolving epidemic and we're seeing nuances come along the way. We'll try to tackle them, but I feel like this is a nice start and I appreciate you for your time. Is there anything that you would like to add at the end? Maybe a summary that you would like to provide our audience with specifically those ones just like to listen to the end of the podcast.

Mike: 39:56

Sure. Skip to the end, right? Yeah, I mean, I think first and foremost, the drug supply is ever changing and evolving. Keeping an eye, an eye on what is being mixed in with the drug supply will help us to predict and understand what kind of complications we may see. You know, medetomidine is what we're looking at right now. In a year, three years, five years, not sure what it'll be next, right? So that's always something to keep in mind for now, always treating the opioid use as the foundation, whether it's with naloxone in acute toxicity or medication for opioid use disorder like buprenorphine or methadone, is still the most critical intervention to save people's lives. And for the withdrawal from medetomidine, which isn't in and of itself. Potentially life threatening and certainly requires critical care. It just requires longer observation, expectant management and guidance for patients to understand that this could progress. And early initiation of alpha two agonists, particularly Dexmedetomidine for those who are really, developing a severe illness with severe tachycardia, hypertension, not controlled with, typical interventions.

Mohamed: 40:58

Thank you so much for your time, Mike. Appreciate that.

Mike: 41:00

thanks. Appreciate it.