Okay. Good morning. I'm very excited to share the podium with four of the speakers. Can you flip to the next slide? Okay. So, Flora Hammond from Indiana, Jamie Ott from University of Washington, Rasifat from University of Missouri, and Tom Watanabe from Jefferson Moss McGee. And next slide, please. Okay. And here are our disclosures. I think Dr. Zapant will have his on his own slide. Otherwise, these are our disclosures, including one at the bottom. So, there are no FDA-approved medications for brain injury or irritability and agitation. So, all of the things that we talk about will be, almost all of them will be off-label. We may refer to some on-label uses. Next slide, please. Okay. So, our strategy here is to present some information regarding the use of medications for post-traumatic agitation in a debate format. So, we're each going to focus on supporting our drug and pointing out problems related to their drugs and why our drug is so great. So, that's the way that we're going to have some balance in terms of these medications. Having said that, I'm confident that we all use a number of different medications in practice, but this is the format that we have. To preserve the debate format, we've all kind of hidden our sides from each other. So, one caveat is we might have a little bit of redundancy there, but we decided we would take that risk as opposed to having more of a straightforward didactic lecture. Could you turn the timer on, please? Thanks. Okay. Very good. Next slide, please. So, did we miss one? Thanks. Hopefully, we'll get a clicker soon. Okay. So, these are the objectives, and our strategy to get that is, just review that. So, we're going to look at efficacy. We're going to look at why some medications might be better than others. We're going to look at adverse events that will come out through the discussion as well. So, next slide, please. Okay. So, by introduction, we know that behavioral disturbances are very common after traumatic brain injury. Over 70% of patients may demonstrate this type of behavior while in the inpatient rehabilitation unit, but it's not just an inpatient rehab problem. Even in cases of milder TBI patients, you might see straight into outpatient. The instance of at least irritability is estimated to be as high as over 60%. So, it's certainly a big problem. Next slide, please. So, the impact on rehabilitation. Agitation certainly affects participation in therapy, and this is the case even when severity of injury is taken into account. So, we see this across the spectrum. It definitely slows progress in rehabilitation, at least if you define it by FIM efficiency, but there are several studies that support that. And we know that it really has a great impact on patient and staff safety, and we've all had patients who are loud and boisterous, and then you show up the next morning and nobody in the unit slept. So, there's a lot of impact across the board. One thing to consider, though, is whether the behaviors that are exhibited always require intervention. So, some patients may be, quote, unquote, agitated, but if it's really not impacting the process, you may not need to intervene. So, that's just something to consider. Next slide, please. In terms of differential diagnosis, we want to consider some other factors that may be in play and factors that you might be able to impact as well. So, they're listed here, delirium, neuromedical complications, side effects of medications that patients are on, problems with sleep, problems with pain, cognitive deficits. There's a lot of overlap here between those issues and what manifests as agitation, and I'm sure that the speakers are going to talk about that. Next slide, please. One thing that you may want to consider when you're addressing patients who have these problematic behaviors is getting some sort of an objective measure of what's going on. I think it's human nature to just recall, you know, the worst of the worst. So, if I come in in the morning and a patient yells at me and throws something at me, and then I leave, my impression of that patient might be, this patient's really out of control, we need to do something. If I don't get information from other people, for instance, that might have been the only problem that they had all day. So, you want to get information from a variety of people in an objective, hopefully quantifiable fashion. The agitated behavior scale shown here is just one of those options in terms of what to use. Next slide. And in terms of using the ABS, there are different ways to use it. So, you may get different ABS scores across the day, get a mean, and then over the days, see if there's a trend for improvement or worsening. This may help you in terms of your decision of whether an intervention is helping or not. On the right, I show an opportunity to look at whether this problematic behavior is worse in certain types of therapies. Maybe it's worse in PT that might suggest some things, some activities that they're in, or maybe pain is driving the problematic behavior. In this case, it's with nursing interventions, so then you can take a look and maybe develop some strategies focusing on that. So, there are a few different ways to assess this agitated behavior. Next. One other thing that we want to highlight is some of the challenges of using as-needed medications. One of the biggest challenges we think is that it's a lot of difficulty in determining whether they're effective or not. And here's a typical case. Somebody gets called at 2 in the morning because the patient is agitated. You go down, you assess the patient, you review the chart, you choose a medication, the medication gets delivered. This is maybe an hour or more process, and then 30 minutes after that, the patient's better. So, your question is, did the patient get better because of the medication or is this just some episode that would have burnt itself out on its own? And this is an important issue because if I gave the patient lorazepam and I falsely believe that lorazepam is the best medication for this patient for agitation, it may turn out that I'm really doing something that is worsening the outcome. So, this is something to consider in terms of use of PRNs. We're going to be talking about our medications primarily as straight medication orders. Next slide, please. So, with that as an introduction, let me introduce the case and get it started here. So, a 24-year-old woman is admitted to your rehabilitation unit five days ago. In terms of the injuries, TBI from a bicycle crash, bifrontal contusions, no surgical interventions, fairly unremarkable acute hospital stay from a medical standpoint. Thank you so much. Tox screen is negative, no significant past medical history is known. Some agitation is documented, and it seems that there was fairly aggressive use of Halperidol and at times restraints in acute care. No seizures. She received her seven-day course of prophylactic levator s10, which is now off, and this was stopped three days prior to admission. So, now she's in a rehab unit. Since rehab admission, she's shown good motor strength. She is confused. OLOG score is 16. She did seem fairly sleepy early on, and sleep has also been inconsistent through day and night. Blood chemistry is unremarkable, no fever. The Halperidol was stopped because they're trying to avoid this sedative effect. The patient is demonstrating more and more problematic behavior. So, on the ABS, last two days, the scores are 35 and 37, so quite elevated. She's been getting physically aggressive with staff, nurses more than therapists, refusing interventions, including medications, not really participating well in therapies. And the ABS scores note problems with inattention, impulsivity, frequently yelling out, and restlessness. So, at the initial team conference, the team says, you guys need to do something to help us out here. Isn't there a medication that may help? So, with that as an introduction, what medication should we choose? And we'll start with Dr. Hammond. Fantastic. So, Tom asked us to choose from between one of four medications. So, the medication I have chosen for this patient is methylphenidate. And I've chosen that because I want to improve daytime function to be able to facilitate rehabilitation as well and recovery. So, overview of my talk of why methylphenidate. I'm first going to start with the evidence and then focus in a little bit, give a framework for thinking about mechanism, and then wrap up with the targeted approach to the case. So, what's the evidence for the management and treatment of brain injury? So, first of all, the evidence for this is a problem is mile high and the evidence for how to manage it is not as big. So, here's just a summary of some of the evidence-based reviews that have been done over the past couple decades and do a nice job of summarizing the evidence at that time. Focusing in on these four drugs, you can see that the beta blockers have the most evidence with four randomized controlled trials, three of which were positive, leading to guideline-level evidence, level one. Next is methylphenidate with one small randomized controlled trial, option level, expert opinion recommendation level two. Followed by valproic acid, there is one randomized controlled trial that was not available at the time of those recommendations. It's now been published, and neuroleptics, more about whether to avoid or no harm. So, focusing in a little bit more on the evidence and why I would or would not use one of these medications. So, think about propanolol and the highest level of evidence we have. You have someone who's agitated in acute care, and they look up the evidence, and they say, well, you know, propanolol has the highest level of evidence. So, they start propanolol, and they now come to your unit, and so you've probably seen this a lot, that they're on propanolol by the time they come to you or if you're on the consult service. But think about what dose you're seeing someone on. It is probably not the therapeutic dose that's been shown in the evidence. So, the evidence shows that 420 to 520 milligrams is the effective dose for managing aggression post-injury, and it would take about 20 days to get to that dose. And the problem is, when you're at that big dose, and you now want to taper someone off of it to try to see if maybe it's sedating them and hindering their recovery, you don't want to abruptly withdraw from that dose. Also, so, one of the things is there are a lot of side effects. I'm mostly concerned about sedation, hallucinations, nightmares. Valproic acid, another choice that we're going to be talking about today. I would be thinking that perhaps specifically if I'm thinking it's limbic irritability. I'll give you a framework for that in a minute. There is a one randomized controlled trial, and there's several case reports. To keep in mind, there are a lot of less frequent but serious side effects to think about. More common would be worrying about sedation, and then also worrying about weight gain if someone's going to stay on the medication. And again, wouldn't really want to abruptly withdraw, especially as you get up on the dose. So antipsychotics, particularly quetiapine, is a medication we've been asked to think about today. It's a medication that's been used very widely for other psychiatric conditions, including bipolar disorder, schizophrenia, depression, PTSD, ADHD, conduct disorder, dementia, anxiety, insomnia, OCD, generally reported to be effective in the doses of 200 to 600 milligrams for those purposes, and found to help with agitation, insomnia, and psychotic symptoms. In dementia, it's been found to have modest effect size, but was associated with increased mortality rate in cardiovascular events, as well as cognitive effects and metabolic issues and falls. In brain injury, there is some evidence, this open label case series, suggesting that it might be helpful in chronic brain injury. Again, I think I would use this if the risks are outweighing the benefits. The benefits are outweighing the risk, I mean. And I'd be worried about particularly sedation and confusion, and then worried also about having someone continue on the medication post-discharge where you might be starting to experience weight gain and metabolic complications like diabetes and other metabolic complications. And again, you also wouldn't want to withdraw suddenly. I worry about it when they come into my acute rehabilitation setting when they're on it, and I really want to address their sleep because they're still having sleep disorder, and the drug we want to choose is Trazodone frequently. And Trazodone and Seroquel have drug-drug interaction that can cause QT, interval prolongation, and I worry about that. So, to the drug that I've chosen, Methylphenidate. I want to use Methylphenidate because I want to improve the person's attention, which Tom pointed out was a problem here, and their arousal, and increase their processing speed, their impulse control, and really get them functioning the best I can during the daytime. I do worry that it may make it worse, but it may make it better. So, it's a little bit of a gamble, but it's short-acting. So, you can introduce a drug, and you can stop the drug if it did have a paradoxical effect. And I would start at a really low dose because it may not take much of a dose to get that. The evidence to support this is a small, single-blind study that was done back in 1993. It's a the publications in 1993 didn't require as much of the information about the study, but there is some evidence there, and as I said earlier, the Warden Review, combining expert opinion and this one study, suggested that it would be an option for use. So, all of that evidence about propranolol doesn't equal effectiveness, right? So, we're not using it necessarily in the same way it was studied in a controlled way. The little bit of evidence with methylphenidate, someone just hasn't done the study. So, our evidence is limited by someone deciding to study something, getting funding, doing the study, getting their results, following through with trying to publish it, and then positive publication bias. So, we need to be careful with how we use and don't use evidence. So, a framework for thinking about all this. So, Seaver does a really nice, gives a really nice framework about the initiation and modulation of impulsive aggression in non-brain injury individuals. And basically, they said a stimulus comes in, is perceived as a threatening stimulus, and processed in our brain that way, triggering the limbic system to react with the cortex saying, hey, wait a minute. Remember last time? It didn't work so well when we had that behavior. So, kind of a top-down, bottom-up with the limbic drive and the top-down brakes. So, you can see there's ways in brain injury where this whole system can go wrong. So, first of all, a non-threatening stimulus being perceived as being threatening based on maybe medications that they're on, the brain injury causing cognitive impairment, metabolic disturbances, sensory impairment perhaps after brain injury. So, we could be perceiving things wrong, processing it wrong, and then of course, with cortical impairment, might be also unable to readily engage the brakes. And then we could also be having the limbic drive. So, Seaver also does a great job, has a nice table indicating, well, what would be the implications of that that I just told you? And so, he suggests that in regards to the cortical brakes, the things that might be helpful in improving that frontal inhibition are the serotonergics, the stimulants, and the anti-neuroleptics. He does point out in the text that stimulants also could make it worse, but he does have this table indicating it also could help. He also points out from this limbic drive standpoint, we might use the other medications that we're talking about today, the neuroleptics, beta-blockers, anticonvulsants, might be helpful for that purpose. So, going further with mechanism, thinking about neurotransmitters, and essentially that's what we're doing with these medications is enhancing neurotransmitter availability for the brain to work. And so, here we really want to think for, when we're thinking about cognition and behavior, we wanna be thinking about dopamine, noradrenaline, and serotonin. And when we're thinking about this particular case about aggression, you can see how dopamine and serotonin really have an impact on aggression, dopamine, noradrenaline, and serotonin with mood and cognition. We've got the overlap with noradrenaline and dopamine focusing on attention and motivation. We've got noradrenaline particularly helping with alertness. So all of these can, addressing these neurotransmitters can really help you in targeting improved behavior and cognition. So thinking about what is methylphenidate doing. So methylphenidate, it has an impact on, actually the dopamine, noradrenaline, and serotonin, particularly the dopamine and noradrenaline, to increase the levels of dopamine and norepinephrine that's in the synaptic cleft. It does that by inhibiting the dopamine and the noradrenaline transporters, so inhibiting that transportation and decreasing the reuptake of those two neurotransmitters. It also is a 5-HT1A agonist. So just depicted here is that in the synaptic clefts of those noradrenaline and dopamine receptors, that there's increased availability of those neurotransmitters. So back to the case. First, as Tom pointed out, you'd wanna really think about what could be causing the agitation besides just adding a medication. So you're first gonna step back and look at what kind of things could be making it worse or causing it, and in this particular case, I'd wanna really look at what medications a person's on in case there are maybe some medications that weren't mentioned already. If there's sleep disturbance, I wanna treat that. And perhaps there's pain, fractures that may have been missed that I really wanna look for. Tom mentioned that there were labs done that were normal, but I'd wanna look to see, well, what labs were done? Perhaps maybe there's neuroendocrine dysfunction or metabolic dysfunction that hadn't been addressed yet. And then definitely, there's probably some environmental factors at play. But given that we're gonna want to use a medication after addressing those things and we still see a problem and the behavior is problematic, then for this particular patient, I really want to optimize the recovery and the rehabilitation and I wanna avoid sedation. So I'm gonna be thinking about targeting arousal, impaired attention, processing speed, impulse control, maximizing the function of the brakes, and so I'm gonna be choosing methylphenidate with some caution, just trying to watch to see if it makes it better or worse. Whereas I might choose something else, particularly if I was gonna also try, if I was seeing something else I wanted to treat, like if I was seeing psychosis or tachycardia or seizures, well, then I might choose one of these other medications and get more money for the drug, address two things at the same time. So that's my summary of why I would choose methylphenidate and we'll move to the next defendant. Thank you. Okay. Thank you, Drs. Watanabe and Hammond, for your excellent start to our educational debate on the best drug for acute post-traumatic agitation. It is an honor to be presenting alongside the leaders and legends of our brain injury field today. I'm an attending physiatrist and assistant professor at the University of Washington Harborview Medical Center in Seattle, and I previously trained at Shirley Ryan Ability Lab for my brain injury medicine fellowship and Kessler Ruckers for my PM&R residency. So, let's see. All right, so I wanted to introduce you to the cast of characters today, and you all might or may not know Snow White and the Seven Dwarfs, but she is a princess who had to escape from her evil stepmother and found herself in the house of seven dwarfs. Their names are Doc, Grumpy, Happy, Sleepy, Bashful, Sneezy, and Dopey. And so, unfortunately, her mother eventually found her and was also a sorceress and gave her a poisoned apple, and she fell into a disorder of consciousness. Our patient is a little different, thankfully, and is awake, but unfortunately agitated. She's a 24-year-old female who was a bicycle versus motor vehicle accident, luckily helmeted, about 12 days ago, now in inpatient rehabilitation. So she's, unfortunately, kind of more of a moderate with the GCS, a presenting of 10, focal closed brain injury. She had found to have bifrontal contusions on her CT head and is still in post-traumatic amnesia with an O log of 16. And now staff is having a really difficult time trying to manage her agitation and have her participate properly in therapies. So Propranolol gets to be Doc, because he's going to be the most helpful. And Propranolol is a beta blocker, antagonist of beta-1 and beta-2 adrenergic receptors. It decreases norepinephrine, and really we can think of it like our fight-or-flight kind of system. It's lipophilic, so it does cross the blood-brain barrier, and it's thought to act both centrally and peripherally. Lutolin gets to be the anxious happy, and really, you know, it's originally used for increasing arousal and inattention deficit disorders, but it increases dopamine and norepinephrine. Depakote gets to be sleepy, originally an anti-epileptic medication and also used as a mood stabilizer. The exact mechanism is actually unknown, but it should increase GABA, which relaxes. And then Q-typing gets to be dopey. The second generation anti-psychotic, that decreases dopamine in the brain. Okay. So this is the agitated behavioral scale that was mentioned previously with work from Bogner and Corrigan in the late 1980s and early 1990s. It's out of order because I rearranged it based on three factors that had been kind of organized into in the early 1990s, aggression, disinhibition, and lability. It has since been kind of decided that there might only be two factors, and maybe it's just better to take the overall score in mind instead of break it down. However, this was kind of helpful in thinking about which medications for me to use. So when we look at her agitated behavioral scale, it was 35 and 37. Just remember that moderate is 29 to 35, and severe is equal to or greater than 36. The way that she was described was physically aggressive with staff, noted nurses more than therapists, probably in her ADLs, not understanding what they're trying to help her with, and refusing needed interventions, including medications. Her high ABS scores also noted regarding inattention, impulsivity, frequently yelling out, and restlessness. So what I highlighted here was kind of those symptoms mapped onto different aspects of these in the agitated behavioral scale. So under aggression, violent and or threatening violence toward people, indisinhibition, short attention span, impulsive, impatient, and restlessness. So really I wanted to focus with propranolol on these kind of subtypes of aggression and disinhibition, because the patient isn't necessarily presenting with a lot of per se lability. Okay. So my case today is that propranolol will decrease the patient's agitation without increasing sedation or confusion. That propranolol will decrease the patient's physical aggression with the nurses, and propranolol will decrease the disinhibition described as restlessness and impulsivity. So I wanted to kind of take a brief walkthrough, kind of some of the original studies. And the earliest that I could find in relation to brain injury patients and agitation was from 1977 by Elliott. And he showed us a case series of seven patients who had suffered acute brain injury. Propranolol was dosed from 60 to 320 milligrams per day. And these seven patients were a variety of non-traumatic and traumatic brain injury patients, so a variety of different types, some acute, some chronic. There was a chronic post-concussion syndrome associated with chronic irritability, as well as some having intermittent attacks of explosive rage. And what he said was that in all these instances, the belligerent behavior was controlled without inducing general sedation. So fast forward to a review article and care recommendations in 2016. And this was recommending that the efficacy of beta blockers and anti-epileptics with mood regulation effects, like carbamazepine and valproate, yield the most compelling evidence and should be used preferably for standing medications, that neuroleptics, antidepressants, benzodiazepines, buspirone, may be used but are considered second-line treatments. And then this is a busy slide, I apologize, but I wanted to briefly go through just some of the studies that have been done, given that there aren't many. This was a review of reviews in 2021 that looked at what is available and what has been studied, and what are the results. So I'll just take you first to fifth, like from top to bottom, and you can kind of scan across, but I'll tell you what the overall result was. So for that first Green Dyke study in 1986, it was a crossover randomized controlled trial. They went up to 520 milligrams per day of propranolol. They definitely showed significant reduction in aggressive behavior, but seven out of nine patients developed bradycardia or hypertension. So it's actually recommended maybe not to go all the way up to 520 milligrams per day, but to stay at the cap of 420 milligrams per day, but indeed to use a higher dose. I see a lot of patients on like 10 TID, and that's in the acute phase, probably not going to be as effective as you need it to be. Then the next one, Green Dyke and Cantor in 1986, they studied pindolol versus placebo. And pindolol is very similar to propranolol, but it should not have as much effect on blood pressure. So if you have a patient who has low blood pressure, the pindolol is actually a really good medication to try as it shouldn't lower the blood pressure as much as propranolol, but still be effective as a beta blocker. So this showed significant improvement in the frequency of assaultive behavior with an optimal dose of 40 to 60 milligrams per day. Green Dyke again, the third one in 1989, did a pindolol versus placebo with significant improvement. And then Brook, which I'm going to break out a little bit further because it was a really good study, in 1992 was a randomized controlled trial with propranolol versus placebo. And that had doses of 60 to 420 milligrams per day with an improvement in the intensity of agitation and restraint use, but no change in the number of episodes. And then lastly, Brossard in 2008 had a crossover randomized controlled trial using ABS scale and showed propranolol versus placebo. The dosing was 60 to 180 milligrams, so lower dosing, and the results were not as significant. All right, so this is the study by Brook kind of broken out in more detail. And the article was called The Treatment of Agitation During Initial Hospitalization After Traumatic Brain Injury. The objective was to test if propranolol is effective in reducing episodic agitated behavior. It had subjects that had traumatic closed head injury with GCS less than eight, so it's a little different than our GCS less than 10 case today, but this is severe brain injury. Treated at a combined level one trauma center and rehabilitation center, happens to be Harborview. And 21 subjects met the criteria of agitation and were treated with propranolol or placebo in a double blind fashion. What they found really difficult was to define agitation. This study was from 1992, just at the time where the agitated behavioral scale was coming out and being validated. And so for this study, they defined it as episodic motor or verbal behavior that interfered with patient care, therapy, or safety. They had a criteria of any agitation severe enough to be scored on this overt aggression scale that you see on the right. And then the presence of clear documentation of this behavior by direct observation, staff interview, or chart review. And then the appropriate use of restraints or medications for agitation. So really interestingly, this study actually allowed the primary teams to use whatever other medications they wanted for agitation or sleep or pain. And then you can kind of see the scale that they use for aggressive behavior, verbal, physical, against objects, self, and others. And then here's the results. So the intensity of agitation was significantly lower in the treatment group, although the number of episodes were similar. The use of restraints was also significantly lower in the treatment group, which as we all know is critical for the patient participating more in therapies, but also progressing through the hospital, especially acute care, to their next phase of rehabilitation. And then the results support the effectiveness of propranolol in reducing the intensity of agitation during the initial hospitalization after closed head injury. So this is one of the few studies out of any of these medications that actually look at the acute phase of agitation and TBI. There are many studies that are actually looking at agitation at six months and beyond. So you look here at the graph, it's agitation from that overt aggression scale on the y-axis to time in weeks on the x-axis. And they had titrated up this medication over several weeks, and then they had titrated down the medication over time as well. So you can see the darker line that goes down as time evolves is the propranolol group and the placebo group stays at high. And then on the right side, although it's really hard to kind of aggregate all these numbers in your head, is three groups is placed in restraints group, receiving propranolol, but also like any other medications for agitation at the time. And so kind of just thinking about what medications were available in 1992 besides propranolol, maybe haloperidol, maybe benzodiazepines. And then receiving propranolol medications for pain, sleep, et cetera. So there was kind of a comparison of like, okay, we're just gonna let the primary teams do whatever they want, but we're gonna kind of see if we can still find a significant difference, and they did, which is really kind of remarkable. So disinhibition in a motor context, propranolol may decrease the restlessness. So restlessness after TBI, Brooke had done a study of 100 patients just prior to this study, and trying to tease out the differences between episodic explosive kind of agitation and then lower level continuous agitation that he defined more as like this low-lying restlessness. And they felt like it might be kind of those who didn't quite meet the overt aggression scale but still had a lot of like kind of restless, like agitation. So there's other indications besides in TBI patients for propranolol and the treatment in the movement disorders that may have a similar pathophysiology in TBI. So it's used, it's known to treat restless leg syndrome, it's known to treat essential tremor, and it's known to treat drug-induced akathisia, and akathisia is restlessness. And then there's bad motor side effects of the other medications. Depakote can cause Parkinsonism and tremor, quetiapine can cause antipsychotic medications, may cause, or antipsychotic medications may cause akathisia, which is highest with the first generation, or typical antipsychotics such as haloperidol, and methylphenidate might cause a tremor or restlessness in and of itself. And then propranolol can treat more than just agitation in TBI patients. So it's really nice to think about killing two birds with one stone, like, you know, if this patient also is first having paroxysmal sympathetic hyperactivity, propranolol is great to start then and just continue potentially for agitation, migraine prophylaxis, essential tremor, hypertension, some other comorbid indications, neuropsychiatric, we know it can help with performance anxiety, drug-induced akathisia, lithium-induced tremor, some of these other indications. Depakote and quetiapine are not recommended for this case because they will worsen the patient's agitation by sedating the patient during the daytime and impairing cognition. So Depakote, there's only one controlled study supporting the use of it for the management of agitation in chronic, mild, or moderate TBI. Depakote may be suggestive for the mood-lability subfactor on the agitated behavioral scale. However, our patient case was not so much presenting with lability and then needs monitoring with liver function and ammonia blood work. Quetiapine was an observational study demonstrated, which demonstrated longer post-traumatic amnesia in patients who received antipsychotics, mainly quetiapine, that the side effect of potentially irreversible movement disorder could occur, like tardive dyskinesia, and needs EKG monitoring for QTC prolongation. Methylphenidate is not recommended for this case because for this patient who presents with insomnia, I would actually correct the patient's sleep first and hopefully not need any more medications, actually. I would recommend adding Trazodone nightly, and after sleep is improved, then consider if I wanna add a morning stimulant such as a Mantidine or Methylphenidate. And then current literature on Methylphenidate used for TBI-related agitation, irritability, addresses the chronic phase greater than six months and has had mixed results thus far. Potential side effects include anxiety, tachycardia, nausea, vomiting, restlessness, and mania. And currently Methylphenidate is controlled by the DEA as a Schedule II, which means it has a high potential for abuse and may lead to severe psychological and physical dependence. So a lot of our TBI patients have addiction histories and it's very much a consideration, especially if you're gonna continue it into the chronic phase. So the winning argument for Prohenol is that it will increase, it will improve the patient's agitation without increasing sedation or confusion. And since this is a debate, the Depakote and Q-Type E will sedate the patient and may worsen confusion, worsen the sleep-waste cycle, and Methylphenidate should only be considered after sleep is improved. And then we can all agree that no one recommends Haloperidol or benzodiazepines for TBI agitation. And lastly, the best medication for TBI agitation is Propranolol. You know, Snow White has this happy ending, the prince found her. One of his compatriots happened to drop her from her glass coffin, and apparently she spit out the apple that had poisoned her, but she was really just not able to breathe for a very prolonged amount of time. But by miracle, she didn't have any brain injuries, she just woke up and they lived happily ever after. So I would just kind of leave you with these last thoughts that I would use higher doses of Propranolol for improved effect, 60 to 420 milligrams per day. It has been studied in the acute phase of TBI where most have not. It's well tolerated with limited side effects. And for future studies, we definitely need large longitudinal multivariate studies of TBI recovery, looking at medications for agitations in a more homogenous population. Thank you. So I'm going to talk today a little bit about a drug I haven't endorsed for three decades, but only Tom gives me this assignment. But I'm going to bring up mostly the good here of catepine rather than the challenges of the others. So these are my disclosures, mostly related to my work in football and a couple of scientific advisory committees and research funding. So to my point, a principle from everything from governmental theory to Tuesday night, how you view everything is Miles' Law. It's a critical business principle we don't apply enough in medicine for how we think about controversial ideas. Miles' Law is where you stand on a controversial issue depends on where you sit. What is your background or what is your situation versus Laura or Jamie's learned situation? And I congratulate them both on making fabulous quotes. The other thing is we all get into debates about what Jamie closed at is absolutely right. There is a need for further randomized controlled trials and I'm sure Robert Kennedy will fund them. But perfection is the enemy of the good. You all live in a scenario where you have to treat these patients, in Tom's great case, with some speed, with some alacrity. You don't have two weeks to titrate up propranolol. You don't have the time to worry if you have methylphenidate over agitating somebody or producing excessive initial tachycardia. So speed and a lack of monitoring means something. Convenience means something in the real world. We have a case of somebody who is sleepy, who needs to sleep, and has an ABS of 37. I see many of you whose ABS over the last several days was above 37. So let's look, at least with some vision, about what cataepine is. Now my colleagues argued, I think brilliantly, fair enough to them, that antipsychotics are a bad thing. I've spent 30 years arguing that they were a bad thing. I would argue that this is an atypical antipsychotic, whose weight is really, as Flora made the argument for me, on clonal inhibition, on 5-HT2A antagonism, rather than its dopamine effect. And that's where it drives its function. It is not the same, as I will show you, as haloperidol, right? And it is among the only ones that in the laboratory, and in a small clinical study, has been shown to be neuroprotective. Now data suggests that people's injury pattern goes on days, weeks, beyond what we really believe. So what is, right, so it really modulates 5-HT2 receptors, much, much more than D2. And you get all of those side effects that we worry about, many of them, the anesthesia, the motoric effect, out of D2 blockade. In fact, it's a relatively very weak D2 blocker, as I will show you. And here is the critical point. It's metabolized quickly in the liver. So if you get it on and you get in trouble, you get out. Sort of a quick flight, right? Where my wonderful colleagues are going to take some time to get there, Myles Law says, you don't have that time. It's available in immediate release, and you get a steady state in 48 hours. That's pretty good. There is no way you get somebody up to optimal levels with propranol, valproate, or even methylphenidate in 48 hours, certainly not from the assumptive that I'm going to get frontal functioning. Now, Flora was right. Getting somebody clearer is the right thing to do. I would argue that regulating their frontal function and focusing in on 5-HT2 receptors might be the way to go. Now, receptor binding is an important issue, even for those of us who, as Jamie refers to us, are dopey. But this is an old paper from Eli Elevick in which he, I think, thoughtfully looked at all of the atypicals at the time. There's certainly a much larger list now. But what he did here is he classified where the activity was for these various atypical antipsychotics, which, by their primary nature, were more targeted drugs than their driver and were not designed to produce as much EPS, extrapyramidal symptoms. If you look at where catiopine is, you see very weak-to-weak dopamine activity. Your odds of getting heavy lipid dysfunction, diabetes, and extrapyramidal effects are muted. Not zero, but muted. And you're not looking to put this person on catiopine for a lifetime. You're trying to get them out of the rehab unit, because that's the Miles Law, the real world you live in. Now, let's come back for a second and talk about the fact that serenity inhibition or regulation is also important because we don't know why people are agitated. Some of it is that the world in front of them is confusing and they're anxious. And serenity regulatories have a superiority from that effect. I want to give you now some preclinical data. This is work by Beal and Weeks in both the animal models that suggest that catiopine both acutely and paraacutely decreases vasogenic edema and inflammation. There is a long series of data that suggests the inflammatory response is longitudinal in our patients, whether that's via severe TBI model or other. And then this paper, Weeks et al., that Anthony Klein's group did at Pittsburgh, they compared haloperidol, catiopine, or sham. And the catiopine rats got better. They also didn't exhibit some of the negative haloperidol effects that were shown all the way back in Feeney-Gonzalez et al. So what you have here is a different agent. Let's not group it naively with the others that seems to act rapidly and has a unique mechanistic. Now I want to look at the ICU data. This is Samer et al. And there's one other that I will show you because so many of us have to do consults in the ICU and bring people through, Miles' Law, the system quickly. This is a paper from Samer et al. in which they, I think, looked at about 45 or so people. And what I have for you on that one side is a Kaplan-Meier survival curve where they showed a decrease mortality and improved acute neurologic outcomes in critically ill TBI patients. And in another study by the same group, they showed decreased ICP and better cerebral perfusion pressure. Now the data was small, fair enough to my colleagues. But certainly more enticing than a study from 30 years ago. I had black hair in 92. Now let's look a little bit here at this asthma study. Critically ill patients, again, supporting utilization early on, and we're getting people earlier and earlier, Miles' Law, in a matched cohort of a lot of folks, higher doses, which I wouldn't necessarily favor, associated with lower ICP, intracranial pressure, lower mortality, and higher mean Glasgow Coma Scleral at discharge. We have a path forward. The clinical data showed no strong data on side effects. You're just not using it long enough. And you're not using those kind of doses. There's no competing data on negative recovery. And there's some data on neuroprotection. And I would argue to you, at least in that para-acute, acute agitatory moment, it's quicker. Now let's look at a couple of post-acute studies that don't go back 30 years, a study by Cicerone and Al demonstrated that catepine in the post-acute setting reduced agitation in patients with brain injury, showing improvements in behavioral symptoms. All I want is some frontal regulation to get me through that period in behavior. I don't want to last forever. I'm not sending people home on this forever. Another study by DiAgostino et al. reported significant reductions in agitation scores among TBI patients treated with catepine compared to placebo. Yes, the numbers were small, but certainly of interest. The typical dosage is 25 to 100 milligrams. That is very different than what we use for psychosis, bipolar disorder even, or other, you're talking 2, 3, 600 milligrams. In catepine, there appears to be a relatively strong linkage between dosage and side effects. Being able to be low and its unique mechanism gives you speed and the advantage of a lower portfolio of side effects. It's generally well tolerated. You've got to monitor for sentation and metabolic effects. I wouldn't give it to somebody who is remarkably diabetic, remarkably unstable from a cardiopulmonary perspective. That is a more limited group of people. Propranolol is a lovely idea, a fabulous one, but many of our elderly patients can't tolerate high enough doses or conflicts with other meds. Methylphenidate may produce tachycardia or interact in some other way with what, I see Adam in the room, is an increasingly older population of people. Catepine produces a rapid onset of sleep and frontal regulation. So summary, it's quicker acting. There's no need for blood levels. Tom's going to talk about valproic acid, but you really do have to think about liver toxicity. This is a younger female patient. Do we want them going out on valproic acid? There are worries there. There are modest interactions with catepine. It's not going to make your life miserable. In Miles Law says, your perception is where you sit. It's the only agent with some mixed known neuroprotection. It's not the same as haloperidol. It's a modulator of some dopaminergic activity, but not the same kind and it's clearly a frontally active serenic agent, potentially beneficial on both the anxiety side and the frontal inhibition side. There are cautions, I admit them, but not as many as the other, and I gave you the reason to reflect forward. So thank you all. Okay, I'm back. Even though I was sleepy, I woke up and I'm ready to go. I didn't realize we would get down to name calling here, but that's okay. At least I'm not dopey. All right, so I am going to talk about why valproic acid is the best choice. Before I do that, I just want to apologize for a second. In one of the introduction slides, I wanted to refer you to introductions for the speakers to the program. Also in the app, if you're not aware of the background of folks. When Jamie introduced herself, I said, I forgot to mention that. Take a look there if you want. Okay, so we've been talking a lot about a lot of different medications that might play a good role in treating this and other cases. I would say the best drug would be one that decreases agitation quickly and for a large percentage of patients. I could have narrowed in just on this patient, but I think there are many unknowns when you see a patient in the beginning, so you take what you can about the patient but you realize that there's some things you don't know so you may want to choose a medication that has the best chance to help the broader population. And so part of that is a medication that might have multiple mechanisms of working to cover a lot of different grounds. You may want to have a medication that controls symptoms that might be increasing agitation. You might want a medication that has a neuroprotective effect and maybe one that has some at least theoretical evidence to enhance outcomes after TBI and one with fairly minimal adverse side effects. And there is a medication that can do that, felbroic acid. It has there's been discussion already about mechanisms of action but it's worked via GABA, via NMDA receptors, via ion channels. I'll go into these in a second and inhibition of histone deacetylase which leads to alterations in gene transcription. Ross had mentioned that the other medications might not have this neuroprotective or effect on improvement but I'll show some evidence that suggests that felbroic acid might. So what are the proposed mechanisms of action? They've been touched on briefly and so I won't spend too much time on that but GABA is an inhibitory neurotransmitter. It is probably the primary way that felbroic acid works. Administration of felbroic acid does lead to increases in GABA levels within the brain. It also does inhibit NMDA activation so it can blunt that glutamate excitotoxicity pathway and that's a potential way that it might reduce neuronal damage after traumatic brain injury. It's likely another reason why it has the anti-epileptic effect. It does have effects on monoamines. Monoamines have been discussed previously. Flora did that but felbroic acid can also increase levels of serotonin, dopamine, and norepinephrine so something to consider in terms of implications for mood and cognition. It's well known as a neuronal membrane stabilizer. Jamie did say that that's actually unclear of what that mechanism is but in any event it's probably the primary mechanism for anxiolytic activity and this is something else that may be relevant in this population or in this case. And for neurogenesis, felbroic acid can induce BDNF. So this does play a role in neurogenesis and neuroprotection so there's some evidence that it may be helpful that way. And in terms of neuroprotection, now there's been a lot of discussion of you know weak studies and studies that may not be relevant and I will concede that this is a study by Dash in rodents but nevertheless it's a model. So felbroic acid was given 30 minutes after a cortical impact to the right parietal lobe and there is evidence that felbroic acid decreased the contusion size as demonstrated here. Decrease in blood brain barrier permeability and improvement functionally on a balance beam test, a Paul placement task, and in the water maze, Morse water maze test which assesses cognition. So maybe a bit of a reach but something to ponder in terms of why this might be the best medication. Felbroic acid does have some FDA indications for instance for bipolar disorder specifically more focused more on the acute mania side. Its role is well established as a mood stabilizer. There's also an interesting study by Landgraf looking at circadian rhythm disorders which are common with traumatic brain injury and common in mania, the manic phase of bipolar disorders. So the phase does tend to be elongated in mania. Felbroic acid does tend to reduce that phase so the elevations of dopamine in mania might be counteracted by the suppression from felbroic acid kind of normalizing circadian rhythm disorders. I'll borrow a little bit from affective disorders in general but look at the TBI population so we know that there is a high prevalence of affective disorders in TBI. There's a little bit controversy whether pre-injury affective disorders will increase the likelihood of TBI but nevertheless a large number of patients with TBI do have pre-existing affective disorders. So this is just one study it says looking at the first five years following moderate and severe traumatic brain injury but they also looked at pre-injury data and show that in this population the prevalence of mood disorders 23 percent, anxiety disorder almost 22 percent, alcohol and drug abuse disorder 38 percent. So again going back to this case we're not sure I think you know that when you admit patients you know sometimes it takes a while to really get information of about the patient so I can't say that even though the past medical history was benign whether some of these things might be lurking past or maybe have not been diagnosed at all so something else that felbroic acid might cover in terms of helping to manage this patient. So other indication FDA indications for felbroic acid so for seizures of course it's well known as an anticonvulsant. Some seizures especially pre-frontal or mesiotemporal areas can manifest themselves as these problematic behaviors so it's possible that some of the behaviors that we're seeing are mediated by epileptic activity. The Tempkin study in felbroic acid among other things did demonstrate that felbroic acid didn't demonstrate any significant adverse cognosqually so this is some other information that gives us an idea of whether felbroic acid might be a good medication to choose in a case such as this. Felbroic acid is also indicated for migraine headache prophylaxis so I mentioned before how a medication that might cover some of the comorbid medical conditions from trauma such as this might be important. So we know that headaches are very common after traumatic brain injury and sometimes when people are very agitated it's unclear exactly what is driving that but headache may very well be one of the drivers and migraine headache has been demonstrated to be the most common headache type after traumatic brain injury so something else that felbroic acid might help us with. I did throw in neuropathic pain it's not an indication that's why it's not in blue but there is some evidence that felbroic acid can also help with neuropathic pain which can also be problematic in traumatic injuries in general. Evidence is good but for felbroic acid especially regarding post-therapeutic neurology so another consideration as to why felbroic acid might be a good choice. Acute delirium so Flora had mentioned delirium as part of this picture of what to consider when you're dealing with the patient who has agitation. It's a very common complication in a general hospital setting I think 10 to 25 percent even just on a general hospital unit higher in the ICU and for a patient like this consideration that some of what we're seeing is related to delirium may be considered. Here's one study using felbroic acid in the ICU setting for delirium 44 patients. The medication is titrated upwards so day one 500 milligrams day two 750 875 and a thousand by day four and you can see a decline in both measures of agitation and delirium the Richmond agitation and sedation score and the CAM ICU demonstrating that the percentage of patients who are having these problems is decreasing over time and related to administration of felbroic acid. So I haven't said much about TBI related agitation. You've already heard that the information regarding the use of felbroic acid for post TBI agitation is a bit weak and I have to concede that although I really haven't heard anything tremendously robust about the other medications either. Broblewski a small study and of five these patients notably were had already failed some other medications but in doses of between 750 and 2250 did demonstrate improvements in agitation. It's a case series. Chatham, Showalter this is an acute inpatient rehabilitation unit 29 patients enrolled 18 patients did demonstrate an improvement within seven days so there is some evidence that this medication might work fairly rapidly unlike some other information that you might have heard today and eight of these had very rapid improvement and all these patients were started on felbroic acid after already being on other psychotropics they're all on benzodiazepines and some on other medications as well and even these eight patients had a very rapid improvement with that and the other medications were withdrawn so there is some evidence there that felbroic acid might be helpful in post TBI agitation. The Beresford study I think was mentioned indirectly it's a veteran population double-blind placebo-controlled demonstrating improvements in mobility on the ABS and no adverse events and I mentioned this issue of no change in alcohol use this is a more chronic population but another consideration of felbroic acid more acutely is that it does have some potential impact on alcohol withdrawal. I concede that in this case there's no indication that alcohol withdrawal was an issue but thinking more broadly this is something else that felbroic acid might be able to help you with in dealing with patients with post-traumatic agitation. So some of the problems with other medications I think they've already been highlighted to some degree but why not pile on a little bit right atypical antipsychotic some evidence that they're epileptogenic this is a population that might be at risk of seizures the QTC prolongation has been mentioned use associated in an acute care setting the CUDA study patients who received an antipsychotics in acute care within seven days of injury and I will say that quetiapine was the most commonly utilized I know some of the literature gets blurred with hell parallel but quetiapine was the most commonly used one in this study increased duration of post-traumatic amnesia the Kemp study was already mentioned I believe but fairly significant issues with sedation and anesthesia. Propranolol we've heard some literature supporting use and I there is some literature there we've heard about some of the side effects there's a study in TBI with Brosser 2008 which did not demonstrate any association between the use of propranolol and improvements 13 patients single case design type study two patients got better two got worse nine with no significant change so not the most robust support for that medication either. Methamphenidate so one thing that I think hasn't been this tachycardia and increased blood pressure has been discussed but the impact overall on regulation of the nervous system is something that might you might want to consider as well there's a lot more information coming out about autonomic dysregulation after traumatic brain injury I think there's actually a talk later this week about that so something else to consider. In a general adult population weight loss is the most common or adult ADD population weight loss is the most common side effect but anxiety irritability moodiness are all side effects I don't know that we want to introduce that in this population. The Wilmot study is a brain injury TBI population increased irritability and difficulty sleeping were noted in this study. Johansson is another study with patients with traumatic brain injury and that's where this table comes from and you can see that there are fairly significant numbers of adverse events including restlessness anxiety headache which again I don't think that's what we're looking for in this population. What are others saying? Planteer in a systematic review and expert consensus from France. Carbamazepine and Viroproid seem effective on agitation and aggression and are recommended as first line. There is no evidence of efficacy for neuroleptics and I'll concede again that some of that information is held up but hey I'll still throw it out there. Another study from 2019 a review article a regimen including propranolol well there's propranolol but although antibiotics such as valproic acid is reasonably supported by limited data I think it is fair to say and we've all highlighted there's very limited data but despite that they made that conclusion. So in summary valproic acid does have multiple molecular mechanisms and each of these may aid for some patients in decreasing agitation after TBI so I think you might have the opportunity to treat more broadly conditions for patients with agitation than some of the other medications that have been suggested. It can have a positive role in addressing other common sequelae of traumatic brain injury that contribute to agitation. It may aid in neurologic recovery or limit damage after TBI and there's limited evidence about that but something to consider and I would argue that there is support that there's relative lack of adverse effects there certainly are some that I would concede that. Okay so yeah it's clear what the winner is right? Okay so we saved a couple minutes left I'm going to invite the speakers back up then you can come on up. One of the things I realized was going last I kind of did it just to be polite but I realized maybe it's kind of advantageous because you can hear what others say so I'm going to give everybody. Yeah I'm a cheater. I'm going to give everybody at least a minute to give some sort of rebuttal to what they've heard and we'll go in reverse order so we'll start with Ross. So I think I think all all of my wonderful colleagues points are fair. I would go back to my primary argument is the real world which is you need speed of onset a de minimis portfolio in this patient of side effects in this patient you need to get them frontally regulated and sleeping within a very proximal period of time. You don't have time for loading for waiting for effects for other issues. I would also say that valproic acid as Tom referred to in his time in the Temkin study was associated with a higher mortality rate although there are other things so we probably have the one most associated with katiopine with neuroprotection validity and early use and rapidity of onset with a de minimis portfolio of side effects. I believe nothing of what I just said. So to highlight propranolol again it as everyone has said it is the most evidence-based support for the treatment of agitation after TBI. You know patients who have even moderate TBI and then moderate to severe do still have quite a long potentially hospital stay. So you know you could start at 60 milligrams per day and increase every three days to get a good effect for your patients and and it doesn't have many side effects and Pindallol is an option if blood pressure becomes a problem. So it is the reason why it is widely used both by experts and non experts. It's often used in combination with other medications because it doesn't often interact with a lot of other medications. And even though this a lot of the data is from you know the 1970s and 1980s if something is good and well done then it stays and it has. So that's why reminds me of me. So just remembering the really short stack of papers. This is really confusing when you're going to go pick a medication is we really don't have a lot of evidence and it's all based on what somebody decided was their drug and they even went to the effort and got funding and published. So for methamphetamine there's one person that did that. I think the study needs to be redone. I think it's a great medication. Our goal in rehabilitation is we see people that we want to get awake and functioning during the daytime and when they come to inpatient rehabilitation and they're already on sedating medications or we're starting sedating medications it gets really hard to do rehabilitation or spend your time tapering off of sedating medications when you really want to be getting them functioning. Methamphetamine is a short-acting medication. You can start it. You can stop it. See what kind of result you get. Thanks. I apologize we won't have time for questions from the audience and I think a couple came in virtually. We'll try to answer those as we can. Thank you very much.

post-traumatic agitation

traumatic brain injury

TBI

medications

off-label drug use

methylphenidate

propranolol

valproic acid

quetiapine

rehabilitation outcomes

clinical preferences