E193: "Hail to the Receptor in Chief" w/ Dr. Peter Antevy

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Hey everyone, this is Dr. Peter Anteve. I'm so excited to be speaking at Fast 21 again this year. I hope to see everyone in person soon, but I wanted to thank Eric and Ashley, Mike and the entire gang. Thank you for having me again and I hope to see you all soon. Let's get started. So the title of this talk is Hail to the Receptor in Chief. NMDA as a Panacea for Pre Hospital Care. So why do we name it that? Well, I think that all of us have a toolbox full of medications and oftentimes we give the drug without really understanding the biochemistry, the physiology, the pharmacology of it. And so today I'm going to take you a little bit on a tour of the brain. Some receptors, some medications and we're going to wrap it with a case, a real case with a video at the very end. So I think you'll like it, you'll enjoy it and hopefully you'll take some great points home on your next patient. Okay, first the disclosures. Many of you know I'm the founder and chief medical officer of Hantevy. But that will not be a focus of this talk today. Okay, so let's start with the case. Let me introduce you to Jenny. Jenny is a 23 year old college student at Carlow University. She developed some signs and symptoms that seemed mild. But let's take a look at her entire course and see what happens to her as she goes through it. Jenny started with a flu like condition with headache and nausea for about 10 days she has been having problems in school because of unusual memory loss. At home she seems lethargic during the day but is unable to sleep at night. Her family then says that Jenny Started to become irritable, out of character for her. She has an uncle who has bipolar, and the family thought, hmm, maybe Jenny's bipolar too. They brought her to the ED after she was found outside wandering and confused in the yard. On evaluation, Jenny has a temperature of 100 degrees Fahrenheit. Baseline blood work and physical and neurological exam are normal. Connecticut is normal. A psych assessment finds symptoms consistent with mild depression, but Jenny is still alert and oriented. There's no findings to support admission, and therefore Jenny was sent home.

A few days later, Jenny returned to the ED agitated, paranoid and experiencing auditory hallucinations. She's admitted to the psych unit where she exhibits bizarre behavior, including giggling, echolalia and posturing. She has frequent cycling leg movements and now believe that staff members are plotting against her and that her food is poisoned. She's hyperkinetic, screaming, hallucinating and sexually disinhibited. Antipsychotic medications do not seem effective and prominent orofacial dyskinetic movements develop.

She experiences altered mental status followed by a generalized tonic clonic seizure. Although she has no history of seizures, she does not return to her previous level of consciousness. Autonomic instability develops and she is then transferred to the ICU. She requires sedation and mechanical ventilation, and subsequent EEGs reveal only non specific slowing the brain. MRI scan shows non specific small hyperintensities. What is going on with Jenny? There's something clearly wrong and is being missed by these healthcare professionals. Let's discuss. Ah, the brain seems so small. You can hold it on one hand. It's about eight pounds, but boy, is it complicated. What is going on with Jenny? Is it a CT scan? An MRI that will find it? Is it blood work? A tox screen? Is it a metabolic problem? Is she really becoming bipolar like her uncle? Hmm? What are we going to do now? Well, I know that if I was with Tyler right now, this is what he'd be thinking. Jenny, Jenny. Who can I turn to? And for those of you who don't get that joke, talk to Tyler. He probably doesn't get it either. So what do we do here? What is really the problem and who should we really turn to? What? Well, what about this guy? Dr. House? We really need someone here to think through what exactly is going on with this girl, because obviously letting her rot in a psych ward until she requires mechanical ventilation in the ICU clearly wasn't the right thing to do. I'm going to give you a hint, though. This all had to do with the NMDA receptor. How do we Know that? Well, I'll show you that at the end. But the point of the matter is, you heard the constellation of symptoms that Jenny developed and I'm telling you that one receptor at the end of the day was responsible for all of it. This is the key and why I wanted to start with a case that perhaps wasn't so relevant to your day to day practice, but will be relevant to the concepts that we're about to discuss next. So we talked about the brain, but obviously there's highways and biways in the brain called nerves. And you can see here that this image depicts a nerve with the axon and then at the end the dendrites. But there are chemicals that allow the signal to pass from one neuron to the other. And those signals are neurotransmitters. Now so those neurotransmitters are chemicals that are just hopping from one neuron to the next. And they're either telling that neuron to get excited and keep going or they're actually shutting it down. So let's take a look at exactly how those connections are happening at the edges. And they're happening at the receptor level. So here you could see on the left hand side and on the right hand side two receptors at the nerve level on the left hand side you see the GABA receptor. Many of us know the GABA receptor. When you stimulate it, it inhibits the firing of that neuron. And of course the drug we know is the benzodiazepines, midazolam, diazepam, etc. Now here on the right hand side you see a different kind of receptor. It's different than GABA because this one is the NMDA receptor. It's excitatory. That means that when neurotransmitters come to this receptor and activate it, it causes stimulation. Now there are medications that can block this receptor, right? And therefore if you're blocking or you're antagonizing the receptor, then you cause a slowing down of. So on the left hand side, GABA you give a benzo and you slow things down. On the right hand side, you, you give an antagonist to the receptor like ketamine and it slows things down or changes things. So very different receptors, but these are how different neurons work. It's similar to the cords we have for our computers that are ever changing, right? First we had a USB and then we had a USB C. Well, think of the receptor as that plug. It only will accept certain things into it that will either make it work or stop it from Working. That's what the receptors do. All right, we know now that ketamine is an antagonist at the NMDA receptor. But more importantly, dose matters. That means that you could have an NMDA receptor blocked by ketamine, and then right next to it, another NMDA receptor is not blocked. Why? Because the dose of ketamine you gave wasn't that high, and therefore those receptors are not saturated. And this is the beauty of this drug, is that it does not saturate all the NMDA receptors at lower doses. And therefore, we have what we call the dose continuum. And many of us have in our protocols many different doses of this drug. And therefore, understanding that those different doses will saturate the receptor differently. Let's take a look here at the dosing protocol. Many of you have these protocols, and you know that at the lower range for analgesia, 0.1 to 0.3 milligrams per kilo, then you see what they call the recreational range. 0.2 to 0.5. Then we have the partially dissociated range of 0.4 to 0.8, and then the fully dissociated dose, where oftentimes you're actually doing surgeries on people. And at one to two milligrams per kilo, purely because the NMDA receptor saturation levels are different based on the amount of drug that you give that particular person. Now, we know that ketamine is a true Swiss army knife of medications. You see one protocol that may have it for one thing, and you have another protocol that may have it for seven different things. So I wanted to really take you through a quick tour of all the things that we could be using ketamine for in the field, obviously in the hospital and the ICU as well. Let's take a look at what we use it for in ems. So if I had to guess which protocol you started using ketamine for, it must have been excited delirium, like many of us did. We had one county who started using ketamine much earlier than the other, and their outcomes were better for these patients. Why is that? Well, when ketamine antagonizes the NMDA receptor for these patients, it slows them down. It allows them to continue to breathe off their CO2. Remember, they have a severe metabolic acidosis. These people are hyperthermic. So we would cool them down, IV fluids and so forth. Sometimes these people needed bicarb. But the bottom line is that ketamine was able to help us get these people metabolically in the right place, because we know this is a medical diagnosis. What other protocols do we use it for? What about severe trauma with severe pain? And many of us have fentanyl. You may be still using morphine, but at the end of the day, we all have those patients who are still in severe pain. Ketamine to the rescue once again. You can use it IV IM intranasally. And there's even more studies now coming out on nebulized ketamine for acute traumatic pain. It's a wonderful drug and very safe. You just have to remember when you give this drug, you shouldn't be using the highly concentrated 100 milligrams per milliliter concentration of Ketamine IV for pain control. You have to dilute it. You have to give it slowly, preferably over 10 to 15 minutes. What about the patient who needs sedation? Again, ketamine is a great medication because it doesn't drop the blood pressure. It stabilizes the blood pressure. It allows you to comfortably sedate somebody. And then pretty rapidly, that patient will be back to and around again. Great drug for sedation as well. The next big thing is airway management. If you're doing RSI or dsi. Thank you. Jeff Jarvis at your agency, you should be using ketamine for that. Why? Again, ketamine spares the airway reflexes, meaning that that patient still has a gag reflex. They're breathing on their own. They're breathing at the rate that they're supposed to be breathing at, rather than some altered rate because of the other drugs that we would want to use. Ketamine should be used, I believe, for almost all, if not all, cases of RSI or dsi, unless, of course, there's a contraindication. Okay, now, here's the. What else? The last couple of items, you probably say, yeah, we do that already, but here are some items that you may not have in your protocol that you may consider. And again, this is all because of ketamine's action on the NMDA receptor number one. On the top left is refractory seizures. In Palm beach county in Coral Springs, Florida, we did a great study where we had patients, 22 patients with refractory status epilepticus who were resistant to midazolam. They did not stop seizing Ketamine to the rescue. We were using 1mg per kg IV or 3mg per kg IM or IN. And it worked. 21 out of the 22 patients had complete and full resolution of their seizures without any untoward effects. So if you don't have it yet. You should look into that data and consider it. What about the patient with severe asthma? Those patients you don't want to intubate, but we want to bronchodilate them. We want to improve their respiratory function. And if we have to intubate them, boy, do we have to be careful with the drugs that we use. So I would recommend considering ketamine for the severe crashing asthmatic and even consider a ketamine only intubation for those patients. Now, if it's not on your protocol, don't do it. But this is a great idea for patients who we do not want to remove their negative inspiratory pressure by paralyzing them, and then they suddenly go into cardiac arrest. If you've seen it, you know exactly what I'm talking about. Now, some things that are just coming into the literature, hospice patients, patients with depression. Ketamine is now being used in very small doses to help people with their anxiety and depression. Again, it's because of how the drug works on different receptors at different doses. And so this is a field that's continuing to expand. And you will see ketamine being used more and more on the patients that you see out of the hospital, perhaps even more so than inside the hospital. Great times for ketamine ahead. As with any drug or procedure therapeutic, you want to see what the data is, and especially in ems, what is the EMS level data? And recently I was very privileged to be part of a very esteemed group, including Antonio Fernandez, Remley Crowe, Brent Myers, Ken Schepke, Scott Bourne and Stein Bronski, where we actually looked at ESO data from thousands and thousands of patients and evaluated, did ketamine really have any untoward outcomes? These patients. First, a big thanks to ESO and Tony Fernandez for allowing me to use these slides. Let's take a look at the database. You could see here that there were 12,386 patients who got ketamine in the field in 2019. You could see the patients who met the exclusion criteria and they were removed, leaving the analysis population of 11,291. Take a look at all the different things ketamine is being used for here. Trauma, pain. We talked about that. Altered mental status, behavioral patients. Those are the excited delirium patients. We talked about cardiovascular, pulmonary. Those are patients who needed airway management more than likely or perhaps needed ketamine because they were waking up after some CPR being done in the field. The ketamine for seizure patients, and then other. So again, this is from EMS in the United States. And you can see the number of uses of ketamine is pretty high. What about the dose? The total range for all patients was about 1.5 milligrams per kilogram. You could see the pain dose, the behavioral dose. Again, they all fall nicely in a range of between 0.5 and 3.7. Now mind you, there are cases in the literature of significant ketamine overdoses, some even 100 fold overdoses with no untoward outcomes. Unfortunately, however, in the literature and in the, in the media, there are those people who are getting, I'll give you a number of 500 milligrams of ketamine and those patients are dying. And the details are a little bit confusing as to did those patients die from the ketamine or did they die from their behavioral issues or did they die from the way that they were being managed by the folks on scene? So these are all questions that we really can't answer. But we sought to look at the data from 2019 to see what is in there. Let's take a look. You can see of course that the EMS disposition for almost everybody who got ketamine was transportation. Of course you could see that there is some released on scene and dead on scene. Very, very few in each of these cases. So you can see here the disposition from the hospital. And again, a majority of these patients are admitted. But then look, you have sometimes 40 or 50% of the patients who are discharged from the emergency department or they just walked out. Some patients were transferred. And then again you can see the small number of people who actually expired in the ed. The question is, did ketamine really have to do with the death of these patients or not? We looked at this paper and we looked at all the patients and we ended up getting the narrative and we looked at the hospital side data for these patients to really try to evaluate were these patients affected negatively by ketamine or not. Okay, let's take a look at this slide from the top. We had 11,291 patients in the, in the total population.

Eight of those patients died on scene. Of the remaining 11,274, you can see that over 9,000 of them we did not have the ED disposition, meaning we don't know what happened to them after they got to the ED, but 2,000 of them we did. And of those 2,030 you could see that 121 were deceased. When you combine that with the eight that died on scene, that gives you a total of 129 that we reviewed, meaning that we reviewed the EMS run and we reviewed the hospital side data to really get a good understanding of whether or not ketamine was the actual cause of death. You could see that in one case, ketamine was not even administered. In 114 cases, we easily excluded ketamine as the contributing factor in the patient's death, leaving us with two unseen deaths in which ketamine could not be excluded as a contributing factor, and 6 in hospital deaths in which ketamine could not be excluded as a contributing factor. This means that in those cases we couldn't be 100% confident that ketamine could be excluded. So it's data like this that gives us more confidence that ketamine indeed is a safe medication. When used appropriately and monitoring is put into play and protocols and cqi, Ketamine can be a panacea. It does hit the NMDA receptor in different ways. And this is why I brought all of that together, because you need to know the drug, you need to know how it works, and then you have to do studies like this to prove on a large scale that ketamine is indeed a safe medication to be used. Okay, so what happened to Jenny? She was a 23 year old vibrant college girl who ended up going into a psychiatric unit, then being intubated. She's seizing and unfortunately she ended up in a vegetative state. And that's how she died. A very unfortunate ending because no one picked up on the diagnosis. No one recognized what was really going on with her. But there are cases that have a positive outcome because somebody picked up on the diagnosis. And in this particular case, it was a physician who said, hey, I'm going to keep looking. And this is the case of Susanna Cahalan. Susanna had the same exact diagnosis as Jenny, but this time she had a good outcome. Let's take a look at her video and what the outcome was.

It all started with when I thought I had a case of bed bugs. And when I had an exterminator, he came in and said, you don't have bed bugs. Then after that I was feeling very tired and lethargic and really I just didn't want to go to work. I felt not like myself. And then I started having numbness in my hands and my feet. And at that point I went to a neurologist who first diagnosed me with mono. After that I started acting paranoid. I had hallucinations, and then I had a seizure because I literally don't remember the good part of the month that I was in the hospital. I had to rely on medical records, interviews with doctors, interviews with my family, interviews with my boyfriend. You know, pretty much I had to just recreate that time using the skills as a journalist. There's video that exists of me in the hospital, and when I watch it, I. It's very much I'm watching this other Susanna, this other person that is so far divorced from who I am now. I mean, she's frightened, she's angry, she's just terrifying. And in a lot of ways, I've been trying to reconcile who that person was with who I am now and what part of me is this kind of monstrous person. And through the course of researching this, I've come a little bit closer to understanding that other Susanna. But she's always. She's always a stranger. She's someone who I have to dig really deep outside of myself to really understand. I have to. Have to ask other people. I have to read pages of medical records to get anywhere close to understanding who that person was. Towards the end, I stopped being paranoid and I started. Stopped having these unbelievable hallucinations and I started becoming catatonic. I just had no. I hardly moved. I had no emotional register. I just kind of stared off into space. I had very rigid movement. And basically now I know, looking back then, after my research, that I was heading towards what would most likely have been a coma and for some people, death. I was ultimately diagnosed by Dr. Suel Nudar at NYU.

He was the first doctor to really sit down and see the whole thing. Picture the bedbugs, the paranoia, the hallucination, the catatonic state. He also noticed I had high blood pressure. At one point, when he visited me for the first time, he did something that no other doctor asked me to do. He asked me to draw a clock. And it's a very simple procedure. I had gone through a million dollars worth of blood tests, MRIs. This is one clear step that he asked me that cost nothing. Basically, he asked me to. He gave me a piece of paper and asked me to draw in one through 12. And I drew every single one of those numbers on the right hand side, which showed that I had inflammation in the right side of my brain. After a brain biopsy and a spinal tap, they ultimately diagnosed me with what is called anti NMDA receptor autoimmune encephalitis, which is, in short, when your body. When your body's immune system attacks the brain. The hardest part for me was the recovery. And it was the hardest part to write as well. At that point, I had lost my identity, who I was. Everything about my personality was just gone. And I had to rebuild that from scratch. I just am reminded of the scar I have from my brain biopsy on my head. And I know I'll never be the same person that I was before. And I think it's given me such purpose in my life because I feel like this story and living through this horrible time has given me, given me know, the strength to help other people and the ability to help other people, which I think is the most wonderful gift of the whole thing.

Wow, that was a great video. And it really, to me, enhances and shows the power of the NMDA receptor. The two cases of Jenny and Susanna, those receptors were completely wiped out. That's NMDA receptor encephalitis. We're not really dealing with that in EMS every day, but we are dealing with the NMDA receptor itself. And we're dealing with it because of the medications that we give and the protocols that allow us to use ketamine for these conditions. And so understand nmda. Know the receptor, know the drugs in your toolbox, and go and use them. Use them carefully, effectively. Make sure you have a great CQI program behind it. This has been Dr. Peter Untevi. And again, thank you to everyone at the Fast 21 team. Thank you for having me again, and I hope to see you all soon.