Okay, so I have no disclosures relevant to this presentation. All of the medications that I'm going to be talking about will use generic names and they're all off-label. There is no medication that's approved for autonomic dysreflexia, for patients with spinal cord injuries, so everything we typically do is off-label anyway. I also want to give the disclosure, the the Cucurillo disclosure, that if you're preparing for your boards, make sure you're using those those few paragraphs in Cucurillo to talk about autonomic dysreflexia. Don't overthink things. Generally the boards are rooted more in the classic literature and what we're going to talk about today is updates on those things, so clinically useful, perhaps not as beneficial for board prep. Okay, so objectives today, really to explain the basic underlying mechanisms that lead to AD following spinal cord injury, to identify clinical and pathophysiological insights into presentation AD, because everyone's going to present a little bit differently. We're going to be able to describe at least three methods for attenuation of AD and to really highlight why this is relevant in the current scenario with the COVID pandemic. First, I wanted to start with a clinical vignette. So imagine if you were that you are a neurorehab consultant at a local hospital. You're consulted to a medicine floor for a patient with spinal cord injury. This is a 35-year-old female with C7 asian permscale atetraplegia. She's coming in with a urinary tract infection. You look over her notes. She has intravenous catheterization. She's sweaty. She's got some flushing. She's got goosebumps. She's having episodic hypertension. The medicine team, bless their heart, ask you for recommendations on where she should be discharged. You say she has a C7 asian spinal cord injury. She's coming from home. She should probably go back home, but you overhear that they are planning on starting her on amlodipine for her hypertension and doing a workup for a pheochromocytoma because this has happened episodically and it's happened in flushing. Based on your clinical knowledge and the title of this talk, you gently tell them that another thing they should consider is autonomic dysreflexia. That's really what we're going to talk about today. So the way I like to explain autonomic dysreflexia to patients is like this. Before a spinal cord injury, you have an intact neural axis. The brain connects to your spinal cord, connects out to your peripheral nerves. So when you have some mildly painful stimulus, your bladder is overly full, that signal goes to your spinal cord. And when it gets there, it sends a reflex arc back to the blood vessels in the area, basically saying, hey, there's something painful here. Let's squeeze down. Make sure we're not going to bleed to death. That brings your blood pressure up a little bit. That signal then ascends up to your brain and your brain says, nope, we're not going to bleed to death. We just have to go to the bathroom. We shouldn't have had four cups of coffee this morning. It's already noon. And because I have access to a coffee machine doesn't mean I should continue to drink that much. I'm assuming that everyone's laughing at me for this case. The signal then descends down your spinal cord, back to your bladder, tells those blood vessels in the area that they can relax a little bit. The blood pressure does not appreciably go up in this scenario without a spinal cord injury. However, after a spinal cord injury, you no longer have an intact neural axis. So while the first part of that reflex arc is intact, telling those blood vessels to really squeeze down as tight as they can, that signal never makes it to the brain. The signal that's coming down never makes it to those blood vessels. That means those blood vessels squeeze more and more and more, eventually bringing your blood pressure up to potentially dangerous levels. There's been documented cases of people's fist valve blood pressure going to 325 millimeters mercury, which is clinically just an insane number to get to. When blood pressure gets that high, there's obviously side effects and complications that can come from it. Things like stroke, retinal hemorrhage, death can and have occurred from spinal cord injury with autonomic dysreflexia. So just to go through the basics of this, something that most of you are probably familiar with, spinal cord injury at or above the neurologic level of injury of T6, classically at risk. Autonomic dysreflexia is defined as an increase in systolic blood pressure of more than 20 millimeters of mercury over your baseline. Baseline here is important. Many people with cervical spinal cord injuries can live in the 80s to 90s. So if your baseline blood pressure is 85 for your systolic, and going to 105 or 106 is autonomic dysreflexia for you. And last, there's consortium guidelines that really guide us on identification and management of dysreflexia. I think these are important. Any pharmacologic management should be reserved for when patients have systolic blood pressures of more than 150 millimeters mercury. These AD guidelines were developed in 2001, and there's an update that's been in the works for the last three years or so. I've taken a look at the drafts of those, and it's not going to appreciably change in terms of our management from where they were before. Okay, so those are the basics. We're going to try to dig into things a little bit deeper, really hitting on the pathophysiology. We're going to start with some cord anatomy. So the sympathetic preganglionic neuron cell bodies live here in the lateral horn of the spinal cord. Sympathetic signals pass through this, and then go out to the sympathetic chain ganglia on the side. At sympathetic chain ganglia, there's connections up and down level. So there's some new signal that can get introduced there from opposing levels. And then it goes out to the periphery and acts on those vessels to cause basal constriction. The way I like to think about it is that below the level of injury, primarily sympathetic responses. And that's where you're going to get your basal constriction. At the same time, you have a disengaged parasympathetic system. It's sensing this increase in blood pressure through your carotid baroreceptors primarily, and brings out all this parasympathetic outpouring above the level of injury. And if that was the whole story, that it was the sympathetic parasympathetic balance, then neurological level of injury would really determine what someone presented with autonomic dysreflexia. And it'd be very easy to identify, and this whole thing, this whole presentation would be done 45 minutes early. That is not the case on many cases. Okay, so there's multiple contributors to how someone presents with autonomic dysreflexia. One part of that is apparent signals. So we know that where the pain is coming from, where this noxious stimulus is, can change how it presents. A-delta fibers primarily present with increases in heart rate when there's sympathetic engagement. C-fibers primarily manifest as increases in blood pressure. So within the same individual, if you have pain from a pressure injury in your skin, that's primarily A-delta activation. You're going to get increases in your heart rate more than blood pressure. That same person, if they've got over dysentery in their blood, after a spinal cord injury, primarily C-fiber mediated, you're going to get more increases in your blood pressure than your heart rate. So within people, where the pain is coming from can change the presentation. There's additionally some evidence that autonomic signals can be regulated by spared fibers, basically an autonomically incomplete injury. These are serotonergic, gamiotergic fibers, and can change how reactive your spinal cord is. So if you have some signal, you're able to regulate some connectivity, and we'll talk about that a little bit more. And finally, within the cord, there's also evidence of amplification that can happen. This is interesting. This happens via the CGRP fibers, which is calcitonin gene related peptide reactive after. Basically, after spinal cord injury, there's all this outpouring of nerve growth factor. And these fibers now synapse onto a bunch of new connections. The figure on your left, figure A, is a rat spinal cord injury stained for these fibers. And you see that they're all relatively in rex delamina one and two. This is an uninjured rat. On the right is a rat. So I did these experiments during residency, so I'd like to put them in there. On the right is a stain of an animal with spinal cord injury. And you see that there's all this extra green, all these new connections that are formed. In the absence of some super spinal signal that's regulating things, these new connections get stronger. So human plasticity cells that wire together, or fire together, wire together. And so if you all of a sudden grab on to a new target, and that new target is an interneuron, it's going to change the regulation of that interneuron. If you all of a sudden grab on to a motor neuron, or a sympathetic preganglionic neuron, every time there's a sensory signal that's coming in, it's going to fire with that accompanying neuron. Along these lines, if you block the sprouting of those fibers, you see greatly attenuated autonomic dysreflexia. And this has been shown in animal models about 20 years ago. So not to be outdone, there's also evidence of peripheral amplification. So alpha-1 adrenal receptors get upregulated after the spinal cord injury. Again, on the left, you see a rat arterial without a spinal cord injury. And on the right, you see a stained rat arterial with a spinal cord injury. The brown here is standing for alpha-1 adrenal receptor. On the left, we see much less brown, right, more brown. What all this brown is basically saying is that if before the injury, you have 10% sympathetic engagement, you get 10% phase of constriction. After an injury, 10% sympathetic signal might lead to 20% phase of constriction, or 40% or 80% phase of constriction. That's going to be a variable based on the individual. So there's a lot of different contributing factors here. In terms of presentation, all of this altered pathophysiology can manifest in different ways. The classic symptoms that we see are hypertension, part of the definition, and bradycardia. So the way we think about this is that if you're a neurologic level vendor, we'll talk about this a little bit more, if at or above T6, you are going to get vasoconstriction of the splanchnic vessels. Basically, that tennis court worth of surface area squeezing down tight, bringing your blood pressure up. At the same time, you should sense that change in your carotid baroreceptors. You have a vagal output to your SA node, which says, hey, we need to do everything we can to normalize your cardiac output, and it leads to bradycardia. So those are the symptoms that we always hear about, hypertension, bradycardia. Other symptoms really can be broken down into thinking about parasympathetic above and sympathetic below. So parasympathetic signals are things like headache, flushing, increased secretion. Headache is due to, largely to increased vasodilation in cranial vasculature. That's pain sensitive. Flushing is vasodilation, again parasympathetic, in the skin. And then increased secretions is also parasympathetic. I think it's important to think about increased secretions, especially for those patients that are 30 days out in your inpatient rehab units, still in a bed, having a lot of trouble weaning because of secretions. Think about sympathetic engagement and corresponding parasympathetic outpouring as one potential cause of that. Below the level of injury, we're thinking primarily sympathetic. So blurred vision, sweating, acute asansurina, which is the fancy name for goosebumps, and neurogenic pulmonary edema are all potential things that originate from below the level of injury. So blurred vision is pupillary dilation, sympathetic signal. Sweating, even in the upper body, originates in the T1 to T5 region. So a little bit of disconnect there. And pulmonary edema, I think, is also really interesting. There was a case of a patient who died in the Tampa VA because of neurogenic pulmonary edema. Basically, the hydrostatic pressure in the vessel became so much that it drove fluid out of their lungs, and they drowned, which is awful and something that we should all know about. Or potentially the scariest symptom, one that happens most frequently is no symptoms at all. We'll talk a little bit more about how commonly that happens, but it's very concerning. Okay. Now to challenge a few of our classically held beliefs. Mechanistically, I talked about how bradycardia really is a vaguely mediated process, but how common does that actually happen? Classically, I think we hang our hats as psychiatrists on those two paragraphs that we learn, at or above T6, hypertension, bradycardia. But there isn't a great reason why we hold bradycardia at such high esteem. I think going back to that previous slide, we talked about all the different presentations. We want to say that you don't have goose bumps, and so you aren't having autonomic dysreflexia. We might need to evaluate bradycardia and similar symptoms. So a pediatric study from a few years ago looked at 16 different episodes of dysreflexia, and only 12.5% of them, a small number, had bradycardia. Half of them actually had tachycardia. In a larger study that we did when I was in residency, we had 445 episodes of AD. This was in a chronic VA population, so people that had been injured much longer, and only 0.3% of them had bradycardia, which is ridiculously low if we're going to use it as a pathognomonic part of the definition. Instead, 68% had tachycardia. Potentially something we need to re-evaluate. The reasons for this aren't totally clear, but probably have something to do with reduction in baroreflex sensitivity. So those carotid baroreceptors that you have basically have some set point where when they dilate to a certain degree, they slow your heart rate down. And that baroreflex sensitivity is a known quantifiable value that is known to be decreased in spinal cord injury patients. Part of that is probably due to being able to engage less in physical activity. You're not able to increase your heart rate to the same degree. And the other thing, especially in chronic patients, is the incidence of cardiovascular disease. So if all of a sudden you have a very stiff vessel that just isn't allowed to be pried open very much, you're not going to get necessarily a decrease in your heart rate. All right, so bradycardia is far from a slam dunk. How about neurologic level of injury? So we use that T6 classification, like I said, but there's been cases of autonomic dysreflexia that have been documented in patients with injuries down to T12, which is mechanistically kind of hard to rationalize how it would happen with someone that low if we're thinking about neurologic level injuries as a hard cutoff. We additionally did some evidence that anxiety can cause people with autonomically incomplete injuries to have increases in their blood pressure. In these cases, it was someone, two people, who came in for urodynamics. And as everyone knows, urodynamics is not the most pleasant experience, especially if you have some disparate sensation. These patients got anxious and their blood pressure came up just the same as you or I might have their blood pressure came up. So additionally important to think about anxiety as one of the presenting factors. And then I touched on this briefly, but thinking about injuries in terms of autonomically incomplete. So the T6 level that we determine based on our INSCE exam is a motor and sensory level and kind of guesses at autonomic completeness. At T6, we're actually more or less guessing at motor level as well. So really, we're saying your sensory level is the same as your autonomic level. Might not always be the case. So we really shouldn't be surprised and use T6 as a hard cutoff if someone with T7 or T8 injury is necessarily presenting with something that looks like dysreflexia. There are established ways to look beyond neurological injury. One of the oldest and probably best studied is the sympathetic skin response. So for those of you who are doing injury now or are into neuromuscular physiology, sympathetic skin response is a very easy nerve conduction study where you set up these electrodes on both hands and you surprise someone with a shock. You basically say, I'm going to shock you on the count of three. And you go one, two, and then you wrap it. And what you're looking at is the galvanic skin response on their palm. Basically, the surprise component of that will make them sweat just a little bit. And change the skin conductance. The same mechanism that we use for things like a lie detector test. Fundamentally, this falls victim, I think, to some of the same fallacies as using neurological injury, motor and sensory, for determining autonomic because this is looking at pseudomotor responses with sweating compared to basomotor responses with facial construction. But that's the new thing here is this is actually pretty good at predicting if someone is going to have autonomic dysreflexia. Taking this to the next level, we've been working on a battery of tests here to develop autonomic phenotyping and really pin down exactly how people's autonomic systems respond to sympathetic engagement. So one nice test for that is a cold presser test. And this would take a patient's hand and dunk it into a bucket of ice water. So this is a patient with a participant without a spinal cord injury. We take their hand, dunk it in water. On the bottom, you're seeing a trace of their blood pressure. So it starts around 140 and goes up to about 160. And on the top, you're seeing a sympathetic neurogram. So this is a technique called microneurography, which is basically a single fiber EMG of their sympathetic system in their leg. This is a normal response. You see their blood pressure increases. You see increasing spiking activity and relatively high amplitude. Hand stays in the ice water for about three minutes. You take it out. Blood pressure comes down. And in general, you see less spiking activity, both amplitude and frequency that happens. Now, if we do this to a patient with a spinal cord injury, we see this is a patient with a T3 spinal cord injury, Asian pyramid scale A. We see their blood pressure increases about 10 millimeters mercury on the bottom. And they have appreciably one, two, three, three spikes of activity in their lower extremity. So this is not an autonomic response in their lower extremity when their hand goes into the ice water. When we take their hand out of the ice water, though, it becomes very interesting. So they have all of these fluctuations that we see in their blood pressure, at one point going as high as 185 or so for their systolic having, by definition, dysreflexia. We see all of the spiking activity that they're able to elicit in their lower extremity, despite having a motor sensory complete injury. This is really important. In that same individual, if we take their left foot and put it in the ice water, recording on their right leg, we see that their blood pressure increases. So it goes up 20 millimeters mercury. It is, by definition, dysreflexia. But on their right side, they're not having any increase in spiking activity. This tells us something about what's happening inside their spinal cord. So we talked about that CGRP reactive after it's kind of branching out and sprouting out to new targets. This tells us that there's not a lot of cross reactivity within their cord. Painful stimulus on one side, not spreading on the other side, despite activation of their vasculature. So this is important, and this is the beginning of really defining what is happening for patients with spinal cord injury in terms of what's happening on the autonomic front. Subsequently, so this is a person with, I'm sorry to get excited about this, this is a person with Asian impairment scale A spinal cord injury, who is autonomically incomplete and does not have evidence of spreading of signals inside their cord. So this is a very favorable phenotype that we would imagine. This person is 20 years out from spinal cord injury, has never had any issues with their skin, never had a pressure injury, has had two UTIs in their entire life, has had AD once when he broke his leg. So the ability to regulate blood pressure in your lower extremities and your body in general definitely looks like it's going to be a favorable phenotype. So that's all interesting in a very academic sense. But putting back on my clinician hat, AD isn't something that I see that commonly in the clinical practice. Maybe once a month, once every few months, someone comes in and explicitly says, oh, I'm having problems with my blood pressure or with AD or something like that. So we're going to open up the chat for this and hopefully I can figure out how to see this. But for an audience response, how often do you think patients who are at risk for autonomic dysreflexia have episodes? Are they having zero to two episodes? Are they having three to five episodes? See if I can look at the chat at the same time. I unlocked the ability to unmute yourself. I'm assuming that there's responses coming in that I can't see, but I will assume that. We got a three to five. Okay. At least two is another response. Zero to two is another response. I'll give it five more seconds. All right. I want to be held accountable to that. More common in the acutely injured. Somebody else says in two months of inpatient, they never saw it. Three to five. Someone else? Okay. We'll close things there. Three to five was the closest, but it was a little ways off. So the average number of episodes of dysreflexia, but someone who's at risk, neurologic level of injury after above T6 has in one month is 403. So that is a baffling, baffling number. The studies that back this up are all looking at ambulatory blood pressure monitoring. So patients that have blood pressure cuffs that inflate on a Q10 minute or Q15 minute And have shown consistently that people have, at least in this study, in the first study, at least three episodes of AD where their blood pressure is going up more than 40 milliliters mercury in 48 hours, a subset they're having 25 episodes in 48 hours. Another larger study saw an average of 13 episodes in a day. There's a figure here where someone had 60 episodes in a day. We are either just seeing the worst of it. So noting when blood pressure increases are really high in people having emergent situations or we're catching it incidentally, and it's going to be something that resolves on its own. And we're getting very worried about it. We're seeing the forest or we're seeing the trees instead of the forest in that situation. Okay. So that is a shockingly large amount of dysreflexia, especially as someone noted that you never really see it on the inpatient side. So it's hard to pin down. But if people are having 400 episodes of AD in a month, people aren't having 400 strokes or 400 retinal hemorrhages, is it really that big of a deal? I would argue that it might be. So we know that cardiovascular disease is the number one source of mortality for individuals with chronic spinal cord injury. It's higher than renal, higher than pulmonary. If you've got tetraplegia, it's about 20% higher chance that you have cardiovascular disease than paraplegia. If you've got a complete injury, about 44% more likely to have it than you have incomplete injury. How dysreflexia kind of ties into this is that there is an incredible amount of vessel shear stress that occurs with this. So if your pressure goes 90 to 115 to 85 to 120, 40 times a day, that's really, really bad in terms of trashing your vessels. It's increasingly becoming apparent that those changes in systolic blood pressure are probably worse than if you had a central hypertension, you're hanging out at 150. To me, I like to think about it in terms of like the NFL linemen. So super strong, gigantic dudes whose blood pressure is at baseline a little bit higher but have to increase their blood pressure very quickly for brief periods of time. Routinely, those individuals have terrible cardiovascular disease complications, much worse than age, gender, BMI matched cohorts. So just those changes in blood pressure are really bad. Other implications are potential for immune paralysis, which has been shown in animal models. Really after dysreflexia and sympathetic engagement, you get this outpouring of norepinephrine, which accumulates in your system, along with some glucocorticoids, and that causes a transient immunosuppression that happens after a spinal cord injury, right, where you have dysreflexia. In mouse models, they've shown that this leads to splenic leukopenia and immunosuppression that can accompany all of this. While patients aren't necessarily coming in to me and telling me about problems with dysreflexia, the story that I hear more often is this, and tell me if this sounds more familiar. So a patient comes in and says, hey, I had, this is pre-COVID, hey, I had a really great weekend with my kids, I went to this amusement park, we were riding roller coasters all day, and I usually cast every four hours, and I get volumes of like 400, and, you know, I forgot, it was six hours, and I got 800 mL, and I had a really great time, but Tuesday I come in, and it feels like I've got a UTI. That's a story I hear pretty commonly, and in my mind, I'm starting to think about AD in that setting. So even if patients aren't necessarily feeling it, they're not feeling all those episodes every month, dilation of the bladder from being overly full leads to some breakdown of the urethelial lining, the bladder already has bacteria that are in it, it's part of the urobiome, now all of a sudden your bladder's spasming and driving pressure, so you have some focal ischemia, and a little bit of dysreflexia. So you have a bladder that already has some breakdown in its defenses, an immune system that has transient immunosuppression, and you get a UTI. That's something that I see much more commonly, and we'll talk about how that's relevant for a COVID patient, or patients at risk for COVID. And then, finally, what I want to talk about in terms of implications is just the psychologic component of it all. So there's a certain fear which patients have conveyed to me with being at risk for dysreflexia. So imagine that you knew that you could have a stroke if you didn't take a pill every four hours for the rest of your life. There's a real fear that accompanies that, and I think something we can address as providers telling patients that yes, they need the calf, yes, it can lead to dysreflexia, but in many cases it's not the sort of dysreflexia that's necessarily going to lead to a renal hemorrhage or something else. It's really terrible. So rethinking how emergent of a situation it is for low-grade dysreflexia, in light of what I just talked about for cardiovascular disease. Another psychological component is just having to explain the diagnosis. So I have a number of friends with spinal cord injuries who have unfortunately told me about this calculus that they go through, where they say, I know I'm having dysreflexia. I know I've tried to address different sources of it. I don't have any medication at home, but is it the type of dysreflexia that's going to eventually lead to a stroke or something like that? Or can I avoid going to the emergency room for eight hours and having to explain to the provider who might not be familiar with AD that I'm not just anxious and I shouldn't breathe into a paper bag in a dark room? That's something that I think we can address as well. Okay. So kind of recentering the clinical view. This is a 23-year-old female who presents to clinic, T3, Asian Pyramid Scale B. She has a current stage three pressure injury. She's having sweating episodes. She's having headache. Can you check her blood pressure? It's 135, which is 40 millimeters up from her baseline. Let's talk about management. How do we address this? Luckily, as I mentioned, there are the Autonomic Dysreflexia Guidelines. These really have three core tenets, and I mentioned these tenets are going to be unchanged. So the first one is conservative management, doing what you can right away to bring the blood pressure down. Second, identify the source of dysreflexia. And third, pharmacological management if the pressure is higher than 150. Okay. So conservative management, this is going back to boards mode. This is always the correct answer that they'll give you a case where someone is in dysreflexia and they'll say, what should you do? And the answer invariably, put the patient up. That's the first thing. First thing you do, put someone up. If you can, allow their legs to free float. That'll bring their blood pressure down below five to 10 millimeters mercury, but you're looking for conservative things to buy you time. Second, remove any constrictive clothing. So if they have a stripes on or head stockings, take those off. If they've got an abdominal binder, take that off. Do what you can to bring that blood pressure down. Then look to identify the source. My SCI mentor in med school used to tell me that the 10 leading sources of autonomic dysreflexia are bladder, bladder, bladder, bladder, bladder, bladder, bladder, bowel, bladder, skin. So really think about bladder a lot. The guidelines talk about using a lidocaine to help pass catheter if you have time, using lidocaine before. Sometimes that can be tricky. So I know as a, as a resident, I wasn't commonly asked to, to place catheter, but in some scenarios nursing could not get it placed and they would say, well, we need to talk to urology or something like that. So here's, here's a couple of quick tips how you can get that catheter, especially with patients with dysreflexia where their external urethral sphincter might be spasming and really hard to get it. Okay. So you got your catheter. That's really quick. Instead of just jamming it over and over into a closed external urethral sphincter, apply a little bit of gentle pressure. That usually allows a little bit of relaxation in their external urethral sphincter. Catheter goes in, bladder drains, there's your, you saved your urology consult. A second way to make sure or to increase your chances of getting the catheter in is by knowing the physiology. So we know that the external urethral sphincter is wired up more or less in parallel to your, your anal sphincter. So we can take advantage of that, just the same as you, same as you would do a DigStim with one finger. Go in with two and do what's called scissoring. So you kind of make a scissor inside the anal sphincter. That relaxes the sphincter, you're basically causing the stretch. And at the same time, you'll get a relaxation because it's wired in parallel in your external urethral sphincter. Catheter goes in. You get a cupcake the next day, you can't see, just save this patient, there you go. After the bladder, you want to look at bowel, you want to look at skin, make sure that those, those areas are adequately addressed and that there aren't painful stimuli coming from those. If those things aren't working and the pressure is still going up, you want to look at medication options. So classically, and you still might have some attendings and talk about this, the medication that was used was nifedipine. This was a bite and swallow, where they kind of bite it and spray it underneath your tongue. Pretty limited study. There was a patient, a study with 10 patients that showed nifedipine seemed like it was helpful. However, in 2001, there was a black box warning, which was issued from the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure, saying you should not be using nifedipine. It lasted in the system a fair amount of time, people with blood pressure was voting loud. People also talk about captopril as one option. This was a pretty small study for captopril, five patients, and prazosin being used as a, as a prophylactic. Prazosin is actually a decent medication, not for use necessarily in acute management of dysreflexia, but it acts as an alpha blocker and, and can help with some prophylaxis or people are having dysreflexia all the time. Not for acute management, but some evidence that it seems like it helps for prophylaxis. Okay. The management, which is preferred by the consortium guidelines, which we studied a few years ago, is a progression through conservative management and then nitroglycerin paste and oral hydroxy. So as I mentioned in this study a few times, we did conservative management first to try to decrease the dysreflexia that people might be having. That resolved about 10.6% of nitro, or of AD. That's a gross underestimate. As I mentioned, people having 400 episodes of AD aren't using this management protocol all the time. So probably 90, 95% of dysreflexia is resolved in some, or with conservative management. If those conservative steps, sitting someone up, taking off their abdominal binder, don't work, we used one inch of nitroglycerin paste. You can apply it either to the chest or to the forehead. Doesn't seem like it makes a huge difference. That resolved another 40% dysreflexia. And by resolved here, I mean that the blood pressure stops going up and starts coming down by at least 10 millimeters per minute. So really reversal of your dysreflexia. If after 10 minutes, blood pressure does not come down, we gave another one inch of nitro paste. That increased the cumulative resolution to about 85%. 10 minutes later, you're still not getting a response. We gave 10 milligrams of oral hydralazine. And 10 minutes after that, you still don't have resolution, giving another 10 milligrams. Cumulatively kind of going through that protocol resolves over 97% dysreflexia. There were four individuals who needed further escalation of care in this model. All of them had their blood pressure come down too low. So one of them needed midodrine. Two of them were ICU transfers. So people were a little bit worried that someone's blood pressure went from 200 to 80. And one person received normal saline. Again, thinking about nitro paste in this setting especially is great as a first-line agent because you can just take it off and lose the effects that go with it. We'll talk about that in a second. A couple insights that have come in terms of nitro paste. Again, a big proponent of that as a first-line agent. Kind of onset of action. From that large retrospective study, showed that it was around 9 to 11 minutes. Again, this is chronic SEI population with dysreflexia that's really revved up. Blood pressure stops coming up, comes down within 10 minutes. In a smaller prospective study where we did cystoscopy, so much more acute dysreflexia, applied nitro paste, we had a response within 90 seconds. Somewhere between that 90 seconds to 10 minutes, expect that there should be something. If there isn't, think about escalation here. The other really great thing about nitro paste is that there's good evidence that had dual action. So not only is it causing systemic vasodilation, kind of bringing the pressure down, but there's a nice study done in 2004 in France that showed that there is relaxation of that external urethral sphincter at the same time. Nitric oxide causes relaxation. So think about that, not only causing peripheral effects with vasodilation, but potentially relieving some of the initial source with the external urethral sphincter relaxation. We went back and looked at our large database and showed that people with bladder-related dysreflexia had a faster onset of action when using nitro paste compared to non-bladder AD, and they also had a greater decrease in their systolic blood pressure when we used that medication. Other important considerations of nitropaste, I mentioned that you can just kind of wipe it off, which is one nice effect. When you do that, you need to watch out for rebound hypertension. So assuming that you're having some rip-roaring AD from your bladder, you give them nitropaste. The blood pressure comes down because you're causing the vasodilation. You take it off. You need to be watching that that initial source is not still kicking up their sympathetic tone and their systolic blood pressure. So we did a small study that's still enrolling patients that basically shows that nitropaste wears off in less than two minutes. You're starting to see some blood pressure come back up. It's a pretty wide standard deviation at this point. But 95% confidence interval captures that 95% people have blood pressure that's coming up within five minutes. So at that five-minute mark, check blood pressure again. Make sure that you've addressed the initial source of dysreplexia and that that pressure isn't coming back. OK, way behind on my slides. OK, other considerations are intrathecal baclofen. And this is a resident on a study that I like in theory, and it shows really pronounced findings. They had 34 patients. They did a retrospective chart review, had a relatively standardized list of questions that they asked people. Patients received baclofen pumps for spasticity, but they looked at it and said, before you had your baclofen pump, 75% of these people were saying that they also had dysreflexia. Afterward, 5.9%, so very, very precipitous drop. Far from slam dunk. Definitely need more research on that area. But mechanistically, that kind of makes sense. If you're decreasing connectivity within your cord for spasticity, you could have some potential autonomic effects. It's something to watch out for. If you have a patient with a lot of spasticity, you're dosing them full of Botox all the time, and they've got bad AD, think about a pump. It's not that out there to be doing that. Another medication to consider is lidocaine. So we talked about this being recommended for pre-treatment before placing a catheter in that consortium guideline. We did another study showing that pre-treatment with 2% lidocaine before a catheter change in 50 individuals with sonocord injury really decreased the risk or decreased the incidence of dysreflexia from about 50% to 15%. The magnitude was also decreased. Onset of action for the lidocaine was 90 seconds. So totally clinically feasible. If you were thinking about, what can I do to decrease dysreflexia in my patients, using lidocaine before a catheter change is definitely appropriate. Is there fully catheters and therapeutics for plant changes? Okay, specific relevance in the age of COVID-19. So we talked about the transient immunosuppression that can happen with dysreflexia. Doing what you can in counseling patients to stay on top of their cath schedules, stay on top of their dial programs, not only to keep them out of the emergency room or other complications, but to make sure that their immune system is as healthy as possible I think is important. Along these lines, if people have leg bags or they're suprapubic or fully, you want to make sure that those aren't more than 80% full. Bags that are especially plump and full don't drain your kidneys and can lead to dysreflexia and bladder complications, things you want to avoid at this time. Hand hygiene, especially important for patients with manual wheelchairs, realizing that you're probably touching your rims with those hands and that's touching the ground over and over, so making sure that you are washing your hands. This goes for everyone, but especially people with manual wheelchairs, thinking about personal care attendants and really kind of that web of connectivity of who all they're interacting with, making sure that they're also washing their hands and staying hygienic. Because in the end, this all kind of comes down to respiratory worries, and this is what I've been talking to my patients about. Most places are not at the point of having rationing for ventilators, at least as far as I've seen, but there have been guidelines that have come out. And if you are someone who might be on a ventilator for a long period of time, you're going to be looked at differently than if you are a otherwise healthy individual who might be on the vent for a day or two. If you've got a C5, atrial impairment scale A spinal cord injury, and you were on the vent for 25 days initially, you might be someone that's looked at differently. And part of this kind of ties into the ARDS that comes with COVID-19. In my mind, whenever I see ARDS, I always think about critical illness myopathy and polyneuropathy. We know that a lot of the recovery that happens after spinal cord injury happens because the peripheral sprout. So you might gain respiratory function back because those motor neurons have sprouted. Those motor neurons are at risk for things like myopathy, polyneuropathy, and in turn, you being on the vent for a long time. So doing what you can to stay off the vent and steer clear of COVID is the way to go. Okay, so we talked about this a little bit, staying on top of potential sources, also making sure your skin checks are as regular as possible, and that you're staying out of the hospital. General patient advice is something you can do to address AD in general. Education is another key component. So we have this YouTube video that has kind of a more patient-centered, briefer version of this talk. Feel free to share that with your patients. There's also printout cards that we give to everyone that I would also recommend from the model systems. It's nice for them to just, for patients to just have that card, hand it to the emergency room physician and say, hey, this is a real thing. I don't need to tell you about the pathophysiology of CGRP fibers right now because I have the worst headache in my life and I really need care. Okay, so take-home messages. Tachycardia or no symptoms are both very common presentations for dysreflexia. Neurological level of injury isn't the whole story. Looking at motor and sensory scores might not give you everything you need to know, so don't use T6 as a hard cutoff. AD is very, very common. 400-plus episodes a month on average have serious implications. Thinking about cardiovascular disease and transient immunosuppression as some of those complications and trying to tie that into what's happening with our patients I think is really important. In terms of management, nitropaste is definitely your friend. Using it in conjunction with hydralazine, that protocol, 97% effective. I think that should be widely implemented for most places that have that medication available. I know it's not available in Canada, so we're working on advocacy there. For onset of action, think between two and 10 minutes for when you should start to get some response from the nitropaste. Improved pharmacodynamics for bladder-mediated AD and then probably watching for five minutes after checking that blood pressure, making sure you don't have rebound hypertension after you wipe that medication off. Lidocaine pretreatment has shown good availability towards decreasing AD incidence. And that's easy something that you can do to decrease how much dysreflexia patients are having. Okay, so that was a whirlwind topic tour. Hopefully you now feel better armed to identify dysreflexia in clinic, really consider its role in presentations and ultimately help patients. I think we hopefully have a few minutes for questions if anyone has any. We do, and we have a few questions. I'll read these out. Go ahead, go ahead. Okay, and if you don't get your question asked because I ramble on about things and get excited, I put my email up and my Twitter handle, so feel free to keep this conversation going. Okay. Perfect, thanks. So first, sticking with the nitro topic, do you give your patients a prescription for nitro to have at home? Some of them. If they're having frequent dysreflexia and you have a fair amount of trust in them, then I do give them a home prescription. If nothing else, even if they don't use it, I think it's nice that it sits on their med list and they come into the emergency room and it says, oh, they were prescribed this nitro paste and there's some record of maybe I should be using this. Otherwise I make sure that I always counsel them to train their caregivers, make sure their caregivers are wearing gloves and people usually think it's entertaining anecdote, but it's very realistic that people don't put gloves on, they think there's an emergency situation, they should come in, they put their nitro paste on their loved one and then they both pass out. So make sure that they wear gloves and that's something you can help reinforce. Noted, thanks. Second, I've heard some, this is, somebody said that they've heard some SCI specialists advocating for applying nitro paste to patient's foreheads, primarily to prevent folks from forgetting to wipe it off and causing severe iatrogenic hypertension. Is that something you've heard of and are there any pharmacological concerns about that? Yeah, so I've talked to a number of people about this. It's very regional, depending on where you apply the nitro paste. Forehead is someone that's commonly used, as you said, just so that people don't forget about it. It's hard to forget when people have a card sitting on their head. Other places that are trained on the West Coast, they put it on the chest. I think pharmacodynamically, it probably doesn't make a huge difference. As long as you're applying it above the neurologic level of injury, thinking that that's an area where you're having vasodilation, so you should get increased absorption. Technically, if someone had a C2 injury and you're applying it, and they have a short C3 cape and you're applying it here, and it happens to hit T2, T3, maybe it doesn't absorb as quickly, but I think it's still getting into the body. I don't think there's, there definitely has not been any clear literature on where you should apply it. So using the anecdote of we don't wanna forget it is pretty safe. Okay, that is- Similarly saying, putting it on the upper chest is also reasonable if you don't wanna be putting things on people's heads. Yeah, okay. And that also kind of addresses another question about above or below the level of injury for nitro paste. Not a lot of literature, it sounds like, but the idea of vasodilation certainly sounds like it might help. Right, and it's variable if people are going to have clear vasodilation. Some people have very pronounced lines where they say, oh, everything above this is very red, and other people have, and pale below it, but that's far from a slam dunk. Okay. Are serotonergic agonists, such as buspirone, ever given for AD, or would they at least help temporarily? I have not heard of people giving it specifically for AD. I hesitate to say that it would help. There's some evidence that other serotonergic activating treatments, like intermittent hypoxia, actually increase sympathetic engagement, and medications like SSRIs in some people cause increased spasticity. I think in general, using things like buspirone, intermittent hypoxia, SSRIs, are going to increase the signal at a time when you really wanna be tamping it down. So I wouldn't necessarily have that be one of my go-tos. Okay, going back earlier, considering the increased synapses below the injury and increased adrenergic receptors, why do most patients with SCI present with hypotension? At baseline? Yes, I believe so. Okay, so that's a really good question. In general, you have low sympathetic levels of engagement, so your blood vessels are not being told to constrict at all. So they're just kind of hanging out. That's one of the reasons why you get the alpha-1 adrenoreceptor upregulation. Your blood vessels are, for lack of a better term, kind of bored. They're not seeing that activation, so they're looking for any signal that they can to squeeze down. Tied in with that, neuropinephrine levels are classically very low in patients with spinal cord injury. They're just not having that sympathetic engagement at baseline. So it's a low-level sympathetic engagement, so you don't have anything that's kicking your blood pressure up, more or less. People usually get a little bit of recovery in their blood pressure, typically during inpatient rehab, but that's happening less, it's happening probably less from sympathetic engagement and more from upregulation of your renin-angiotensin-aldosterone system. Okay, and I think we have more questions than we have time, but if you have a second for just one quick hit, treatment of silent AD, is it something that we should be doing at all? And if so, how? And second, any special thoughts regarding pregnancy? Those are both really good questions. I don't think presentation of symptoms necessarily correlates with what we should do for management. If someone is feeling totally fine and has silent dysreflexia and their pressure is 220, we should be doing something to bring the pressure down. I don't think that those are safe levels to be at, regardless of how you're presenting. So I wouldn't change how the treatment or how the management is really going there. Pregnancy is a really, really hard situation. It kind of goes along with the group of planned surgeries, things that we know are gonna cause pain below the level of injury. So for patients with pregnancy, it's usually a conversation with high-risk OBs and anesthesia, making sure that they have usually a planned C-section and that they have an epidural. Even a few weeks ago, I had conversations with inpatient docs for patients with complete spinal cord injury who were getting bullets removed from their leg without any anesthetic. Anything that's gonna cause pain is something that we need to be aware of for dysreflexia. So for pregnancy patients, getting an epidural I think is totally appropriate, making sure everyone is on board with a planned procedure. That makes a lot of sense. Thank you very much. I appreciate it. So just quickly, I want to thank Dr. Solinsky for his help. Whoop, I've got a lot of, I don't know what all you guys can see, but I've got a lot of stuff popping up all of a sudden. Thank you very much. Again, we're gonna continue this series every day at the same time. It's noon Eastern, 11 o'clock Central. These lectures have been recorded and the information and links to the recorded versions will be posted at that website there that also has the updated schedule, Zoom information, meeting information, passwords, that sort of thing. If you have any further questions, feel free to reach out. You can reach either of us on Twitter or via email there. And again, thank you very much for participating.

autonomic dysreflexia

spinal cord injuries

systolic blood pressure

bladder distension

bowel distension

complications

management

conservative measures

pharmacological management