Good afternoon everyone and welcome to today's Member May session. This is the update on medications for patients with brain injury, reviewing best practices using a case study approach. We're excited to have you with us. My name is Joy from the Academy and I'm just going to review a few housekeeping notes and reminders before we get started. The views expressed during this session are those of individual presenters and participants do not necessarily reflect the positions of the Academy. AAPMNR is committed to maintaining a respectful, inclusive, and safe environment in accordance with our code of conduct and anti-harassment policy available at aapmr.org. All participants are expected to engage professionally and constructively. This activity is being recorded and we will make this available on the Academy's online learning portal. An email will be sent after the webinar with a link to bring you to the recording and the evaluation. For the best attendee experience during the webinar, please mute your microphone when you're not speaking and to ask a question, please use the raise your hand feature and unmute if you're called upon or use the chat feature and we'll make sure that we are checking those regularly. And just a note to the time may not permit the panel to field every question. So I will now hand it over to Ashley Mohan, our presenter, who will be guiding us through the webinar. Thank you so much. Take it away, Ashley. I will unshare. Great. Can everyone see the screen okay? Great. So thanks for the introduction, Joy. We're very excited to have everyone here. We have a great set of speakers and talk for you all today. And so my name is Ashley Betty Mohan. I am the medical director of the inpatient rehab program at Advantis Health in Lodi, California. I will be the moderator today. Our session directors, Dr. Diane Mortimer, she is faculty at the University of Minnesota in the Department of Rehabilitation Medicine. Our speakers today are Dr. Sheetal Babashi. She is an associate professor at the Ohio State University. She is also medical director of the brain injury program and residency program court director. Dr. Sarah Legal is an assistant professor at the University of Wisconsin-Madison. She is the medical director of the inpatient pediatric rehab program. And Dr. Matthew Puterbaugh is a brain injury physiatrist at Hennepin Healthcare in Minneapolis. Our learning objectives for today are to understand neurotransmitter physiology and changes that can occur with brain injury, to describe best practice medications used in the management of brain injury, and to discuss medication weaning during the rehabilitation process. So our presentation today is designed with a longitudinal case study, and then you will hear different topics interwoven throughout it. So I will start off with a brief stem. Our case is an 18-year-old male with a history of ADHD who presents after an ATV crash. His initial GCS on the scene was six, and his head CT showed a large right frontal parietal subdural hemorrhage with multiple subarachnoid hemorrhages. His MRI of the brain showed grade three diffuse axonal injury. So I will turn it over to Dr. Babishy to talk about neurotransmitters now. All right. Hello, everyone. I'm going to take us back to our physiology days a little bit. And, you know, I don't know if many of you are, you know, educators as well like me, but, you know, typically when I see someone with a brain injury, I just kind of know what drug to give people and what their clinical presentation is. But we definitely want to educate and understand what neurotransmitters we're using to affect with these medications. So next slide. So really what I wanted to do was kind of go through our most common neurotransmitters and their function and understand where the locations of a lot of these neurotransmitters are. Next slide. So our main neurotransmitters that we use are acetylcholine, norepinephrine, dopamine, serotonin, and glutamate and GABA. The reason why we look at these specifically is because, one, there's a lot of data and research on how these neurotransmitters are affected with brain injury. And then also we have a lot of medications that can affect them. Now, also we have a lot of medications that can affect them. Next slide. So for acetylcholine, you know, primarily we go through what its function is. And so I think you have to hit again. Okay, there we go. So acetylcholine is excitatory and the motor neurons, it produces muscle contractions. In the hippocampus, it works on memory formation, learning, and general intellectual function. Its location in the CNS, or the central nervous system, synapses throughout the brain and the spinal cord. In the PNS, or peripheral nervous system, it works at the neuromuscular and neuroglandular junctions and synapses in the autonomic ganglia. Next slide. So when we really look at where acetylcholine plays a factor in the brain, this is a picture depicting where it starts. So, you know, looking at the pedunculopontine and interpenuncular nucleus, and how it sends out projections of the acetylcholine from there, affecting areas in the hippocampus, in the frontal lobe, into the thalamus, into the cerebellum. So it is used more, it's quite a bit in our central structures, but also in our frontal lobe for some of our executive functions. Next slide. So when we have too much acetylcholine, we can have paralysis or muscle weakness, and it can cause memory, sorry, if we have too little, it can cause paralysis and muscle weakness and memory impairment. But if we have too much or effective surplus, then that's where we get a lot of our muscarinic effects. So the salivation, tearing, sweating, bronchoconstriction, bradycardia, and then some of the GI issues. In the nicotinic receptors, it works and creates muscle fasciculations and spasms. And then the CNS, there could be confusion, headaches, and drowsiness. So we definitely don't want to use acetylcholine too much, because you could have, you know, lots of potential side effects, but you also know that it can cause memory impairment and its deficits. Next slide. So with norepinephrine, the next thing we look at is the function of norepinephrine, and it's excitatory and inhibitory. So, and it can cause tachycardia, trouble with arousal, learning, memory, and eating. So when we think of medications that primarily, you know, use some of the norepinephrine in them, we think of some of these side effects such as, you know, Ritalin having trouble with eating. So its location primarily in the CNS is in the cerebral cortex, the brainstem, the hypothalamus, cerebellum, and spinal cord. And the PNS, or the peripheral nervous system, it's at the neuromuscular, neuroglandular junctions of the sympathetic division of the autonomic nervous system. So it does do a lot with our, you know, autonomic functions such as heart rate, blood pressure, et cetera. And the main things that we're looking at with this, you know, when we start thinking about the case that we have with diffuse axonal injury of grade three, is really start thinking about what does grade three diffuse axonal injury mean, and where are these neurotransmitters being affected. So next slide. With norepinephrine, as you can see, it is all over the cortex. It also affects some of our central structures such as the hypothalamus, the amygdala, into the hippocampus. But it really is affecting quite a bit of our neocortex as well, and goes into the cerebellum and some into the spinal cord. So again, norepinephrine is one of the neurotransmitters that can be affected in a grade three diffuse axonal injury. Next slide. So with norepinephrine, if we don't have enough, we can see depression, ADHD, memory problems, sleep disturbances. If we have too much, we can see anxiety, irritability, aggression, elevated heart rate and blood pressure. Again, the side effects of the medications that we're sometimes using. Next slide. Dopamine. So dopamine is our neurotransmitter that we use for everything. If you have taken care of any brain injury patients, and we always talk about, you know, how much dopamine plays an effect. And you'll see in future, in the rest of the presentations tonight about dopamine's significant effect in brain injury management. It is excitatory, and it's involved in voluntary muscle contractions as well. So it has different pathways, though. And the significance of these pathways, especially in the mesolimbic, mesocortical, nigrosteroidal, and the tubero-infantibular pathway, it regulates various hormones. It can also have some motivational and emotional responses. It's associated with pleasure and reward. It's also involved in a lot of coordination of movement, especially in the basal ganglia area. Next slide. So with dopamine, there's multiple dopamine receptors. Primarily, a lot of our medications are the D1, D2 receptors. Some of our medications will hit the D3, 4, and 5 receptors. But primarily, that's what we're looking at is the D1 and D2. And if you look in the schematic, the dorsolateral prefrontal cortex, or the DLPFC, is one of the main areas where you're looking at, you know, class 1 dopamine receptors and the ventromedial prefrontal cortex. So those are some of our areas that we're looking in our disorders of consciousness patients. But then we also look at our central structures, especially in the substantia nigra, in our thalamus. And so a lot of those areas are doing some of our motor functions, as well as our arousal. So when I go through dopamine and their different pathways, you really want to think about when you have a brain injury and you're looking at their imaging, where are the structures primarily affected? Again, diffuse axonal injury, grade 3, you're going to have your, you know, your cortex, your gray-white junction, you're going to have your corpus callosum, and you're going to have going into the brainstem. So dopamine is very much indicated in a diffuse axonal injury patient. Next slide. So if you don't have enough dopamine, we think of our Parkinsonian symptoms. So our muscle rigidity, bradykinesia, tremors, depression, and fatigue. If you have too much, though, you can go the opposite and have a lot of hallucinations, anxiety, and aggressions, and impulse control issues. So things that you also want to be aware of when you're using some of these dopaminergic medications. Next slide. So serotonin. Serotonin is another big neurotransmitter in our brain. It affects quite a few areas of our brain as well. Primarily, we always think of serotonin in mood and behaviors, but we also can see its role in pain perception, sleep, eating. It can also affect our body temperatures as well. Primarily in the CNS, it's located in the hypothalamus, limbic system, spinal cord, cerebellum, and the retina. Next slide. So with the serotonergic system, again, like the other neurotransmitters, it's heavily involved throughout all parts of the brain. But the biggest thing that I wanted to bring up with the serotonin is not just the hypothalamus and the cortex, but it also has quite a bit in the raffinucleus. So when you're thinking of serotonin, you also have to think of its excitatory or inhibitory effects as well. Next slide. And there are a number of effects of serotonin. Behaviorally, we are the common ones that we think about when we're thinking about serotonergic medications. But there's other CNS effects too, affecting motor control, cerebellar regulation, sleep-wake cycle. And then you also think about some of your central serotonergic medications, which is primarily all of them that we really use. But thinking about serotonin not just for mood and behavior, but also looking at it for motor recovery as well. Next slide. So when you have too much serotonin, you can have serotonin syndrome. So that's with our rigidity, you have your sweating, you'll have some of those effects. When you don't have enough, you'll have mood disorders primarily, but you can have insomnia and anxiety as well. Next slide. So glutamate. Glutamate is the one that's having some more recent research coming up with it, and especially looking at how we regulate glutamate in the neurocritical care setting. So it is excitatory. It can be involved in memory and learning. In the CNS, it's in the cerebral cortex and the brainstem. Next slide. So when you have too little glutamate, you're going into little glutamate, you're going into having mood and behavioral changes. It can have cognitive deficits with concentration, memory, and learning. But when you have too much, you can get migraines and seizures and then can lead to neuronal damage and death. So this is really where glutamate has a lot of studies behind its regulation during the acute neurocritical care phase. Next slide. So GABA. Traditionally, we always think of gabapentin or GABAs as our pain regulators and our antiepileptics, but it can also help with mood regulation. It can help with PSH symptoms. It can help with restlessness. So it is inhibitory, and it communicates primarily messages to other neurons and helping to balance and offset. Its location in the CNS is primarily in the cerebral cortex and the cerebellum, but it also goes through some of the interneurons throughout the brain and spinal cord. Next slide. So when you have too little GABA, you can have tremors, loss of motor control, can have anxiety, depression. You could have seizures. But when you have too much, you can have sleepiness, eating disorders, and like I said, drowsiness. Next slide. So the last thing that I wanted to kind of talk about is really, you know, I gave you all the neurotransmitters, and I wanted to show you, you know, from the central structure standpoint in the cerebellum, what are primary neurotransmitters that are affecting some of those. And as you can see, serotonin is quite a bit in the mix, as well as dopamine. And there is some structures like hippocampus with GABApentin, and of course the cerebellum. So really, when you start thinking about your patients, you're looking at what you're seeing in front of you, thinking about your head imaging, you're really trying to look at what are all these areas of the brain doing, what are the potential neurotransmitters that are being effective, and what am I seeing clinically to help determine what medications you're going to use. So next slide. I will turn it back over to Ashley. Okay, so thank you for that wonderful overview. Now that we have a better idea of the role the neurotransmitters play, we will go back to our case and follow along with the patient's course. So upon admission to the hospital, our 18-year-old undergoes an emergent right-sided craniotomy for subdural evacuation. Around day three, it's noted that he's still not following directions when sedation is lightened. And then he subsequently develops a pneumonia and remains intubated. Around the end of the first week, he starts to become intermittently tachycardic, hypertensive, and hyperthermic, associated with episodes of sweating. So now I will turn it over to Dr. Legal to go over proxismal sympathetic hyperactivity treatment. So as we see on day six with this patient, they have the constellation of symptoms of that tachycardia, hypertension, increased temperature, sweating, that we all recognize as PSH, or neurostorming as we used to call it. So we'll do a little overview of what it is and what we can use to treat PSH. Next slide. So just to kind of review PSH a little bit, we get this common grouping of symptoms with the tachycardia, tachypnea, hypertension, hyperthermia, diaphoresis or sweating, and then dystonia or increased muscle tone. And there are some ways to measure PSH and to be a bit more objective in looking at what the symptoms are that our patients are having. And there's one scale called the Paroxysmal Sympathetic Hyperactivity Assessment Measure, or the PSHAM, that I like to use at my hospital. And it has two different assessment scales that we use in combination. First is the clinical feature scale that helps us look at the different clinical features kind of in that top dark orange line to see how severely abnormal they are. And then the diagnosis likelihood tool to see what is the probability of PSH being kind of the cause or what's going on. What we also have to remember when thinking about PSH is that we have to rule out other overlap syndromes that have very similar findings in our patients, namely sepsis, withdrawals from medications in the ICU or otherwise, or even having elevated intracranial pressure. So we always have to think about kind of what else could be happening and use PSH more as a diagnosis that we've ruled out other things before we've come to this diagnosis. So the PSHAM, to go through the clinical feature scale, it just kind of lists out all those common features of PSH with the heart rate, respiratory rate, et cetera. And it kind of lists them on a scale of zero, meaning normal, one, slightly abnormal, two, a little more, and three, kind of severely abnormal. What you do for your patient is you can take a look at what are their vital signs and symptoms at that moment and give them a score and add it up. Overall, what I see in patients that have PSH I'm looking at adding in treatment is they typically are kind of in that score of two range for about four symptoms or so, leading to a clinical severity of moderate before I'm looking at really calling this PSH and needing to intervene significantly. Next. The diagnosis likelihood tool is the second part of the PSHAM, which I usually use kind of at the onset or if the team is wondering, is this PSH that we're seeing in this patient? And it just lets out different features that are associated with PSH, like the episodes are paroxysmal, we have sympathetic overreactivity to normally non-painful stimuli, it's happening more than three days in a row, the features might present or persist for over two weeks after a brain injury, et cetera, as you can see on here. I usually score this up kind of once at onset to say, yep, when you add this score plus the clinical feature score, you can see how probable is it that this is PSH. It also helps you think, is this PSH versus might it be something else like sepsis going on because we aren't seeing these other features in the diagnosis likelihood tool. So next slide. PSH namely can have triggering of episodes and it's an exaggerated response to physical or environmental stimuli. So very, very common causes of triggering would be suctioning of their ET tube, are patients still intubated? So certainly that could be happening in our case here, having pain from various sources, including constipation or urinary retention, having emotional stimuli or loud noises, so environmental stimuli, and then passive movement, even just range of motion or turns or bathing just normal typical cares that the nursing team might be providing to our patient in the ICU or afterward. Next. So the first step in management of PSH is to think about our non-pharmacologic methods to control it. So first we wanna try to prevent it with keeping a low stimulation environment, managing pain or preventing pain, so adding medications as needed, and then preventing bed sores and doing proper repositioning of our patient and getting on top of the bowel and bladder program. Then when an episode happens, again, trying to avoid further stimulation of the patient, so avoiding any unnecessary touch or movement, possibly even stopping the care that is happening at that moment if it isn't essential to happen right then, looking for causes of discomfort, and if even fever is one of the key features, adding on a cooling blanket, decreasing the temperature in the room, adding a fan, and then overall trying to prevent PSH by clustering care as much as possible. So even if we know PSH is happening, we're giving less opportunities or less interventions that are triggering an episode. Next. So I have a three kind of pronged approach. First is to do prevention, like we mentioned with the non-pharmacologic, and then to treat these patients with first acute medications or abortive medications kind of during an episode, and then to think about what can we use for maintenance to prevent episodes from happening in the future. And I choose my medications based on the predominant features that were seen in that patient at that time. So first and most common medication that I'm using as an acute treatment is morphine. So it's an opioid, has receptors in the brain, spinal cord, heart, blood vessels, all areas that are kind of affected or that we're seeing affected in PSH. The features that I'm targeting with using morphine as needed is hypertension, allodynia, and tachycardia. We know it's side effects with sedation or respiratory depression, bradycardia, constipation. So we use it carefully and try to kind of mitigate the side effects that might happen. You'll see in the boxes on the right, I have dosing for both PEDs because I'm a pediatric physiatrist, but also from the adult standpoint. So I want us all to feel comfortable that we can treat both adults or like our patient, a very young adult, 18 year old, or even younger. So I have dosing listed out as kind of initial dosing for these medications. For morphine, it's onset if given orally is in about 30 minutes or IV within five to 10 minutes. So it's a wonderful medication to help abort an episode when it is happening. And then we can repeat using it every two to four hours as needed. And some of this kind of depends on those side effects that we're seeing as well. And this is a medication that might titrate up over time based on its effect. Next. The second group of medications that I use for acute treatment would be the benzodiazepines. And commonly, and some of this might depend on the preference of your hospital system or yourself, I'll be using lorazepam or maybe even midazolam in the intensive care unit. And those two I like for using as acute management of episodes because they do have a pretty quick onset when we're giving them IV and you can kind of repeat use as needed. Diazepam and clonazepam I'm using a little more as either an acute management for diazepam, especially if we need to switch over to using it orally. And clonazepam sometimes bridges onto a maintenance medication in how I use it. But the benzos work as GABA-A agonists and they have receptors in the brain and spinal cord. And the features I'm targeting with them are agitation, hypertension, tachycardia, and posturing. And the biggest side effect is sedation or when we use this in addition to the opioids looking for a respiratory depression. I'm picking benzos as an as-needed medication more as my first line, especially if the features that I'm seeing tend to be more tone-related or agitation. And then I might choose to use a benzo over that morphine as a first line as needed, but sometimes I am using it in combination with morphine. I think we all know a brain injury and we like to avoid the use of benzodiazepines as much as we possibly can. This is one of those special cases when I see severe PSH that I will use a benzodiazepine, but no, I want to wean off of it if possible. Then the next medication we can use both as an acute treatment and also for maintenance would be propranolol. So propranolol is a non-selective beta blocker. Alternatively, we could look at the use of labetalol and I would use that more as a maintenance medication instead of an acute medication. The target features of these would be the hypertension, tachycardia, and agitation. So this is my go-to med when I hear a patient has a brain injury in the ICU and is agitated and hypertensive. This is what I'm adding on, sometimes in addition to abortive medication right at that moment. Biggest side effects would be bradycardia, hypotension. I also worry about our patients, especially in kids, I see patients with asthma and worry about that bronchospasm as a possibility. But starting it from the adult side at 20 to 60 milligrams every four to six hours, and PEDS, 0.5 milligrams per kilogram every four to six hours, the onset is slower. So it's not the best at aborting an episode unless this is something that's been going on a long time, but is wonderful for maintenance. And we start with that dose and can increase it as needed based on the effect and side effects. Next. Next would be clonidine. So clonidine is an alpha-2 agonist. It activates the inhibitory neurons in the brainstem. So our end result is reduced sympathetic outflow from the CNS. The features that I use to target with clonidine are hypertension and tachycardia. And sometimes it can be used more as a behavior stabilizer, but that's not typically the use that I'm choosing it for in PSH at the moment. Side effects would be sedation, hypotension, bradycardia, and if we're stopping it abruptly would be rebound hypertension. The onset of clonidine is fairly quick, 30 to 60 minutes. So it could be used as needed if we're seeing significant hypertension, but I tend to, if I'm starting that, to keep it on for a longer time. And this can also help with weaning patients off of medications that are being used in the ICU. Clonidine has the option of being given as a transdermal patch, which could lead to more steady state of the medication. However, in patients with PSH, we're often seeing a lot of diaphoresis. And so that patch might not stay on. So we might not be getting adequate dosing. So I tend not to go to a patch too soon. Next would be baclofen. And the target feature that I'd have with baclofen is spasticity and dystonia. And I think we're all fairly comfortable with using baclofen if we're treating brain injury patients or stroke patients. But baclofen is that GABA B agonist. Its biggest side effects would be sedation, could be nausea, and the risk of withdrawal if we're stopping it abruptly. We do have the option of using oral or enteral baclofen or thinking about intrathecal baclofen. In our patients with PSH, usually I'm trying oral baclofen if we're seeing a lot of tone or posturing as a feature. However, in those patients, especially with anoxic brain injuries or the really severe DAI that are having a lot of tone issues, we occasionally will think about the earlier use of intrathecal baclofen to really gain better control over PSH in general. And the big key for baclofen is to wean it gradually after we've started it if we find we aren't needing it in the future after PSH is controlled. And then bromocryptine is a dopamine agonist. So as we just heard, dopamine is all over. The target feature that I'm using bromocryptine for is for fever, diaphoresis in our patients with PSH. Now we have other uses of bromocryptine later on in TBI that we'll talk about, but in PSH specifically, I'm really looking when we're seeing somebody is having elevated temperature or sweating. The side effects could be hypotension, confusion, agitation, dyskinesia, nausea. So I am thinking a little bit carefully about who I want to use this in and really carefully choosing it's somebody that's having a lot of the hyperthermia going on that isn't maybe not quite as agitated as some of my other patients. I do wean it gradually after I start it, but I'd start it as a twice daily medication. We have that dosing in adults as 1.25 milligram twice daily. Next. And gabapentin. So that's working on the presynaptic voltage gated calcium channels in the brain and spinal cord. I'm using this primarily for patients that are having spasticity or allodynia, but sometimes kind of using it if we're just having overall agitation. The side effect could be sedation and fatigue, but usually I'm seeing that side effect kind of lessen over time with use. And I tend to see less problems with sedation than some of our other medications that we had discussed like the clonidine or morphine or benzodiazepines. Gabapentin could potentiate the effects of opioids. So I think about that a little bit, but I don't hesitate to use it in combination with the PRN morphine if needed. This has a slower onset. And so again, I'm not using this typically as a acute treatment, but more from that maintenance standpoint. And I'd start at a hundred milligrams every eight hours in adults or five mgs per kg every eight hours in children. And then titrating up to effect. And dantrolene, this blocks the release of calcium from the sarcoplasmic reticulum. So specifically is working more peripherally for our patients. And the target feature of this is the posturing or muscle spasms. So I'm picking this when I'm seeing a patient that either has the elevated temperature because of high muscle tone, or where tone and posturing is one of the predominant features that we have not been able to control. Side effect of dantrolene would be weakness since it does work in all of those skeletal muscles and the potential for hepatotoxicity. So it does require monitoring of LFTs. I usually am checking that before I start to make sure they're normal first and then monitoring on a weekly basis, especially as I'm titrating the medicine. And adults, I'd start at 25 milligrams Q8 hours in peds 0.5 mg per kg. And then you can increase the doses needed. Typically, if I'm able to move slowly with increasing this medicine, I'd change it on a weekly basis, but acutely in the ICU, we could titrate the medication slightly more rapidly. But I tend to use this more as a maintenance medicine for that tone and kind of use it as a slow titration up. So back to our case, our patient was six days post-injury. They remained intubated. They're tachycardic, hypertensive, hyperthermic, and sweaty. So when thinking about what I do for this patient with the tachycardia and hypertensive features, I'd be looking at adding propranolol at this time as both an acute management and then leaving it on scheduled to prevent PSH in the future. With the hyperthermia and diaphoresis, I wouldn't be necessarily adding on a medication like bromocryptine immediately because we may see improvement with that propranolol. I'd also be considering adding in a PRN medication such as morphine to try to abort any episode that's happening right then and kind of having it on board if we're seeing these episodes creep back up. Thank you, Dr. Legal. And now that we are aware of how to manage PSH in our patient, we will continue to follow along in his hospital course. So by day 10, he now has a trach and PEG tube placed. A couple of days later, he's able to be weaned off of his ventilator. And by day 20, he's now getting his IVs. His ventilator. And by day 20, he's now getting ready to transition to a disorders of consciousness rehab program. So I will turn it over to Dr. Puderbach to discuss awakening agents in DOC. All right. Good evening, everybody. I hope everybody's having a wonderful Cinco de Mayo. We're going to be going through some awakening agents in just, like, very short order. Forgive me if I'm cutting out away a lot, but we're going to be focusing on some of the bigger items and some of the other agents you might not necessarily think of. For a good review was that review by Marino et al, or by Marino if you'd like to. So the first agent that we're always thinking about, the only agent that's recommended for the ACRM slash AAN guidelines is imantadine. So imantadine is a partial NMDA receptor antagonist. It also has some presynaptic and postsynaptic mechanisms with dopamine, can delay the reuptake, which leads to an increase of dopamine concentrations inside the synaptic space. Postsynaptically, it may also help to increase some of the dopamine receptors as well. So it's kind of pretty cool in terms of all the different little mechanisms that it kind of interacts with. And it has a half-life of approximately 16 hours. It is recommended to start at the 28-day mark. That was with the trial by Gina Sino-White that was published in New England Journal of Medicine. Now, there have been some studies published since then about looking at starting it earlier. Now, the two American studies were retrospective. They were Hintz and Gramish. And what they did is they were looking at some retrospective cases and they found that there was actually some perceived harm by increasing the use of opiates, medications, and more sedation medications. And they didn't think that there was any earlier benefit to starting. I believe that the usual day of starting it was around day eight. I think that was in the Gramish article. However, those were both retrospective. So definitely what I'm talking about with residents and our brain injury fellows, I'm really kind of saying, pointing this out. It's like you really have to be cautious when it's coming to retrospective. Because the two prospective studies, which were Galanovi and Shafee, both found that starting at mantadine early on, I believe they both had them within day three, they demonstrated an improved GCS by about day seven. Now, they were also looking at some secondary endpoints such as length of stay and didn't seem to really change that but there definitely was some improvement in that initial GCS and there wasn't an increase in other agitation medication usage. The two contraindications that you really have to think about, one is that it's renally excreted so you have to be very cautious when it's coming to people who are in AKI or have a very advanced CKD. The other one is more of avoiding in active seizure patients. Mantadine does theoretically lower the seizure threshold, it can make seizures more apparent and so in general, when somebody is on more than three AEDs or is being uncontrolled, I am avoiding the use of a mantadine. There is currently an IV study that's being done, it's being recruited for right now and it's looking at early administration of a mantadine from a prospective study. So this should be very interesting coming up. All right, we'll go ahead and go on. So the next agent that probably has the next best level of evidence is actually zolpidem. So five to 10% of people respond atypically to zolpidem. When I was a prior flight surgeon, we'd always be testing this on our pilots to make sure they didn't go and sleepwalk, but that's the kind of effect you're actually banking on when you're utilizing this medication because it can cause all sorts of these strange motor behaviors. And we are thinking that this might be the way that we're using it to restore consciousness. White and all did a study in 2014 where they did a placebo-controlled double-blind crossover study. And they found out, yeah, about 5% of people did seem to respond. There really wasn't any clear characteristics of responders and it can cause some increased sleepiness. When you are thinking about doing a zolpidem trial, you actually wanna do this during the day because you're trying to maximize the wakefulness that someday might be occurring. So you're thinking maybe about 10, 11 o'clock during the daytime, periods that we tend to think of as being more peak wakefulness. If you are doing this within a facility, the idea would be to administer a 10 milligram dose and do serial CRS about once an hour for three hours. If you have the ability to do EEG monitoring, that is also recommended. If offsite, you can have a caregiver try and monitor for a three-hour period to see if there's any changes in alertness or consciousness. And then what you're looking for is two days worth if they are a consistent responder to that. There was a recent study in 2023 that was looking at whether or not zolpidem may be helpful early on. And what they found is that if you give zolpidem and or EEG, and you see more of this increase in beta band power, that it may be a predictive factor in improved consciousness six months later. So this might be one that I might be more thinking about doing a trial in the ICU while I might have EEG access more readily to see if there is some sort of improvement or change on the EEG with this. Now, methylphenidate is probably the one that we have historically reached for often, but it doesn't seem to really hold up under scrutiny. There's been a few review articles that have looked at it, and it just doesn't seem to be as helpful as an awakening agent. Martin and White did a study of 17 patients back in 2007, and it didn't seem to really do much in terms of responsiveness as well. It does seem to activate the norepinephrine and dopamine circuits, so we think that this might, that you would tend to think that that might be helpful. So it's just not getting what we think out of it in terms of our reports. Now, there is a protocol that I believe is undergoing recruitment right now when I was looking up on clinical trials. It's Edlow, they're doing a stem pack in a clinical trial that they're doing a stem pack. It was, if I'm remembering the title of it right, it was personalized connectome mapping to guide targeted therapy and promote recovery of consciousness in the intensive care unit. What they're going to be doing is they're going to be doing escalating doses of methylphenidate up to two milligrams per kilogram. IV, what they're looking for is over a four day period if there's any improvement on a resting state of fMRI and EEG. So this is going to be some very high dose methylphenidate. And so that'll be very interesting when that one gets more recruitment and some more information underneath it. Next. Bromocriptine, as you were just hearing about, this is a helpful agent when you're thinking about PSH. It is a dopamine-restricted agonist and its idea is that it's stimulating those dopaminergic synapses. This one doesn't have as much evidence for it, but there is some evidence in terms of a retrospective study and a small single arm trial looking to see if this may help in improvement. Now that single arm trial didn't seem to really do very much, but the retrospective study seemed that it may show some improvement on the CRSR. Its main limitation is the side effects of it, which is going to usually be more hemodynamic instability. Dizziness, hypotension, some increased nausea, vomiting were reported when White et al did their study with moderate to severe traumatic brain injury. This might be more helpful as an agent as you're progressing something in PSH, for example, and then you're using it early on to potentially promote consciousness. I also use this because it does not seem to lower the seizure threshold as much. There was a study that was published that looked that may lower the seizure threshold by possibly 5% in comparison to other agents. Again, really hard to quantify, but this seems to be a helpful agent when seizures are being of a concern and to try and help kind of promote more of that restoration of the arousal network. Go ahead. Now, modafinil was another one that was thought that, hey, maybe this will really help. It was theorized to promote more wakefulness through this histaminergic pathway, and it has a whole bunch of actions, including being an atypical weak dopamine reuptake inhibitor. This one also got studied in a few patients. It looked like it was really helpful for maybe promoting more wakefulness or fatigue, but it doesn't seem to actually improve wakefulness in terms of a disorders of consciousness pathway. So this one is one that I don't utilize as much. There is also a recent study that was looking at amantadine versus modafinil in stroke patients who had disorders of consciousness, and that one, it just did not seem to be as helpful either. So amantadine seems to be more of a leading agent as opposed to modafinil. Next slide. All right, so apomorphine. Apomorphine is one that you might not hear about as much. Apomorphine is not an actual morphine molecule. It's just a derivative of that, and it's actually a non-selective dopamine receptor agonist. Now, one of the main limitations to apomorphine is that it has to be administered through a continuous subcutaneous infusion through like some sort of external pump, kind of like an insulin pump for diabetics. So that's what has really made it more limiting in terms of a medication to be able to be utilized. But in some very small studies that they've utilized, they have found that for people who are in a chronic traumatic DOC, that they do get some improvement. Friedman noted that all eight patients seem to improve with four of them within four days. So it can potentially have a dramatic effect. We're just limited by the amount of studies. Now, there are two large studies that are going on. One is in Belgium and one is in the Netherlands. I believe the one in the, or sorry, Denmark, I believe, sorry. Denmark, I believe is the open-labeled feasibility study, or sorry, is the 30-day treatment for apomorphine that they're looking at right now. And then Orthman is going to be the ongoing placebo randomized control trial looking at methylphenidate and apomorphine. Next slide. Levodopa is another one. This has been very limited due to just case reports. It's a precursor to dopamine and it's converted by dopadecobarxylase into dopamine. As you can see, it's just been very small numbers, but it may potentially have that impact, especially if you're looking, and they may have more damage to things like the Cysanthia nigra, leading to more of a dopamine deficiency. So we're really limited in terms of what trials there might be. So this is definitely more of that third line, fourth line agent. Next slide. Lorazepam. So Lorazepam is a medication that, again, as Dr. Ligel had said, we tend to avoid benzodiazepines inside brain injury. The one caveat would be, are we dealing with catatonia? So catatonia is, again, it's that neuropsychiatric syndrome that's extreme withdrawal, very flat affect, stupor, catalepsy, waxy flexibility, and just some very other strange things that might not necessarily fit that picture of a disorder of consciousness you might have. So Lorazepam is the drug of choice for treatment of that. And what you're looking for is doing a Lorazepam challenge. That's one to two milligrams of IV. That can be very effective in reducing a lot of the symptoms through varying catatonia measures. Bush-Francis catatonia rating scale seems to be the most common one. Some severe catatonia, though, may require some significant doses. So sometimes if you're seeing maybe some response to the two milligrams, you might need to increase that up. It's been reported up to 30 milligrams a day of Lorazepam to help with symptoms. Now, what about for just, okay, our actual brain injury? Well, they did a retrospective review, believe these were patients down at TIER, that were looking at patients in a DOC program, and they were comparing it also with how they responded with Zolpidem as well. And they found that about 14% of the patients that had a Lorazepam trial for disorders of consciousness seem to improve. So this might be another option to consider, especially if you're not getting much headway with things like imantadine or bromocriptine. Stroke patients were non-responders, so that would be the one caveat to this, that I would not be applying this to other non-traumatic causes right now. And it may be best paired with Zolpidem, because Lorazepam in their trials didn't seem to be helping much with mutism, whereas the Zolpidem did. So maybe it's a double hit that's just trying to help the brain heal. Next slide. Danezepazil, this has been one that has been kind of kicked around as whether or not this might be an effective help in terms of DOC, but there hasn't been any real studies that have really been looking at this. It has been effective in helping to improve some of the cognition later on in moderate to severe, especially helping to kind of move that brain closer in terms of improving its cognitive scores, but in terms of awakening agents, it just hasn't seemed to really pan out. Okay, next slide. Since we're short on time, I'll just go ahead and keep going, but this was a really helpful chart from Neurotherapeutics that was just going through all the different mechanisms. Go ahead. All right, so in all, again, Amantadine is our frontline treatment. It's recommended to start 28 days. I started at about day 14 when I feel like the conditions are right. That's kind of allowing that initial biochemical cascade and that risk of seizure to decrease before starting it, but you have to be mindful in case there is going to be more increase in agitation. Bromocriptine may be used earlier, maybe possibly used a little bit better in patients who have an increased seizure risk. Methylphenidate may consider this, especially if they have a lot of AEDs that are going on. And then Zolpidem, I do consider a trial if I'm not getting any benefit with Amantadine. Okay. All right, thank you. So we are going to be switching gears a little bit now, and we're going to be moving on to a panel discussion of our case and the medications that we have discussed in the presentation today. We are also opening it up to the audience for interaction and discussion, so feel free to unmute yourself or put questions in the chat if you would like to participate in the discussion. So to summarize, our case is an 18-year-old male with a history of ADHD who presents after an ATB crash. He sustains a severe TBI, and hospital course was complicated by respiratory failure, pneumonia, paroxysmal sympathetic hyperactivity, and disorders of consciousness. By day 50, he is now following directions intermittently. So to start our discussion, our first prompted question to the panel is, when and how would you start weaning these medications that we've discussed today during their rehab course or at outpatient follow-up? And Dr. Babish, if you could start us off. Sure. So this is the age-old question that we get, is when to start looking at titration or weaning of the medication. So sometimes I will start during rehab. However, in this particular case, I would not, because he's just starting to follow commands intermittently at day 50. So I would continue the drug until we either see a plateau or we see improvement in command follow, communication, et cetera. Now, as an outpatient, the way I usually do this for patients is once they get to a point where they are kind of plateauing in that progress or you start seeing things kind of slowing down with their progress or they're having side effects, I would start weaning the medication. And then if we start seeing a decline or a reversal of any of their cognition or anything like that, then I bring it back online and I say, okay, we'll try it again in three to six months because you're still having effect from the medication. So there's no right answer. It's patient dependent in my case, but I would, some patients I do consider coming off the medications. If we're starting to see, we've emerged them from a Rancho 3 to a Rancho 4 and they're starting to get super agitated and we're worried are the medications kind of creating some of that. Now there's data on using some of these stimulants to help with behaviors as well, especially with the pre-morbid history of ADHD. So it really depends on what I'm seeing in front of me. So sometimes I do wean prior to them completing rehab and sometimes I'm weaning down the line three to six months, but I'm always watching to see if there's any regression before I decide to completely wean them off of it. I'll jump in next. I would agree what you had just mentioned about timeline of weaning medications. I'd also think about, since I'm working with kids, if we are returning to school or something like that coming up soon or returning to work, I'd also take that timing into consideration on when I'd start weaning medicines that I wouldn't want a major change to happen right as we're about to go back into school or into work if they have been stable. You know, where our patient is right now, I'm not sure where we'd be thinking about them returning to work, but sometimes we are going back into the school setting. I'd also comment if our patient had been titrated up on medications for PSH prior to going to rehab, such as starting clonazepam, if tone became an issue, or if we have been on higher doses of propranolol and adding in clonidine, I would be looking at weaning off that clonidine while they're on inpatient rehab and weaning off of like a clonazepam if we had it. Propranolol, I would be leaving on longer term, especially if we're still seeing some of that agitation coming out. It would probably be my last medication that I'd look at weaning the patient off of in terms of medications that were used for PSH. And there I'd be looking at what are their vital signs showing in terms of symptoms from either a PSH standpoint or what are they doing in terms of agitation that if I'm still seeing agitation, I'd hesitate to wean off of that propranolol at that time. I totally agree with my co-presenters. It's going to be kind of a matter of following along with their symptoms and deescalating as they tend to start turning over those corners as well. I had at one point in time told, oh, well, why don't you just keep imantadine for 12 weeks? And when I'm on the outpatient side, that might be one of my first things to kind of pull back, especially if somebody might already be well out of PTA and might be well-established in terms of their symptoms. Any other comments or questions from the audience on that particular question? I just wanted to bring up one of the comments in the chat that was brought up about imantadine. We have always been traditionally taught that it lowers seizure threshold, and so there's a lot of fear to use it. And the comment is relating to an article that was from Dr. Ma and Dr. Zavant. Dr. Ma is the one who actually put the comment in. It is dose-dependent, so the higher dose of imantadine has the higher risk of lowering seizure threshold. So if I do have somebody with seizures, I will still use imantadine, but sometimes dose adjustments with it. So I just wanted to make sure that everyone saw that comment. Next question. Any considerations or changes to your management approach for those with specific prior medical histories, such as our patient who had a history of ADHD and those that might be on stimulants previously or other similar behavior medications? And I'll let any of you start. So I always tell everybody that if they were on any, whatever prior medical history they have, whether it's depression, anxiety, ADHD, we're dealing with a new brain after an injury. And as we talked about with all the different neurotransmitters and neurochemicals that can be jumbled up. So sometimes I will use a stimulant that they previously had good effects on because their body knows the drug and risk of side effects. However, sometimes I have to either use a higher or lower dose compared to what they were on pre-morbidly. So I always try to go with the drug that they've already used, but also recognizing that I am dealing with a new brain and new neurochemical changes. Thank you. Any other comments from the panel, or we're in agreement? I think that was well stated. Okay, next question. Any specific counseling that you do for your patients on these types of medications, if they're still on them long-term in the context of returning to school or work? I think I had mentioned a little bit about that return to school for kids. We're seeing a return to school much sooner than we might see return to work for adults with the same level of brain injury and recovery. For returning to school, that's, you know, a new setting for a patient. We may see changes kind of in different directions with how they're doing from a behavior, from an attention standpoint, from a fatigue because it is, you know, going back to a long day with a lot going on, a lot of stimulus. So sometimes I'm cautious if I was just on the brink of changing a medication right at the time that we'd be returning to school, I hesitate a little bit. I let them get established in where they're at and then kind of get a new baseline of what are the symptoms, what are our behaviors, and then look at we need the medication so I can have a nice pre- and post-medication change level of data. Returning to work certainly may have some different implications. You know, if we're returning to work with heavy machinery, I'm thinking about what medications are on very differently than if I'm returning to work that is requiring high cognitive function versus if we're returning to work that's more sedentary and kind of rote type of activities. So it really depends on what type of work we're looking at getting back to for me. In addition to that, depending on the job, Department of Transportation as well as the FAA has regulations for medications that people can and cannot be taking in order to maintain their licensing. So just looking at some of those regulations as well, sometimes medications such as neurostimulants like Adderall and things, you know, FAA requires them to be off of them for five years before they can return as a pilot. But the DOT, you know, they question some of the things like Provital and the stimulants as well because of concern for fatigue and drowsiness and falling asleep behind the wheel. So just looking at some of those other regulations that are out there too helps me to consider what we're doing with medications in the context of returning to work or school as well. Yeah, I very much agree. I think really focusing on what is the occupation and what are their job requirements and in terms of schooling, what level of schooling are they at, what kind of things are they doing? And it might be more of changing things around what they may be trying to do. So what other activities can we do to potentially get them into work earlier that might not necessarily have as much effect on the medications or what kind of interventions can I do to school, like give them earlier time to register their classes so that they can choose classes that might work better in the morning when those medications might be more effective than in the afternoon. I usually, for most of these medications, I would hopefully have started to peel and wean these off before getting to that point of returning to work or school. But I've been able to return people to work with imantadine pretty effectively, and people seem to tolerate that fairly well. I'm going to stop sharing and then maybe we can take a look at the chat and see if there's questions, but also feel free to unmute yourselves if you have questions. Yeah, thanks. I was just noticing there was one from Dr. Hasan. He said that he really appreciates it. I know maybe you guys can see that too, but for PSH, how maybe would you determine whether to start on combination therapies, any common pairings, and any type of indication for antihistamine for PSH? Yes. So I do have some common pairings. I think my go-to, and I almost say this in my sleep, is I'm starting propranolol because usually there's agitation or hypertension, tachycardia involved. And then at the same moment, also starting more of an acute treatment with a PRN of morphine. And then in addition to that propranolol as more of a maintenance medication, it really depends on what else I'm seeing. So my first step might be increasing that dose of propranolol as tolerated to get better control of our symptoms. But if I'm seeing tone in addition to this agitation, I'm often adding in baclofen or sometimes a benzodiazepine, kind of depending, again, on whether the morphine is working as an acute abortive treatment. And if not, I might switch to using a benzo as more the acute abortive treatment. And if there's significant high tone that for some reason baclofen is not being tolerated or I'm maxed out on my baclofen, I might be adding in then an additional medicine to target tone specifically. And then it really kind of depends on the patient what I'm choosing. If I have worry about pain, I might be adding in gabapentin to try to mitigate pain that could be leading to increased tone. I might be considering dantrolene if it's really just tone is a high issue or might be looking at clonazepam if overall I don't have wonderful control of symptoms and I feel like I need the clonazepam from a tone standpoint and to address other symptoms like the hypertension, tachycardia type thing. Yeah, I agree with all of that. The main thing is I try to use one medication to hit multiple symptoms. So if I'm seeing fevers and tone, then sometimes I'll use dantrolene for both of those. But propranolol is typically my go-to first. Sometimes I will use clonidine to help with tone, pain, and blood pressures and tachycardia. So it really just depends on what I'm seeing in front of me and what I think they can tolerate. But propranolol is typically my go-to and then start adding things as I'm seeing other symptoms. I don't normally add two things at once unless it's a maintenance and a PRN. If there's going to be multiple maintenance, I start with one and then add the others as I'm going along. And then the other question was if there's indications for antihistamines. So when I am thinking baclofen withdrawal, I'll use periactin, but I don't usually use antihistamines. For PSH, like hydroxyzine or Benadryl or anything like that. Because typically you can take care of the other symptoms of the sweating and the flushing with your propranolol, bromocryptine, dantrolene. I agree. I'm often pairing propranolol with clonidine. I'll usually start propranolol first, but I'm usually quicker on adding in clonidine as well. I see that my ICU likes to utilize bromocryptine pretty often and a little bit earlier than I would. So sometimes I'm kind of adjusting my medication recommendations based off of what they may be doing at that present time. So it's always kind of good to make sure you have a good open communication with the primary team in the ICU as to what they're thinking about doing and what they may be wanting to look at. Thanks. We have a couple more minutes here and a couple of really great questions and comments in the chat. Dr. Vazquez made a really great point that driving precautions and processes can change from state to state, so being aware of those. Dr. Warden has a really great question that I think is kind of a nice one for us. They're all nice, but maybe we have time for this one. Many of these agents are off-label uses, and does that change your tendency to use them, and is there any way that you talk to families about that? I'd agree. Many of these might be off-label for the specific indication of TBI or stroke, but they are on-label for the specific symptom that I'm targeting. So I don't really hesitate to use it. There may be some families that question because they're looking up the medicine and seeing, hey, it doesn't say we're using it for brain injury, and I tend to reframe and shift and say we're using it for the specific constellation of symptoms that we're seeing. I agree. I have the same approach. Yeah, I'll kind of use a phrase of saying we need to use these medicines to help cool the brain down or put it in a place where it can help to heal itself, and that seems to be a good approach when I've been able to talk to families about why we're using these certain medications. That's great. That's great. Dr. Patel was wondering, do you have any specific guidelines for weaning off medications, like is there any dose or, I don't know, Dr. Patel, did you have a specific, maybe you could ask that one. If you had any specifics for meds, any specific weaning protocol. I think the main question is, from my standpoint, is how long they've been on it. So if they've been on it a very short time and I'm weaning in acute care and I can watch them closely, I wean off a lot quicker, you know, sometimes every two or three days or even every four or five days, depending on if they're, you know, inpatient. If they're outpatient, I'm weaning a lot slower just because I can't see them every day and see what their symptoms are. So I'm typically weaning by dose over kind of a one to two week timeframe. And sometimes I will increase the interval of dosing depending on what the interval is. So, you know, if it's me and Teneen and I'm doing morning and afternoon, I'm not going to increase the interval, you know, to, you know, I'll do like once a day instead of twice a day. But I'm not going to do typically like every other day or something like that, because the TAF life is still 16 hours. So then you run that risk of potentially having some withdrawals of it. But other drugs like Baclofen, depending on the dose, again, how much they're on and what setting they're in, that one definitely can have withdrawal symptoms to it if you wean too fast. So it depends on the drug and it depends on the length of time that they've been on it. But typically I'm going down on total dosage rather than time between. Yeah, thank you. That's exactly what I was thinking too, because I'm in an outpatient setting. I get patients from other places. And then I'm wondering how quickly I can wean them off. And the issue often ends up being because you can't see them frequently. And I think you answered me perfectly. That's exactly what I'm doing. But there are no other new revelations or anything like that up there. As far as like, yeah, some drugs, I will just decrease the interval, increase the interval, and most of them I just decrease the dose generally and just monitor them. For imantadine on the outpatient, if they're on 200 milligrams twice a day, I've done just decreased by 100 every week until they're off over a month. And then if they did run into more symptoms, side effects, then I just have them keep at that dose until I'm able to see them again. Thanks. I think maybe we have time for this last question about, because there's so much dopamine in what you all talked about, have you heard of anything like, I'm sorry, I lost it, primoprexol or ropinerol use? Yeah, I got asked this a little while ago too. And I looked it up and I just re-looked it up. There's nothing that's been published on ropinerol or, sorry, was it the primoprexol? There was a rat study that just got done on primoprexol, which might show some benefit. I'd say anecdotally, I have seen primoprexol and ropinerol. And I haven't seen any changes in consciousness on those individuals. So I don't think it's doing much in terms of this space. But I don't know if anybody else has more experience on that. No, I have not seen any data on it. And I haven't used it in the DOC setting at all. I do use it, but just not for disordered consciousness. Yeah, I've had a handful of people that they just get restarted on their restless leg syndrome dosage and I don't see any changes. So I have not thought that it's doing much in that space. Well, if there's no other last minute questions, thank you everyone for joining us and we look forward to seeing you in other Member May sessions.

brain injury

neurotransmitters

paroxysmal sympathetic hyperactivity

case study

personalized treatment

awakening agents

propranolol

Amantadine

disorders of consciousness

pharmacotherapy

rehabilitation