Good morning, and welcome to the Lung Transplant Session, Assess How Fit is Fit, Assessing and Optimizing Fitness in Preparation for Lung Transplantation. My name is David Nunley from the Lung Transplant Program at The Ohio State University, and I'll be the chair for this session. I think most of us in the transplant world struggle sometimes with knowing how fit our patients are and how prepared they are to undergo transplantation, to not only undergo transplantation, but have the fitness level to not only to also recover, but also to benefit from the precious gift that they've received. And when we do identify someone who is maybe not as fit as we would like, what sort of things can we do to intervene to make them better candidates for transplant so they can benefit from this? So our slate of esteemed speakers this morning, hopefully, will give us a number of updates in this area. So without further delay, allow me to introduce to you Dr. Cassie Kennedy from the Lung Transplant Program at the Mayo Clinic in Rochester, Minnesota, where she's gonna speak about pre-transplant interventions and how to optimize candidates. Cassie. Good morning, thank you, David, for inviting me to give this talk. This is near and dear to my heart. I like to focus on optimizing pre-transplant status to improve post-transplant outcomes. And so I'll be specifically focusing on pre-transplant interventions for candidate optimization in my section. I hope that you will understand what pre-transplant risk factors may respond to pre-transplant intervention and discuss some possible pre-intervention strategies. I have nothing to disclose. I won't be discussing off-label medications. So this is how I like to set up my research paradigm. I think that when I joined Transplant in 2008, there was a lot of people who felt that our job was the above cartoon. So basically, we have a slate of candidates who approach us, and our job was to sort out the candidate versus the non-candidate, and they were either one or the other. And what I found was more the second scenario, that we actually had a lot of people who were in this vague in-between space. And so if you were a conservative program, you were saying no and putting them in the not-a-candidate space. And if you were an aggressive program, perhaps you were saying yes, and you were putting them in the, let's-go-ahead-and-list-you space. But not much was happening to the candidates themselves to move them in either direction. And so what I proposed to do was to take these candidates and start to try to move them from this nebulous in-between space to try to make them more definitive candidates. So what can we do to optimize some of these risk factors that we know are going to be a detriment to transplant outcomes and make everybody comfortable, including the candidate and their caregivers, that this is a good idea? I don't think it's actually a novel concept, really, when you think about it. I think there are risk factors that we know are going to be not modifiable. I cannot change anyone's age. So we know that advanced age is a risk factor for long-term survival following lung transplant. I can't fix that. If they have a malignancy that is at high risk for recurrence or metastatic, I can't fix that. And so there are not modifiable risk factors. But then there are potentially modifiable risk factors. And I think there even were potentially modifiable risk factors when I joined transplant in 2008. And for example, if we had somebody with nocardia, we're gonna treat the nocardia before we go ahead and list the patient and transplant them. If we have somebody who has cardiac blockage that is amenable to stenting, we're gonna stent, we're gonna plavix, and then we're gonna list the patient. So there were already some people who had risk factors that were deemed modifiable. There were some weight-related risk factors that were deemed modifiable, but there weren't a lot of programs who were doing active interventions. There was a lot of, please lose weight, you exceed the BMI of 30, which is the cutoff in 2008, and we'll see back when you lose that weight and when then we'll get you listed. But not a lot of active interventions. So now I think we're faced with some risk factors that have moved the spectrum to what is transplantable, what is not transplantable, but we're still left with a BMI greater than 35. Most programs would not transplant. A BMI less than 16, especially non-cystic fibrosis patient, most transplant programs would not proceed. And then we have this nebulous limited functional status with poor rehab potential. And I think that's the crux of the talk here, because what is modifiable about poor functional status? What can we expect from these patients who have limited oxygenation, limited ventilation, and have been sedentary for quite some time? So obesity was one of the first pre-transplant interventions that I looked at. And we were able to show that definitively people can lose weight pre-transplant. The average weight loss for overweight and obese patients was 8.5 kilograms in a 341 patient study. And that indeed every unit reduction in BMI was associated with a reduced risk of death and a decrease in mechanical ventilator days. This study was replicated by Duke and they indeed confirmed that they also saw improved survival with weight loss pre-transplant. And they saw improved clad-free survival in their cohort as well. So I think we know definitively that obesity is a modifiable risk factor. This is gonna make your overall fitness for transplant improved. However, weight loss does take time. And so I think the crux of the matter remains how much weight and how long are we going to persist in asking patients to lose weight prior to getting them on the list. On the opposite side of the coin, we have patients who are underweight. The WHO criteria for underweight would be 18.5. In transplant world, people have variable cutoffs. We have found that the patients who have cystic fibrosis do have a reduced survival if their BMI's less than 17 kilograms per meter squared. However, their reduced survival is still superior to overall survival for most diagnoses going into transplant at an average of seven years, where the average survival following lung transplant is around six years. And so I think as a community, we have decided that that is an acceptable long-term survival and that patients would definitively benefit from transplant. And so it becomes about the transplant urgency for the cystic fibrosis patients. Do we wanna try to push them up to the average 8.2 year survival by helping them gain weight pre-transplant, or do we wanna proceed and embrace that average of seven year survival? When you look into pre-transplant nutritional optimization, I think most programs would say that they do some degree of nutritional optimization. At our program, we do supplemental nocturnal feeds or we do nutritional supplements. Sometimes we use appetite stimulants for patients who have decreased appetite. But I don't think that there's a standard of practice in the underweight approach pre-transplant. And I don't think the evidence is very good. I really sincerely tried hard to find you some definitive trials. And this is one example where it was 10 patients versus 10 controls, and they did nocturnal feeds. And it was six months. So six months is a long time to wait for transplant listing if you're in the ballpark. And so I think that the evidence for pre-transplant optimization for underweight patients needs a little bit of attention by the research community. And then there's frailty, which I think you're gonna be hearing more about by the next three talks. And frailty is a syndrome that makes you at increased susceptibility to adverse outcomes. So we talk about it in kind of a multi-dimensional or multi-system state where it can reduce your response to vaccines. For example, you could be at higher risk for fall. You can be at higher risk for mortality. And in the transplant community, we know that the weightless survival and the post-transplant survival are reduced when patients have frailty. So the question is, okay, we know it affects survival, but how effective is it going to be with these hypoxic or hypoventilating patients to try to put them into some sort of exercise program? And there are exercise interventions that have been tried. You could see them listed at the bottom here. And we know that we can improve the six-minute walk. We can preserve or improve the exercise capacity. And we can improve the sit-to-stand test. We can improve shortness of breath. But I'd like to draw your attention to the durations here. So there's anything from a four-week inpatient study to a four-month outpatient study. And so the question at hand is, do we have four months of outpatient time for these patients in order to optimize them for transplant? So I will just leave you with these questions today as we prepare to listen to the other speakers, because this is the tension right now for me as a frailty researcher who believes strongly in pre-transplant optimization and kind of the rest of the colleagues, how much optimization can we tolerate pre-transplant? Can the patient wait? Do they want to wait? And how long should we design these interventions? What is acceptable pre-transplant for an intervention? And it's not a small stakes game. So this is a Keppemeier from one of the early frailty studies where we looked at the frailty deficit index and looked at if you had pre-transplant frailty by the frailty deficit index, how was your survival post-transplant compared to if you were robust or non-frail pre-transplant? And the difference was a 28.3% mortality versus a 7.1% mortality. So this is a high stakes scheme. All of the transplant centers are trying to meet CMS and UNOS expectations for survival outcomes. We're trying to compete with other transplant centers and achieve around that 90% one year survival. And so you can see that the non-frail patients are definitely gonna achieve that 90% survival on average. The frail patients are not. So if you're doing a lot of high risk, frail patient transplants without any pre-transplant optimization, that could potentially be harmful to the program and compromise our societal obligation to get maximal outcome. On the other hand, we also know that frailty compromises pre-transplant weightless survival. So how long can the patient wait? And I think that's the crux of this discussion today. Thank you very much. I'd be happy to take a couple questions if anybody has any. Our next presenter is Dr. Josh Diamond from the University of Pennsylvania. Dr. Diamond is going to discuss pre-transplant assessments of cardiorespiratory fitness. What are the most reliable metrics? Thank you very much for the invitation to present today. This is also a topic that I find to be extremely important. And hopefully I'll actually be able to answer your question from a slightly different perspective in terms of sort of which metrics and how to utilize those metrics. So this is my family. This is actually us in the Galapagos this summer. I'm the associate medical director of the transplant program at University of Pennsylvania. There's my disclosures, which is not at all applicable to the talk that I'm gonna be presenting today. I do have a couple of audience response questions, so feel free to scan the, scan anything. Perfect, okay. So two objectives for today. So I hope that at the end we can understand the importance of assessing frailty prior to lung transplantation, as well as be able to review some of the metrics that currently exist for how to assess the potentially frail transplant candidate. So I'm gonna start off with a case. This is probably a case many people have seen before. It's a 66-year-old patient with IPF. FEV1 and FEC are both rather low at rest. It requires four liters of supplemental oxygen. On evaluation, BMI is 22, six-minute walk distance is 180 meters. They have no evidence of any extra pulmonary disease that would get in the way of their potential transplant candidacy. And they undergo multiple different frailty metric assessments. So the short physical performance battery test, we'll get into more detail, is the one that we utilize at the University of Pennsylvania is the six. The higher the score, the better you are. So six is a low score that would be consistent with frailty. The freed frailty phenotype, four out of five. Here, the higher the score, the more frail. And the cumulative frailty index of 0.18, this would actually be indicative of not being frail, where the cutoff is 0.25. So the question is, is this patient frail? And which is the metric that we should be utilizing? So I wanna start off with the importance of being able to identify whether somebody is or is not frail prior to transplant. And there's multiple bodies of evidence that demonstrate that frail candidates have an increased weightless mortality, they have an increased risk of death after transplant, and they have an increased likelihood of being readmitted after transplant. From a conceptual perspective, I think this figure tells a lot of the story. So if you have a patient who's not frail and they undergo an acute critical illness, in our case, this is organ transplantation, which is a significant physiologic stressor, everybody has a decline in their level of physical function, regardless of their preexisting level of function. But if you're not frail, you have sufficient reserve such that you're able to suffer this decline and then have a relatively rapid rate of recovery back to your pre-intervention baseline. If instead you start off frail, significantly lower in this functional class, and you have the same intervention, again, lung transplantation, there's multiple different pathways that might exist. One, which we unfortunately see, is where a patient has a rapid decline and is unable to recover and rapidly passes away. Another where there's a slower decline, but again, the patient's unable to recover. And perhaps one of the worst is when the patient has a rapid decline and then stabilizes, but remains in this sort of setting of chronic critical illness or persistent debility, and they're unable to actually get the benefit for the intervention that they were supposed to get. So I can identify that frail patients are more likely to be chronically critically ill, become severely disabled, die in the hospital, and they're unlikely to live the expected life expectancy of the average transplant recipient. Okay, I think this is my first question. So I'll open it up. Are you currently utilizing a frailty assessment clinically? No, not at all. Yes, but only to identify folks who need prehab. Yes, as part of a multidimensional evaluation. Yes, it's a key part of transplant candidacy or something other. Ah, so a nice mixture. So about a quarter of people are saying no. There is no correct answer to this question. So about a quarter of people are saying no. About a quarter of people are saying yes, but just to identify folks who need prehab. About a quarter are saying yes, that it's part of the overall evaluation. Very few people are saying 10%, less than 10% saying that this is a key part of transplant candidacy. So if you're using it, what frailty assessment tool do you use? So none, clinical judgment, the sort of, you know, eyeball test, cumulative deficit or frailty index, the FFP, the frailty phenotype, short physical performance battery test or something else. Okay. So, again, about 10% of people saying no test, a third saying clinical judgment or the eyeball test, 44% are using the SPPB, which, again, is the intervention or the evaluation that we use at Penn. And I'm going to challenge this 33% here who are only, quote, unquote, using the eyeball test. I imagine you're actually utilizing components of other formally developed tests in a way that's probably relatively regimented as opposed to just sort of taking a look at the patient. Okay. So, how can we measure frailty? So, yes, we could use the eyeball test. We can use these cumulative deficit models, which are these counting models. We add up the number of deficits a patient has, or these phenotypic models, the FFP, the SPPB. So, we'll start off with the frailty index. This is a cumulative deficit model. There are 44 potential deficits in multiple domains, comorbidities, physical attributes, cognition, and psychological issues. You count them, the number of deficits for an individual divided by the total number that you measured. And if you have less than 0.25, you'd be considered to be not frail, greater than 0.25, you would be considered to be frail. So, this is a reasonably well-accepted threshold for frailty. But this metric was not made or evaluated in a transplant patient population. Most of these metrics are evaluated in an elderly community-dwelling population. Similarly, the frail, the freed frailty phenotype. Five metrics, weakness, slowness, shrinking, exhaustion, and low activity. It's a simple yes, no, you count them up. If you have none, you're not frail. One or two, you are pre-frail. Anything three or higher, you're frail. Again, this was generated in an elderly community-dwelling population of patients, but has been applied to our transplant patients. This is the system that we use, and it sounds like a lot of the people in the audience are using as well, the SPPB. There's sort of three different components. There's the chair stand, the gait speed, and the balance. One of the nice things about this, compared to the six-minute walk distance, is the gait speed test is a very short distance, and so it's unlikely that you're going to be limited by hypoxia. You're more likely to be limited by physical weakness. And again, you count up the numbers. Less than 10 is considered frail, greater than 10 is not frail. We consider 10 or 11 to be the pre-frail state that, hopefully, you can get intervention in. I do want to highlight, though, that there are four new transplant-specific frailty measures, the cumulative deficits frailty index, the frailty risk score, the frailty index, which is a CF-specific metric, and the lung transplant frailty score. So we'll start off with the cumulative deficits frailty index. This was generated at the University of Toronto in Canada, a retrospective chart review of a large number of solid organ transplant recipients, so this is not lung-specific. They identified 40 variables, comorbidities, labs, BMI, INA, ADLs, hospitalizations, and they identified that this score was associated with the risk for discharge to rehab post-transplant as opposed to a discharge to home. It was also associated with death or delisting before transplant, with a reasonable hazard ratio for a single unit increase in their score, and with a reasonable area under the curve. The frailty risk score, this was generated in 84 lung transplant-specific patients, 15 different factors that are listed there, each scored present or absent. You're considered frail if you have three or more of these different factors. What's interesting is 75% of those 84 patients were deemed to be frail, and a high score was associated with post-transplant readmission or death, so a reasonable level of validity. The challenge with a lot of these scores is that each of these factors is considered the same, right? There's no weighting for an individual score, so having depression is the same as having chronic pain, but we don't really have evidence that these things are weighted equally in reality. This is a CF transplant candidate-specific metric that was derived in Toronto and then validated in two independent Swiss transplant centers. They evaluated 66 different variables from CF visits and lung transplant evaluations, again scored 1 or 0. Frailty was higher than 0.25. This is an index. Again, you count the number of deficits, divide by the total number of deficits assessed, and it also correlates with weightless, worsening death, post-transplant mortality, length of stay, hospital length of stay. The challenge with some of these is 66 variables is a significant number of variables to be counting each time you're trying to assess a patient. I'm going to give a little bit more detail about a metric that we at Penn were part of the development for, so this is the lung transplant frailty scale. We looked at multiple different domains, the frailty domain, and then how to operationalize those different domains. You can see we looked at things like slowness, multiple different ways of assessing, weakness, multiple ways of assessing, and then various different biomarkers that sort of indicate the underlying physiologic and cellular mechanisms that lead to the development of the frail state. We generated multiple different models for different specific purposes. There's a base model that's relatively simple. The balance metric from the SPBB, the grip strength metric from the FFP, the gait speed from the SPBB, and one biomarker, high CRP, and you can see reasonable C-statistic. We did another model that actually included a measure of biocomposition. We utilized BIA, and you can see same model plus the BIA, slightly improved C-statistic, and then this last one is more of a research tool that we generated for folks who want to actually be able to utilize this for sort of research-based purposes, and it utilizes several different cellular markers that we don't routinely use from a clinical perspective, so it was made as a research tool, and you can see that when comparing the C-statistic for our three different models, they're superior to the SPBB as well as to the FFP, and they're relatively simple. For those of you who are interested in accessing it, this is the web address for it, LungTransplantFrailtyScale.ucsf.edu. This sort of lead investigator was John Singer at UCSF, and you just plug in the information and you're able to sort of get out a score out of this metric. In conclusion, pre-transplant frailty is associated with weightless death, post-transplant mortality. There are multiple tools that are available now for frailty assessment, many of which are now becoming lung transplant-specific so that they actually have been validated and developed in a patient population that we take care of. Identification of frailty is key prior to transplant. You can risk stratify, as you heard from Dr. Kennedy before, there's the potential for intervention and risk factor mitigation, but the key part of this is identification beforehand. The challenge is how to utilize these metrics. I think most programs would not say that this metric alone would result in a patient not being listed or being delisted, but it's part of a more complete evaluation of patients. We take into account all the other factors about the patient. We recently published a paper looking at the impact of pre-transplant physical therapy in our COVID ECMO ARDS patients who are extremely limited in their ability to participate, but how we can get those patients up to even do minimal physical therapy to improve their post-transplant outcomes. So young patients, different than elderly patients, so I think this is an important metric in a sort of overall holistic approach for assessing patient candidacy. Thank you very much. Thank you, Dr. Diamond. Our next speaker, Dr. Thomas Decato from Harbor Medical Center, UCLA, is a well-recognized expert in cardiopulmonary exercise testing. He's going to speak to us about the physiology of exercise limitation in common advanced lung diseases. Dr. Decato. Thanks for having me. Okay. So my name is Tom Decato, and I am from Harbor UCLA, where I do a lot of exercise testing and research in that space. I also have a couple questions, so if you don't have the QR code yet, I'll give you a second here. And so I am not a transplant doctor, as you have now gathered, and so I'm going to give you a little different take, perhaps, on some things and talk about exercise limitation in common advanced lung diseases. So I'm going to talk about COPD, interstitial lung disease, and PAH. Briefly, I'm going to use CPET. We're going to take kind of a 30,000-foot view, and so you may be familiar with exercise limitation, but perhaps not so much on the CPET side. And I want you to think about, while I'm showing you a couple examples, about deconditioning and what that means and what it is. And we'll come back to that at the end. CPET, in and of itself, really is the gold standard for evaluating exercise capacity. There's many indications and applications of it, and it is having an increasing role in clinical medicine. And we'll see where that takes us and if it makes its way more into the transplant world. But certainly we do use it in advanced lung disease, outside of transplant evaluation context, but I was wondering people's experience with CPET. Okay. Okay. Great. So, somewhat divided, but the majority say they sometimes use it and generally someone else interprets them, yeah. So these can be difficult, hard to remember from fellowship, et cetera, and if you're not using it all the time, it can be a challenging test to interpret. So before we get into our CPET case, I wanted to ask, which of the following is true regarding exercise limitation in CPET? Is it characterized by ventilatory inefficiency, by dynamic hyperinflation, by muscular dysfunction, or all of the above? Of course, all of the above. Great test takers. So I'm going to show you then a 62-year-old man with COPD who I don't have the lung function test up here. I'll show you why his lung function is bad. You can tell that from the test itself. But did a 10-watt ramp, so the cycle, the resistance changes such that the work rate increases by 10 watts per minute. And this patient stopped due to dyspnea. And you can see here in the first box that the peak VO2 in red is quite low, below predicted, so oxygen consumption is reduced. This is something called oxygen pulse. It's more or less a surrogate for stroke volume, increases across exercise. Here's VCO2 on the y-axis, VO2 on the x-axis. We use this to look for anaerobic or lactate threshold, and you identify that by a change in slope here. I think the patient starts to hit their anaerobic threshold right when they stop exercise in this case. The ventilatory equivalents are in panel four here. This is VEVCO2 in blue, and we use this as a marker of ventilatory efficiency. And so the nadir here, again, probably anaerobic threshold does occur right here at the end of exercise. The nadir, or the anaerobic threshold value, are about the same in this case, and it's in the high 20s, about 30, which is a normal value. And then end tidal CO2 is here. It's a little high in the mid 40s and increases across exercise. We actually have blood gas data, so you can see this patient's partial pressure of oxygen also goes down. And then the crux of it in this case is here. So this is tidal volume and minute ventilation here in panel nine, and the patient does increase their tidal volume, and then as exercise goes on, increases their minute ventilation by their respiratory rate. So you can see tidal volume maybe starts to come down at the end, but they run into their maximum voluntary ventilation, and so it looks like they stop because of their lungs. And so we call this breathing reserve. Breathing reserve, there is no breathing reserve here. Typically people have a lot of breathing reserve. But this is a crude measure, and so there are more sophisticated ways we can look at that. I told you here that ventilatory efficiency looked normal, but what you need to account for is how we determine ventilatory efficiency, and so I skipped a few steps to get to this. But what makes ventilation inefficient is high dead space or relative hyperventilation. And so the reason VEVCO2 here looks normal, even though this patient has inefficient ventilation, is because their CO2 is high. And so the dead space fraction using blood gas is actually a little high at rest and decreases very minimally with exercise, which is abnormal. So it should decrease a lot more than this. And we can obtain inspiratory capacities with exercise. Call it dynamic operating lung volumes, and it allows us to place the exercise tidal volume within a resting flow volume loop. Normally end expiratory lung volume should decrease and end inspiratory lung volume should increase. And what happens in COPD is that end expiratory lung volume does not decrease. It increases. People breathe at a much higher lung capacity sometimes with a very small inspiratory reserve volume up at TLC, and that's a very uncomfortable and disadvantageous place to be breathing. But even within COPD, there's different phenotypes, if you will, of how people can have mechanical ventilatory constraints and aren't able to expand their tidal volume. So this is probably the patient we were just looking at. Their end expiratory lung volume increases. They can't really expand their tidal volume. This patient has an OK inspiratory reserve volume. This patient has dynamic hyperinflation, but with a really low inspiratory reserve volume. And this patient has a low inspiratory reserve volume, but actually somehow is able to decrease their end expiratory lung volume and allow for some tidal volume expansion that way. But people are different. And lung function in and of itself, your FEV1, doesn't necessarily correlate with these phenotypes. So there's an association there, but it's not that strong. So people with mild reductions in FEV1 can still have a mechanical ventilatory limitation and a low breathing reserve. So this is ILD. This happens to be a 55-year-old with asbestosis. You can see that they do have restrictions suggested by spirometry confirmed with lung volumes, did a 10-watt ramp, and also stopped due to dyspnea. This patient gets closer to their predicted peak VO2, but is still reduced. Oxygen pulse, again, surrogate for stroke volume, looks like it increases. They get near their peak heart rate. There's a change in slope here. They exercise past their anaerobic threshold. Ventilatory efficiency here, the VEVCO2 is elevated in the mid-30s. So not too bad, but suggestive of inefficient ventilation. End-tidal CO2 is at a normal range here, but an abnormal response. Normally, it should increase across to anaerobic threshold, and then it decreases towards the end of exercise. And then again, like in COPD, this patient is encroaching on their MVV. So they have little to no breathing reserve. And you'll notice this is more of a linear change here. And so there's not much tidal volume expansion. And so typically, this panel looks more like this. And this patient, their peak respiratory rate was 60. Their dead space fraction was on the high end of normal, and this patient was able to decrease it reasonably across exercise. But these patients have low compliance, stiff lungs, rapid shallow breathing, classically. And this can also look differently when you obtain inspiratory capacities. But the crux of it is they have reduced tidal volume expansion, rapid shallow breathing. Now pulmonary hypertension is a common comorbid condition in ILD. And so often, you'll have perhaps those ventilatory constraints in a patient with ILD and the findings that you'll see in this case. So this is a patient who just had group 1 PAH, a 74-year-old who was on a very low ramp, 5 watts, stopped due to dyspnea, and felt lightheaded. The peak VO2 here, this is half a liter, so very low, even for a 74-year-old. Her predicted is a little above 1 liter, so this is less than half. The oxygen pulse here is really quite flat, so not able to augment stroke volume. Anaerobic threshold is here, probably met really early in unloaded exercise, meaning there's no resistance on the bike. And these are very high and abnormal patterns for our ventilatory equivalents. So in the high 60s to 70 range for VEVCO2. Now this green one is actually dead space fraction with the numbers here over here on the right side of this panel. And this is using transcutaneous CO2 monitors, so kind of a replacement for blood gases. It's been validated to be pretty similar. So this patient's dead space fraction is above 0.4 at rest and increases across exercise, so wildly abnormal. And again, here, end title, CO2 in red, transcutaneous CO2, quite low, characteristic of pulmonary hypertension or pulmonary vascular disease in a flat or decreasing response across exercise. So that's what pulmonary hypertension, the pattern. And you see that pattern because, of course, changes in the pulmonary vascular bed. So high pulmonary vascular resistance, high pressure. You can't recruit and distend your pulmonary vasculature, which causes problems augmenting cardiac output and lots of high VQ areas, which lead to those changes that I showed you on CPET. Now, are any of those patients deconditioned is the question that I have, and hopefully you've kind of been thinking about. But it might help if we consider what deconditioning is, and so here's my last question. Is deconditioning a decrease in muscle mitochondria, a decrease in muscle capillary density, a change in muscle fiber type, or is it changes to the autonomic nervous system resulting in reduced cardiac output? Okay. So great. There's a little bit of spread, but people are in B or C here, change in or decrease in muscle capillary density, change in muscle fiber type. And the answer may be all of them. People have proposed changes to the autonomic nervous system, but probably there's changes to muscle. And all of these things have been shown essentially in sedentary individuals or change with fitness where you increase your muscle mitochondria, increase the capillary density and change your muscle fiber type depending on the type of training you're doing. And so another term for deconditioning might be relative unfitness. And here's an example showing the changes from a sedentary individual to a fit individual. So VO2 on the X, and in this case cardiac output. So fit individuals achieve a higher cardiac output. Their heart rate VO2 slope in unfit or sedentary individuals shifted left. So you have a higher heart rate for a given VO2. And then AVO2 content differences might be different as well with a similar change. Stroke volume is lower in sedentary. And so with fitness you increase your stroke volume. And it's hard to identify on CPET. This is reference to the 2003 CPET guidelines and not much has changed since then, 20 years now of how we can use CPET to identify deconditioning. So a low normal or low peak VO2, low VO2 at lactate threshold, this left shift in the heart rate VO2 relationship and or a low O2 pulse. The problem is this overlaps of course with a lot of cardiac disease and diseases that or excuse me, the pathophysiology that people have as part of their disease. And so why is this important? Well, cardiorespiratory fitness peak VO2 has strong associations with mortality in every disease studied to date. And there is also a surgical literature base showing not only peak VO2, some other variables from CPET that are associated with mortality and outcomes. And so I want to take it back briefly to neuromuscular dysfunction in COPD. And we do think that there is neuromuscular dysfunction in COPD. It's actually been fairly well described. And part of the problem with that is that you generate more lactate and carbon dioxide in your muscle, which then you have to, your inefficient lungs have to breathe. And so we do think muscle changes are part of exercise limitation in COPD, for example. And pulmonary rehab, what that does is it allows you to, by reconditioning yourself, there's less lactate, less carbon dioxide production, and so there's less minute ventilation for a given work rate. So you can do more work at a lower minute ventilation. And so the question then I have for deconditioning is can we assess the muscular system with CPET? And the answer right now is not really. We're pretty good here at the pulmonary gear, the cardiovascular gear, but not so much the muscle. And people are trying to change this. This is kind of in its infancy, but growing quickly. I just put one reference here, but there's a few other papers that look at something called isokinetic power of the muscle, and this changes over the course of work. And so using some of these variables, we think we can identify people who need to work on strength training, need to improve aerobic training, and so we can individualize rehab or training to improve people's exercise capacity and peak VO2, which in theory will improve outcomes. So I'm going to stop there. Thanks. Okay. Well, I'm going to try to bring this home and talk a little bit about what we know. We've heard a lot about metrics in exercise physiology and how does all this ultimately relate to how patients do after transplant. I have some funding from one small grant, which will be relevant only for one slide. So I will also have a couple of questions if you haven't scanned. I think most people, no one new has come in, so I think everybody has pretty much scanned. So we've heard a lot about the frailty concept or construct today. We know that this involves many, many aspects, including neurocognitive issues, nutritional issues, stress, physical activity. So it may be arguable that looking simply at measures of physical frailty or muscle mass, sarcopenia, may not be completely legitimate. But if you look at the literature, I think most of the literature really targets on things that are tangible, measurable, and therefore you'll find a lot of the literature focusing on these particular areas. Not exclusively, but a lot. So let's start with the first question. We've heard some about some of these tests already today. But to answer this, results from which of the following tests of physical performance, that is when they're performed prior to transplant, have been shown to correlate with clinical outcomes following lung transplantation. Six-minute walk, the performance battery, which you've heard about, four-meter gait speed, five-time sit-to-stand test, all of the above, none of the above. Okay, I think nine is what we've been looking at. And all of you have known that. So good spread here. It's kind of a trick question because if you look at the literature, you will find tests or papers that will talk about each one of these being, correlating with clinical outcomes. You will also find papers where none of them correlate with clinical outcomes. So essentially any answer here is probably correct. But there's certainly been no consistency. So again, Dr. Diamond talked a little bit about some of these, and I'll go over them briefly. But the six-minute walk test, if you look at the literature, probably most programs still look at this test mostly as a measure of physical fitness and performance. I know our program uses this test heavily. I personally have some concerns that the six-minute walk test alone is not very comprehensive. I think it gives us good information, but it's not comprehensive. And then, of course, you heard about the battery, which is the gait speed, the chair stand test, and balance test with the feet in three different orientations, the four-meter gait speed, which, again, is over a very short distance. The five-time sit-to-stand test, which is demonstrated here. And then more recently, we've had some studies come out that talk about measures of muscle mass as a potential predictor of outcome after transplant. And then we just heard about cardiopulmonary exercise testing in advanced lung disease. But using cardiopulmonary exercise testing as a measure of how people do after transplant, there's really not a lot in that particular domain as of yet. So this slide basically shows, this was an analysis, a review that was just published in Transplant Direct at the end of 2022. And it basically was a summary of all the studies that looked at measures of physical performance only and transplant outcomes. And you can see here that the sit-to-stand, the gait speed, the six-minute walk, and the performance battery, you can see that a number of tests were performed, but only the ones that are in dark showed actually any correlation. So you can see that in terms of hospital length of stay post-transplant, six-minute walk test, roughly 50-50 in terms of prediction, the performance battery even less. ICU length of stay, not a lot of correlation. Maybe one study that showed the six-minute walk test might be helpful or predictive. Time on mechanical ventilation, again, one study showing that maybe the six-minute walk test helped in prediction. Mortality, which is the one I think most of us are really keyed in on, none of these tests really showed that this was a predictor of mortality after transplant. Again, there was one, excuse me, three studies out of seven that showed that maybe the six-minute walk test was somewhat predictive. So again, quite a smattering. So I'm going to use the rest of my time really just to highlight a couple of these studies. And we'll go through this pretty quickly because we're down to about six or seven minutes. This was a study that was a single center study that was presented at the ATS meeting in 2017 where patients, again, using the six-minute walk test, which again has its foibles, but they looked at patients who walked 800 feet or more prior to transplant and compared those with less than 800 feet. Why 800 feet? It's arbitrary for this study, but basically of the people who got a transplant, the percentage of days they spent in the hospital during the first year was a little bit, I mean, it's kind of close, but it was statistically significant. So if you walked less than 800 feet, you were probably going to spend more of your survival days in the hospital after transplant. And the interesting thing about this study was that even patients who initially walked less than 800 feet but then went through pulmonary rehab and improved to greater than 800 feet still fell more into this category. And there was also a significant increase in the percentage of additional days that this group spent in dedicated inpatient rehab facilities after they were able to make it out of the hospital following their transplant. We've heard a little bit about cardiopulmonary exercise testing. This was a study that we've done where patients on bicycle ergometry and looking at how well the CPET test matches up with a six-minute walk test. And at least in our study with 23 patients with advanced lung disease, we found that the oxygen consumption and also the peak watts that were performed both very positively correlated with six-minute walk distance. So maybe that makes us feel good saying that, well, when a patient walks further, they're actually more conditioned at a cellular level, maybe. And then we also have patients who perform more than one CPET and more than one six-minute walk test, changes in that six-minute walk distance correlated with changes in peak oxygen uptake. So the interesting thing about this part was that these patients improved their six-minute walk distance by an average of about 250 feet. But the peak oxygen consumption in those patients was actually relatively small. So even though they correlated moving in the right direction, you know, we would normally think, wow, they walked 250 feet more. That's great. But maybe that doesn't reflect so much of what's going on at a cellular level. This study is still going on, or this investigation is still going on, but to date, no associations have we been able to make with post-transplant outcomes. What about muscle mass? This is gaining a little bit of traction here. And this is a paper from 2017 where using software on the CT scan that's able to identify certain muscles on the CT scan. Here in orange, we have the pec muscles, red's paraspinal, green intercostal, and the blue are the latissimus dorsi and serratus anterior muscles. And the authors in this study basically looked at those CT slices and the square centimeters that were there, and patients who were candidates for lung transplant, they had in the male group and the female group, people with advanced lung disease waiting for lung transplant and had significantly lower muscle mass on this CT scanning. And when they looked at these people after they went to transplant, basically what they found out was that the more muscle mass you had before transplant correlated with higher odds ratio of reducing their hospital length of stay. And they had a couple of correction models here that corrected for their initial diagnosis and also their six minute walk test. But essentially, their hospital length of stay was affected. Their disposition to home after transplant was only for one of these models that was corrected for height and their pre-transplant diagnosis. But still interesting to another way to look at conditioning before transplant and how it affects post-transplant. Our friends at Duke University came out with this paper here in 2023, so it wasn't part of that initial meta-analysis that I showed you. But basically, here they looked at what, and I think you heard a little bit about this from Dr. Diamond, the frailty index, which were 40 different variables divided into four different areas, comorbidities, social vulnerability, lab values, functional status. Now, I didn't put all 40 in here, but just some representatives from each one. But basically, this frailty index being used as a reflection of their performance really did not correlate with any measures of physical performance. However, the index itself did correlate with worse survival at one year. So if you had a higher frailty index, then your odds of surviving one year were less. In their study, even though they didn't correlate with the other performances of physical activity, the muscle mass, six foot walk distance, there was an association with the performance battery. That is, if you had a worse score of your performance battery, your chance of surviving one year was less. Also, they looked at this in the 90 days post-transplant group, and your odds of having hospital-free days was also significantly affected by looking at this frailty index, and not so much by the battery score. So we're running out of time, so I'm going to finish up with this study that Dr. Diamond was an author on and has already alluded to, where they looked at a composite frailty scale, so lumping a lot of these things together. What have we found? That if you have a base score, and then your base score with body composition, and your base score with looking at certain markers, metrics of inflammation, there were significant differences in terms of their survival probability at one year after transplant. So again, this score composed of not only physical performance, but also other metrics together, seemed to be predictive. My last question, medical literature supports a physical performance metric threshold below which lung transplantation should be considered prohibitive. Is that true or false? Yes, absolutely. So as of right now, we have no test that says that transplant should not be performed because the risk is too high. So to date, no measure of pre-transplant physical conditioning has been shown consistently to predict superior outcomes following transplant. Some combination of physical measures may be shown to be predictive, but this combination remains elusive at this time. And as a result, this time there's no pre-transplant measure of physical performance that conclusively prohibits transplant. Unfortunately, most of us still go by the eyeball test. So thank you for your attention and for attending this session this morning. Please do not forget to evaluate and we'll be hanging around to take questions.

Lung Transplant Session

fitness assessment

pre-transplant interventions

weight loss

underweight patients

frailty

cardiorespiratory fitness

post-transplant outcomes

physical performance assessment