Hello, everyone. I'm Dr. Maia Tsurgeladze, moderator for this MNAMES webinar on Clinical Practicalities for Phenotyping Oral Appliance Non-Responders by Dr. Jonathan Lowne. Thank you so much, Maia. Thank you. So let's get started. Of course, my name is Dr. Jonathan Lowne. I think some of you know me, hopefully. So we're going to talk about Clinical Practicalities for Phenotyping for Oral Appliance Non-Responders. Whoops. So that's me. I'm boarded in internal medicine sleep, and I am a OSA patient. I'm actually a compliant CPAP user. So objectives tonight, we're going to discuss the theoretical phenotypes of sleep-related breathing disorders. We're also going to describe the non-anatomical factors affecting oral appliance treatment response. We're also going to mention collaboration with referring physicians to provide personalized treatment plans for our patients. We know that oral appliances are efficacious. They're specifically efficacious in terms of reducing snoring and reduction of HI and also daytime sleepiness. We don't have any outcomes data in terms of mortality. Hopefully that will be forthcoming somewhere in the future. What's also important to remember is this is data from the Orange Registry. The Orange Registry obviously is looking at a number of different studies with oral appliance therapy. What's interesting about this is that some of the patients in the Orange Registry were using monoblock therapy. And yet, overall, the HI success, less than 10, was significant. It was about two-thirds of patients in the Orange Registry actually had an HI less than 10. That's actually a very good number. In terms of a 50% reduction in HI, we had 35% of patients being successful. Overall, about half of patients who were using oral appliance therapy had an HI less than 10. The other important thing that I'm sure we're all aware of is the fact that CPAP therapy is difficult at times. As much as I love CPAP, and I think it really should never be poo-pooed, we know that compliance is not always the greatest. And really, compliance is the number one issue, or the main issue, I should say, in terms of treatment. This is data from both short-term and long-term studies with oral appliance therapy. Now, granted, some of these studies are small, but overall, the compliance, or the usage, I should say, for oral appliance therapy was excellent. It was 6.7 hours. So, this is a lot better than the compliance we typically get with CPAP therapy, which is, unfortunately, under four hours, typically, in large clinical studies, which is one of the reasons why I think we're all here discussing oral appliance therapy and how to better manage patients with oral appliance therapy. So, along that line, because we have this 64% that's achieving an HI less than 10 that's great, we still really want a lot more patients to be successful in terms of reduction in HI. And that's where I think endotyping and phenotyping, specifically, can be helpful. And initially, when Trish Braga suggested endotyping and phenotyping, I kind of thought this was a little too esoteric and wasn't very clinically practical. And I've really ate humble pie on that one. So, I have to give her kudos. I usually try to do that, not too much. But initially, I thought the phenotype and endotyping would be useful at determining who's going to be successful with oral appliance therapy. And there's some utility in that regard. But I think the other way to look at the endotype and phenotyping paradigm is that we may be able to achieve a lot better success or a lot better results with a lot more of our patients. And that's why it's important to understand that, that we really should be able to get a lot more patients with an HI less than 10, not just that 64%. So, what is phenotype and endotyping? Well, phenotyping is just the observable expression of any individual's characteristics resulting from really their genes in the environment. But it has really no discussion about the implication of mechanism. Whereas, endotyping is really trying to explain what the pathophysiological mechanism that underlies somebody's particular phenotype. So, an example is that we know that as we get older, there's a higher likelihood of having sleep apnea. So, the phenotype would be OSA in the elderly patients. And the endotype, at least part of the explanation, could be that they have a more hyporesponsive genioglossus. So, that's really the endotype, the hyporesponsive genioglossus. The phenotype is the manifestation in older folks. So, I don't know if it's that important to understand the distinction between phenotype and endotype, but it's important to understand that at least endotyping is trying to explain what the underlying pathophys is. And a lot of the discussion we're going to have in a second comes from Danny Eckert's data. There's a number of researchers that are involved in this area, but this is actually from a paper from Danny Eckert that I think most of us are familiar with. And if you look at the epidemiologic data, we obviously have about at least 23% of women who have OSA and probably about half of men, especially between the age of 40 and 85, that potentially have OSA. And the majority of undiagnosed sleep apnea is occurring in non-obese patients. We know that probably about 30 to 50% of OSA patients are non-obese. And we also know that 50% of patients are going to be non-compliant, like I mentioned, and really are going to use their CPAP for less than four hours a night. And so an approach here is to try to understand what really is the underlying mechanisms that are occurring that are causing sleep apnea in each individual patient. And so Danny Eckert and colleagues really broke down the data and came up with four key traits or phenotypes, and we're going to talk about that in two seconds here. The first thing to remember is that really almost all patients that have sleep apnea have some degree of anatomical compromise or narrowing or increased collapsibility. And that's happening, like I said, in almost all patients. But the significant non-anatomical component, and it can be broken down into three things really, namely ineffective upper airway dilator muscle function, unstable respiratory control, or high loop gain, and low respiratory arousal threshold. And so they broke it down into a simple acronym of PALM, which stands for PCRIT, arousal threshold, loop gain, and muscle responsiveness. And let's talk about PCRIT to start, because I think it's something that is still very valid, and there's definitely some confusion about PCRIT. When I first heard about PCRIT, I had plenty of confusion. It really should be that confusing, excuse me. It's really based on a Starling model. Starling model originally had to do with blood vessels. It wasn't really about the airway, but Starling model can be applied to a lot of different things. And so in this model, we have a sealed box, and we have a tube that runs through the sealed box. And the portion of the tube that's in the sealed box is really a collapsible segment. So anatomically, that would be really from the velopharynx down to the epiglottis. And then upstream, we have a bony segment, namely the nasal portion of our airway, and that's relatively bony. And although there's turbinates and soft tissue, it's ostensibly non-collapsible. So the upstream segment is non-collapsible. On the downstream segment, namely the trachea, because of cartilaginous rings, is non-collapsible also. So we have two segments up and downstream of this collapsible segment that are non-collapsible. And the idea is that the collapsible segment resides in the sealed box. Now the pressure inside the box, which is not inside the tube but outside the tube, is really the P-crit. So for example, if I was to put a tube inside this box and pump air in, I would actually increase the pressure or increase the P-crit and increase the pressure outside of this collapsible segment, and I would tend to collapse that segment inside the box in the collapsible segment. I think that should be pretty clear. So if I increase the pressure on the outside of the collapsible segment, it should collapse. If I decrease the pressure, if I make a negative pressure, it would have a tendency to keep that collapsible segment open. And that's really all P-crit is saying. And this is somewhat another view of this. Obviously, the bony segment of the nasal cavity is upstream, and the lower or downstream segment is the tracheal component. And then we obviously have this collapsible segment, as we mentioned. And I like to put it this way, upright, because this is obviously more anatomical. And so the nasal segment we're talking about would be up until the velopharynx. And the reason why I bring this one up also is that although we like to believe that improving nasal patency will change the apnea hypopnea index, the data is that it doesn't really do it by much overall. Most of the data is that it really doesn't work that well. You can definitely improve nasal patency and improve sleep quality, but that doesn't really mean much because there's a lot of things that can improve sleep quality, not to poo-poo sleep quality. But if I give a patient Ambien, I can improve their sleep quality. I won't change their apnea hypopnea index at all. And if you think about if I put a straw down or like a object that was non-collapsible down the nasal segment in this picture, and it didn't run through the pharyngeal or the collapsible segment, it really wouldn't affect collapse in the pharyngeal segment. And that's unfortunately what we're talking about when we improve nasal patency. So as a result of that, most of the time patients that have sleep apnea have either a more positive PCRIT or a PCRIT that's greater than zero. And so if you look on the right here, you have different degrees or different measurements of PCRIT theoretically. And what we're saying is that most patients who have a negative PCRIT, namely more negative than minus 10 centimeters of water pressure, will have a patent airway and won't have sleep apnea. And as you increase the PCRIT again, increase the pressure outside of that collapsible segment, then you have the airway more collapsible. And so this is all good and the understanding of this is pretty clear. The problem with this is that there are patients who have a positive PCRIT and don't have apnea, excuse me, and there's patients that have negative PCRIT and still have apnea. So there's obviously other factors that play a role, but PCRIT's important. And so obviously PCRIT is the liminal pressure at which the airway collapses, as I discussed before. And there are some simple factors that can affect PCRIT besides obviously weight can affect PCRIT. There's also rostral shifts that occur as rostral shifts. And when we lie down at night, there's rapid shifts from our lower extremities up to our neck. It's one of the reasons why compression stockings, actually the study on compression stockings in OSA was positive. It's not like it took patients with severe apnea and made them normal, but it definitely improved AHI. And the explanation was that you decrease the rostral shifts of fluid, which are tending to collapse the airway as you lie down. And you get this also from exercise. There's definitely evidence that exercise independent of weight loss is associated with reduction in HI. And at least part of the reason why that may be the case is it may actually have decreased rostral shifts. But so PCRIT definitely plays a significant role. We shouldn't overlook that. But the other non-anatomical factors that we mentioned before are also very important. That's again, low rostral threshold or A for low rostral threshold and L for high loop gain and M for poor upper airway dilator muscle control and function. So Danny Eckert and colleagues felt that again, about a hundred percent of patients with OSA have this degree of anatomical compromise, but it really only accounts for actually 30% of the major explanation why patients are having OSA. And so they viewed that about 70% of patients have this anatomical or non-anatomical, excuse me, component and probably about a third, a third, a third, namely upper airway, excuse me, ineffective muscle dilator activity, low rostral threshold and high loop gain. So let's talk about that specifically. So this is just looking at the, all the possible factors in OSA patients. Let's talk about individual reasons. So the first one is the arousal threshold issue. Well, believe it or not, I was always initially taught that the arousals that occur in sleep apnea occur because they're lifesaving and namely that the airway has to open up. And so you have to wake up to open the airway. And it turns out that's not exactly true, that there's definitely data and a significant number of patients that there's actually airflow restoration before there's even arousal. And so about two thirds of patients at least may have actually an improvement in airflow before an arousal. It's not that the arousal doesn't occur, it's that there's an improvement in airflow even before it occurs. In adults, at least 20% of events resolve without any arousal. In children, we know that's a lot more, it could be as much as 50%. In infants, probably about 90% of the events are resolved without any arousal. And there's really quite a significantly higher arousal threshold in N3 sleep. We don't really see much apnea in N3 sleep, which has always been a little bit of a mystery, but is at least partially an explanation you'll sort of see later on in this talk. So what we're referring to a low arousal threshold, and I'm sure you've heard this before, but I'm going to repeat it all. And that is that as the epiglottic or thoracic pressure is dropping as you're trying to breathe and your diaphragm is contracting and you're sucking air in, there's a drop in thoracic pressure, epiglottic pressure. As that is occurring, if the airway is partially collapsed or totally collapsed, what should happen is there should eventually be enough of a stimulus where you wake up. And what we're seeing with low arousal threshold patients is there's only a small perturbation in airflow and they're immediately waking up. So the dotted line in this graph or in this picture, I should say, really represents what most patients should do. In other words, it should be a significant drop in thoracic pressure. It should be a significant drop in airway patency to cause an arousal. And what we're suggesting is these patients are arousing much easier. With kind of a sub-threshold stimulus, they're arousing. And so again, the black line represents the low arousal threshold and the dotted gray line represents what's theoretically should be normal. And so these patients in particular are very twitchy. The analogy we could use or have used before is if you put your hand over somebody's mouth and have them breathe through your fingers, they could breathe through your fingers okay. The problem is that wouldn't be very comfortable and they wouldn't like it and they probably would wake up. And that's really what we're saying is that these individuals' brains is sort of set up where it's too twitchy. So they easily wake up from just any small reduction in airflow. How about the unstable ventilatory control or high loop gain? Well, this is a little bit more complicated. We're going to try to break it down. But suffice it to say that CO2 at night is the only controller of our breathing. We don't have any behavioral component because our cortex is asleep. So we're relying on CO2 changes in the medulla. And obviously if you hold your breath or you stop breathing, CO2 levels will rise and that will eventually cause increased firing in the medulla, namely to all the pattern generators in the medulla that are controlling breathing. And so when CO2 levels rise, our medulla starts to fire and we start to try to breathe or we do breathe. And what can happen though is, and this only happens when we're asleep, is if you drop your CO2 level enough, you could actually convince the medulla to not send out any input. And that's what we call central apnea. And the first part about central apnea is if you want to get your carbon dioxide low, you have to hyperventilate. So there's really two things that have to happen with a central apneic event. And that is you have to have real exaggeration to any kind of perturbation. So in other words, you have this ventilatory response, which is much greater than it should be. And that's one. And then two is you really have to have a very high apneic threshold. We're going to explain that hopefully in a second. But so the solid line represents what patients are doing. Unfortunately, they have high loop gain and that is they have significant increase in ventilatory drive and they hyperventilate and that drops your carbon dioxide. And they really should be only having a small increase in ventilatory drive. And so there's a breathing disturbance and it could be a disturbance of pain. And the patient, instead of having a slight increase in breathing and then that quiets down, they have a significant increase in breathing that drops the carbon dioxide level and it's able to drop the carbon dioxide level below what we call the apneic threshold. And the patient stops breathing. So what's common in central apneic patients, really all central apneic patients? Well, it's a relative respiratory alkalosis. It doesn't really have to be greater than 7.4. Alkalosis is considered when the pH is greater than 7.4. It's really, that's why I say it's a relative respiratory alkalosis. And another way to view it is respiratory alkalosis also means a low carbon dioxide or low CO2. So let's try to look at that in a little bit more detail. So the yellow part of this graph represents theoretically where the normal carbon dioxide level and the average patient is during sleep. And obviously there's a fairly narrow band of pH and CO2 levels while the patient is sleeping. And again, because the medulla is monitoring all this. And when the medulla sees that the CO2 level is rising, it increases respiratory drive and that drops the carbon dioxide level back down. And what we're saying is, is a thing called the apneic threshold here. And the apneic threshold is just a fancy way of saying it's the level of carbon dioxide that you stop breathing. And so the apneic threshold is not a real number. It can change from each individual. Men tend to have a much higher apneic threshold. Women tend to have a lower apneic threshold. But the point is, if the apneic threshold, if I just throw out numbers here, so pretend we're normally spending time at a PCO2 of 40. And let's just pretend the apneic threshold for this individual that we're talking about is 38. It doesn't take them that much to blow off enough carbon dioxide to get their carbon dioxide level below 38. And if that happens, they'll stop breathing. Now, what happens as a result of them stopping breathing? Well, there's actually no output. There's no output to the genioglossus and no output to the diaphragm. So they've stopped breathing completely. And now CO2 levels will rise. And there'll be a point where the CO2 level rises enough where the medulla starts to fire. And if it's a patient who has high loop gain or is very oversensitive to CO2 and their ventilatory response is too high, they'll hyperventilate again and blow the carbon dioxide below the apneic threshold and just keep repeating this. So how is that germane really to apnea that we see in our patients? And how is it germane to mixed apnea? And how is central apnea related? Well, so by definition, central apnea is occurring when there's no total cessation of airflow, but there's absolutely no effort to breathe. So if you look at the left panel here on your screen, you'll see that there's no airflow in the PTAF channel. It's a total flat line. And before that, you get this normal breathing pattern up and down sine wave. And then the person stops breathing. Eventually, they'll start breathing again. The sine wave occurs again. But if you look at the diaphragmatic excursion, which is really saying looking at effort, there's no effort. And that's by definition what a central apnea is. An obstructive apnea, the patient's airway is collapsing and there's no airflow, but they're making an effort to breathe. They're trying to breathe, but the glottis is closed. How about a mixed apnea? So mixed apnea means that the initial portion of the apnea is actually a central event. And going back to our little model, what we're saying is that the CO2 level is now initially dropped because they hyperventilated. And that's why they stopped breathing. And remember, there's no output to the geniogloss. There's no output to the diaphragm. So they're not making any effort to breathe. And when the CO2 level starts to rise to a high enough level, the medulla will say, let's try to fire. Let's start firing. Let's try to stimulate respiratory drive. The problem is the airway can collapse because there's no output. There's no muscular output. So mixed apnea means that the first portion of the event is central. The second portion is an obstructive event. And it's occurring because there's, again, the central apneic event causes no output. And so you have basically an attempt to breathe and the airway is collapsing. And the reason why that's important is that there's a significant number of these patients. We believe that there's at least a third of patients. And I would argue that we miss this a lot. It gets missed a lot because if you're scoring, especially with an HST, you may miss these subtle central events, especially if you don't have what we call a sum channel or some way to really gauge very accurately effort. And so there are patients out there that have high loop gain that we definitely are missing. And these are patients that we should be aware of, just as we should be aware of the low RASL threshold patients. How about the upper airway dilator muscle ineffectiveness? So what we're talking about in this case is basically that the genioglossus is not responding properly. When there's a drop in thoracic pressure, even a small drop in thoracic pressure, epiglottic pressure, the genioglossus should become active. And unfortunately, it's not. And so we're saying about a third of patients, this is happening. It's much more noticeable in REM because we are paralyzed in REM and also because we have increased cholinergic tone that really shuts down the genioglossus, unfortunately. And I would argue that this is very germane to the sleep dentist because the poor muscle response of patient is really one that often doesn't respond well to oral appliance therapy as well. And so what we're showing here is there's an EMG tracing up top, and that EMG tracing is obviously electromyelogram. And what we're saying here is that you should get this gray line up top. That should be the normal response that when the thoracic pressure, if you look down on the bottom where it says epiglottic pressure, epiglottic pressure is dropping. It should be increased in genioglossus activity. That's normal. Unfortunately, in the poor responsive patient, they have no activity at all. So the genioglossus is basically asleep throughout the whole period of apnea. Why is that important? Like I said, this occurs commonly in patients that are poor responders to oral appliance therapy. And I did want to mention a medication trial that's now actually they're looking to actually get this drug approved eventually. What they noted over years of research was that there's two major inputs to the genioglossus, and that's both adrenergic as well as cholinergic. And so it turns out that the cholinergic tone that is occurring is occurring in REM sleep. So we know in REM sleep, REM sleep is unique because there's a significant increase in cholinergic tone. And what that does is it basically shuts down or can shut down the genioglossus. And in terms of noradrenergic tone, well, during a non-REM sleep is actually a drop in noradrenergic tone or noradrenaline that occurs. And that's partially responsible for the genioglossus also being under responsive. So this group in particular looked at the combination of two drugs that would affect changes, namely in cholinergic tone as well as an adrenergic tone. So they selected oxybutynin and atomoxetine. Oxybutynin is an overactive bladder drug. Atomoxetine is commonly known as Triterra. It's a drug we use for ADHD. So their hopes were that oxybutynin would block the increase in cholinergic tone that you get from REM sleep. And in other words, protect the genioglossus, keep the genioglossus awake during REM sleep. And then the atomoxetine would increase noradrenergic tone during non-REM sleep and then therefore keep the genioglossus awake during non-REM sleep. And surprisingly, they had a tremendous response. So they showed that the HI was reduced by 63%. So the HI went from 28.5 down to 7.5, which is a wild thing, again, with the use of these two medications together. Now, the weird part about this is that when they used, they had nine patients. This is a study of only 20 patients. Each patient actually crossed over. But they had nine patients who were on monotherapy. And those nine patients on monotherapy, believe it or not, it didn't work. So this is graphically the reduction in HI, which we said was about a 63% reduction in HI, which is ridiculous. An improvement in O2 sats, obviously. And this is what I was referring to. If you look here, the individual therapy, namely oxybutynin and atomoxetine individually, for bizarre reasons, didn't work in monotherapy. You would have expected the oxybutynin to work in REM sleep and the atomoxetine to work for apnea in non-REM. But it turned out it didn't really work at all, only the combination. So that's still not clear why that is. But very interesting. And again, a potential therapy in our future for the under-responsive or poor muscle responder in terms of OSA. So once again, we got peak creatinine arousal threshold, loop gain, high loop gain, and poor muscle responsiveness, as we showed before. So let's just talk specifically about that. What would that mean? So if we have a patient, for example, with low arousal threshold, we could consider them to be on azapiclone, which is also called Lunesta and even trazodone. And I've definitely utilized that. In fact, really after becoming interested in the whole idea of phenotyping, I've started using other therapies like this with significant success too. In terms of the unstable or high loop gain patient, well, we know that CO2 sensitivity is a problem. And for unclear reasons, if you give oxygen to patients, you can actually decrease CO2 sensitivity. So giving oxygen to high loop gain patients, believe it or not, can help significantly with central apnea and complex apnea. You could increase CO2 by increasing dead space ventilation. And I more commonly tend to use acetazolamide, which an easy way to understand acetazolamide is it really just acidifies the blood. So it's keeping the pH on the acidic side, always keeping some stimulation of the medulla and preventing that kind of relative respiratory alkalosis that I mentioned. In terms of the ineffective upper airway dilator muscle activity, we mentioned before that there is theoretically drugs that may be coming down the pike. And that's namely the atomoxetine-oxybutyne combination. We'll see what happens. There is something to be said about myofunctional therapy and upper airway muscle training that definitely seems to be effective. And of course, hypoglossal nerve stimulation also fits nicely into this. And one thing I'd say about hypoglossal nerve stimulation is none of us should be afraid of this. This is really a subset of patients in the original STAR trial, about only 10% of the original patients that were screened were found to be eligible for hypoglossal nerve stimulation or INSPIRE. And again, these are patients that we wouldn't expect to be that responsive to oral pine therapy anyway. In terms of the affecting PCRIT, we talked about compression stockings, weight loss can definitely affect PCRIT exercise and also positional therapy. So this is just another review. This is a little bit of a nicer cartoon here. But again, the therapies that we're talking about, I mentioned for low arousal threshold is apiclonar trazodone, the high loop gain possibility of increased CO2, oxygen, or acetazolamide. The under-responsive genoglossus would be myofunctional therapy, possibly these medications we mentioned, and possibly hypoglossal nerve stimulation. So let's just talk briefly about some anecdotal cases. This was a patient of mine that had significant OSA and was actually using oral appliance therapy and had a persistence of central apnea, a real significant persistence of central apnea. And by the way, he had originally been on CPAP twice and failed, was actually very comfortable in sleeping well with his oral appliance, but obviously his HI was significantly elevated at 76. And this is, of course, an HST we're talking about. So I put him on acetazolamide because I saw that he was having some significant central apneic events, even by the HST, and we were able to reduce his HI down from over 70 down to 35.9. Now, this isn't perfect, but I'm very happy with this result, especially because the patient is compliant with his oral appliance, is taking acetazolamide, and he was not compliant with anything before. And so this is, I would say, a home run. This is a patient who really has predominantly had UARS, had some apnea, was using oral appliance therapy, and this was their residual HI and RDI with oral appliance therapy, and we had maximally titrated her. And because she still had some significant errors by this HST, I decided that this is probably most likely to be low arousal threshold. And so I put her on Lunesta or Azapiclone, and Azapiclone was shown to be effective in two studies in patients struggling with CPAP, and it's also been studied in terms of its effects on the jenoglossus, and there's really no adverse effect on jenoglossus activity. And this is what we got. We got a significant reduction in RDI and HI from Azapiclone, and the patient also felt well. So this is, you know, some applications, some basic applications of using or understanding phenotypes or endotypes in our OSA patients. So just to review that, obviously, we have the anatomical compromise in the majority of patients. It doesn't make up or explain about 70% of patients who have OSA. We have other factors, and now we potentially have a lot of other things we can actually employ to really try to get patients to as low an HI as possible. We don't want to forget about adequate sleep, good sleep hygiene, circadian misalignment, and of course, assessment for other sleep fragmenting components, and I would say that that is a tremendously important thing and complicated, because what we know is that anything that fragments sleep can cause daytime sleepiness. So we're going to shift gears and talk about collaboration, why is collaboration important? Obviously, collaboration is really most effective when we're talking about a number of different modalities, too. So, and I think that's the beauty of collaborating with physicians, particularly sleep physicians, is we have the ability to use other modalities. We can recommend, obviously, bariatric surgery in patients. We could recommend certain medications that could be very helpful in weight loss. We can also, you know, think about not only oral appliance therapy, but obviously using potentially combination therapy with CPAP. And I would argue that most dentists who are doing sleep really should have a level of understanding of OSA at the level or above primary care physician, which unfortunately isn't saying that much, because most primary care physicians don't really understand OSA well, and they definitely don't understand oral appliance therapy or even really CPAP. So I think it behooves us all in this area to be very familiar with this subject. And sleep physicians and sleep dentists obviously look at OSA in a completely different ways, but it doesn't mean we can't work together to improve outcomes. And there's a tremendous benefit for the sleep physician, namely referring back for testing, and that benefits patients, but obviously also can benefit the sleep physician as well as the sleep dentist. And unfortunately, there's a lot of lack, there's a significant amount of a lack of understanding and arrogance, and I know that's a major impediment, and I apologize for that. But it doesn't mean we don't want to keep trying to move forward on this. So historically, sleep physicians, I would say, have not been amenable to collaborating with sleep dentists. I think that just needs to change. It's an essential part of us getting patients to goal. One thing that we want to remember or remind our sleep physicians and our colleagues, our physician colleagues, is it really offers more choices when they think about oral appliance therapy. It also demonstrates that we're thinking about comprehensively treating OSA patients, and in particular, I think patients like that. I think patients have come to my practice in particular a lot because we offer more than just CPAP therapy. And then theoretically, it can improve compliance. We definitely have combination therapy patients as well that I would never have gotten to goal because of high mask leak, for example, that oral appliance therapy combination has helped immensely or measurably. So if we're looking at the sleep physician's analysis, about 50% of patients who are in CPAP are non-compliant with discontinued PAP therapy. Those patients are unlikely to follow up with a sleep physician because obviously, the sleep physician is only focusing on CPAP therapy. So having a sleep physician have a referral base, namely a sleep dentist, where they can say, listen, I also offer oral appliance therapy through my colleague and friend, Dr. So-and-so, who is going to also treat you for sleep apnea, but with their approach, namely with oral appliance therapy. So it's an obvious great symbiosis because not only allows patients to continue some type of therapy now, but also allows the sleep physician to start monitoring the patient, a patient that probably was lost to follow up, and that can definitely drive tremendous income for sleep physicians and sleep physicians want to hear that, as opposed to the patient being not treated at all. And as I mentioned that case before, that patient, if I didn't offer oral appliance therapy to that patient, they would be on nothing. And it also allows the sleep physician to go back in their files and find patients. We've done that. We have patients that have discontinued PAP therapy a number of years ago, and we've brought them back to be re-evaluated with the offering of oral appliance therapy. So really, it's a one time we potentially could get paid better theoretically for better management. And again, driving sleep testing is no sleep physician would argue about increasing their sleep testing and obviously more follow-ups. And why, what do I mean the evidence from the SAVE trial? We know all, we all know about the SAVE trial and the big problem with the SAVE trial was when patients were, whoops, I don't know how I just did that, but when patients, excuse me, when patients were using CPAP therapy, there was a significant reduction, about a 48% reduction in stroke. Unfortunately, the average usage in the SAVE trial was 2.3 hours. So pretty abysmal. So we have to be honest with our physician colleagues about that. We should all have read the SAVE trial if we haven't. I just want to explain what I, we do specifically my model. I have a rental agreement with my sleep dentist. That's Dr. Arthur Feigenbaum. He pays me a monthly rent. We've vetted this model with a healthcare attorney. We have a contract for professional services and he basically, we've attempted to credential Dr. Feigenbaum in as many insurances as possible. And that's also important because it allows the majority of my patients to be treated with insurance and not have to pay a huge amount of out-of-pocket expenses. Now we obviously look to ensure compliance, all the state and federal regulations. We as, me as the sleep physician, I'm doing the evaluation of the sleep testing and then referring for oral appliance therapy. And Dr. Feigenbaum is obviously fabricating the oral appliance, seeing the patients in follow-up and then referring back for further testing as well. And we get to collaborate a lot and that's nice because now I understand a lot more about oral appliance therapy more than I've ever. And that's an imperative. We have a sleep lab, obviously we have myself, we have a NP who's trained in sleep. We have a DME as well as we do a lot of home sleep testing. So it's very one-stop shopping and I think it's a great model and I would definitely recommend if you can, if there's any possibility for you, a sleep dentist to work in individual sleep physicians' offices, I would strongly recommend you try to do that. And I'm more than happy to answer any questions along that line. And again, it fosters learning and it really is better for the sleep physician because the sleep physician now will start to understand oral appliance therapy better. If they're better at understanding oral appliance therapy, they're better at messaging to patients. And I think it's also better because I think the sleep dentist also is going to think more about the possibility of CPAP, especially if they have an oral appliance failure. And that's only good for patients at the end of the day. I just want to mention one thing about the joint paper from 2015 from the American Academy of Sleep Medicine, as well as American Academy of Dental Sleep Medicine. And what's interesting is there was a meta-analysis that was done on CPAP versus oral appliance therapy and systolic and diastolic blood pressure. And if you look closely at the Forrest plot, you'll see that the, excuse me, the oral appliance therapy actually is favored in terms of blood pressure reduction, both for systolic as well as diastolic blood pressure. And that's a very profound thing. That means that technically speaking, oral appliance therapies is better at reducing diastolic and systolic blood pressure. And I think the average internist PCP really needs to know that namely because they're critically involved in blood pressure management. I think interestingly, most patients are very, very uncomfortable when they hear their blood pressure is up. It's one thing that we've sort of inculcated our patients to think about strongly that it's a problem if their blood pressure is up. So I think this definitely becomes an easier talking point with our physician colleagues, namely that you get a slight blood pressure reduction, both systolic and diastolic. And that's really because of the compliance effect. And obviously I think we're all familiar with the Kate Sutherland data and namely that overall the effectiveness is very similar with oral appliance therapy in comparison to CPAP, namely because compliance is so much better, even if efficacy is specifically not better. So what's the protocol? I recommend you go to as many offices as you can. Don't give up. Try to navigate the front desk. That's unfortunately really your major obstacle in bringing some gift cards, which is legal in a limited fashion, is fine to do. And try to set up and try to set up lunches and making it clear that the imperative here is to discuss briefly what you do as a sleep dentist. And that means bringing oral appliances to the office potentially and bringing even like a laminated explanation of the benefits of oral appliance therapy and what you specifically do. And by the way, I didn't know anything about oral appliance therapy way back when. And it really did help. And it often helps to actually have models in my office. So when I'm telling patients I want them to go on an oral appliance therapy, it's great to show them a model. I think most of us do that, but it's nice to have your sleep physician colleagues also have that. So I obviously want to give the, never give the impression that you're going to steal the patient, that you're working together to help outcomes. And this is only beneficial for the patient as well as for the sleep physician. And it's a huge advantage, as I said, because you can really drive a significant increase in revenue. And you don't want to self aggrandize. I definitely am not that amenable to a sleep dentist who tells me that they know everything and I don't have to worry. The better approach is obviously that their sleep dentist is always willing to learn. I'm willing to learn from them. So what's my approach? And just some final thoughts. Obviously I always like to work together or collaboratively if I can. We want to try to always reassure patients that we're going to work together to solve the problem. It's not always that easy. We don't always get complete success with patients and not to forget that every patient is a snowflake. And boy, do I mean that. And don't forget about adjuncts to therapy and good sleep hygiene, circadian alignment, diet and exercise, weight loss, compression stockings, nasal decongestants, all these things, elevation of the head of the bed, all these things can potentially help. We want to try to understand the idea of phenotyping and pass that on to our physician colleagues if we can because this really, I think, improves outcomes, as I mentioned, and makes you think about other modalities of therapy. And I think it also shows that you as a sleep dentist are very interested in this whole gestalt of OSA. And it's surprising how many sleep physicians and my sleep physician colleagues don't really know anything about phenotyping or this whole paradigm. So compliance, unfortunately, is still the number one goal here, or one of the most important goals, I should say, namely, as I mentioned, from the SAVE trial, which really had, it was abysmal, except for the patients who were using CPAP. We want to remember about combination therapy. We want to also not forget about that if we can get the HI as low as possible, that's definitely one of our goals. And it's a great opportunity for both the sleep dentist and sleep physician to work together. And I'll open it up to any questions. Thank you, Dr. Long. It's been a pleasure, and it's always a pleasure. So I'll be asking the questions. Question one, what are the side effects of acetazolamide? How about atomoxetine and oxybutynin? Have you been using the combination of those drugs? Okay, so atomoxetine and oxybutynin, I've never used, and namely because that study was only 20 patients. And my only concern with the atomoxetine is that the potential for fragmenting sleep, because it is increasing adrenergic tone, and in general, we don't have much adrenergic tone at night when we're sleeping. So we'll have to see from their clinical outcome trials, what's happening with that. So I really haven't used that. But it is very interesting. In terms of acetazolamide, usually it's 250 milligrams QHS. I rarely get side effects from it. You can get tingling the next day. It's a short acting drug. Usually you get that from the longer acting like the acetazolamide sequels or if you use higher doses than 250. So for all intents and purposes, it's usually well tolerated. Okay, thank you. The next question, are you aware of the effectiveness of myofunctional therapy on muscle responsiveness, or does that just increase muscle tone? So the data on myofunctional therapy, the one interesting data was a reduction in HI. It was actually a Brazilian study. And I think we all know that in Brazil, they tend to have many more people doing myofunctional therapy than we do in the United States. And it was a series of exercises that they actually showed on YouTube how to do. The only issue I have with that is obviously patients have to be compliant, but there was a significant reduction in HI. So it really is helping. And it's probably helping both by improving, I don't know if we know exactly why, but it's definitely seems to be helping at least probably lower PCRIT, that's one. And two is it may be improving the genia glossis activity. There is a device called the OSA Excite, I think you've all probably heard of. That doesn't really seem, it definitely seems to work. It's really in patients that have UARS more and have really pretty mild apnea. It hasn't really been evaluated that well in patients who have moderate to severe apnea, but it's a very attractive idea. It could be maybe a potential combination therapy with oral appliance therapy, but it looks like it improves endurance of the genia glossis. It's not actually improving, believe it or not, muscle fiber hypertrophy though. So we really have to suss some of this out more. But anyway, I'm sorry. Okay. What else? Sure. The next question. What if the physicians we work with have never heard of the palm scale? It is a hard conversation to start. Yeah. No, I don't disagree with you. I, what I'd say is I would, I would give them, that's where I'd say, you know, you could bring them an article. This happens all the time. I mean, drug reps bring us articles, sometimes we read them, sometimes we don't, but I would bring the article if you want to, and if there, if you can pique their interest and you understand the topic, I think it's very attractive. And I think the general idea is the messaging that you should say is there are patients that have OSA that are using whatever therapy that aren't really at goal in terms of their AHI being low, that you, you potentially, if you evaluate them in terms of this phenotypic approach or phenotypic paradigm, that you may be able to intervene a lot more patients. And so that's very attractive. And so I mean, planting the seed, I think is the first thing, but in order for you to be really able to discuss it, I think we really have to read that article a few times. And hopefully this lecture tonight gave, made it a little bit, elucidated a little bit better too. Thank you. Why did you say that oral appliance therapy failure is more likely to have poor muscle responsiveness? Yeah. So, so that's really the, the thing that you don't get from oral appliance therapy traditionally is you don't get a complete resolution often in patients that have significant severe hypoxia. I think we know that there are definitely some exceptions to the rule and in REM related hypoxia, especially when patients have, you know, these big drops in REM sleep. The reason why they're having that is because they have this increased cholinergic tone, which is normal in REM sleep, but the genioglossus is totally asleep. And those are patients that really aren't going to respond that well to oral appliance therapy. So traditionally the under responsive genioglossus patient is the poor oral appliance responder. Now there's exceptions to every rule, but that's in general, that's the, that's the paradigm. And that's where the hypoglossal nerve stimulation or inspire really works. And that's why I'd say we shouldn't be concerned about hypoglossal nerve stimulation because it's only 10% of the OSA population. And those are patients in general that probably aren't going to respond that well to oral appliance therapy anyway. I mean, they may, but, and obviously malfunctional therapy we mentioned, and that's why it is attractive to think about the atomoxetine and oxybutyne. And as much as we don't know if it's really going to work long-term, we, it would be really kind of cool if you could throw that in the mix in a patient who's using oral appliance therapy. And I'd say the same holds true for hypoglossal nerve stimulation. We know this, there's that one paper, it was a really a case report from Ryan Seuss where they use combination therapy, namely HNS and oral appliance therapy to have a tremendous improvement in the AHI. So these are things that I think, you know, we should obviously all be thinking about. Okay. Thank you. The next question, I'll bear with me a little longer. Regarding patients with highly collapsible airways, positional therapy was mentioned, but that by that, I assume you're referring to elevating the head. Have you seen patients get worse with head elevation due to the tendency to sleep more supine as elevation is increased? You know, that's a really good question. I, so anecdotally I haven't really, but we, we definitely know that there's, there is data that there's a reduction in AHI from elevation ahead of bed, but positional therapy, I meant not necessarily elevation ahead of bed, but I meant literally positional therapy, namely sleeping on your side. And that obviously can change PCRIT. And that was the point of positional therapy and positional therapy obviously can be very helpful, especially in our OSA patients who are using oral appliance therapy, but it, overall, the tendency is that it tends to work better in women than in men and patients who have kind of lower AHI to begin with, but no, but what I meant by positional therapy was really side sleeping, not, not a elevation ahead of the bed. Okay. Thank you. Are there any close to these endotypes on the HSAT or do they all have to come from a PSG? Would a history of sleep fragmentation prompt you to use a hypnotic or a trial basis? Yeah. So, so the, the problem with, it's a great question. We're not, this is not completely ready for prime time in terms of our assessment from HSTs. I happen to use that, that HST that I was using that we're talking about that definitely has an ability to pick up rares pretty well. So we're talking about patients having predominantly or excessive amount of rares, either initially or residually. And that's obviously the lower arousal threshold patient. And, but you're right there, there are definitely times that if you look on a PSG or even on HST, if you see a lot of fragmentation, it's something you may want to think about. And my point about Azapaclone, as much as you don't want patients on medications, we've, it's been studied, it's been studied in moderate to severe OSA that it doesn't worsen genioglossus activity. So it's a great, great question and a great idea because there are some patients that may actually have improvement in their HI who aren't doing well, let's say, who are, you put them on Azapaclone. And the other interesting thing about Azapaclone or just really any kind of sedative-hypnotic is we do know that it can affect possibly central apnea as well. Namely, because what it's, if you think about it, you have to have this hyper-responsiveness or increased ventilatory drive that where the patient is really over exaggerating hyperventilating when they have some, some kind of disturbance, usually a respiratory disturbance. And if you give them a sedative-hypnotic, like for example, Azapaclone, you actually can decrease central apnea because you're decreasing that hyperventilation. So whoever asked that question, I commend them because it's a great idea. That's always a possibility. And that's where I think working with a, you know, your sleep colleague, your sleep physician may be very helpful because sometimes you just have to empirically try these things. I see. Thank you. Are there any ways to screen for non-responders for response therapy? Are there any ways to screen? To screen for non-responders for? Yeah, I mean, there are, there are. There's actually, there actually was a paper by Dan Olivandowski, looking at actually temporary appliance in, in using actually a positional therapy device as well as using HST. And there's, there's definitely some ability to determine who's going to respond to our appliance therapy with that. And obviously there's dice that we could, we, most people don't use dice, but you could use dice. And we, in the old days, when we used to use the matrix, theoretically obviously could use the matrix as well, but unfortunately it's still, and that's what I was suggesting from the outset is I, I don't think we should be thinking about phenotyping patients in terms of who's going to respond to, oh, say I said to oral appliance therapy, excuse me, but more about just thinking about the gestalt that when they have, whatever their residual HI, if it's elevated and you want to bring that down, you should be thinking about, okay, so what, what's really the underlying problem here? And that's where I think the phenotyping, endotyping can be very helpful. Excellent. Thank you. The question is what is the device excite that you mentioned? Oh, so that's really a, theoretically, it's really stimulating the genioglossus. It's really stimulating the tongue. And you use it for a short amount of time. It's 20 minutes a day for a few weeks. And then afterwards you actually have to do it at least once a week. And what was shown was that there was a reduction, there's a reduction in HI. Again, the patients were, were pretty mild. And there's definitely improvement in rares. And so, and very well tolerated device, relatively easy mechanized device that, and so it's interesting. It really has to be studied in a larger scale. The problem with this, it's an out-of-pocket expense, but definitely in your motivated OSA patients, it may be a nice add-on. We'll have to see. But the idea is that it could be a good adjunct. And obviously the patients who have, you know, residual significant HI elevation who are using our appliance therapy, we'll have to see.

phenotyping

oral appliance non-responders

sleep-related breathing disorders

non-anatomical factors

collaboration

personalized treatment plans

oral appliances

outcomes data

phenotype