Thank you, and for coming in for the early morning session, hopefully everybody's jet lag is getting better, and it will as you enjoy the day and spend more time exposed to light in the evening, or you can stay for the next session that deals with that. So welcome everyone to CHESS 2023. This session is the Sleep Medicine Ear and Review, and I'm going to start with obstructive sleep apnea. So this is the QR code for you to get on your phones so that you can participate in the ARS. So by way of introduction, I'm Sunita Kumar. I am at Loyola University Medical Center in Maywood, Illinois, and I'm the past chair of the Respiratory Disorders of the Sleep Network. So the outline today, I'm going to discuss a few articles on CPAP and cardiovascular risk reduction, CPAP therapy and renal function, different ways of trying to phenotype patients with sleep apnea and seeing how CPAP setup can impact adherence. So our first question is loading up now. So in a recent article analyzing the results from the RICARDSA trial, investigators showed that CPAP therapy reduced the risk of major adverse cardiovascular events in A, sleepy individuals with any CPAP use, adherent and non-adherent, sleepy, more than non-sleepy individuals who were CPAP adherent, or C, non-sleepy, greater than sleepy individuals who were CPAP adherent. Polling starts now. All right, in the interest of time, I'm going to move forward to the next question. So in animal studies, showed improvement in genoglossal activation during sleep with the use of this topical agent, A, intranasal spironolactone, B, intranasal oxytocin, C, intranasal etamoxetine, and D, intranasal oxybutynin. More people know the answer to this question. All right. So I'm sorry, I don't know what happened there, but we'll go back to the first question that they first do studies. And so the correct answer actually was A. So I hope you stay till the end of my talk. And the last question is, CPAP discontinuation rate was highest if the initial CPAP setup was A, home delivery and a virtual visit with instructions, B, an in-person pickup at clinic with or the sleep lab with instruction as needed, or an in-person pickup with group education, or D, home delivery by a respiratory sleep technician with education. And so the majority of you picked A, that was home delivery with virtual visit, I guess. And that was the correct answer. Sorry, this is the last question. So in patients with a low inflammatory cluster at baseline, after three months of CPAP therapy, there was A, no change in protein expression, B, there was an increase in protein expression, or C, there was a decrease in protein expression. And again, in the interest of time, I stopped the poll, but the majority of you or those who responded picked C, which was a decrease. Actually the answer was A, or sorry, B, that there was an increase in protein expression. So that's a good start for the talk. So one of the major papers that was published this past year was the evidence report or a systematic review that was requested by the AHRQ, which is the Agency of Healthcare Research and Quality. So the investigators looked at the data on the efficacy of CPAP on health outcomes, as well as the use of metrics to define OSA severity. And their conclusions were that currently used measures of OSA severity, which is the AHI or the RERA, they do not describe sleep apnea or correlate with signs and symptoms. Non-randomized control trials do not provide evidence that CPAP affects all-cause mortality or various cardiovascular outcomes. Non-randomized comparative studies show an association of CPAP use with reduced risk of all-cause mortality, but not with other cardiovascular outcomes. And that NRCS do not show whether the effect of CPAP varies based on disease severity, patient symptoms, or other criteria or definition of sleep measures. So this was, I think, kind of a report card on what our literature has shown so far. And as most of you know, the argument or the explanation that has been forwarded for the lack of the cardiovascular benefits from CPAP in randomized control trials was thought to be due to enrollment of patients who did not have excessive daytime sleepiness. The poor CPAP adherence that was seen in all of these trials, which was less than 50% for most studies. And the fact that the patients who were enrolled in these studies did not really represent the kind of patients we see in our sleep clinics. So the first paper I'm discussing is the cardiovascular outcomes in adults with coronary artery disease and obstructive sleep apnea with versus without excessive daytime sleepiness in the RICARDSA trial. This was a trial that was published previously and is one of the randomized control trials that was used in that systematic review that basically randomized patients who had been admitted in the hospital after an acute MI and had undergone revascularization. They randomized non-sleepy patients to CPAP or no CPAP. And these investigators then looked at a secondary analysis of the study to answer the question whether the presence of concomitant sleepiness, what effect that had on the incidence of major adverse cardiovascular events and whether the cardiovascular benefit from CPAP adherence differed between the sleepy and non-sleepy patients. So this was the flowchart of the study. Like I said, it was a secondary analysis. And so for this study, they included patients with sleep apnea and excessive daytime sleepiness who were prescribed CPAP. There were 122 patients who did not have sleep apnea who were randomized to CPAP and 122 who were randomized to no CPAP. The investigators used a statistical method called inverse probability of treatment weighting to use sleepiness as a way of randomization because that was not possible or ethical for us to consider randomizing sleepy patients to not get treatment. So in the baseline characteristics between the sleepy versus non-sleepy, those who had sleepiness were likely to be slightly younger. They had a higher prevalence of obesity and a higher prevalence of stroke. Other cardiovascular risk factors and the medications that they were prescribed were similar between the two groups. In terms of indices of oxygenation severity on their sleep study, those who were sleepy were more likely to spend time less than 90% and had a lower oxygen saturation nadir. However, there was no difference between the two groups in terms of the total AHI or sleep state-specific AHI or the arousal index. And they also noted that the total sleep time was longer in the sleepy patients and they had a shorter sleep onset latency. So when you look at the CPAP use between the two groups, as is expected, those who were sleepy were more likely to use the CPAP in terms of total duration and percent of night of CPAP use. And the metric that we used for describing adherence, which is use greater than four hours, was significantly greater among the sleepy patients. So of the almost 400 patients, 85 reached the primary endpoint, so roughly equal numbers in all three groups, about 22% in those with sleepiness randomized, without sleepiness randomized to no CPAP, 18% in the non-sleepy patients randomized to CPAP, versus 23% in the sleepy patients on CPAP. And they looked at the incidence of the major adverse cardiovascular events. They did not differ between the sleepy versus the non-sleepy patients. The hazard ratio did not reach significance. And they found that among patients who were either not treated or those who were not adherent to CPAP, there was, again, no difference based on sleepiness in the incidence of the major cardiovascular events. However, surprisingly, they found that the incidence was lower in the CPAP adherent group if they were non-sleepy compared to if they were sleepy. So this is against what was floated as one of the explanations for the lack of benefit noted in the other randomized control trials, that it was because patients who were sleepy were not enrolled in these trials. But what this study shows is that the benefit of risk reduction was greater in the non-sleepy patients compared to the sleepy patients. So as this was the study conclusion, that presence of sleepiness did not increase the risk of major adverse cardiovascular events. And that benefit from CPAP was greater in the non-sleepy individuals. So the authors gave some possible reasons as to why this might be the case. And it could be that sleepiness is a marker of less reversible cardiovascular disease and that it might reflect other comorbidities of poor sleep that increase cardiovascular risk but which are not treated by CPAP. The longer sleep time in EDS may result in less percent of night of CPAP use. So in other words, the protective effect was less because the patients were sleeping longer and we used the four-hour metric. And the sleepy versus non-sleepy patients may represent different endotypes of OSA that have varying cardiovascular risk. Limitations of the study could be related to the study design. Like I said, it was difficult for them to randomize patients based on sleepiness alone to treatment or no treatment. As a result, there were very small numbers of patients of untreated sleep apnea who were sleepy. And then there are other cardiovascular factors or factors that can affect CV outcomes such as exercise, diet, or medication adherence which was not included in the study results. So as I said, enrollment of non-sleepy patients is probably not that much of a reason for the lack of benefit from the RCTs. The next study is from France. It looked at positive airway pressure adherence, mortality, and cardiovascular events in patients with sleep apnea. This was an observational cohort study. And the study authors linked the results from the cohort study with administrative claims data and CPAP was prescribed to patients with severe OSA and mild to moderate OSA with sleepiness or cardiovascular risk factors. They also had access to their CPAP adherence data. And they also looked at adherence to cardiovascular drugs using a measure called medication possession ratio. And they used a threshold of NPR greater than 80% as calling them treatment adherent. So as you can see from the flowchart, they had almost 7,000 patients that they started out or are in this cohort. And based on the presence of their insurance information, you know, they ended up overall with about 5,000 patients in this study. So a really large observational cohort study. And if you look at the differences between the group that experienced a major cardiovascular event and those that did not, demographic variables were significant for the patients being older in the group that suffered a cardiovascular event and that they were males. And the other risk factors that you see which are significant are ones that we expect as, you know, common cardiovascular risk factors. What I wanted to point out was the metrics of, on their sleep study that were significant between the two groups. Primarily the severity was greater in the group that suffered cardiovascular events and the indices of oxygenation were worse in the group that suffered a major cardiovascular event. When you look at medication adherence, patients who were using their CPAP more were more likely to be treatment adherent as well. So they looked at adherence in terms of quartiles and used the group that used CPAP for less than four hours as their reference. And then four to six hours, six to seven, and more than seven hours were the other quartiles in this study. Overall the follow-up was about 6 1⁄2 years and almost 1,000 patients suffered or reached the study endpoint of having a major adverse cardiovascular event. A third of these were deaths and the two-thirds were a non-fatal cardiovascular event. So this is the Kaplan-Meier survival curve and compared to patients who were using their CPAP for less than four hours, there was an incremental survival benefit in patients using CPAP for a longer duration. And when they looked at this outcome using a binary variable of CPAP use greater than six hours is where they noted the hazard risk to be statistically significant. Other factors that they felt increased the cardiovascular benefit from CPAP was presence of male sex, absence of prior cardiovascular disease. So again, patients who were non-sleepy were more likely to have benefit. And in terms of the hypoxic burden, also those who were less sleepy, those who had greater desaturation were the ones to see the most benefit. So the conclusion from this study was that, again, risk reduction was seen in patients who were using CPAP for at least six hours and the benefit was greater in those without a prior history of cardiovascular disease. The limitations from this study was that the mortality endpoint was related to a cardiovascular event as an inferred assumption. This is based on their previous work from the same group that looked at CPAP adherence and mortality from cancer. And so they infer that since cancer and cardiovascular events are the main causes of mortality in this cohort, the likely benefit was because of the mortality benefit was from preventing a cardiovascular event. So that, again, is an inferred assumption. So going back to the reasons for the lack of cardiovascular benefit, we talked about CPAP adherence looking at the threshold use of more than four hours. So what this study shows is that the metric, the binary variable that they found was six hours. So these patients in the RCTs were even more CPAP non-adherent than what we have already seen. So this study at least looked at patients that we see in our clinical practice. So the takeaway points from these two studies was that, for me, is that sleepiness should not factor into treatment decisions as there are results on both sides of the aisle, sleepy versus non-sleepy in terms of cardiovascular risk, and that the benefit for CPAP is what we tell our patients. You've got to use it the whole night or perhaps a threshold of six hours giving improvement. And that primary prevention, so treat the patients before they actually develop a cardiovascular event, might be more beneficial. And so that brings up the question that if non-sleepy patients before they have an event are the ones who are most likely to get benefit, should patients with cardiovascular risk factors be screened for OSA and diagnosed early? So this next study is on the effect of CPAP on renal dysfunction in patients with diabetic kidney disease. As you're familiar, sleep apnea is associated with impaired glucose tolerance, insulin resistance, and increased risk of developing DM, and severe OSA is associated with worsening kidney function. So this is a study from Spain, and it was called the Diana study. It's a multi-center, randomized, open-label study, inclusion criteria of patients with diabetic kidney disease who had at least mild sleep apnea, and they randomized them to CPAP or no CPAP irrespective of sleepiness symptoms. And the main outcome they looked at was percent change in the urine albumin creatinine ratio. The flowchart, they had randomized 185 patients, and the intention to treat analysis, there were 90 patients in each group, and the per-protocol analysis included patients who were CPAP adherent and those who completed the study. This was defined as greater than four hours, so the average CPAP use in the group as a whole was about four hours, which is better than some of the other trials for cardiovascular studies, and the CPAP adherent group was using their CPAP for at least six hours. And in the intention to treat analysis, there was no difference between the two groups, and a benefit of decreasing UACR was seen in the group that was CPAP adherent. Again, the groups that showed most benefit were those who were less sleepy, those who had a duration of diabetic kidney disease for less than five years, and severe sleep apnea. And these were the mechanisms of benefit from CPAP that were proposed. Takeaway points are that it's, again, it ends up being a small study when you look at the CPAP adherent group, but again, benefit being seen in non-sleepy individuals and earlier intervention being the theme of the day. And quickly, this is a small study from Avaish Navikundo in New York, and they basically looked at the expression of inflammatory biomarkers at baseline, and after three months on CPAP, using a O-link proteomic platform, which is a proprietary platform looking at different inflammatory markers, and they looked at 92 markers, and using unsupervised clustering, they identified three clusters of high, low, and middle inflammatory protein expression. Those in the high inflammatory cluster tended to be older and had a higher prevalence of hypertension, but they found that after three months of CPAP use, this was the group that showed a decrease in the overall protein expression, but the group that was in the low inflammatory group actually had an increase in expression of the inflammatory proteins, thereby suggesting that there might be some patients who are harmed or have an increase in inflammation as a result of CPAP use. Again, it's a small study, but I'm sure there'll be results looking at larger number of patients, but kind of suggests maybe there are some patients that could be harmed, but also provides us a way of phenotyping some patients with sleep apnea using their inflammatory protein signatures for incidence of cardiovascular risk. In the interest of time, I'm going to run through these slides. So this is just the summary of the adherence data, and the reason I bring that up is because I think most of us, or especially at the VA where I work, all of the patients get their device delivered in the mail with instructions for them to call and get instructions or find instructions, and you can see that the discontinuation rate is the greatest in the group where there was home delivery. And in this study, actually, the home delivered CPAP patients actually had very lengthy instruction in terms of video and virtual visits and so on, and yet it was significantly greater than in-person pickup with a group education. And the answer to our last question, this is, again, two studies looking at intranasal or topical application of agents that could potentially help OSA. So this was looking at something called TWIC-related acid-sensitive potassium channel that showed a benefit, and the last one was the oxytocin. So the correct answer was oxytocin. Again, in the interest of time, I'm going to move to our next talk. We can do questions at the end. My next speaker is Dr. Bernardo Selim from the Mayo Clinic, and he's going to discuss the update on central sleep apnea. All right. Welcome, everybody, to Sleep Medicine Review 2023 at CHESS. I wanted to thank very much to Dr. Kumar for inviting me here today. I'm going to be talking about central sleep apnea syndromes, and I have no relevant financial relationship to disclose. This is less an objective, obviously, to review the literature, but hopefully also to give you some impact in your practice about the new literature coming in. You know your code to answer the questions, and this is, to me, just giving you a little bit about the search strategy. On your left, you have what are the parameters that I have chosen into our search in between September 2022 and 2023. On the right side of your slide, you have a visual idea about the gravitation of the publications in this last year about central sleep apnea, primarily in the heart failure and therapy. Then after that, first place was epidemiology, and then has been focused on stroke, TXA, pathology, and medications. So I have the next questions coming, hopefully, or maybe not. Nope, it looks like we have no questions, but I hopefully that we're going to be going through these articles, and we're going to be discussing some of the important things for you to take home. We're going to talk about epidemiology in central sleep apnea. So the question about the prevalence of central sleep apnea in the heart failure populations, this is the article that I bring to you is the prevalence and predictors of sleep disordered breathing in chronic heart failure. This is, the question is, what do we know about the prevalence of heart failure, predominantly of preserved ejection fraction, and this is one of the most prevalent heart failures based on the most recent epidemiology. The lifetime risk is approximately 10%, and is one of the most comorbidities that it has if we disrupt disordered breathing. So in these patients, the prevalence of a sleep disordered breathing based on all literature put us somewhere in between 50 and 60% of these patients, obstructed sleep apnea and central sleep apnea based on publications as matches to a large cohort of 700 patients, has been 50-50 in between obstructed sleep apnea and central sleep apnea. So I bring you this study that give us an idea about what is the determinant of the prevalence of central sleep apnea across obstructed sleep apnea patients with heart failure with preserved ejection fraction. We know a lot about reduced ejection fraction, but preserved ejection fraction we do know very little, and we compare it with a mildly reduced ejection fraction and reduced ejection fraction. This is a study, more than 3,000 patients with chronic heart failure, adults, this is the literature coming from Europe, particularly from Germany, that we're treating currently with cardiovascular guidelines, so they are optimized medically-wise, and there was follow-up of these patients with type 3 polysomnographic studies, and the cutoff was a sleep disordered breathing of 15 events per hour to determine if they have or not sleep disordered breathing. And if you have AHI that is more than 50% obstructed sleep apnea, that was classified obstructed sleep apnea, less than that was central sleep apnea. So what did they got? These are the results. The main result of the heart failure with preserved ejection fraction shows that these patients have their low prevalence of central sleep apnea in comparison to obstructed sleep apnea. We find out also that in comparison to those with reduced ejection fraction, 7% versus 15%, they are predominantly more obstructed sleep apnea, and their prevalence in heart failure with preserved ejection fraction of a sleep disordered breathing is 36%, in comparison to reduced ejection fraction that was 48%. So central sleep apnea, take-home message, central sleep apnea in heart failure with preserved ejection fraction is low prevalence, and it's the lowest in that spectrum of heart failure based on ejection fraction. The second part is based on gender, not surprisingly central sleep apnea is much higher prevalence in males than in females, and again, obstructed sleep apnea rate was significantly greater for patients with heart failure with reduced ejection fraction. So where are the critiques of this study based on this largest registry of stable heart failure patients from Europe? They were done with type 3 polysomnoreptic study that's not allowed to differentiate with hypopnea, so that is one of the critiques. But I think that heart failure with preserved ejection fraction, which we, it's pretty frustrating because we don't have many medications that they can be affecting these patients, comorbidities as prevalent as a patient with sleep disordered breathing may have there in treatments some significant impact in this population. What about mortality of patients with central sleep apnea? And this is a study that I'm bringing to you, this mortality patterns associated with central sleep apnea among veterans. This is a large retrospective longitudinal study by Dr. Agrawal and colleagues. What do we know about mortality in central sleep apnea? Not surprisingly, this has been focused predominantly in heart failure with reduced ejection fraction. In this five-year survival study of 963 patients from Oldenburg, it tells us in patients with reduced ejection fraction, the central sleep apnea mortality is approximately 50% in comparison to 70% in obstructed sleep apnea. This is where we're coming from. But what is the data here in the United States? And this study will give us an update. So the objective, again, is to identify mortality pattern and time to death. This was a large study in which you have 2,000 patients with central sleep apnea, 16% were heart failure patients, the other were related to stroke, they were related to medications such as opioids, and they compare with most than a million patients with obstructed sleep apnea. This is a large, huge database from the VA. They recruited their patients in 1999 for one year, and they collected information for 20 years, and they measured their mortality. The results that you see is what you see there. On the left that you can see is the graphic that it will show you, and will be divided about obstructed sleep apnea and central sleep apnea without heart failure and with heart failure. And the first result that is quite impressive, the central sleep apnea, the median time to death, almost three years in comparison to five years for obstructed sleep apnea. So very short up on the diagnosis of central sleep apnea, the patients will or is likely to die. Higher central sleep apnea mortality, no surprise, and you have the adjusted hazard ratio, and the adjustment is at the bottom of that slide. And also important is that as soon as you have a patient with a sleep disorder breathing, independently if they have central sleep apnea or obstructed sleep apnea, as soon as they have the comorbidity of congested heart failure, their mortality goes up to the roof. Look at that hazard ratio. For central sleep apnea with concomitant congested heart failure, three, almost four times more mortality in patients with obstructed sleep apnea, they double their mortality. So pay attention to these patients who have congested heart failure as a comorbidity independently of what type of sleep disorder breathing you have. What about central sleep apnea in those who have been prescribed opioids? We don't know about anything about the intake, the amount, unfortunately this database cannot go to that details, but they find out that this population, being prescribed opioids, they have a higher mortality in patients who develop central sleep apnea in comparison to obstructed sleep apnea. Their predictive central sleep apnea mortality, all of that you were expecting to, but particularly a low BMI. Keep that in mind because the next and following studies will give us an idea. So you know your conclusions there. The critique, again, is an administrative data and some clinical data that they are all ICD-9, ICD-10 codes, and a non-therapy lack of hypopneas classification. But what do I take from this article? I take from this article that everybody who you have a clinical suspicious of having congested heart failure, you need to be looking very, very hard to see if this patient have a sleep disorder breathing. And you need to really pay attention to those with low BMI, which is not necessarily picked up by this top-down questionnaire. So what about pathophysiology? Central sleep apnea, this is a very interesting article from Shabahiri, the association between low CO2 production in central sleep apnea men with heart failure. So the question is how the plant gain play a role in central sleep apnea development. We all know that central sleep apnea in congestive heart failure is related to an increase in loop gain, meaning that some of the components like the controller gain, the chemoreceptors is increased, and therefore these patients enter into an instability of the respiratory centers. But we know very little about how the plant gain, the plant gain is the amount of air, or amount of ventilation that the patient needs to do to push that CO2 below the apneic threshold and produce the central sleep apnea. We don't know what is the real role of these patients with that CO2 and their plant gain. So we are gonna be looking into that PCO2 reserve, meaning how much of that CO2 needs to be pushing down below the apnea threshold, sorry, below the apnea threshold in order to get this patient into a central apnea event. So this is a study that look into the metabolic rate in the pathogenesis of central sleep apnea, 28 males, heart failure will reduce a section fraction, and they look it up into the VO2 consumption, the CO2 production, the BMI, and then central sleep apnea index. And they collected that information through PSG and PFT's data. What did they got into the result? The low CO2 production was associated with high central sleep apnea index. Obviously, if you have low BMI, you're gonna have low CO2 production. But the correlation now is that the low CO2 production will be increasing the high CSF, central sleep apnea index, secondary to an increase in ventilation effectiveness. So plant gain is inversely proportional to the carbon dioxide production. So the lower you produce CO2, and look at me, don't look at this slide. So if you produce low CO2, you're gonna get this patient closer to the apnea threshold. So any low ventilation will push this patient below the apnea threshold and will produce the central apnea. So it's very important for patients with congestive heart failure with low BMI to be thinking about this mechanism as a way to produce central sleep apnea. Regular BMI, chemoreceptive hyperrepositiveness in these patients with low BMI may be the low production of that CO2 that put a plant gain that is elevated. Therapy. All right, phase two study. So the question about now is ASB. That has been the pain of our existence. Who needs ASB, why, and who does not and could be dangerous? So what do we know about ASB in heart failure patients? Three studies that have been driving the data for your practice impact. They serve heart failure. You know very well about this high cardiovascular mortality in these patients. They cut heart failure. They talk to us about inpatient with sleep disorder breathing. And in these patients, they find a subgroup that maybe ASB was beneficial for patients with heart failure with preserved extraction fraction. And the event heart failure that Dr. Bradley is giving us, some results preliminarily, but it has not been yet published. So the phase study is a French study that I found that you need to know because it's trying to phenotype patients that you will be feeling more comfortable to giving ASB patients with different degrees of heart failure, meaning divided into those with reduced extraction fraction, mildly reduced extraction fraction, and preserved extraction fraction. And they look it up into patients with central sleep apnea. They could be from central sleep apnea, central sleep apnea USA, and TEXA patients. And they look it up into the two years and they look it up as an outcome two years event-free survival. You need to know the phenotypes. And in the phenotypes, I'm gonna tell you this is the axis that is gonna give you the degree of central sleep apnea versus obstructed sleep apnea. This is the axis that will divide in between reduced extraction fraction up to preserved extraction fraction. I want you to pay attention particularly to these three phenotypes. What do you see there? Predominantly male that tends to be with higher weight. And they tend to be having mild reduced to preserved extraction fraction. Keeping in mind that cluster, cluster four and five. All right, so let's go to the results. There's a greater two year event-free survival in these patients who accepted ASV compared with the controls who refused ASV. So we know that ASV can increase the survival in these patients of two years. What do we know about the cluster? Now, who in your practice are more likely to benefit from ASV? That is gonna be the cluster four and five. These are gonna be predominantly male. More hypoxic burden. They will have heart failure with preserved extraction fraction or mildly reduced extraction fraction. These are the ones that are gonna benefit the most. What happens with the ones that they are more, the served heart failure group? They didn't have any benefits from ASV. So what do we know about? These are the conclusions that we just reviewed. So there's a lack of randomization and there are few members in some of the clusters. So this is a big down into this study. But the practice, to me, at least, is the patient selection and phenotyping is very important. So now I'm practicing of giving ASV to patients who have preserved a mildly reduced extraction fraction. Not because there is no data and it was not an inclusion criteria in the served heart failure patients, but now because I do have data that these patients do have survival benefits and it's still safe to give this treatment to them. What about the next study that is talking to us about the impact of ASV in certain parameters in heart failure? This is served heart failure randomized ancillary study. This is the serval ventilation in patients who have muscle sympathetic nerve activity. And in these patients, they took these patients from this study and they look it up into the muscle sympathetic nerve activity. And what they find is that the suppression of the central sleep apnea in ASV did not change the sympathetic tone. But something that I find even more interesting, the simultaneous reduction of the sympathetic tone and the central sleep apnea has increased mortality in this patient. And you're gonna say, well, how do I get this information and how do I put it into my practice? Well, I do believe that central sleep apnea has certain protective mechanism for which the elimination of that central sleep apnea in patients in an acute way can produce the compensations in these patients which heart failure will reduce the fracture fraction. So that is cool that says, oh, this is a compensatory mechanism. I think that we are building data to be supporting that presentation. And the last study that I will be sharing with you is a transvenous phrenic nerve stimulation for the treatment of central sleep apnea. This is a group of patients that we know through the pivotal trial that do very well with phrenic nerve stimulation in central sleep apnea patients. And we do know that the hypoxemia in patients with heart failure has produced increased mortality in these patients. So in this study, what they tried to do is look it up into the hypoxemic events through the intervention of phrenic nerve stimulation. And they take certain parameters like ODI, baseline oxygen saturation, saturation oxygen nadir, and desaturation T90. And this they divided into respiratory events and non-specific events. Not surprisingly, the phrenic nerve stimulation, they produce a reduce in ODI, they produce a reduce in the T90 related to respiratory events, but it has no events into the baseline oxygen desaturation of these patients, meaning that there is other comorbidities, pulmonary hypertension, respiratory pathologies like COPD, or increase in BMI, other hypoxemic events that needs to still be treated in these patients, because again, their baseline oxygenation not necessarily will be impacted and their oxygenation burden may continue despite resolution of the respiratory events. I think that I'm gonna be leaving it there because these are the main articles that I bring to you about central sleep apnea. Thank you. Thank you, Sunita, for inviting me, and it's a tough act to follow Bernardo and Sunita, but I'll try my best. I'm Babak Moklesi. I'm at Rush University in Chicago. The good news is that there wasn't a lot of publications on OHS to give you an update, so that makes my job a little bit easier. So what I'll do is I'll give you a little bit of what we have done with the clinical practice guidelines that was published a few years ago, and then share with you a couple of studies. I'm gonna skip this for the sake of time. And the reason I like to start with this serum bicarbonate issue because I think frequently it's a source of confusion and sometimes pain, and many times my fellows ask me how do you use this serum bicarbonate level? So this is what we did in the clinical practice guidelines. What we did is we looked at the data from five studies that looked at serum bicarbonate. Most of the studies had serum bicarbonate, and we pulled the data, and what we ended up finding is that you can use serum bicarbonate if the level is below 27 millimoles or milliequivalents per liter to make an assumption that the patient most likely doesn't have hypoventilation. So it's a good test to rule out. And how can you use this? Well, imagine you're seeing a patient in clinic who has severe obesity, and you're wondering should I order a sleep study with transcutaneous CO2 and you have limited resources in your lab, meaning not all your rooms may have transcutaneous CO2 monitoring. And I tell the fellows, well, open up Epic or EMR and see if the patient had any recent blood work. Many of these patients have had recent blood work. And if the serum bicarbonate is normal, I would say, well, maybe you don't need to do it. But be mindful that, at least in our EMR, normal bicarb is anywhere from 24 to 31, and we're looking at 27 milliequivalents. Below that, I think you can feel confident. But I just put one caveat here. Don't forget kidney function. If a patient has advanced CKD and they cannot retain bicarb, then you have a problem. So you can't use it. So then how do you use the bicarb if the bicarb level is high? Well, when it's high, at least our study showed it's a coin toss. So it's not good to rule in. It's good to rule out. With that said, there's always gradation and there's a spectrum. I always tell people, you can't be very dogmatic. If the level is 28, I don't feel that strongly about it. And if I suspect OHS, I ask for a blood gas. But if the level is 35, that's a whole different ballgame. So think about it that way, in my opinion. It will be useful. If the serum bicarb is below 27, the probability that you will miss somebody with clinically significant hypoventilation during the daytime is extremely low. And the ones that you miss probably have very mild hypoventilation with the arterial blood gas of around 45, 46, something like that. So why treat OHS? Of course, I don't need to tell this audience. They have really worse outcomes compared to your garden variety severe OSA. Many of them develop corpulmonale and pulmonary hypertension, and we'll talk about that in a second. And here are your alphabet soup of all the treatments that we have in terms of PAP. And one of the things that we tackled in the clinical practice guideline was when to use CPAP versus non-invasive ventilation. And the bottom line is that when we compiled the data, there was no difference in short-term and long-term outcomes in ambulatory patients who have OHS and concomitant severe OSA. You notice the word ambulatory is all caps. So remember that, and they have to have severe OSA. The few studies that informed the ATS guideline members were a lot of the short-term data actually came from Australia. In fact, one of the authors is here, Dr. Berlovitz, did great work on this area. You can see that in this first study when they compared CPAP versus bi-level with a spontaneous mode, there was no difference in short-term outcomes. We're talking about two, three months of follow-up. And in another follow-up study, a little bit larger, bi-level with a backup rate versus CPAP, similar outcomes at three months. Again, these were medium-term follow-ups which led to the PICWIC trial which randomized patients to either CPAP or NIV if they had severe OSA. And 70% of patients had severe OSA with OHS. And those who didn't have severe OSA just got NIV versus lifestyle modification. And you can see that there's 36 months of follow-up. So these three studies really are the ones that informed the clinical practice guidelines. And the PICWIC trial showed that after a median of five years of follow-up, if the patient had severe obstructive sleep apnea and OHS and was an ambulatory patient, ultimately there was no difference in outcome. And I always remind people that in the PICWIC trial, if you were randomized to CPAP and your CPAP titration didn't go well because you had a lot of hypoxemia on CPAP, what's the right word of saying it was tough luck, essentially, you were randomized to CPAP. You could get oxygen, but you were randomized to CPAP. So CPAP titration failure didn't apply here. You could have had a bad titration, you still got CPAP, which is important because ultimately you can see at the end of the day, adherence was similar between the two groups. The average pressures that CPAP patients were getting was around 11. The group that was getting volume-targeted pressure support like AVAPs, IVAPs, on average, they were getting around 20 over eight, so 12 of pressure support roughly with a backup rate of 14. Adherence, median adherence was around six hours. So these patients are more symptomatic. They tend to have higher adherence rate compared to OSA patients. And then hospital days, incident cardiovascular outcomes, events, and mortality rate was no different between these two groups. Again, here you can see a long-term Kaplan-Meier survival curve. And again, CO2 gets better in these patients, not surprisingly, over time. Oxygen level gets better over time. Need for daytime supplemental oxygen goes down over time as their ventilation gets better. They need less supplemental oxygen during the day. And there's a significant change in dyspnea. Again, both groups, CPAP and NIV get better, but no difference between CPAP and NIV. Sleepiness gets better significantly in this group. As you can see, again, no difference between CPAP and NIV. So it begs the question, when should NIV be considered? And what we essentially came up with in the clinical practice guideline is, of course, it goes without saying, if you have an acute and chronic hypercapnic respiratory failure and you're hospitalized, you should be treated with non-invasive ventilation. If you have milder forms of OSA and you don't have severe OSA, you should strongly consider non-invasive ventilation. And if you try CPAP and the patient's adherent to CPAP and they remain symptomatic and they remain hypercapnic, then you should probably consider switching to non-invasive ventilation. But I always tell people the main reason patients remain hypercapnic on CPAP is lack of adherence. That's the main reason. Or if they have CPAP intolerance, of course. And again, be mindful that many of the trials that use non-invasive ventilation use either bilevel with a backup rate or volume-targeted pressure support, which has a backup rate. Because when you start ventilating these patients, particularly when they're supine, many of them experience central apnea, so the backup rate could be important for them. So this brings me to how these patients look, the hospitalized patients versus ambulatory patients. And again, here I compiled data from a lot of studies that were published before 2008. Here's a study from Spain that had ICU patients. And here's a study from Chicago that one of my former fellows, Nathan Nowak, put together. And you can see here that in general, there's some differences between these patient groups. You notice that the group of patients who get hospitalized with acute and chronic hypercapnic respiratory failure are predominantly women. And they tend to be, at least in the study from Spain, they were older. And of course, you can see that they have acute and chronic hypercapnic respiratory failure. Now, this is relevant because we also know that women with OHS tend to be on average 10 years older, and they tend to have milder forms of OSA compared to men with OHS. And along those lines, we tried to compile data for the clinical practice guidelines. And what we looked at was around 1,100 patients who were hospitalized and were either discharged on some form of pap therapy, which 91% of them was NIV, versus discharge without pap therapy. And you can see the great majority were discharged on pap therapy. None of these 1,100 patients were from the United States. These are all from Australia, who shared data with us, the UK, France, Spain, and Sweden. And because I think if this was all from the United States, it would have been the reverse. The majority of patients would have been discharged without pap therapy. And you can see here that of the 119 people who were discharged without pap therapy, there was a much higher mortality, 16, 17% versus 2% at three months. So this is what led the clinical practice guideline committee to say that we should consider starting NIV therapy at discharge, and while the patient's waiting, outpatient workup, and come to the sleep lab and undergo sleep studies and pap titration and whatnot. The reason we said three months is because many sleep labs have similar wait times, two months, three months or so. But mind you, very low level of certainty. You know, so this data is very biased, and you have to be cautious. I think more research is needed in this area. Now, when we then later analyze, this is unpublished, difference between men and women, you can see less women were getting discharged with pap therapy. Again, none of these are from United States. These are the studies from the countries I mentioned earlier. So less women were getting pap therapy on discharge compared to men. And when you look at their outcomes, you can see that most of the mortality is driven by women. So there were 95 women on no pap, and you can see they're much higher burden on mortality compared to men, which didn't, you know, wasn't significant. Pap versus no pap. And again, once, so, you know, women had worse outcomes. But once you adjust for age, because women were on average 10 years older, and had a little bit higher burden of apricapnia. Even if you adjust just for age, there's no difference between men and women. So now the problem here in the United States is how do we discharge people on pap therapy? So, you know, Dr. Peter Gay and Bob Owens gathered a bunch of us to kind of brainstorm on how can we come up with new recommendations for Center for Medicare and Medicaid Services to change our reimbursement criteria. And I had the privilege of working with some of the folks here, including Bernardo. And essentially, when we published this, we, you know, I always joke, we asked Dr. Mazzone, who's the editor-in-chief of Chest, do not send these to reviewers from Australia, Canada, Europe, because they won't understand what the dilemma is. This is a Medicare issue. We need American reviewers who have felt our pain, how difficult it is to discharge people, and why we need to change these. Because as you saw earlier, most of the other countries, patients get discharged on some form of non-invasive ventilation. It's not that much of an issue compared to us. But here are the barriers. If you look at Medicare reimbursement criteria, you have to undergo a trial of BiPAP titration without a backup rate to get a device with a backup rate. You have to have a spirometry that rules out COPD. You have to have a repeat ABG during or immediately after sleep to demonstrate higher, this is nuts. Anyway, so I'm venting now. And without an ABG, I said she because we had a, in the paper that we publish, if you read it, there's a clinical vignette that we wrote, which was a real patient. You need to go over all these things to be able to qualify a patient to get a device. Of course, as physicians, we're not stupid. You know, we know that there is this other loophole that if you have hypercapnia in the hospital, you can just use that ABG or VBG and prescribe somebody with a home mechanical ventilator. And what's even sillier about that is nobody even pays attention to the pH. The pH could be 6.9, you know, but anyway. So it's not surprising that the Office of Inspector General when they saw a spike in home mechanical ventilators, they started looking into it. Why is there so many ventilators being ordered? And I always joke that it's not like we're getting kickback by ordering ventilators. We just wanna get our patient the right device at the right time. That's what we wanna do. We wanna do what's good for our patients. And this is a loophole that we found. And the reality remains that many of these patients, when they get a home mechanical ventilator, these devices are very expensive and it costs a lot of money because there's no adherence criteria anymore because it's a life-sustaining device. So it could be sitting in the closet, the DME provider gets $1,000 a month for that device being there compared to if you would have given a respiratory assist device or a CPAP device, would have been much cheaper. And these are the arguments we're making to Center for Medicare and Medicaid Services as advocacy to suggest that there has to be some change in Medicare reimbursement criteria. So this was one study that came out. How much time do I have? And this was one study that came out from the UK, Patty Murphy's group and Nick Hart. And I thought it was an interesting question and dilemma they were dealing with. Many times what happens, at least at Fox Lane where they work at St. Thomas Hospital in UK in London is patients get admitted to these non-invasive ventilation units as an outpatient and stay there for multiple days and they go extensive and exhaustive titrations and adjustments so they minimize the synchrony within the ventilator and they spend a lot of resources there. And they were thinking, okay, well, what if we come up with an outpatient home setup with a device that has an auto EPAP, AVAPs with an auto EPAP? Would it be feasible? Would it work? And what they demonstrated in this study that was published recently was that, actually there was a higher setup cost in the inpatient model, not surprisingly, but the folks who were randomized to outpatient NIV setup had a higher utilization cost compared to that with more emergency room visits. Ultimately, there was no difference in cost. There's another study ongoing looking at, do we get the patients in the lab to do a PSG and in-lab titration? Or do we do an HSC, OHS, mind you, do we do HSC and give them AVAPs with auto EPAP? And then download the device and see what happens. This is a study ongoing in Spain. The studies are not out yet, so we'll see what that shows. But here, it shows that it's feasible, but how do you apply this in United States remains a challenge at this point. Now, pulmonary hypertension, again, is very common in these patients. 50% of these patients, at least 50%, have evidence of pulmonary hypertension by echo. And here's data that we published some time ago showing that whether you got CPAP or NIV, there was a significant reduction at three years in prevalence of pulmonary hypertension. And you can see here that if you had pulmonary hypertension at baseline, here's the millimeters of mercury pressure, whether you got CPAP or NIV, on average, eight to 10 millimeters of mercury drop in systolic pulmonary artery pressure by echo over time. This is echo every year. Pulmonary artery hypertension can get better in these patients. This is, again, your classic type three pulmonary hypertension due to respiratory disease. Weight loss, you would think there would be a lot of data on weight loss, but there wasn't. And we were struggling to put together recommendations for the ATS clinical practice guidelines. But what we could muster from the literature, we thought 25 to 30% reduction in actual body weight would be something that would get these patients out of hypoventilation. And bariatric surgery tends to be the most effective way. With that said, this study got published last year from the Cleveland Clinic Group, led by Reena Mehra. I thought it was an interesting study because it's retrospective, but a large sample size. And at the Cleveland Clinic, they were doing end tidal CO2 on polysomnography. So what they demonstrated is that if patients who had evidence of hypoventilation during sleep, they didn't have necessarily daytime data, but they had evidence of hypoventilation during sleep, they were interested to see if they had worse outcomes on bariatric surgery. And when you read the abstract, the conclusion says that there's increased complications. But in my opinion, there wasn't. Because if you look at intubation rate, 30-day readmission, long-term mortality, there was no difference. So my conclusion is overall, bariatric surgery can safely be performed in patients with OHS. With that said, here's data from three centers in Chicago, Rush, University of Chicago, and Loyola. This is just ICD-10 codes. You can see how many bariatric surgeries are done in these institutions over a few years, and how many people have OHS, and how many of the OHS people got bariatric surgery. I don't understand why this is not happening. Is it because patients don't want it? Or is it because we're not referring? Or is it because surgeons don't wanna do operation on these patients because of high risk or combination of those things? But ultimately, my point is we're not doing a good job. And lastly, I'll leave you with this. I think these drugs are gonna give bariatric surgeons a run for their money. And this was published last year in the New England Journal of Medicine. Again, this is not in OHS or OSA. Eli Lilly is sponsoring a study in OSA. There's nothing on OHS yet. But look here, at the highest dose, these patients were losing around 50 pounds. At a little bit more than a year. So this is, I think, significant weight loss that can lead to improvement in OHS. But again, we don't have any studies on OHS. So with that, I'll stop. And hopefully, we'll have some time to get some questions. Thank you.

CPAP therapy

obstructive sleep apnea

cardiovascular risk

RICARDSA trial

sleep apnea symptoms

adherence

central sleep apnea

mortality rate

non-invasive ventilation

obesity hypoventilation syndrome