Drs Glatter, Goodloe, Pepe, and Scheppke explore the role of ketamine as a rescue drug for patients experiencing benzodiazepine-refractory status epilepticus in the prehospital setting.
Assistant Professor, Emergency Medicine, Department of Emergency Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, New YorkAdjunct Professor, Department of Management, Policy and Community Health, University of Texas Health Sciences Center at Houston, School of Public Health, Houston, Dallas; Medical Director, Emergency Medical Services and Fire/Rescue Department, Dallas County government, Dallas, TexasDeputy Secretary for Health, Florida Department of Health; Chief Medical Officer, Palm Beach County Fire Rescue, West Palm Beach, FloridaProfessor; Chief Medical Officer, Department of Emergency Medicine, University of Oklahoma School of Community Medicine, Tulsa, OklahomaHi.
I’m Dr Robert Glatter, medical advisor for Medscape Emergency Medicine. Joining me today to discuss the role ofAlso joining me is Dr Ken Scheppke, an EMS physician. He’s Florida’s Deputy Secretary of Health and principal investigator of this study, which we’ll be discussing today: “ Also joining us is Dr Jeffrey Goodloe, an EMS expert who also discussed the impact and implications of the study’s findings. Welcome to everyone.Paul, I’ll let you begin. As one of the authors of the paper along with Drs Scheppke and Goodloe, with your background and expertise, can you discuss the importance of this study?Well, thank you. I have been on the streets for a half a century, and one of the things when we face this particular problem, it’s pretty catastrophic and demanding on us — both physically and, at least to some extent, emotionally too, because we know it’s a critical time-dependent emergency. Benzos work for most seizures. If we have someone seizing, we get them under control. We chose to use midazolam and we know, that midazolam is pretty effective. Especially if you have a dose of about 10 mg total, it probably will stop up to 75% of cases, but that means 25% of the time it doesn’t. So now you have an actively seizing patient, with long-standing seizing that’s been going on for a while. Often, when we come upon these patients, they try to treat them in a facility or at home, and they’ve been seizing away. What’s the problem with that? Well, first of all, they’re still having seizures and there’s some injury from that. The other thing, when you’re continuously convulsing, you don’t get good breaths in. We documented that at least in one third of the cases, there was significant hypoxemia. The third issue is safety. Trying to get a seizing patient down a stairwell, or even getting them out of a crowd of people or extricating them as they’re seizing away, the risk for injury goes up very high. Then you’re trying to transport them to the hospital, you’re trying to get them on a stairway, they could fall, they could get injured. There have been lawsuits where patients were seizing away, they’re trying to be held down, and they did get injured. It’s a risk for all. That was the background. Then, about 8 or 9 years ago, a very brilliant man who we are going to talk to next — our principal investigator, Dr Ken Scheppke — said, “I think I have a solution.” Tell them why, Ken, if you don’t mind.This actually came from a real call. I had one of my EMS captains call me and say, “Doc, we’ve got a status epilepticus patient. We’ve maxed out on benzodiazepines, still seizing, still have a good drive to the hospital. What else can we do?” Unlike hospitals, we carry a very limited pharmacologic armamentarium. I was already aware that ketamine had some potential antiseizure effects. Sorry if I go a little into the biochemistry of this, but most seizure medications we use work on the, which is basically a suppressive receptor in the brain. It’s the off switch. When you stimulate the off switch, that’ll generally get a seizure to stop. The problem with ongoing seizures — and we know this from basic, tabletop studies — is that GABA receptors disappear. The longer somebody is seizing, the less likely our normal seizure medications are going to work because the receptor they work at is disappearing. is increasing. That’s basically what I call the on switch. If you can block the on switch, that’s theoretically as good as an off switch. Fortunately, we carry ketamine for a number of different indications, not for seizure prior to this point, but I was aware that ketamine blocks the NMDA receptor. Pretty much on the fly, we decided, let’s give this thing a try. Sure enough, we gave 100 mg IV and the seizure resolved. From that, we said, “You know what? We may have a real tool here that EMS carries routinely and is very familiar with for a whole bunch of other indications. It’s a very safe medication and well known to be used both in pediatrics and adults.” With the right training, right monitoring, and good supervision, this medication could be really helpful in a situation like Paul just described. That’s where we started.Why is it that 100 mg was selected as the dose, and for children, 1 mg/kg? How did that come about?. We used to use a large amount of dopamine and the effects of dopamine change with the doses that you get. Ketamine is much the same way. At lower doses, you might have some pain control. With higher doses, you might have some dissociative stuff. At the elevated doses, between 100 and 200 mg in adults, now you’re really getting some good sedation. I’m about to get into the sedation realm, which is why we started at 100 mg, understanding we can always give more. I had no problem giving more than 100 mg, if it didn’t work. It just happened to be that 100 mg worked just fine. What Paul will probably tell you is that probably less than 100 mg will do, because when we give the IV, we don’t necessarily get the whole dose in. Go ahead, Paul.One of the things we did is that we really were very conscientious about the study. We went and reviewed with the paramedics to see what happened in this case, how long did it take, and were there any complications. We went through everything. One of the things that struck me time and time again from individuals telling us in different places the same story, which was that they would get about half of that in. It’s a 50-mg diluted dose that we give — it’s 50 mL of solution. We put it in there, and that usually goes in over 2 or 3 minutes either by IV or the intraosseous route. What’s striking is that they said almost every time when they had half of the dose in, the seizures stopped, just like that. We did give the full dose on purpose just in case, but nevertheless, it’s profound how fast it worked in every single case. There was one exception, and maybe Ken can tell us about that, which was in some kids who we gave it intranasally because we don’t give IV or IO in this case. In a population of 1 million, it only happens once a month. It’s not that common, but when it happens, it’s catastrophic. Here’s the thing: If you’re seizing and you can’t get an IV or IO right away, you could go the intramuscular route as well. There are many advantages about this particular drug under the circumstances. We collected data over the course of 7 years. We had over 80 cases, in children, adolescents, and adults. When it comes to adults, we really wanted to say that 100% of the time in adults, the convulsion stopped. We did have one case where the convulsions had stopped for 20 minutes or so, and the paramedics were still in the emergency department even though they had already given a report, and the patient had a secondary seizure after that. That was the one outlier that brought us below the 100% mark.That is an absolutely great question and something we were very concerned with right in the beginning, especially when you combine sedatives. Ketamine alone does great. We know it preserves the respiratory drive, and it preserves cardiovascular functioning. When you combine central nervous system depressants, you start to start having unpredictable results. We monitored that as close as you can in a patient who’s seizing, and we were able to get complete datasets in the vast majority of patients. Interestingly, we saw, and Paul already alluded to this, that about one third of the patients were hypoxic while they were seizing pre-ketamine. Once we gave ketamine, that went away. There was not a single case where we had to do airway intervention. All the airway issues were from the inadequate ventilation and oxygenation from the seizure itself, which resolved when the ketamine resolved the convulsions.I’m glad we cleared that up because that’s what many people are concerned about ─ an airway issue. Ketamine alone is safe, we know that.From our point of view, it was a 100% successful from an operational point of view. You have these patients who are seizing for half an hour, and one guy was seizing for an hour and a half. They were being treated at a facility, and they were getting loaded with things. In one woman’s case, she had been seizing for about a half an hour. We stopped the seizure within 2 minutes, and then for the next 20 minutes she was fine. It turned out later that she had a very seriouscase and she ended up dying. From our point of view, operationally, ketamine was 100% effective. We purposely wanted to make sure we had full disclosure. In fact, in two of the cases in children, we called them seizures, and we got rid of whatever seemed to be the seizure activity, but there was something else remaining. In one case, it wasn’t a seizure. She had an anoxic injury. The convulsive stuff was a little bit better after we gave it to her. In another case, it was a particular syndrome and what we were observing was not abnormal neurologic activity; it was a typical postictal state for them. It actually behaved better for us than we reported at first, if you drill down on the individual cases. As Ken said, the most important thing was that we didn’t have to do any interventions, whether it was breathing for them, creating an airway, giving fluids, or whatever. They did just fine. It ended up being not only safe, but in my opinion, it was protective because we were able to get rid of the seizure and make it better for them.There are patients we know with nonconvulsive status epilepticus that do have electrographic findings when you hook them up. You stop the motor aspect of the seizure, but are patients still having evidence on the EEG of a seizure?That’s a phenomenal question. We actually raised that as one of the weaknesses of our paper and an area for further research. You’re absolutely right. That is something that could be going on. We don’t have a way of monitoring that. We don’t have ability to do EEGs in the field. I can tell you just from the follow-ups, these patients largely wake up. We know with the vast majority that’s not happening, but could it be happening in minority cases? Yeah, it could be, because we don’t have the ability to measure that.We said that was a limitation that we didn’t do the hospital follow-up, but as Ken said, we did have hospital follow-up, broadly speaking. We just didn’t look at the EEGs, and so on. We think in this case, though, it’s more successful and we want it to be proven, which is a very good segue to what’s going to happen next. , which includes ketamine, but it’s in the emergency treatment of status epilepticus. They’ve gotten approval for it. It’s going be done not in the prehospital setting. We’ve done our prehospital study, but this will be done in the emergency department setting. They have many great centers that are going to be involved with that. I thought that’d be a good pitch to Dr Goodloe. Let me just quickly say, Dr Goodloe is extremely well known not only in the EMS world, where he is the medical director for two cities, not just one — Tulsa and Oklahoma City — but he has also been a major player at the American College of Emergency Physicians and our key liaison in terms of EMS.Jeff, can you discuss the impact and implications of the study, and recommendations you have for caring for patients based on the conclusions of the paper?Sure, happy to do so. Thanks for the inclusion in today’s discussion. I certainly have a large amount of appreciation for Ken, Paul, and the whole team of researchers on what I think is just such a fundamental paper that impacts not only the practice of EMS medicine but also the larger practice of emergency medicine. We know that fundamentally when someone is in a refractory seizure, particularly in a status epilepticus type pattern, whether that person is at home, in a public location, or in a hospital emergency department, that pathophysiology is still the same. This is just as much a challenge for us, not only on the street but also in the hospital emergency department. , for instance, in these benzodiazepine-resistant seizures. Great success is not 100% success. What I also find really compelling about the use of ketamine here is that when we just think about the logistical factors, the timeliness of care, many emergency departments still do not haveimmediately available in an in-department pharmaceutical cache. Then comes the process of requisitioning that from a central pharmacy, the processing of that order, transporting that pharmaceutical to the emergency department, receiving that, and then getting that administered into the patient. We know, despite the best of efforts, there are times that that can easily take 30-plus minutes. That is a timeframe that patients in this type of pathophysiology just don’t have the luxury of having. When we’re receiving these patients from the field that continue to be in status epilepticus, I think as Paul and Ken both noted, sometimes these patients have already been seizing for 30 or 60-plus minutes. We don’t want to have to add another 30-plus minutes just for the administrative procedure of some of these other secondary agents. We know, as Ken alluded to, that regarding the use in his EMS system, ketamine was already in the formulary. It was being used as an analgesic, as a chemical, severe agitation, and those type of indications. Now, we have a pharmaceutical that is increasingly commonly immediately available in the emergency department setting. I think when you couple that reality with how effective to date ketamine appears to be for these benzodiazepine-refractory status epilepticus patients, this really is a practice-changing paradigm that I think we’re in. Again, Rob, thanks to you and the whole Medscape team for helping to cover this.You said it all: Ketamine really should be first line when a trial of benzos is ineffective, as the paper states. I think that going to these other cache armamentaria of medications is just too time consuming. We should just go to a medication that we know that works reliably.Some of the lessons learned here include that not only is it great under those circumstances where we’ve given the maximum of benzos and maybe added even more because they got more before we got there. Now you have that concern, and it’s been shown in other studies, that you do have respiratory. As Ken said, you can add more stuff, and more stuff, and they’re not going to break. The lights are off right at that point in time. What was interesting — and we didn’t mention this, but I should because it’s in the paper — is that we had nine cases, one child and eight adults, who didn’t get benzos ahead of time, at least from us. In four cases, they did get some benzos before we arrived or had a history of an allergy to benzos. If that’s true or not, I’m not sure. Either way, we had history to lead us to say, “Okay, let’s just go straight to the ketamine.” We had nine cases where we went straight to ketamine and it worked the same way in every single case. This is pretty impressive stuff. This was performed in a single-center system, so is it applicable elsewhere? I think it’s pretty intuitive that it’s going to be, but nevertheless, it was a single center, it wasn’t a controlled trial, but it was a prospective study. We said, “Let’s see what happens when we do this and observed it,” and it worked in every case. We went to our statisticians and said, “Do we need to do this?” They said, “To compare your data to the control groups that didn’t respond to the midazolam in the RAMPART trial, theThe other thing is about the single center is that Palm Beach County is an amazing place. It’s very progressive under the leadership of its chief medical officer, Dr Ken Scheppke. They performed these great studies, including some really great ground-breakers in various regions. They are a really well-run and well-supervised system. Supervisors were called out for every case to see if there were any problems or any issues, whatever it might be, and also to see if there were any complications, and so on. The database they used when this study started captured everything. We had all the data collected, and we didn’t have to go back. If you had to do a preliminary study somewhere, it was there. In terms of trying to change the guidelines for, say, critical care societies or emergency medicine societies, do you see this happening as a result of your trial?I think we need more evidence. First, we have to realize that the physiology of seizure changes over time. We’re treating things really early or at least as early as possible when we do it in the prehospital phase. Is it going to work in the ER? Probably. Is it going to work a day or half a day later in the ICU? I don’t know. We have to have more evidence before we can make that really broad statement. I will add a couple of things. I know we’re staying all rosy about ketamine. I’m not sure I trust intranasal for children. I would say that, for the kids, the intranasal did not work as well. It’s 100% in adults . For the children, if you take away the two that weren’t really seizures, there were actually two true seizures that got intranasal but it didn’t work. I suspect it’s not absorbed well intranasally, and I would stick to IM for the kids. That is one other thing we noticed. IM ketamine is very simple to give and it’s very quick to give, but it’s a little slower onset. When you add the total time that it takes to start an IV and run an IV, it’s probably about the same amount of time. Parenterally, it’s been really a game changer for us in the prehospital field, whether you give it IV, IO, or IM.One of the intranasal cases, by the way, did work. It just took a few minutes longer. It was so striking to see that, when you gave this, you stopped the seizure within a minute or two. That’s what was a little different. I agree with Ken. My recommendation, and you guys have already made the recommendation, is to go with IM. These are in the smaller children, of course, because we don’t put IVs or IOs because it’s too much volume for them in that subcategory.I’ll go back to the fact that we have limited choices in the prehospital field. I’d say yes. From an EMS standpoint, yes, if benzos fail, in my mind, ketamine should be your next choice.While we still have a higher grade of evidence to prove, I really appreciate where Ken and Paul are coming from this. We’re talking about the solid benefits of this one study and simultaneously talking about the importance of additional studies and certainly in additional locations, the emergency department, intensive care units. There’s more to be done. It’s not going to surprise me to see this eventually appear in consensus guidelines and national society guidelines. It is interesting, the grassroots adoption of this that we’re seeing already. Literally, just before we started filming this, I was talking to one of my trauma surgery colleagues and said, “I’m doing this great interview with Medscape on ketamine for status epilepticus.” He says, “Oh, I love it. I was flying a helicopter unit over the weekend,up having a status case, wound up giving 100 milligrams IV. Are you using it? What’s the dose you’re using?” This was obviously benchmarking off of the paper here from Ken, Paul, and others, so the word is getting out. I think that’s exciting to see, and the results are, at least to date, pretty consistently positive.We have, as you alluded to, a network of medical directors for the 50-60 largest cities in the United States. They cover about one third of the US population. We quickly were able to get the word out to them, even while the study was going on. After the first 2 years, we already saw it was a near-perfect score. WeKen received the Star Research Achievement Award that year because of the concept and what we were doing. We said, “Let’s press on.” We purposely published in, because worldwide, many EMS systems are run by critical care specialists. The critical care guys really take care of it. This way, we could get the word out to even more people. Hopefully, that will add to the consensus. I’m going tell you that almost everybody that I know, based on the data, are adopting it around the country. I don’t know if there is equipoise here anymore, from my point of view, because of my experiences. Ken, I don’t think I’d enter my patients into a study at this point in time, right?Again, I keep qualifying in the prehospital field, where we really don’t have all the choices that you have in the hospital. I would say there’s no equipoise. I mean, your when your choices were used to be benzo plus Desal and the patient keeps seizing, or benzo plus ketamine for those that benzos don’t work on, clearly the choice is ketamine.Our message to go out to other EMS medical directors is that we would highly recommend it. You judge for yourself. If you do, monitor for complications, tell us how your outcomes went, and see if you could reproduce what we did. That’ll be important. We’ve given you the directions about how to do it. That’s part of what we hope will happen, that people will be careful to not just willy-nilly introduce this, but do it in a thoughtful, constructive manner under those circumstances.Let me add a caution to that. When we do this in the field, the patient is monitored as if they’re in the operating room. We’ve got end-tidal CO, pulse oxygen, continued cardiac monitoring, and monitoring of the blood pressure. This is not something done with zero monitoring. The medics that give this are calling their EMS supervisors as they’re doing this. They’re all airway experts that get trained on airway. We have a very high-functioning prehospital system in Palm Beach County. I wouldn’t say that you can necessarily translate what we do to all EMS systems. You have to have those necessary safety measures in place, where there are airway experts that know how to do all the monitoring, know the dangers of combining CNS depressants together, and so on. We drill on that quite a bit. Obviously, we didn’t see any negative effects in our study with 81 patients. That’s decent for a study like this, but when you start adding it to many more magnitudes of patients, who’s to say that you won’t start to see some outlier cases.You and I are in total agreement. You have to have all those same tools. I’m glad you actually elucidated that a little further. If people do adopt it, let’s make sure they’re looking at it and they’re controlling it very carefully.If this seizure has been going on for quite a while, that’s downregulating on the GABA-A side and it’s upregulating on the NMDA side; there is a kind of a rationale there. I think it’s a separate study because benzos really work most of the time and all the patients that we deal with. If it’s status epilepticus, that might be another deal.Benzos are the time-honored first-line drug, and it’s going to take a bit more than what we’ve done to knock it off its pedestal. I will say that if you’re going to pick a second drug, it doesn’t make mechanistic sense in my mind to pick another GABA drug. I would definitely pick something with a different mechanism.Just to jump in on what we do know and what we increasingly can appreciate about how the receptor physiology does change a bit over time. Urban vs rural environment makes a difference, perhaps even more so from a rural standpoint, because we knowdepend upon critical access hospitals and rural hospitals for emergency care. Often the EMS systems that are serving those areas are basic life support. Now, we’re talking about patients that, really by scope of practice of the EMTs caring for those patients, don’t have the ability to receive prehospital benzos or prehospital ketamine. This study is thought provoking for a number of reasons. There are some implications for ketamine utilization, particularly in rural and critical access hospitals. In the setting of those hospitals , one of the things we have all faced are medication supply chain management issues and an unprecedented frequency of challenges over these past 5-10 years. I have lost count of the number of times, even in a tertiary referral hospital, when I’ve been told that we’re out of, so take your pick of another benzo. For a critical access hospital, they may or may not have the benzo supply that we would ordinarily expect. I think you do raise a great question, Rob. This does present us an alternative, particularly when benzos may not be readily available.To your point, there is an ongoing shortage of injectable lorazepam through 2025, as we know. Certainly, we don’t expect that to improve. The oral form is available, but that doesn’t do anyone any good.A couple of things that I would add in, Rob. This study also took into account many things about seizures. Over that period of time, we saw 2000 seizures total. Half of them were in women, half of them in men. One of the things we found that was striking here was that, as opposed to ,say, 55% of the seizures we responded to over that period of time being in women, in this case it was like a 2:1 ratio. Also, among people who had multiple episodes that we responded to, they were women as well. That is hypothesis generating right there. Why is that? What is going on? Almost everybody we were able to document had a history of seizures and was on some kind of medication before. That was another interesting thing. We checked glucose in every case, and they were all fine under those circumstances. We do all those things. The other thing that’s important is that we’re learning if you come upon a 28-year-old woman who’s having a seizure, one of the questions we ask is, “Has she had a baby recently?” She doesn’t look pregnant. She’s a 28-year-old who may be 2 months postpartum. We want to rule out all those kinds of things as well. When we did the study, we didn’t say, “Oh, it’s just a seizure and they didn’t react to midazolam.” We checked everything out with medical histories. The interesting thing, though, is that when we tried to do statistics, we had to correlate with the sex or age, for example. It worked in every case, so the statistician said, “This is a golden thing. We love it when it works in every case.” From our point of view, operationally, it stopped it in the prehospital setting all in every case, except for a couple of the kids. That’s another hypothesis-generating thing, too, because there may be different mechanisms under those circumstances with the adolescents or children. This is a cool study because it opened up a number of other things that we should study.This has been a great discussion. It was so lively and so informative. This is a very important paper that I think everyone should know about, not just folks in EMS, emergency medicine, but throughout critical care and every facet of medicine. You never know where you’re going to be when someone seizes, and you have access to ketamine when a benzo isn’t working. Robert D. Glatter, MD, is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is a medical advisor for Medscape and hosts the, is a professor of internal medicine, surgery, pediatrics, public health, and emergency medicine at University of Texas Health Science Center in Houston. He is also a global coordinator of the US Metropolitan Municipalities EMS Medical Directors Coalition. , is a dual board-certified specialist in the fields of emergency medicine and the subspecialty of EMS. He is the state EMS medical director for the Florida Department of Health and serves as chief medical officer or medical director for multiple fire-rescue agencies in Palm Beach and Martin Counties. He also holds medical leadership roles with the Broward Sheriff’s Office and a major multistate defibrillation program. Scheppke is also a member of the Metropolitan EMS Medical Directors Coalition. , FACEP, serves as chief medical officer for the EMS system for metropolitan Oklahoma City and Tulsa. He is also medical director and a tactical emergency physician for the Oklahoma Highway Patrol. Goodloe is professor of emergency medicine, EMS section chief, and director of the Oklahoma Center for Prehospital and Disaster Medicine in the Department of Emergency Medicine at the University of Oklahoma School of Community Medicine. He works clinically at Hillcrest Medical Center Emergency Center in Tulsa, Oklahoma. Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.All material on this website is protected by copyright, Copyright © 1994-2025 by WebMD LLC. This website also contains material copyrighted by 3rd parties.
Seizure Disorder Seizure Complex Partial Seizure Grand Mal Seizure Tonic-Clonic Seizure Pain Management Children Child Childhood Pediatrics Kids Hospitals Status Epilepticus Fellowship Fellows Residency Residents Receptors Airway Airway Management Management Of The Airway Benzodiazepines Social Determinants Of Health SDOH Social Determinants Of Health (SDOH) Pregnancy
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