So I have the pleasure of co-moderating today's webinar with Dr. Ruben Hernandez. He and I will be walking you through our panel of speakers who are here today to talk to you about acute on chronic liver failure and some of the management principles that go into that. My name is James Hange. I am a transplant hepatologist. I completed my residency and fellowship in gastroenterology at the Ohio State University. I then moved on to complete my transplant hepatology fellowship at the University of California, San Francisco. I served as a professor of clinical medicine and director of hepatology at the Ohio State University before moving on to my current position where I serve as a co-medical director for the Ohio Gastroenterology Group and Ohio Health Comprehensive Liver Program. This program is based primarily in Columbus, Ohio and the Ohio Gastroenterology Group. In association with the Ohio Health Medical System is a footprint that spans over 13 hospitals throughout the state of Ohio. Dr. Hernandez, our other co-moderator is originally from Spain. He completed his residency at the Washington Hospital Center in DC and fellowships in gastroenterology and transplant hepatology at John Hopkins Hospital. He then moved to Baylor College of Medicine and is a transplant physician working for our veterans at the Michael E. DeBakey VA Medical Center. He is passionate about acute and chronic liver failure, palliative care, and risk modeling applied inpatient care. His favorite hobby is to enjoy a Saturday movie night with his three children and wife. And with that, I will turn it over to Dr. Hernandez. Ruben. Thank you, Jim. Thank you very much. Well, I have the distinct honor to introduce my very good friend and outstanding speaker, Vinay Sandaram. So Vinay is currently a transplant hepatologist at the Cedars-Sinai Medical Center. There, he serves as a director of hepatology outcomes research and is the assistant medical director of liver transplantation. He went to medical school at New York University, followed by residency in telemedicine at the University of Virginia in gastroenterology fellowship at the University of Pittsburgh. He there earned a master of science degree in clinical research, completed his transplant hepatology training at Beth Israel Deaconess Medical Center. Dr. Sandaram has research interest in a variety of topics, and most importantly, in acute and chronic liver failure. He does have several publications, five impact journals, including gastroenterology, hepatology, and journal of hepatology. He's actively involved in the NSLD, and in this thing in particular, which is our education committee and incoming chair of the membership and mentorship committee. He also serves as an editorial board for hepatology and hepatology communication. So please welcome Dr. Sandaram, and take it away, Vinay. Thank you, Ruben, for that nice introduction. Let me get my slides ready. Okay, very good. So thank you to all the attendees for taking the time out to attend this webinar. The title of my talk is Whom to Transplant and Hospitalize Patients with ACLF. The truth being told, it's challenging to tell you who you should transplant. I have more data regarding who you shouldn't transplant, which we're going to go through. These are my disclosures, none of which are relevant to this talk. So with acute and chronic liver failure being in its nascency, I understand that there may not be familiarity among all the members of the audience with regard to the concept of the ACLF syndrome. So I wanted to briefly review this. And I think this graph illustrates nicely the concept of ACLF. So on this Y-axis here, we have liver function, and a downward slope indicates a decline in liver function, and on the X-axis is time. There's three different lines representing three clinical states in this graph. The green line represents decompensated cirrhosis. And as many of us are familiar with, among patients with decompensated cirrhosis, the majority of them have a gradual or insidious decline in liver function over time. Acute liver failure, again, as I know many of us are familiar with, is represented here, where the patient by definition has no underlying liver disease. Then in the setting of a severe liver injury, most commonly Tylenol toxicity, there's rapid deterioration of hepatic function, which sometimes leads to death or transplantation. Acute on chronic liver failure is a combination of the two. So among patients who have underlying liver disease, many of whom will likely have decompensated cirrhosis, there is a gradual decline in liver function. Then in the setting of a second insult or a precipitant, the most common being bacterial infection, this leads to a rapid decline in hepatic function, ultimately leading to multisystem organ dysfunction or organ failure, and the potential for high 28-day mortality. Now, ACLF has become accepted in the hepatology community, but there hasn't yet been a consensus with regards to the appropriate criteria to identify patients with ACLF. I'm not going to go into detail regarding the different definitions and the pros and cons of each. That's really a separate talk, but I do wanna highlight that among the many definitions, these are the three most commonly represented in the literature, and this is relevant because as you read the literature regarding ACLF, it's important to understand that different definitions may represent different patient populations. So on the left column here, this is the APOSLE definition, which was derived from a cohort in India. The NACSELD definition was derived from a cohort in North America. And then the EASEL-CLIF definition was derived from a cohort in Europe. And for the remainder of this talk, I'm gonna be referring to the EASEL-CLIF definition, and that's just primarily based on the fact that within the transplant literature specifically, the EASEL-CLIF definition is the criteria used that is most robustly represented in the transplant literature. Before we go into some of the data that I wanna talk, I think it's important to orient the audience regarding the EASEL-CLIF definition, and there are two components to this. First is recognition of organ failures and how these organ failures are determined. One way to categorize them is whether they are intrahepatic or extrahepatic. Intrahepatic organ failures include liver failure and coagulation failure represented by the bilirubin and the INR respectively. Extrahepatic organ failures include renal failure based on the creatinine or the need for hemodialysis, specifically in the setting of acute renal failure, not chronic kidney disease. Brain failure demonstrated by grade three to four encephalopathy. Circulatory failure based on the need for vasopressor, specifically for hypotension, not for hepatorenal syndrome. And then finally, respiratory failure as based on the presence of ARDS or the need for mechanical ventilation due to respiratory distress. And then finally, the second important point with regards to the EASEL-CLIF criteria is the grading system, where the severity of ACLF can be determined based on the grade, which is ultimately determined based on the number of organ failures which are present. So among the three grades, ACLF-1 is the most cumbersome in my opinion to remember, but I would like to go through it. ACLF grade one is the presence of either a single renal failure, again, based on the fact that in the initial study, renal failure alone pretended the highest mortality among the different organ failures. Or if the patient has a non-renal failure, this occurs in combination with either renal insufficiency based on a creatinine between 1.5 to two or grade one to two hepatic encephalopathy, that would also qualify as grade one ACLF. Grade two and three are much easier to remember. Grade two is the presence of two organ failures and grade three is the presence of three or more organ failures. This can be subdivided into 3A and 3B, where 3B is specifically four to six organ failures. So for the remainder of the talk, we'll discuss post-transplant outcomes and ultimately helping to decide whom we should and should not transplant. So when it comes to the notion of transplantation for patients with multi-organ failure, this can be approached with hesitancy because of the fact that we wanna make sure that these patients who we're transplanting survive, not only for patient benefit, but also because of the fact that organs are sparse and we do not want to be using donor organs among patients who would not benefit. This was a study from the UNOS database, which looked on a broad scale regarding post-transplant survival outcomes among patients with varying grades of ACLF. The orange line here represents the survival at one year for patients transplanted with ACLF grade three, which is around 83%, indicating that survival outcomes, though not ideal, are overall acceptable and do indicate survival benefit. The caveat is that with the UNOS database, there is a lack of granularity. So this was purposed to be more of a hypothesis generating piece of information, which required additional corroboration. Now, there are several corroborating studies with regards to the post-transplant one-year survival among patients with grade three ACLF. This was a nice retrospective study from Dr. Artru, which was published in 2017. And they had a total of 73 patients with ACLF three at the time of transplant who they studied. And the survival that they'd found was 83.6%. Again, corroborating an above 80% one-year survival. What's also nice about this study is that they had clear criteria for whom they excluded from transplantation, which included those patients who had active bleeding, uncontrolled sepsis, requirement of noradrenaline greater than three milligrams per hour, which is around 0.07 mics per kig per hour, or the presence of severe ARDS. So among patients with multi-organ failure who did not meet any of these four criteria, it appeared that the survival outcomes were around 83%. This is data from a more recent study from Luca Belli. This was a multicenter retrospective study from Europe of which 98 patients with ACLF three were ultimately analyzed. And what they found was that among the different grades of ACLF grade one, two, or three, there was not a statistically significant difference in survival. With regards to the numerical survival outcomes, they found a one-year survival of around 79%. So slightly lower than that 83%, but again, approaching 80% survival at one year. And then this is a more recent study published from our group. This was published earlier this year in liver transplantation. And so for this study, we evaluated patients throughout 10 centers in North America. And this included 75 patients with grade three ACLF. The study took place between 2018 through 2019. So these were patients who were transplanted relatively recently. And what we found is represented by this black line here was that the one-year survival post-transplantation was 86%. So again, we did find survival outcomes above 80%. And in this example here, the survival outcomes were actually pretty high. So in the last few slides, I provided some data showing that survival outcomes for patients with grade three ACLF can be good, but that does not mean that we should be transplanting everybody with grade three ACLF. And this is the important point to distinguish is that we do need to determine which patients in whom transplantation would not be beneficial so that we are not blanketly transplanting everybody just based on the identification of grade three acute on chronic liver failure. In one of the UNO studies that we published two years ago, we identified several factors which were associated with post-transplant survival among patients with grade three ACLF. Among the factors which were associated with reduced survival included transplantation with a high donor risk index organ, specifically greater than or equal to 1.7, as well as the presence of mechanical ventilation at the time of transplantation. We didn't have the indication for mechanical ventilation, so it wasn't certain that this was due to respiratory failure versus airway protection, but this had the strongest signal for reduced survival post-transplantation. In addition, we also found that transplantation within 30 days of listing was associated with a greater survival. Now, if we look numerically at these three different factors, again, what we see is that the strongest difference in survival was associated with the presence of mechanical ventilation at the time of transplantation. Among patients who had grade three ACLF, if they were not mechanically ventilated, the one-year survival was 85% versus 75% if mechanical ventilation was required at the time of transplantation. Again, substantiating that this was the strongest factor we found in this study. In our publication from the 10 North American centers that we published earlier this year, we did additional sub-analyses, and one of the sub-analyses we did was among patients with grade three ACLF who had respiratory failure. We had a total of 20 patients with respiratory failure, and what we found was that relative to the patients without respiratory failure, their survival was numerically quite a bit lower. 91% among those patients with grade three ACLF without respiratory failure versus 74%. Because we had access to granular data, these were patients who had a specific indication for mechanical ventilation due to respiratory distress, or they had a PaO2 to FiO2 ratio less than 200. So we did have more definitive information as to whether the patients did have a diagnosis of respiratory failure or not. Additionally, we found that the presence of portal vein thrombosis among patients with grade three ACLF also pretended poorer outcomes. And what our study suggested was that among patients with grade three ACLF who did not have the presence of portal vein thrombosis, survival was above 90% versus 57% if portal vein thrombosis was present. Now, it's important to note that there were only 11 patients in our study. So this is just some initial preliminary data which does require further corroboration, but it is consistent with prior studies evaluating portal vein thrombosis and its effect on outcomes post-transplantation, such that studies have indicated that those who are critically ill, survival is lower with presence of portal vein thrombosis. Finally, I want to point out the effect of circulatory failure on post-transplant survival outcomes. This is represented by these two curves here. And what we found is that among the patients without circulatory failure, their survival was 89% compared to 82% at one year among those patients with circulatory failure. So numerically, there was a 7% difference, but statistically, this was not significant. Keep in mind, again, the numbers were relatively small, 28 patients with circulatory failure. So larger studies would be warranted in order to validate these findings. An additional point regarding circulatory failure is that in our study, we subdivided patients according to whether or not they required a low dose versus a moderate dose of vasopressors. We defined a low dose of vasopressors as norepinephrine alone of less than 0.1 mics per kg per minute. Among those patients requiring a low dose of vasopressors, there were a total of three deaths, but one of whom had HCC recurrence. So this may not have been related to the presence of circulatory failure. Among the patients who required a moderate dosage of vasopressors, which was norepinephrine greater than 0.1 mics per kg per minute, or multiple vasopressors, we found that there were a total of two deaths. So based on this initial information, it appears that patients can be transplanted even in the presence of circulatory failure. However, the decision to transplant should ultimately be left up to clinical judgment. For instance, I wouldn't transplant a patient requiring vasopressors where there's clear evidence of sepsis or uncontrolled bleeding. But in the setting of no infection being found, in the setting of no active bleeding, it may be feasible to transplant these patients provided that their blood pressure can be maintained intraoperatively. I also want to introduce the TAM score, which is one of the models which may indicate transplant futility. This was a study published in the American Journal of Transplantation where 152 patients with ACLF grade three were studied. This was the largest cohort of patients transplanted with grade three ACLF. They split the sample into 76 patients in the derivation and validation cohorts. And in the derivation cohort, 22 patients did meet the outcome of one-year mortality. The authors identified these four factors associated with poor post-transplant survival, including an arterial lactate level greater than four, keep in mind this is arterial and not venous lactate, mechanical ventilation with respiratory distress, age greater than or equal to 53 years, or a low leukocyte count less than 10. And if a patient met any three of these four factors, survival was less than 10% possibly indicating futility. Finally, let's finish the talk with regards to how we could potentially optimize post-transplant survival in order to answer that question of whom to transplant. So in one of our studies, again, from the UNOS database, we looked at the survival post-transplantation among patients with ACLF three at the time of listing. And we compared those who had improved to a lower grade of ACLF at the time of transplantation versus those who remained in grade three ACLF. What you can see in these two curves here was that among the patients who never had ACLF three between the time of listing to transplantation, and we used a short window of analysis of seven days, the survival was the highest post-transplantation. However, among patients who were ACLF grade three improvers, the survival was statistically similar and only numerically mildly different about five percentage points. If you compare that to the line here, which is patients who remained in ACLF three between listing and transplantation, their survival was the poorest, indicating that recovery of organ failures pre-transplantation will improve post-transplant survival. We did an additional analysis among patients greater than 60. This was based on previous data from Dean Carvelis, which suggested that age 60 or higher pretended poor survival after transplantation. And what we found in this sub-analysis is that specifically among patients greater than 60, if they remained in ACLF three from listing to transplantation, their one-year survival was the poorest, around 75%. But improvement of organ failures and downgrading of ACLF grade improved survival. So particularly among the elderly patients, if it's feasible to transplant them in a window of organ failure recovery, then that may improve survival. Finally, I mentioned the TAM score previously. So these authors did a sub-analysis to determine among patients who remained in ACLF three, does improvement of the TAM score from the time of ICU admission to the time of transplantation indicate that survival is better? And what they found, again, with a smaller number of patients, but they did find that if the TAM score remained three or higher, that survival was poorer compared to those patients where the TAM score was reduced to two or less, survival was actually quite good, above 80%. So in summary, liver transplantation does provide clear survival benefit for patients with severe ACLF, including grade three ACLF. And several studies have shown that one-year survival outcomes approach 80% or potentially higher. That said, we do need to do additional work in determining whom we should and shouldn't transplant. And data supports that several factors, including the presence of mechanical ventilation and or respiratory failure, high donor risk index organ, portal vein thrombosis, elevated arterial lactate and age above 60 may portend a higher risk of mortality. A TAM score greater than or equal to three may indicate futility of transplantation, but in my opinion, further validation of this model is needed. And then recovery of organ failures and improvement of the TAM score can potentially increase post-transplant survival. Thank you for your attention. Excellent. Thank you, Vinay. Obviously a very, very challenging clinical scenario that many of us face on a daily basis. And we'll certainly take questions from the audience at the end of our talk. As Brian had indicated, our next speaker, Jennifer Lay, has been unfortunately sidelined by a family emergency. So her talk will be prerecorded, but I do have the pleasure of introducing her. She completed her residency at the New York Presbyterian Hospital, Columbia, followed by gastroenterology and transplant hepatology fellowships at UCSF. She is currently an associate professor of medicine at UCSF and director of the UCSF Advancing Research in Clinical Hepatology, or ARCH, program. Her research focuses on the application of aging research principles to the care of liver transplant patients. The foundation for her research is the NIH-funded multi-center functional assessment in liver transplantation study, otherwise abbreviated as FRAIL-T. Many of us have read her work on FRAIL-T, and it has truly revolutionized, I think, our care for decompensated patients with acute and chronic liver failure in the hospital. She currently serves as the associate editor for the American Journal of Transplantation and is a member of the editorial boards for hepatology and for liver transplantation, and a standing member on the FDA Gastrointestinal Drug Advisory Committee. And with that, I will turn our attention to her talk. Thank you for the opportunity to give this talk on integrating FRAIL-T into medical decision-making in patients with acute and chronic liver failure. Here are my disclosures. Dr. Sundaram has beautifully presented data on survival and predictors of survival in patients undergoing transplant for ACLF from studies that look at patient outcomes from the 10,000-foot view. What I'm hoping to do today is to build upon these data to help us integrate these data into decision-making at the bedside for the individual patient. I'd like to start by presenting an overarching framework for transplant decision-making. Let's think about three different patients, patient A, patient B, patient C, each of whom have the same amount of pre-transplant vulnerability to adverse outcomes that is represented by the area in white in these boxes. What differentiates these three patients is what is in the gray box. The gray box represents the patient's vulnerability that will not improve with transplant, whereas the area in the white box represents what will respond to transplant. All three of these patients will undergo transplant and ultimately be left with only the factors that are in the gray box. In other words, those factors which are not responsive to transplant and will not go away after transplant. And it is what is in the gray box that will determine their outcomes after transplant. If there's very little non-transplant responsive factors left, the patient will have favorable outcomes such as patient A, whereas on the opposite end, on the right side, patient C will have still a lot of factors that did not improve after transplant and this patient will suffer poor outcomes. The key to unlocking this framework for real-life clinical practice is to define what is transplant responsive and what is transplant non-responsive using standardized tools and metrics. We all know how to assess transplant responsive factors. These include jaundice or high bilirubin coagulopathy, renal failure, and high-grade hepatic encephalopathy. But we also have a number of metrics that we already use to measure many transplant non-responsive factors. For example, in patients with diabetes, we can measure hemoglobin A1C to assess control. We order TTEs and chest CTs to assess for cardiopulmonary disease. And Dr. Sundaram presented the TAM model in his talk to combine the influence of sepsis, mechanical ventilation, and older age into a single score. But we also know that factors such as malnutrition and muscle wasting often lead to poor outcomes after liver transplant, but up until recently have lacked ways to measure these in a standardized fashion in clinical practice. I propose that we begin to incorporate metrics of muscle health into our diagnostic toolbox. I use the phrase muscle health as an umbrella term to cover two aspects of the muscle, muscle function and muscle mass. Impairment of muscle function is known as frailty, and impairment of muscle mass is known as sarcopenia. In the recently published AA SLD practice guidance on malnutrition, frailty, and sarcopenia, the working group recommended systematic assessment of frailty and or sarcopenia in all patients with cirrhosis using a standardized instrument. Now the challenge is selecting which test to use. Let's start with the construct of frailty, which for patients with cirrhosis has been operationally defined as impairment of muscle contractile function. Frailty has been shown to be associated with hospitalizations for ACLF. This figure shows the probability of hospitalization for ACLF one, two, or three by degree of frailty, and you can clearly see that as frailty increases, the risk of ACLF hospitalizations also increases. Frailty has also been shown to increase overall risk of hepatic decompensation and death in the absence of transplant. In these two figures showing the cumulative incidence of decompensation or death in those with compensated cirrhosis on the left and decompensated cirrhosis on the right, you can see that the patients who are frail as represented by the blue lines have significantly higher risk of the outcome compared to those who are not frail. And even when we look at outcomes after liver transplant, frailty remains highly predictive of death. In this figure, you can see that liver transplant recipients who are frail experienced a statistically significantly higher risk of post-transplant death compared to those who were non-frail with an adjusted hazard ratio of 2.13. Similarly, frail patients as represented by the solid green bars experienced higher healthcare utilization, whether measured by post-transplant length of stay, ICU days, number of hospitalized days within 90 days after liver transplant, and rates of non-home discharge such as an acute care facility, a skilled nursing facility, or a rehabilitation facility. There are a number of tools to measure frailty in clinical and research practice, which can loosely be categorized into those that measure the classic frailties construct with tools such as the free frailty phenotype, frailty index, or clinical frailty scale, disability with tools such as activities of daily living scale, instrumental ADLs or life space, and physical function with tools such as liver frailty index, short physical performance battery, Karnofsky performance status, SF36 physical functioning scale, and PROMIS physical function survey. Today in this talk, I'm going to focus on the liver frailty index, which is a cirrhosis specific index for which there are a number of studies that have demonstrated its feasibility as well as prognostic value in this population. The liver frailty index is a fully performance-based test that includes of three measures, grip strength, chair stands, and balance testing, and takes less than 90 seconds to complete in the ambulatory clinic setting. This figure shows the distribution of liver frailty index values in over 1,400 ambulatory patients with cirrhosis in eight liver transplant centers in the United States. And you can see here that the median liver frailty index score was around 3.9 with a cut point of 4.4 as the optimal cut point to represent those who are frail and most strongly at risk for waitlist mortality. The liver frailty index, although most of the data has been studied and reported in ambulatory patients with cirrhosis, has been recently shown to be feasible to assess in inpatients, and the index still retains its prognostic value. There have been two studies that have been published to my knowledge across four centers in the world that have included almost 400 inpatients with cirrhosis, and in the acute care setting, 50 to 59% were classified as frail using the 4.4 or 4.5 cut point of the liver frailty index, whereas in the ambulatory setting, approximately 18 to 20% of patients are classified as frail. There were no safety issues reported in the administration of the liver frailty index in the inpatient setting. In these studies, frailty as measured by the liver frailty index has been shown to be associated with inpatient death, and frailty has also been associated with death after discharge, and for both of these Kaplan-Meier curves, this is where frailty using the liver frailty index was assessed in the actual inpatient setting. Now, of course, when we're talking about patients with ACLF, there is a subpopulation of our patients for whom conducting grip strength or chair stands or balance is completely infeasible given that they are mechanically ventilated or attached to so many different devices that they are unable to stand up from the chair or so comatose that they are unable to participate with the grip strength testing, and for that reason, I wanna present to you additional data looking at another metric of muscle health, sarcopenia, which is formally defined as depletion of muscle mass by the AASLD working group. In patients with cirrhosis, sarcopenia has been strongly associated with mortality. This figure shows the results from a meta-analysis of 3,249 patients across 14 studies, and sarcopenia was strongly associated with in-hospital mortality, 30-day mortality, one-year mortality, and overall mortality, with sarcopenia associated with an over two-fold increased risk of mortality in cirrhosis patients. There are a number of methods to measure muscle mass in patients with cirrhosis, including those with ACLF, and one of the most common ones is the skeletal muscle index, which is measured on cross-sectional imaging at the L3 level, either by CT scan, which is the most commonly published metric, or MRI. Skeletal muscle index is measured using the total abdominal skeletal muscle area, which is quantified semi-automatically using image analysis software, and the skeletal muscle index, or SMI, is calculated as the skeletal muscle area in centimeters squared divided by height in meters squared. One multicenter study has established cutoffs of skeletal muscle index to define sarcopenia that predict mortality at 50 centimeters squared per meter squared for men with cirrhosis and 39 for women with cirrhosis. Now, what about measuring and identifying cut points of sarcopenia in acutely ill patients with cirrhosis? Well, one multicenter study did find a cutoff for men with cirrhosis who were hospitalized, and this cutoff was 48 centimeters squared per meter squared that best predicted mortality after liver transplant. Interestingly, in this study, the investigators were not able to identify a cut point among women who were acutely ill and hospitalized with decompensated cirrhosis. But among men, this cutoff of 48 to define skeletal muscle index was associated with an 86% one-year mortality after liver transplant and a 73% three-year mortality after liver transplant. And after adjustment for MELD score, which was the only other predictor of mortality after liver transplant in this population, sarcopenia was associated with over a four-fold increased risk of mortality after liver transplant. So now I hope you can see how we can incorporate these objective and standardized methods of measuring frailty and or sarcopenia to identify one component of factors that will be non-responsive to transplant and lead to increased post-transplant vulnerability. I am going to leave you with a final statement from the AASLD practice guidance published last year on malnutrition, frailty, and sarcopenia on how to integrate metrics of muscle health into clinical care. We recommend systematic assessment of frailty and or sarcopenia in all patients with cirrhosis using a standardized instrument. Frailty testing may be particularly useful in the ambulatory setting and for longitudinal assessments to assess natural progression or response to treatment. And sarcopenia testing may be particularly useful for patients in whom administration of tests of frailty are not feasible or are impractical, such as in the inpatient setting, in acutely ill patients, or in very young children. Thank you very much for your time. Thank you, Dr. Lai. This is really a very important topic. And I personally apply every day. My patients read Acute Oncology for Failure and Frailty. Frailty is indeed one of my tools that I've been using thanks to you. But we're going to switch gears towards Dr. Patel. Arpan Patel is a transplant hepatologist and health services researcher at the David E. Effin School of Medicine at UCLA. He is one of my colleagues and is a staff physician at the West LA VA Center, and is a core investigator at the VA Center for the Study of Healthcare Innovation, Implementation, and Policy in Los Angeles. He performed his residency in internal medicine at the hospital in University of Pennsylvania, followed by fellowship in GI in UCLA, and a fellowship in transplant hepatology back in New York at Monsanto. He completed his PhD in health policy and management in the Fielding School of Public Health at UCLA in 2020. Dr. Patel's career goal is to ensure that patients with advanced liver disease receive high-value care that optimize their quality of life. And his research goal is to understand ways that principles of palliative care can be integrated in the management of these complex patients and their caregivers. Dr. Patel, yes, please take it away. Thank you, Dr. Hernandez. And I'll go ahead and share my slides as well. So thank you again to the ASLD for the opportunity of being able to speak to you today. I think this lecture complements well with the trajectory we've seen in which we've seen the predictors of ACLF outcomes being shared by Dr. Sundaram. We've seen how the concepts of frailty and sarcopenia can augment our understanding of ACLF outcomes. And so I want to pose to you how we can actually improve patient-centered care by integrating all these principles and integrating palliative care in the management of patients with acute on chronic liver failure. So I'm going to start with giving you a definition of palliative care. So palliative care, as defined by the National Consensus Project, is a person- and family-centered approach to care for people living with serious illness relief from the symptoms and stress of an illness. And it's important to emphasize that the goal of palliative care ultimately is to improve the quality of life for the patient and the family. We've probably been accustomed to the traditional understanding of palliative care, which is that it seems to be integrated in patients at the end of life. And this came out of likely the understanding that hospice, which was the first manifestation of palliative care in this country, came out of this understanding. But what we understand now is that early palliative care can improve the quality of life for many individuals with serious illness, and early integration is now standard of care for many different disease states. So I want to first start with having us move from the traditional view of what palliative care is to the more contemporary view in which we're integrating palliative care early, and it's considered distinct from the concept of hospice, which is only meant for people with a six-month prognosis or lower. We have now done a number of research studies over the past decade that have been delineating the palliative care needs of patients with cirrhosis, which I wanted to take the opportunity to highlight. On the left, I have the domains of palliative care as designated by the National Consensus Project. These include physical symptoms, psychological aspects of care, advanced care planning, social and cultural issues, spiritual, religious, and existential issues, and end-of-life care. As you can see, we are falling short of being able to provide relief of these different dimensions for our patients with cirrhosis and their caregivers. Patients with cirrhosis have a number of physical symptoms that are burdensome and undertreated. In addition to symptoms of portal hypertension, this also include many other symptoms such as cramps, nausea, anorexia, and pain, which go undertreated, likely because we don't have many available medical treatments. Patients with cirrhosis also have a high burden of mental health symptoms, and this was highlighted quite well by a study by Dr. Hernandez that was published last year. As we all know, that we don't have as much advanced care planning in goals of care discussions for these patients. Caregivers suffer immensely from the experiences that them and their patients suffer, and at the end of life, we fall short of providing high-quality palliative care in the form of high life-sustaining treatments and many hospital deaths and low hospice utilization. Importantly, only 30% of patients with cirrhosis receive specialty palliative care services at the end of life. So it's important to highlight what are these different terminologies of palliative care, and the first thing you're probably familiar with is the term specialty palliative care. So these are usually representing a team, typically a clinician or a physician, a nurse, a social worker, a chaplain, a pharmacist, and particularly other people of this team as well who see the patient and evaluate them to highlight these aspects of palliative care on the left. Typically, these assessments occur in a comprehensive fashion. They occur in both the outpatient and inpatient setting, and if integrated early, this can be a form of ensuring that patients have continuity of care. Primary palliative care, on the other hand, is when physicians or teams treating these patients with liver disease or other serious illnesses get trained in the basic principles of palliative care. There has been a push to not only increase specialty palliative care access for patients with serious illness, but also ensure that primary palliative care in the form of hepatology teams can start to understand these concepts of palliative care. So it's, again, important to emphasize that palliative care is much more than end-of-life care in hospice. The first take-home point, thus, is that the goal of palliative care is to improve the quality of life of patients and their families, and the second is that patients with cirrhosis and their families have enormous palliative needs which should be managed through primary or specialty palliative care early in the disease course. I wanted to take a chance during this lecture to highlight a few important guidances that have come up in the last few years, one from the American Gastroenterologic Association, the other recently published in NAASLD. The AGA guidance statement is important, and I wanted to highlight one of these figures that incorporates some important key aspects of primary palliative care delivery. They use this analogy of a toolkit to better understand this concept of primary palliative care that any teams treating patients with liver disease can implement. The first aspect is ensuring that our teams are being able to enhance advanced care planning and communication skills, that we're able to establish care pathways with specialty palliative care. It goes into a number of different aspects of symptom management, prognostication, advanced care planning, and assessments of caregiver needs, and then talks about how it's important to establish networks with specialty palliative care services. So I just leave you with this figure to let you know that I think a large value of this guidance is to really spell out in a very practical and pragmatic way to clinicians how they can incorporate primary palliative care in their practice. The ASLD guidance is a much longer guidance statement which incorporates many more different aspects of palliative care, and some of those that I'll review are listed here. Importantly, we have many guidance statements on symptom management. This is an important aspect of palliative care that hasn't been incorporated in guidelines in the past. We cover things like, again, pain, nausea, end-of-life symptoms. We also incorporate cramps and many other somatic complaints. In addition to symptom management, we re-emphasize the definitions of palliative care, incorporating the roles of caregivers, talking about current practices and barriers, the effectiveness of different interventions. I also wanted to highlight an important part of this guidance is its incorporation of high quality and well-validated communication frameworks, and I'll give you an example of one of those coming up. And lastly, aspects of psychosocial, spiritual, and cultural aspects of palliative care and end-of-life care. I think these two guidance statements are important when we think about how we integrate palliative care moving forward in our practice. The first is that the evaluation for unmet palliative care needs and specialty palliative care consultation should be considered for all patients with decompensated cirrhosis and their caregivers. And the second statement is that in patients with decompensated cirrhosis, disease-directed care, such as transplant evaluation and listing, does not preclude palliative care delivery or specialty palliative care consultation. This is an example of a communication framework called ReMAP that is used for complex schools of care discussions. I'm not going to go through it in detail, but just to highlight that the guidance has many of these communication frameworks that are helpful in the types of communication we have with our patients. So the second take-home point is be sure to review these guidances. There are lots of important information present in them that I think can be used in your clinical practice. And finally, I wanted to spend the last few minutes talking about integration of palliative care and ACLF, which is the subject of this talk. And just to highlight that in the most recent clinical guidance statement in ACLF, it was recommended that in patients with end-stage liver disease admitted to the hospital, early goals of care discussions and referral to palliative care is considered important. And so I'm going to focus the next one or two slides on serious illness communication. So I think this is an important aspect that we probably don't spend a lot of time talking about, but serious illness communication spans a lot of different understandings that patients and their families have about their medical care that spans from just basic illness understanding of cirrhosis to liver failure, to understanding prognosis and what to expect, and then really preparation for that complex decision-making. And so that not only includes preparation for this idea of transplant, but also preparation for making decisions about life-sustaining treatments, about DNR, about being intubated, about making these really tough decisions at the end of life. And so you can appreciate that the level of understanding that patients and families have have many barriers and facilitators. Unfortunately, in our care settings, there's a tremendous amount of care discontinuity. We have to make medical decisions quickly. Often patients and caregivers don't have the capacity to understand what's going on. And some of these topics are really uncomfortable. But at the same point, if we're able to incorporate palliative care early on in the disease course of these patients, incorporate highly effective communication strategies, and maintain a care continuity setting, we can help prepare patients ultimately for these very complex decisions. This is a nice slide put together that incorporates some high-value prognostication tips. I'm not going to go over them in detail, for the sake of time. But this slide deck will be present to you afterwards. I think I'd just like to say that in terms of delivering serious news and prognosis, as well as preparing patients for complex decision-making, we can really broaden our understanding of how to do this in a high-quality fashion by making sure that we're not just providing patients with survival statistics. We're talking to them about their function, potentially how much time is left. We're able to respond to emotions appropriately when we tackle difficult topics. We not only prepare them for the possibility of transplant, but also prepare them for the possibility of dying. And we not only just sort of have these static views of code status discussions, but we really look at what are the underlying goals and values for these patients that are informing these decisions. I won't have time to, unfortunately, to go through this palliative care intervention that was performed in 2012. It was a structured palliative care SICU intervention that incorporated these high-quality communication skills on prognosis, advanced care planning, and goals of care discussions in a very structured format from 24 to 72 hours. But what I will just briefly show is that there were a number of benefits of this trial that was done over a year period. In fact, over a year, just from a communication intervention, patients during rounds, many aspects of palliative care were communicated in a much more frequent fashion. Patients who died actually end up having a higher likelihood of having a DNR and incorporating limits to life-sustaining treatments. And families actually had a much higher quality of their experience, again, just from a structured communication intervention performed by a palliative care service. This is a study that we performed with Dr. Hernandez that highlights palliative care needs in patients with ACLF. It nicely showcases that you can not only think about palliative care in patients who are being evaluated for liver transplant, also non-transplant candidates, and also in patients with high symptom and caregiver needs. And so this is my summary slide, which is that the goal of palliative care is to improve quality of life for patients and their families. Patients with cirrhosis and their families have enormous needs, and there should be early integration of palliative care. Please make a point to review the AGA and ASLD practice guidances. And I think in the ASLD guidance in particular, they incorporate many serious illness communication frameworks to consider. And I think in ACLF, an important thing to balance is these ideas of not just talking about transplant, but talking about dying in a very honest fashion with families. And so for this reason, incorporating specialty palliative care teams to assist with this communication is essential. And I just wanted to leave you with a quote that came out from a JAMA paper in 2021 from many leaders in palliative care before going to the questions. And this quote is, rather than being concerned that hope is either so fragile that it can be lost or so powerful that it can overwhelm decision-making, clinicians should remember that hope is protective, if not necessary, for managing serious illness. Hope is fluid, expandable, and persistent. Holding complex, flexible, and diverse hopes enables patients to believe in the unlikely while simultaneously accepting the inevitable. The role of clinicians is to support both. So I leave you with this quote, just saying that I think for our patients who are suffering from serious illness and their families, we should be able to not just balance the idea of transplant for them, but the balanced idea is that even if they don't make it to transplant, we can still incorporate their goals and values of decision-making. Thank you so much. Thank you, Arpan. That was fantastic. And thank you to all of our speakers, Vinay, Jennifer, and Arpan. I think this was extremely informative. And I'd like to go through a couple of these questions that we've received in the chat room. The first question sounds like this is going to be directed to Vinay. We received a question about the different definitions that you introduced, North American, Asian, and European definitions, the difficulty in interpreting these different studies and these different classification systems in different continents, and then by extension, how you use these in your clinical practice. Again, a lot of our audience is going to be in different parts of the world. And so interpreting these different studies in different parts of the world is always a challenge when you have three different classification systems. Yeah, that's a challenging concern. It's an important question. And I will try to answer it as concisely as possible because the truth is it probably requires a whole debate in and of itself. So what's important to understand is that the person who asked the question is absolutely right, that these different definitions, this has been studied by one of Ruben's papers and in a paper by another colleague, Nadeem Mahmood, that you are identifying different types of patients based on the different definitions. So it is difficult to translate a study using one definition and apply it to a patient who meets a separate definition of ACLF. And in particular, the different definitions have their benefits. The APOSL definition, and I was speaking at a conference virtually, but it was a conference in India. And some of the things they pointed out with regard to the APOSL definition is that it has the benefit of early identification of ACLF prior to the development of organ failure, so that there is a chance for early identification as well as the potential for early intervention. The Naxel definition has the benefit of being very simple. It's a bedside model where you can look at the patient and if they meet two of the four criteria, then you have an answer, yes or no, they have ACLF. The Easelcliff definition is the most robust in terms of it incorporates six organ failures. And in addition, it's non-binary, that the grades of ACLF are actually determined based on severity and mortality risk. So I would have to say you cannot translate data from one study and apply it to a separate definition of ACLF. For the purposes of transplantation, here's what I would say is that when we're talking about patients who are on the transplant list and who ultimately need transplantation, these patients are critically ill. And the concern is when they are critically ill and they develop organ failure, it's not so much will they benefit from transplant, it's obvious that they will, but rather how safe can we do that? And with the Easelcliff definition having two advantages, one is the incorporation of the extra hepatic organ failures, which are the most challenging patients to transplant, particularly respiratory and circulatory failure. And secondly, the fact that the Easelcliff definition can be graded according to severity based on the number of organ failures, which have developed, it may be the most applicable for the transplant setting. And the final point I'll make is that in the setting of transplantation, there have been other papers using the other definitions, but again, the Easelcliff definition does have the most amount of data regarding transplant outcomes. I hope that answers the question, but I think it's probably more discussion is needed. No, I think that's excellent. And as a follow-up to that, so, you know, you mentioned a more dynamic scoring assessment, maybe not scoring assessment, but you mentioned the TAM score. Do you ever use a Cliff cutoff of 65? Because there was, you know, there is data looking at actual scoring system. And so another question that was posed to us in the chat room was, do you ever use a cutoff of say 65 in terms of determining futility based on Easelcliff? Sure. So that, so futility of supportive care was established. This was a nice paper by Terry Gusteau a few years ago that in a patient who's developed four to six organ failures or a Cliff CACLF score of 65 or higher within seven days from presentation, their likelihood of mortality is very high such that it could, you know, that indicates futility of full supportive care. Now in the setting of transplantation, that may not apply. Probably the best data we have is from the Luca Belli study, where they actually did look at the Cliff CACLF score 65 or higher in multivariable analysis. And they found that there was not a correlation with post-transplant mortality. The one factor that had the highest, that pretended the highest risk of mortality was development of a multidrug resistant organism infection pre-transplant. So, you know, probably larger studies are needed, but based on the data available, I wouldn't, I wouldn't use Cliff CACLF score to determine transplant futility. Excellent. Thank you. Thank you, Vinay. Well, I got a question for Arpan. I'm being in Houston. Arpan, I got a problem. You know, communicating with patients who are both transplant helpful and near the end of life can be very challenging, as you know. So what recommendations do you have for teams treating these patients about discussing comfort-focused options while also maintaining comfort for transplantation? Can you comment on that? Yeah, I think that, and I'll be, I'll be brief because I know it's towards the end of the seminar, but the hard part is that when you have conversations really late, you're fitting in a lot of topics at the end. And if you really have those conversations early, however difficult, they're much easier to have early than they are when you pack it all at the end. And the truth is that especially when you sort of pack it at the end, a lot of people can get suspicious, particularly patients, their families about why you only mentioned death at that point. And people really feel like you're, you're not delivering a transplant to them for other reasons. So I would say that balancing hope, balancing hope for both transplant and non-transplant is critical to do early because patients actually understand it when you, when you were able to talk with them realistically before things go south. And so my only comment to that is being able to do it, or it's hard to do. We have to learn how to react to our patients' emotions, maybe getting a social worker or other people very familiar with this conversation early is a good idea, but the, but the idea is to do it not at the very end. So I think I'll leave you with those tips. Thank you, sir. I had one additional question, Arpan, for you specifically. And so this deals with, I think, a scenario that a lot of us deal with. So as large tertiary quaternary care centers that we work at. So in our case, we're a feeder hospital for 13 different hospitals throughout the state. You know, you get a lot of mixed messages from what patients and their families are being told at these outlying hospitals. It's often a very challenging conversation to bridge when they first get there. Most patients are told in my experience, oh, we're going to send you here for, you know, a lifesaving transplant. And then it's like you come in as the bearer of bad news. And I just wondered if you could comment on, on how you handle like the progression of the information and the education to the families when they are coming from very different backgrounds and very different hospital sittings. Yeah, I think that's a good point. And I think it goes to what you just mentioned, which is it's a progression of conversations and not one big conversation at the beginning. And so even being able to, I think you have to realize that these are all really serious news that we're giving when patients are learning for the first time, they're not just going to the hospital and getting a transplant, that's like a shock. And, and it takes time for them to process that shock. And so everything you say after that is not going to really be incorporated into them until they get over that shock. So I think giving pieces of information and, and to different members of the family consistently as the hospitalization builds is, is a little bit more, is a better way of doing it than just throwing transplant at them. Because when you start throwing transplant at them all of a sudden, they only start to hope for that. And I think so building these sort of expectations throughout the illness course early and starting with morsels of information, giving them time to process, I think is a slightly more successful strategy than, than getting everyone to come to the patient at once and give them a lot of confusing information. So I'm not saying that there's an easy solution to it, but I think giving pieces of information and managing expectations can be successful. Okay. Thank you. Thank you, Arpan. Well, I got a very last question being from the same. I'm going to go a little bit over time. So I hope you excuse me, Vinay, quick question. I guess I'm asking Dr. Vance question, which is very pertinent. Can you come in quickly, the role of plasmapheresis in ACLF patients, because it's something that has been commonly done in Southeast and other parts of the world. Oh, sure. So, yeah, so we actually have a study, which is, it's called the Apache study. And we are in currently enrolling patients. So I'm not sure how much I'm able to reveal. However, since the study is ongoing, what I will say is that among the patients we've enrolled, I was pleased with, with the results. And so I do think that TPE does have a role. And in, and specifically among the patients who we have enrolled, who have been randomized to receiving TPE, it was designated particularly as a bridge to be able to bridge them to transplantation. In particular, there was difficulties with regarding transplanting them in the, in the immediate setting due to concerns regarding alcohol use and alcohol relapse, but this offered an opportunity. You know, in terms of, in terms of, you know, how long we should utilize it for, it's based on clinical judgment, at least per the study protocol, that it's based on clinical judgment where you, if you deem that there's an adequate improvement in the patient's parameters, then you can, you can stop the plasma exchange sessions. Thank you very much. Excellent. Well, I think looking at the clock that we are close to time. And so I again, like to take the opportunity to thank everyone in the audience as well as our speakers for putting together what I thought was a fantastic hour, a very informative hour. I know it's something I'm going to go back and, and watch again, and it is available on the website. So if there are questions about that, I know there'll be a link on the website to, to view again. So again, thank you to all. And with that, I think we will close our webinar.

acute on chronic liver failure

ACLF

management principles

palliative care integration

prognostic factors

frailty assessments

sarcopenia assessments

specialty palliative care consultation

communication strategies

improve quality of life