Relationship Between Intermittent Hypoxia, COPD and Comorbidities

Podcast Transcript

Raed Dweik, MD:

Hello, and welcome to the Respiratory Exchange podcast. I'm Raed Dweik, chief of the Integrated Hospital Care Institute at Cleveland Clinic. This podcast series of short, digestible episodes is intended for healthcare providers and covers topics related to respiratory health and disease. My colleagues and I will be interviewing experts about timely and timeless topics in the areas of lung health, critical illness, sleep, infectious disease, and rated disciplines. We will share with you information that will help you take better care of your patients. I hope you enjoy today's episode.

Dan Culver, DO:

Thank you for joining us for another episode of Respiratory Exchange. My name is Dan Culver. I'm chair of the Division of Pulmonary Medicine at Cleveland Clinic. I'm joined today by Dr. Amy Attaway, the Associate Director of the COPD Center here at the clinic and one of our emerging research stars in COPD and its effects on the body. We're here today to talk about intermittent hypoxia in COPD patients and the effect it has on our patients. Welcome, Amy.

Amy Attaway, MD:

Hello. Thank you for having me, Dr. Culver.

Dan Culver, DO:

So, intermittent hypoxia, of course, is something that, as pulmonologists, we struggle with in day-to-day conversations with patients. What to do with it, what does it mean. None of them want to wear oxygen, of course, if they can avoid it. Maybe we can just start off with what is intermittent hypoxia? What does that mean?

Amy Attaway, MD:

Sure. No, I think this is very often something that we discuss with our patients. So, when you have hypoxia, uh, in general, that means that you have an oxygen saturation less than or equal to the 88 percent. That's how we talk about it in the literature. And if you have persistent hypoxia or if it's affecting the blood, we call it hypoxemia, less than or equal to 88 percent, previous studies have shown that you have an increased risk for mortality. Now, if that's persistent.

However, if you just have episodes of hypoxemia where you're not persistent, you're not persistently below, 88 percent, if it's just when you get up and walk and you have this drop in your oxygen, or if it's while you're sleeping, if you have, uh, nocturnal hypoxemia, studies have previously not shown a clear influence of mortality or increased risk for mortality if you just have these episodes of low oxygen.

So, in general, when we talk to our patients, we kind of weigh the risk-benefit of whether to treat that or not based on the previous literature, and I would say a lot of the times, if they're just short episodes of hypoxia, we don't feel like it's significantly impacting their symptoms, then a lot of times, we say, well, let's just watch it. You're not persistently hypoxemic right now, so let's kind of see how you're doing clinically and follow you clinically.

Dan Culver, DO:

So, imagining the typical 75-year-old male patient who de-saturates walking across out to get the mail, who is in no way interested to take supplemental oxygen, and then asks you, "Well, can I walk longer? And what happens if I go down a little bit at night?" Are those the sorts of patients that we're now talking about?

Amy Attaway, MD:

Yeah, I believe so. So, these are the patients I think we weigh that risk-benefit. So, there seems to be a clear association of mortality if they're persistently hypoxemic, but other studies haven't shown that intermittent episodes really seem to cause increased risk for mortality or morbidity in our patients.

Dan Culver, DO:

And just reflecting back in the time I've been in practice, when I first started training, the knot trial had recently come out. And so, using oxygen at night was something we could easily recommend to our patients. Over time then, we got more data with the lot trial, which is the long-term oxygen therapy trial for these patients dropping. And then, and more recently, a paper that came out, I think this past year, in New England Journal suggesting that, even for patients with more persistent hypoxemia, that 24 hours a day wasn't necessary to supplement them, that they could be supplemented for a shorter period like 15 hours. So, putting all those together, it seems to me like there's still a lot of uncertainty for our clinical practice.

Amy Attaway, MD:

Yeah. I would agree. And, and actually, that's interesting. So, the two trials that seem to show a clear mortality and, uh, effect, that if you treated hypoxemia in patients, the NOTT trial and then the MMRC trial, the interesting thing about those studies was that mortality wasn't really affected within the first year. It's actually you had to follow this, the patients for a longer period of time. For the NOTT trial, I believe it was two years, and then the MMRC, it went out to five years.

So, it's interesting that there was a clear effect of hypoxemia on mortality in patients, but it wasn't apparent right away. And so, when we think about how hypoxemia affects our patients, that, the fact that you don't see a clear effect right away suggests to me that there may be more going on. That, have we studied intermittent hypoxemia enough? Is it impacting our comorbidities? There's actually been some really fascinating association studies looking at the impact of intermittent hypoxemia on COPD patients, like the cardiovascular impacts. There have been studies looking at the neurologic impact that seem to impair cognitive function. So, I think there's a lot more to know about hypoxemia and how it can affect our patients, and what the impact is in more longer-term studies.

Dan Culver, DO:

Can I just pivot for a second to ask you a related question that's come up more in the past couple of years? Quite often, we're, we're assessing this and measuring this by nocturnal oximetry or by a D-set study in a hallway. But skin pigmentation really has become a hot topic. And how does that play into either the, the database that we have, or even just your clinical practice? How do you suggest people handle that?

Amy Attaway, MD:

So, that was also something that came out more recently, that certain populations, including like, African Americans, that the oximetry was not accurate. So, that's a great point. I believe that the practice now is to get an arterial blood gas to confirm hypoxemia. I know an emerging area with a lot more studies going on. But it's totally, you know. Maybe we haven't been diagnosing hypoxemia properly in our patients. Maybe we haven't been looking at correcting for race, things like that. So, we may have missed a fair number of patients as well that were having intermittent hypoxemia or persistent hypoxemia, and we weren't correctly diagnosing it in our patients.

Dan Culver, DO:

I wonder if that issue calls into question, for certain racial groups for sure, some of the findings in these larger studies, these larger trials that have happened. You know, maybe we need to go back and think about those again.

Amy Attaway, MD:

Yeah. Definitely, I think that we should consider that, for sure. Yeah.

Dan Culver, DO:

So, right now, I think you, what you're saying, if I got it right, is, you know, for people who are persistently hypoxemic, those should, those should get supplemental oxygen. For people who are hypoxemic at night, those all should get supplemental oxygen. But for anybody else, the jury is a bit still out.

Amy Attaway, MD:

Yes. So, the persistent hypoxemia, there's, there's been several randomized control trials that showed that mortality benefit, and that those are the patients that we treat with oxygen. For COPD patients with nocturnal hypoxemia, um, we kind of weigh the risk-benefit, and if there's evidence of end organ damage, such as pulmonary hypertension, we recommend to treat those patients, or if they have sleep symptoms. And then for patients who are intermittently hypoxemic, we, again, weigh the risk-benefit. A lot of times, we may not treat those patients because there wasn't a clear mortality benefit in the literature.

Dan Culver, DO:

And so, things like a history of stroke or coronary artery disease or peripheral vascular disease, I presume those would come into your calculation.

Amy Attaway, MD:

So, I think it's interesting. So, actually, the guidelines don't really talk much about that. I think as clinicians, we think, you know, and that's certainly something that I would be concerned about, if a patient has a lot of comorbidities. But that actually hasn't really been explored in randomized control trials, for my understanding.

Dan Culver, DO:

So, we don't know more than we do know. Such is the case for many areas of medicine.

Amy Attaway, MD:

Right. Right. For sure.

Dan Culver, DO:

So, you know, I think it's interesting. You mentioned a little earlier that we may not see a mortality signal with intermittent hypoxia, but there may be some other signals that are perhaps a little harder to ascertain or take longer to accrue, around the effect on different organs. So, I wonder if you can just explore that a little bit more.

Amy Attaway, MD:

Yes, absolutely. So, one of the things that I study in my kind of area of focus is looking at the impact of sarcopenia, or muscle loss, in COPD patients. So, this is a condition that can affect up to 50 percent of COPD patients, where they get this profound muscle loss, and we don't have a clear idea why that may happen.

Dan Culver, DO:

This makes me think of the classic Netter picture with the pink puffers. The skinny person with no muscles who's just working away to breathe.

Amy Attaway, MD:

Right, exactly. And you kind of see clinically on them, you see that muscle wasting. You see, you envision a really thin patient with a low BMI. Those are kind of the patients that come to mind. Now, the interesting thing about, uh, sarcopenia is that we don't have a clear understanding of what causes it. It's believed to be multifactorial. It's interesting, though, because your muscles, a lot of the way we look at it is your muscles are kind of divided into type one or type two fibers. So, the Type 1 fibers are rich in mitochondria. They use predominately oxygen to synthesize ATP. Those are your Type 1, and they're the slow twitch. They're good for endurance activity.

And then you have your Type 2 fibers, which are the short bursts of energy fibers. They predominately use glycolysis to make ATP, and they can build up. They're fast twitch, but they can lose energy pretty quickly, and you can build up lactic acid, and that can lead to fatigue. So, what we found is, and in many COPD patients, is this shift. The fibers shift from Type 1, predominately type. Well, ideally, you have a mix of both. But they'll shift to almost all to Type 2 fibers in the muscle. And so-

Dan Culver, DO:

This is the, these are the breathing muscles? Or all the muscles in the body?

Amy Attaway, MD:

So, it's interesting since it's hard to study all the muscles, but there's a general shift, it seems, in your COPD patients, where they shift a lot of the muscle fibers which maybe were type one before, will start shifting to type two. And we're not really sure why or how that happens, but it's believed to be that oxygen is a, is a pretty big stimulus, especially if you have low oxygen, a shift from type one to type two. We've seen in a lot of models in our patients. You also see that. Now, you see that in COPD patients. You also see that in heart failure patients, a lot of them who experience hypoxemia.

And so, again, we're not really sure why that's happening, but to, one of our hypotheses that we study in our lab is that perhaps these, these episodes of intermittent hypoxia in our COPD patients are kind of stimulating these fibers to shift from the type one to the type two fibers.

Dan Culver, DO:

And this is exactly what you see in your mouse patients, as I understand it.

Amy Attaway, MD:

Yes. We have a study where we looked at this in mice, where we exposed them to episodes of intermittent hypoxia, and we did seem to show this shift from the type one fibers to the type two fibers.

Dan Culver, DO:

And so, you're getting less of those endurance muscles, probably less functional capacity for patients, whether they're humans or mice, and, and then also, do I understand this correctly? There's a general loss of muscle bulk overall? Not just the type of muscle, but the amount of muscle in these patients?

Amy Attaway, MD:

There is, yes. So, the way I look at it is that you'll see these Type 1 fibers that are kind of rich and large with, rich in mitochondria, they'll start shifting to the Type 2 fibers. And then those fibers will actually shrink. And so, you have a general loss of muscle mass, but then it also appears that the function of the muscles is a lot different and reduced once you get to this Type 2 state.

Dan Culver, DO:

And so, you can study this by looking at muscle function in patients? How do you do that?

Amy Attaway, MD:

So, that's interesting. In patients, a lot of times, so we'll measure their muscle mass. We'll measure their muscle function. A lot of times, we'll use like, a quick bedside procedure which is a handgrip strength, which gives a good. It's a good surrogate for your overall body strength. And then for endurance, there's several tests that you can use, like sit-to-stand tests. A six-minute walk test is considered a good test of endurance if you're looking for, for that in your patients. In terms of our in-vivo models that we have with mice, we'll also do handgrip strength in the mice. We can measure the contract-

Dan Culver, DO:

Wouldn't that be called paw grip strength?

Amy Attaway, MD:

They should. They should change it to paw grip strength. And then we also have some ex-vivo models of muscle contraction where we, you know, take the muscle and look at its contractile fibers in like a bath of electrolytes.

Dan Culver, DO:

So, this is interesting. So, what you're saying is that some of the sarcopenia and muscle loss we see in patients, and I think you noticed this even in patients who have normal body mass index, when you look at their lean muscle mass, it's low. That's replaced a lot of the times by adipose tissue. And so, I suppose that that explains some of their functional incapacity, loss of exercise tolerance, and then I wonder, you know, what the role then is of pulmonary rehab and the things we've kind of traditionally used to try to combat that. Is that not as effective if you have intermittent hypoxia?

Amy Attaway, MD:

I think that's a great question, and that's actually something that we're hoping to study further. And it really hasn't been looked at before. But there is clear evidence in the literature that there are, pulmonary rehabilitation, there's responders and non-responders. Some patients do great with pulmonary rehab. They gain back their muscle. They improve their physical performance and their functional capacity. And then some patients just don't seem to respond.

And this is after, you know, a lot of times, you'll see. These studies have all adjusted for, and you know, patients' activity levels, like how active they are. They adjust for sedentary behavior. That's an important compounder in any of these studies. But, yes, there's clear evidence of non-responders to pulmonary rehab, and that's one of the things we're hoping to study, is to understand if maybe intermittent hypoxemia to be impacting that.

Dan Culver, DO:

So, if I understand correctly what you've said so far to this point, you know, in people who have intermittent hypoxia, number one, we should be suspicious about people with differently pigmented skin and look a little bit more deeply, perhaps with blood gas or other techniques. But in people with intermittent hypoxia, it's not as clear-cut as just measuring mortality, that there are other long-term effects on various organs, including the muscles, and that what you've shown is that that has a direct effect on the myocytes, both the breathing muscles and the non-breathing muscles like the limb muscles, in a way that leads to decreased functional capacity and that seems to be oxygen-dependent. Is that a fair exposition?

Amy Attaway, MD:

Yes, I'd say definitely. We were able to look at this in patients in a large sleep registry which is Dr. Mira's registry, looking at patients with COPD who had nocturnal hypoxemia. They had reduced muscle mass and physical performance. This was an associative study. And then at the bench, when we looked in the lab, we looked at the impact of intermittent hypoxia on skeletal muscle cells. We also looked in mouse models, and it did seem to impact performance and also the muscle mass. There were reductions in muscle mass. And it seemed to be clearly affected by episodes of the intermittent hype, or intermittent hypoxia model.

Dan Culver, DO:

So, potentially, this is a pretty important observation in so far as I think we've traditionally dismissed intermittent hypoxia as a nuisance or a measurement artifact. Like many other things in medicine, we don't try to normalize everything back to how it was when we were 18. But this may have more profound, systemic consequences than we recognized before.

Amy Attaway, MD:

I really do. I think that that's, it's an important thing to recognize and to look at in our patients. I think COPD is a disease of comorbidities, and even, you know, we don't have a clear explanation for why patients with COPD have more bone loss, muscle loss. They're at an increased risk for heart disease. It can affect almost every organ of your body. And in the past we, a lot of times, we thought there was the inflammatory impact from COPD, the inflammatory aspect of it. But then we, we see our patients who maybe are, they, they don't have evidence of a lot of inflammation. They're not having frequent exacerbations. But they still show this profound muscle loss, profound bone loss, heart disease, over time.

So, I think there's a lot more to study. I think it's to understand what could be causing that. And one of our suspicions in our practice is that intermittent hypoxia could be playing a role in increasing the risk for these comorbidities in COPD.

Dan Culver, DO:

Last question, and you're a COPD specialist, and that's where you're spending most of your time here. But I wonder if you think that the mechanisms you're studying and the observations you're making about sarcopenia are specific to COPD. Or does this really explain some of the frailty and some of the challenges we have with patients with multiple problems? You mentioned heart failure, but IPF comes to mind. Transplant patients come to mind. There's a lot of kinds of patients who struggle with similar issues.

Amy Attaway, MD:

Yes. I totally agree with you. I think that this, so sarcopenia for sure is not disease-specific to COPD, although we see it in almost up to 50 percent of our COPD patients. But sarcopenia for sure can be seen in other conditions such as congestive heart failure, like you had mentioned. It can be seen in idiopathic pulmonary fibrosis. I know there's a lot of people interested in looking at understanding the mechanisms of sarcopenia in these other comorbidities. I believe in idiopathic pulmonary fibrosis, it's a little bit harder because you need a large cohort of patients, whereas COPD's 10 percent of the world's population. So, it's a little bit, I think, easier to study. But I do. I do think that this could explain the sarcopenia we see in other diseases such as idiopathic pulmonary fibrosis. I think there's a lot more that we need to understand about the impacts of hypoxia, and that it could be an explanation for what we see in our patients.

Dan Culver, DO:

Well, I think this is a very interesting area, and thank you for coming on today. I mean, oxygen is fundamental to life, at least life as we know it, and every time we think we've got the answer about how to use oxygen, we uncover more, more layers of the onion. And so, I appreciate the research you're doing, and the fact that you can tie some mechanistic understanding in with some observational research, or even with understanding groups within clinical trials. And so, encourage you to keep doing exactly what you're doing.

Amy Attaway, MD:

Oh, thank you so much. And I have to say I wouldn't be where I'm at without the support of my institution, with you, Dr. Culver, and then all my mentors. I think even our study, where we looked at the clinical associative studies, I had so many mentors that each brought just a unique aspect to our studies. I have had so much mentorship from so many wonderful people that have got me to this point, and I want to thank them all.

Dan Culver, DO:

Well, thank you, and keep teaching us about hypoxia and helping guide us clinicians about what we're supposed to do and how we're supposed to do it.

Amy Attaway, MD:

Oh, thank you so much.

Dan Culver, DO:

Thank you all for tuning in today. It's been a pleasure. I look forward to next time.

Raed Dweik, MD:

Thank you for listening to this episode of the Respiratory Exchange podcast. You can find additional podcast episodes on our website, clevelandclinic.org/podcasts, or wherever you get your podcasts.