It's a real pleasure to discuss intensive care management of acute onchronic liver failure in the patient awaiting liver transplantation at the ACLF session at ASLD 2020. I don't have any financial disclosures. For the purposes of this study, I'll be using the CLIF definition of acute onchronic liver failure that initially was published back in 2013. In a study of 415 patients with ACLF, patients with cirrhosis, decompensation, and organ failure, Moreau and colleagues demonstrated that patients with three or more organ failures had an 80% mortality at 28 days. So the purposes of ICU management in these critically ill patients focuses mainly on circulatory management for shock, mechanical ventilation for a respiratory failure, hematologic support, and renal support for acute kidney injury. So starting with circulatory dysfunction in ACLF and cirrhosis, we're well aware that because of hepatocellular dysfunction and portal hypertension, portal systemic shunting leads to a lack of clearance of nitric oxide and other mediators, leading to a high cardiac output state with associated splinting and systemic vasodilatation. Normally, the patient is able to compensate for a decrease in systemic vascular resistance by increasing their cardiac output. However, at a point of relative arterial hypovolemia, this results in up-regulation of the renal angiotensin system and the systemic nervous system, leading eventually to sodium and water retention. And one thing that is very important is this hyperdynamic state in cirrhosis can often mask cirrhotic cardiomyopathy, which does pose significant challenges in the patient being assessed for liver transplantation. So one of the biggest challenges in ACLF is assessing volume status and cardiac output. And traditionally, we relied on non-invasive techniques, such as central venous pressure monitoring and mixed venous saturation, that all have their limitations. More recently, though, there's been more widespread use of bedside echocardiography, and furthermore, this has become a mainstay in the training of critical care fellows. Bedside echo allows one to evaluate the left and right ventricular function in real time, assess pulmonary pressures, furthermore, also assessing responsiveness to fluids. In terms of the management of shock in ACLF, well, there is a lack of literature based on best practice statements. Norepinephrine, in general, is considered the first-line vasoconstricting agent, primarily because of its side effect profile. Vasopressin may be used as a second-line agent or an adjunct, and furthermore, if you're in a country where turlopressin is available, this can also be considered, particularly in the setting of hepatorenal syndrome or a variceal bleed. Once again, from borrowed literature from the general critical care population, we generally target a MAP of 65, although one could consider using a higher mean arterial pressure in the setting of acute kidney injury. A secondary cause possibly of hypotension can often be adrenal insufficiency in ACLF patients, so always consider the use of hydrocortisone. One of the biggest triggers of circulatory failure is sepsis, and we know that cirrhotic patients that are at a much higher risk of sepsis because of the loss of the tight gap junctions that we have between the enterocytes and the bowel. This can lead to bacterial translocation, and due to portal systemic shunting and the development of collaterals, often pathogens can escape the portal of the hepatic reticular endothelial system into the systemic circulation, and furthermore, due to poor function of natural killer cells and decreased production of complement, this can lead to bacteremia and spontaneous bacterial peritonitis leading to shock. So we know that bacteremia and septic shock in a patient with ACLF carries a very poor prognosis. This was a sub-study of Anand Kumar's CATS database, which was a multi-centered retrospective American study, and in this study of 102 cirrhotic patients with septic shock due to SBP, the overall survival to hospital discharge was only 18%, and the reason why I highlight this study is probably one of the most important things that we can mitigate this is early and timely antimicrobial therapy. So on this multivariable analysis of patients with SPP and septic shock is that each hour in delay of appropriate antimicrobial therapy increased mortality by 1.86 times. So now focusing on respiratory failure in ACLF, there are causes of respiratory failure that are specific to cirrhosis, such as hepatic hydrothorax, hepato-pulmonary syndrome, and porta-pulmonary hypertension, and then there are more nonspecific causes of respiratory failure, which apply to not just cirrhotic patients, including pneumonia, pulmonary embolus, pulmonary edema, and atelectasis. Once again, while we don't have direct literature on mechanical ventilation in the ACLF population, based on borrowed literature from the general critical care population, it is advocated for a lung protective strategy. And what we mean by this is a tidal volume of approximately six mils per kilo and setting a respiratory rate to approximate baseline minute ventilation. And we target an oxygen saturation of greater than 88%, and we try to maintain a plateau pressure of less than 30 centimeters of water to avoid barotrauma. Furthermore, there's also a growing body of data that a fluid restrictive strategy may be beneficial in oxygenation in these patients. With regards to hepatic encephalopathy, traditional therapies in ward patients are primarily focused on lactulose and rifaximin. One of the biggest challenges you can deal with a critically ill ACLF patient is that, unfortunately, lactulose can lead to bowel distension, which in some cases can precipitate an abdominal compartment syndrome, which can make this type of patient difficult to ventilate or exacerbate acute kidney injury. This one small study that was published in 2014 demonstrated that one alternative is polyethylene glycol, or PEG, and that it may, PEG, just as a cathartic colonic lavage, may be associated with improvements in encephalopathy grade and is not associated with some of the other complications of lactulose. Looking at acute kidney injury in ACLF and cirrhosis, one has to remember that the differential diagnosis is broad. This includes hepatorenal syndrome, which has the worst prognosis in the absence of transplant, but hepatorenal syndrome only makes up one small proportion of the general term of acute kidney injury and cirrhosis. For example, in a patient with hepatitis C that hasn't been treated, one has to consider etiologies such as cryovolvulinemia. You need to rule out nephrotoxic agents such as nonsteroidal anti-inflammatories. And one also needs to remember that in the, particularly the ACLF patient that presents with shock, that sepsis and ischemia can also lead to ATN. Finally, hepatorenal syndrome may exist on a continuum with acute tubular necrosis. And once this becomes more and more established, you can end up with glomerular sclerosis. So more recently, the International Club of Ascites has harmonized its definitions of stages of acute kidney injury in cirrhosis with the general critical care literature, including such external organizations as Candigo and Adkey. This publication back in 2015 defined stage one AKI in cirrhosis as having an increase in serum creatinine by more than 0.3 milligrams per deciliter or an increase of greater than 1.5 times baseline, stage two being a two to three-fold increase from baseline and stage three being a three-fold increase from baseline or a creatinine of greater than four milligrams per deciliter or requirement for renal replacement therapy. As mentioned previously, the etiology of acute kidney injury in patients with ACLF and cirrhosis has significant prognostic information. And as I highlighted before, in this study from Spain, that was a retrospective audit of 562 cirrhotic patients with AKI. And one of the limitations of the study is that there was no gold standard and patients did not get a kidney biopsy, for example, that hepatorenal syndrome actually only made up 13% of the patients with AKI. However, it carried by far the worst prognosis with an 85% mortality at 90 days. And we know that HRS was independently associated with 90-day mortality, even after adjusting for other covariates such as the MELD score, sodium and hepatic encephalopathy grade. Now that's in the absence of liver transplant. However, if we're focusing on the patient that has undergone liver transplant, it's the opposite where we know that ATN or irreversible AKI is not only associated with an increased rate of chronic kidney disease after liver transplant, but furthermore, a significantly worse survival as shown in this study from Nadim and colleagues from USC back in 2012. So in terms of the therapies that we have in the pre-transplant setting, if somebody has hepatorenal syndrome, vasoconstricting agents are the first line in these patients to try to mitigate the hepatorenal physiology and improve circulatory blood volume. So in this study from Boyer back in 2016, it was demonstrated that patients on either who had reversal of hepatorenal syndrome, particularly those that were treated with terlopresin, overall had an improved survival at 90 days. And what they defined as HRS reversal in this study was two serum creatinine values that were taken at least 40 hours apart that were less than 1.5 milligrams per deciliter. However, as we know that currently in North America that terlopresin has still not received regulatory body approval, that this meta-analysis that was published in 2017 demonstrates that likely norepinephrine is certainly non-inferior to terlopresin. However, one of the big challenges that we deal with is that for somebody to be on norepinephrine, they need to be in a monitored ICU setting with a central venous line and possibly an arterial line. There are many controversies with regards to acute kidney injury and ACLF, and one of them is the role and the modality of renal replacement therapy. So there was a large study called the START-AKI study that was just published in the New England Journal of Medicine a couple of weeks ago that evaluated the early use of renal replacement therapy in patients with stage II AKI, where this was done within 12 hours, versus standard of care at the physician's discretion. And unfortunately, this study did not demonstrate a significant benefit with early renal replacement therapy. And this continues to be an area ripe with discussion. Furthermore, there is a lack of literature with regards to what is the appropriate modality of renal support for an ACLF patient in the ICU. Often, these patients are hemodynamically unstable, so we rely on continuous modes such as continuous venovenous hemodiafiltration and continuous venovenous hemofiltration. Often, we tend to make this decision on simplicity. As we often face significant challenges with the use of circuit anticoagulation, for example, patients can develop citrate toxicity with liver dysfunction, and furthermore, we're concerned of the risk of bleeding with heparin anticoagulation. Often, we will choose CVVH as it's simple. It's a simpler circuit than CVVHDF, and often, we don't require any anticoagulation. And some of the more contentious questions are about the role of renal replacement therapy in patients that aren't liver transplant candidates, and that's outside of the scope of this discussion today. And also, is there a cutoff with regards to the severity of ACLF? Just to briefly discuss variceal bleeding, we know that outcomes in cirrhotic and ACLF patients with variceal bleeding have generally been improving over time, and that the most significant predictors of mortality have more to do with the severity of hepatic and multi-organ dysfunction and surrogates of this, such as the hepatic venous pressure gradient. We know that there is data for the use of turlopressin improving outcomes of controlling bleeding and mortality. However, once again, this is not available in North America. As a second-line treatment, octreotide does not demonstrate a mortality benefit, however, it has shown benefit when it's used in combination with endoscopic banding. The use of early tips, as demonstrated in a small, highly-selected study that was published in 2010, was associated with decreased one-year mortality and re-bleeding rates. And finally, based on the Villanueva study that was published in the New England Journal in 2013, it is advocated that in a patient that achieves hemodynamic stability after resuscitation, that a transfusion trigger of seven grams per deciliter is certainly not inferior to a more liberal strategy and may have some potential benefits. Just to remind us with regards to prognosis that more recently, that Jalan and colleagues published the CLIF-C ACLF score that not only combines the six organ failures that were discussed in the original 2013 study, but also added age and white blood count. And this just shows you what was defined as an organ failure in each of the six organ failure categories. As similar to the original Moreau definition, we know that the higher your CLIF-C ACLF score is associated with worse outcomes. And this has now been externally validated outside of Europe. This was a study that looked at patients both in North America and in Europe, and it showed that a CLIF-C ACLF score of greater than 70 was associated with a 90-day mortality in the absence of transplant of over 90% at 90 days. However, one of the most important things to highlight to give at least some optimism is that ACLF can be dynamic. And from the same study, we were able to demonstrate that in approximately 40% of patients with ACLF, that they were able to improve by at least one ACLF grade by 72 hours, that the ICU interventions were able to alter their outcome, as opposed to approximately 50% of patients where there was no difference. So this is important with regards to optimizing patients for certainly those patients that are listed for liver transplant. So in summary, ladies and gentlemen, the key takeaway points on the ICU management of ACLF is that dynamic measures of volume status in ACLF, such as echocardiography, are valuable in patient assessment. Use a lung protective strategy in the presence of acute lung injury if a patient requires mechanical ventilation. Early appropriate antimicrobial therapy impacts outcome in ACLF, and speed is life. For patients with encephalopathy, consider polyethylene glycol as an alternative to lactulose and rifaximin in those patients where there are concerns of bowel distention or abdominal compartment syndrome. Vasoconstricting therapies are associated with reversal of HRS, and responders to vasoconstricting therapies appear to have better outcomes. And more studies are required with regards to the use of renal replacement therapy in ACLF, particularly related to the most appropriate modality and circuit anticoagulation. And I thank you very much for your time on this virtual session, and we'll be happy to answer your questions in the live Q&A session. Thank you very much. Thank you to the AASLD, Acute On Chronic Liver Failure Special Interest Group for inviting me to give this talk regarding liver transplantation and acute on chronic liver failure, recent outcomes. This is my biography and some of my representative publications. These are my disclosures. I've broken down this talk into three topics, feasibility of transplantation in severe acute on chronic liver failure, futility of transplantation in this population, and finally, how to increase survival after transplantation for this population. Additionally, I wanted to state that the majority of published data related to the topic of transplantation in acute on chronic liver failure utilizes the Easel-Cliff definition of ACLF, and therefore, this is the definition I'll be primarily referring to unless otherwise stated. For the first section regarding feasibility of liver transplantation in the patient with ACLF, I'll be discussing data from both multi-center studies as well as public registries. This paper by Artru and colleagues published in 2017, in my opinion, was one of the real landmark studies in the field. This was a retrospective study across three European centers and was the first to demonstrate excellent one-year post-transplant survival outcomes among patients with ACLF, including 73 recipients with three or more organ failures at the time of transplantation. This is highlighted in the figure on the right, which indicates that all groups had a one-year survival probability above 80%. One of the other strengths of this study is that it is the first to provide data regarding which patients can be safely transplanted in the setting of severe ACLF. In particular, patients excluded from receiving liver transplantation in this study included those with active bleeding, those with sepsis controlled for less than 24 hours, patients who required noradrenaline greater than three milligrams per hour, and patients with severe ARDS. Therefore, this paper not only demonstrates the potential for excellent post-transplant survival outcomes, but also illustrates which characteristics allow for safe transplantation in patients with ACLF-3. More recently, the North American Consortium for the Study of End-Stage Liver Disease, also known as NACSELD, published their data, which included 57 patients transplanted with ACLF. Keep in mind, the definition of ACLF utilized in this study is different from the easel-cliff definition in that the NAC cell definition requires the development of two non-hepatic organ failures to meet the definition. Regardless, survival at three and six months post-transplantation were excellent and comparable between patients with and without ACLF, though it is notable that renal function appeared to be worse at three and six months post-transplantation among those transplanted with acute on chronic liver failure. There have been two recent registry studies which evaluated post-transplant outcomes through analysis of the UNOS database. The first was published by Paul Dulebeth and colleagues, which demonstrated in a large patient sample the feasibility of transplantation for patients with multiple organ system failures. On the left side, patients are stratified according to the number of organ system failures at transplantation. Even among patients with four to six organ failures, the one-year post-transplant survival probability was 81%. On the right side of this slide, the cohort is characterized according to the type of organ failure present at transplantation. What is notable is that the presence of respiratory failure was associated with the lowest post-transplant survival probability. The second UNOS registry study was published by our group in 2019. There are some differences between our paper and the one that I previously highlighted. In particular, our paper evaluated all patients with multiple organ system failures at the time of transplantation, whereas the one by Dr. Dulebeth limited their study population to those patients transplanted within 30 days of listing. Nonetheless, the findings were similar, demonstrating a greater than 80% survival among patients transplanted with ACLF-3. With regards to long-term survival outcomes, this paper published in Liver Transplantation demonstrated that patients with ACLF-3 at the time of transplantation had a five-year survival greater than 50% at five years after transplant. Furthermore, although recipients with ACLF-3 did have the lowest long-term survival, the mortality rate was highest within the first year after transplantation, and then afterwards plateaued to a similar mortality rate to those of patients transplanted with lower grades of ACLF. The primary cause of death after the first year among all groups was infection and malignancy, with infection being most prevalent among recipients with ACLF-3 at the time of transplantation. Now that I've highlighted several studies demonstrating the feasibility of transplantation in the setting of ACLF, including ACLF-3, I'd like to transition to discussing futility of transplantation in this population. This is particularly important to highlight, since given the shortage of donor organs relative to the demand, it's of paramount importance to determine which patients should not be offered liver transplantation due to futility. In one of the papers I highlighted earlier from our group, we focused on factors at the time of liver transplantation which portend poor prognosis after transplant in patients with ACLF-3. Multivariable analysis identified mechanical ventilation to be the strongest risk factor for one-year post-transplant mortality. In addition, we found that use of an organ with a high donor risk index was associated with greater mortality, while transplantation within 30 days of listing yielded greater survival. This slide depicts the survival probability associated with the presence or absence of each of these factors highlighted in the previous slide. Primarily, I wanted to illustrate the survival differences dependent on the presence or absence of mechanical ventilation at the time of transplantation. In particular, patients with ACLF-3 who required mechanical ventilation had a one-year post-transplant survival of 75.3%. However, with the absence of mechanical ventilation, that survival increased by 10% to 85.4%. And this was similar to that of patients with ACLF-2. The other variables did demonstrate a significant change in survival depending on their presence or absence. Specifically, transplantation with a high donor risk index organ led to a one-year post-transplant survival of 78% versus 82.9% with a low donor risk index organ. Additionally, transplantation within 30 days led to a greater survival of 82.5% compared to that of 78.1% among patients who were transplanted outside of 30 days. To expand upon these findings, we performed additional analysis in this study to determine whether patients with ACLF-3 who required mechanical ventilation at the time of transplantation could have improvement in their post-transplant survival with use of either a low DRI organ or earlier transplantation within 30 days. In this slide, there are four pictures. Picture A illustrates the difference in survival between those patients with ACLF-3 at transplantation who did and who did not require mechanical ventilation. As you can see, there is a 10% increase in one-year post-transplant survival among patients who did not require mechanical ventilation. In picture B, we compare those patients with ACLF-3 who were not mechanically ventilated to those patients with lower grades of ACLF at the time of transplantation. Although patients with ACLF-3 still had significantly lower survival probability, it did approach that of patients with lower grades of ACLF at the time of transplantation. Finally, in pictures C and D, respectively, we explored whether the use of a low DRI organ or transplantation within 30 days would improve post-transplant survival among patients requiring mechanical ventilation. Ultimately, one-year survival only improved marginally and remained below 80%. Therefore, the findings from this analysis suggest that the presence of mechanical ventilation in the setting of ACLF-3 at the time of transplantation may be an indicator of poor prognosis. Earlier this year, a study was published by Archner and colleagues, which was the first to create a futility score regarding the transplantation for patients with acute on chronic liver failure grade 3, known as the transplantation for ACLF-3 model or TAM score. This was a retrospective study performed among five centers across Europe. 152 patients transplanted with ACLF-3 were studied, which represents the largest cohort of patients where granular data is available. The authors utilized split-sample validation, where 76 patients were used in the derivation cohort and 76 patients were in the validation cohort. Finally, a total of 22 patients met the primary outcome of one-year mortality after transplantation in the derivation cohort. On the left side, the four variables which comprise the TAM score are displayed. These specifically include arterial lactate level greater than or equal to 4, mechanical ventilation with the presence of ARDS at the time of transplantation, age greater than or equal to 53 years, and a leukocyte count less than 10 grams per liter. Each variable is assigned one point, and a total score of greater than 2 indicates futility of transplantation. The figure on the right displays post-transplant survival probability according to TAM score. Patients with a score above 2 had a one-year survival probability of less than 10%, which was also seen in the validation cohort. Now there are some limitations to the TAM score, particularly regarding the small sample size for the derivation cohort. Therefore, this needs to be further validated before it is used routinely. Regardless, this paper has very important findings regarding biomarkers which should be incorporated into future prognostic models to assess futility of liver transplantation among patients with multiple organ system failures. For the final aspect of this talk, I'll review some of the data regarding how to optimize pre-transplant conditions in order to improve post-transplant survival. Based on the available data, there appear to be two components to this. The first is early transplantation, and the second is recovery of organ failures prior to transplantation. Earlier in this talk, I discussed that one of the factors that can improve post-transplant survival in the setting of severe ACLF is the occurrence of liver transplantation within 30 days of listing. This figure displays a sub-analysis evaluating whether survival improves further when transplant occurs within 14 days of listing. Among the full cohort of patients with ACLF3 at transplantation, post-transplant survival did increase marginally by approximately 4%. However, when we break down the cohort of recipients with ACLF3 according to the number of organ failures, it does appear that survival benefit with early transplantation increases with a greater number of organ failures. In particular, among patients with three organ failures, as seen in picture A, post-transplant survival improved by 3%, which was not statistically significant. However, in pictures B and C, which represent those with four and five organ failures at the time of transplant, respectively, survival did rise significantly by as much as 12% in patients with five organ failures who were transplanted within 14 days. Regarding picture D, which displays survival for patients with six organ failures, early transplantation did not yield survival benefit, though the smaller sample size makes it difficult to draw conclusions. Secondly, I wanted to highlight some of the data regarding how the pre-transplant clinical course can affect post-transplant survival in the setting of acute on chronic liver failure. In this single center study published in 2018, patients were categorized as those without ACLF throughout their entire pre-transplant course, those with ACLF prior to transplantation but who improved at the time of transplant, also known as ACLF improvers, and finally, those patients who had ACLF prior to transplantation but who did not recover at the time of transplant, also known as ACLF non-improvers. What is notable is that the patients who were ACLF non-improvers did have the lowest 90-day post-transplant survival. However, ACLF improvers actually had similar 90-day post-transplant survival compared to those patients who did not have acute on chronic liver failure throughout their pre-transplant course. In a paper from our group published last year, we performed similar analysis but isolated to a cohort of patients specifically with ACLF-3 at listing. There are four groups displayed in this figure, but I wanted to highlight the findings specifically regarding two of them, those who did not have ACLF-3 at either listing or transplantation as designated by the solid green line, and those with ACLF-3 at listing who improved to ACLF grades 0 to 2 at transplantation as designated by the dashed blue line. Patients who did not have ACLF-3 during their pre-transplant course had the highest one-year post-transplant survival at 90.2%. However, ACLF improvers had a one-year post-transplant survival of 88.2%, which was statistically similar to those patients who did not have ACLF-3 during their entire pre-transplant course. This slide highlights additional analysis from this study to determine the organ failures in which recovery yields the greatest reduction in post-liver transplant death. This is a multivariable analysis adjusted for age, MELD sodium score, and donor risk index. What was ultimately demonstrated was that recovery of non-hepatic organ failures, specifically circulatory failure, brain failure, and respiratory failure, as indicated by mechanical ventilation, led to the greatest reduction in post-transplant mortality. Therefore, these findings suggest that if recovery of one of these three organ failures prior to liver transplantation is feasible, it may be ideal to wait until this occurs in order to improve post-transplant survival. Finally, I wanted to highlight the role of patient selection with regards to maximizing post-transplant survival. The data in this slide was from a prospective single-center study from France, which was presented at last year's liver meeting. The authors studied approximately 155 patients with end-stage liver disease admitted to the ICU. 36 of those patients admitted to the ICU were transplanted, of whom 25% had ACLF3 at the time of transplantation. Now although the numbers are small, the post-transplant survival outcomes were excellent at 97% survival at three months. In addition, the authors performed multivariable analysis to assess factors associated with not receiving transplantation and found the two strongest factors to be age greater than 60 years and the presence of mechanical ventilation at the time of transplantation. Although it is still too early to draw conclusions, what is notable from this study is that not transplanting patients who are above age 60 or who require mechanical ventilation may yield good post-transplant survival. In summary, liver transplantation can yield good outcomes for patients with multiple organ system failures, including one-year survival greater than 80%. Factors associated with futility of transplantation include age, presence of mechanical ventilation and or respiratory failure, serum lactate level, and serum white blood cell count at the time of transplantation. Early liver transplantation as well as recovery of organ failures prior to transplantation may improve post-transplant survival. However, there are limitations to the currently available data. Although individual patient data is granular and that there is access to biomarkers, it's difficult to collect the large sample size. Registry data does provide that large sample size, however, there's potential for misclassification. Biomarkers such as white blood cell count and lactate are missing and there is the potential for selection bias. Ultimately, what will be needed to advance the field is a large multinational prospective study to evaluate outcomes regarding post-transplant survival, as well as to determine not only the futility of transplantation, but also to determine which patients can be safely transplanted even in the setting of multi-organ failure. Thank you for your attention. Thank you to the organizers for inviting me to speak today. The title of my talk this afternoon is Post-transplant Complications in Acute and Chronic Liver Failure. My name is Jody Olson. I'm an Associate Professor of Medicine and Surgery at the University of Kansas Medical Center in Kansas City, Kansas. My practice includes both outpatient and inpatient general and transplant hepatology, and I practice as an intensivist with a focus on liver disease and post-liver transplant ICU care. I have no disclosures relevant to today's presentation. The objectives for my talk this afternoon are to review post-transplant complications, which arise in the background of organ failures associated with acute and chronic liver failure. I will discuss pre-transplant organ failures and their impact on post-transplant complications and outcomes, with a particular focus on some of the most troublesome complications which arise in the setting of acute and chronic liver failure. These include neurologic complications and respiratory failure. Central nervous system complications developing after liver transplantation are quite common. The majority of these are transient in nature and do not have long-term impact on patient outcomes. The incidence of central nervous system complications after liver transplantation ranges from 10 to 47% of patients undergoing liver transplantation. What types of central nervous system complications occur after liver transplantation, and which of these are associated with complications of acute and chronic liver failure and the organ dysfunctions that are associated with ACLF? Central nervous system complications arising in the post-orthotopic liver transplant period are quite variable in their presentation. These may present as minor transient disturbances and those with significant risk for high morbidity and mortality. These include persistent or recurrent encephalopathy, tremors, hemiparesis, seizures, altered mental status and coma, hemorrhage and cerebrovascular accidents, central pontine myelinolysis, posterior reversible encephalopathy syndrome, and locked-in syndrome. Looking at a single U.S. center evaluating 227 patients who underwent liver transplantation both from living and cadaveric donors, we see that the most common presentation of central nervous system complications were those of encephalopathy, tremor, hallucination, and seizure. Less common were more severe manifestations of neurologic complications, including intracerebral hemorrhage, ischemic stroke, central pontine myelinolysis, intracranial infections, cerebral edema, and posterior reversible leukoencephalopathy. In a separate study looking at approximately 300 patients undergoing liver transplantation in Taiwan, 93 of whom were living donor liver transplantation, we again see that encephalopathy was the most common neurologic complication occurring after liver transplantation. Encephalopathy was manifested as delirium, psychosis, and mild change in consciousness. This was followed by seizures, locked-in syndrome, and drug neurotoxicity, and less commonly cerebrovascular accidents and central pontine myelinolysis. The incidence of seizure development after liver transplantation was reported in older studies to be quite high, with rates as high as 42%. This has fallen considerably in more contemporary studies with reported seizure rates of between 3% and 7% of patients undergoing liver transplantation, likely owing to improvements in both immunosuppression management as well as perioperative management of patients undergoing liver transplantation. The etiology of seizure development after liver transplantation is varied and includes calcineurin inhibitor usage both with and without supratherapeutic drug levels, the development of structural lesions, metabolic etiologies, and mixed etiologies in patients who experience both structural lesions and metabolic derangements. What are risk factors associated with the development of post-orthotopic liver transplant central nervous system complications and particularly which of those are associated with manifestations of acute on chronic liver failure. In this particular series, organ dysfunctions such as liver dysfunction as manifested by high child's Pugh class C disease, history of hepatic encephalopathy, the presence of preoperative hepatic encephalopathy, and hepatorenal syndrome were all associated with increased risk for post-OLT CNS complications. In a separate analysis of patients undergoing orthotopic liver transplant in a single center in Taiwan, looking at approximately 300 patients, again child's Pugh class C disease and the presence of hepatic encephalopathy were both associated with the development of post-OLT central nervous system complications. In a separate study looking at 227 patients at a single center in Los Angeles, again patients who had manifestations of organ dysfunction prior to transplant including patients on dialysis, those with the diagnosis of hepatorenal syndrome, those with renal dysfunction, presence of hepatic encephalopathy, patients with cardiovascular dysfunction, patients with respiratory failure, all were associated with increased risk of post-OLT central nervous system complications. The type of liver failure is also associated with the risk of development of CNS complications after liver transplantation. Specifically, patients with ACLF are far more likely to develop central nervous system complications after transplant than those patients undergoing transplant for acute liver failure or chronic liver disease without acute on chronic liver failure being present. ACLF is an independent risk factor for the development of metabolic and toxic central nervous system complications after transplant. What are the impact of central nervous system complications on outcomes after liver transplantation? Non-metabolic central nervous system complications are an independent risk factor for death, whereas metabolic and toxic central nervous system complications are an independent risk factor predicting a longer length of stay. Metabolic toxic central nervous system complications are more likely to be transient in nature and less likely to result in significant long-term complications after transplantation. Evaluation and management of central nervous system complications after transplantation is varied. Imaging should be considered in patients who have persistence encephalopathy or alterations in neurologic presentation after transplantation. This may include CT with or without contrast. MRI may be more efficient at identifying certain structural lesions such as central pontine myelinolysis or PRESS. Usage of EEG and continuous EEG monitoring may be helpful to identify subclinical seizures. Lumbar puncture may be considered in patients who are at increased risk for central nervous system infections, including those who have a prolonged pre-transplant hospitalization, pre-transplant intensive care unit stays, and prolonged pre-transplant immunosuppression usage such as patients who have undergone transplantation previously and those with autoimmune limb disease. Surveillance for infection is a cornerstone of evaluation and management of central nervous system complications after transplantation and should include blood cultures, consideration of imaging of the abdomen, chest x-ray, and in certain cases bronchoscopy, and consideration of fungal CNS infection in selected patients is important, particularly again those with a pre-transplant intensive care unit stay and pre-transplant immunosuppression usage. Can some central nervous system complications be prevented with progressive management prior to transplantation? For patients who have significant hyponatremia, the risk of central pontine myelinolysis may be decreased by utilization of pre or intraoperative renal replacement therapy to smooth correction of hyponatremia, consideration of delaying the procedure to allow for improvement in serum sodium levels may be helpful. Posterior versatile encephalopathy syndrome is quite unpredictable but may be minimized with aggressive management of hypertension. Delirium can be minimized by limiting usage of CNS acting agents and promotion of aggressive sleep hygiene protocols. Key takeaways, central nervous system complications are quite common after transplant. The majority of these are transient and a minority of CNS complications have long-term implications for the outcome of the patient. The etiology is quite varied. More aggressive evaluation of persistent mental status abnormalities is warranted in the post-transplant period as these patients are at higher risk for more severe complications including cerebral vascular accidents and infection. It is important to evaluate trends in the development of CNS complications within your center to identify potential pathways to which central nervous system complications may be minimized. Respiratory failure is one of the most dreaded complications both before and after liver transplantation. Respiratory failure is typically defined as a PF ratio of less than 200. This is often viewed as a contraindication to transplantation. For example, in the canonic study in Europe prospectively evaluating 388 patients with acute on chronic liver failure of this population 25 patients with active acute on chronic liver failure underwent orthotopic liver transplantation. Of those 25 patients, 64% were experiencing renal failure, 60% had coagulation failure, 56% had liver failure, 36% had cerebral dysfunction, and notably no patients with respiratory failure underwent liver transplantation. Respiratory failure is not universally viewed as a contraindication to transplantation. In a single center in the United States evaluating 164 patients undergoing liver transplantation, 9% of whom had preoperative respiratory failure. Interestingly, preoperative respiratory failure was not a predictor of post-operative respiratory failure when viewed on multivariate analysis. A more recent study from the University of Minnesota looking at 382 orthotopic liver transplant patients in whom 12% developed chronic critical illness as defined by prolonged mechanical ventilation lasting more than 48 hours. In this particular study, pre-transplant ventilator dependence was associated with post-operative respiratory failure on multivariate analysis. While there is some lack of clarity as to the impact of pre-transplant respiratory failure on post-transplant respiratory failure development, what is clear is that post-operative respiratory failure has a significant impact on long-term outcomes. In this study, looking at 98 patients who underwent tracheostomy within the first six months after liver transplantation, there was a significant decrease in 10 year survival in the patients who underwent tracheostomy at 32% compared to 68% who did not undergo tracheostomy. Key takeaways. Transplantation for patients with lung failure remains controversial. The impact of pre-transplant respiratory failure on the development of post-transplant respiratory failure is unclear. Post-transplant respiratory failure is associated with worst long-term post-transplant outcomes. Thank you for your time and attention. Hi, I'm David Mulligan and I'm here to talk to you about liver transplantation and acute on chronic liver failure, particularly is the current organ allocation system appropriate. I'm currently the professor and chair of the Division of Transplantation Surgery and Immunology at Yale University as well as the president of UNOS. I have nothing financially to disclose but I do need to disclose the fact that I have been past chair of liver intestinal committee where many of these policies were developed and passed on to the board as well as former chair of the Advisory Council on Transplantation to the HHS secretary and current president of UNOS OPTN. I want to talk to you about the past two decades of organ allocation as it pertains to the liver. I'm going to talk about introduction of the MELD score where patients were prioritized based on their need and the sickest first which is very pertinent to ACLF and this prioritization was developed and implemented in February of 2002 and the allocation and disposition of these organs were through local, regional and national means. Exception scores like for HCC were done at fixed score points regardless of where someone lived and because of this and because the regions that we had at the time, the 11 UNOS regions, were arbitrary and not designed for organ allocation or distribution, there was a growing disparity over time and many called it the MELD elevator effect which was further pushed by the changes in exception scores and the fact that the exception scores would continue to increase until a patient received a transplant despite the fact that the patients weren't dying on the list and were receiving more transplants than probably originally intended. So by June of 2013 it was realized that we needed to find a better way to get livers to those who were sicker like our status one patients and the high MELD patients. Therefore we came up with a property of broader sharing called regional share 35. So this was an opportunity for us to share patients livers to patients with MELDs of 35 or higher allowing these sicker patients with higher mortalities on the wait list to get livers with greater access. However despite this broader sharing up to regions we still had growing disparities. Therefore after a lot of work we developed and adopted the ACUITY circle allocation model which was implemented February 4th 2020 to reduce these disparities so that regardless of where a patient lived they would have equal access to transplant and people dying in some portions of the country with really high MELD scores and much acute on chronic liver failure would have access to the life-saving livers that were being enjoyed in more abundance in other parts of the country where people were transplanted with much lower MELD scores. This results in more livers to high MELD patients, fewer deaths in those high MELD groups that had the highest death rates and slightly fewer transplants to those in the 15 to 25 MELD score range but they would be able to tolerate these without having as many deaths on the wait list. So let's talk about the impact of this broader sharing in more detail and especially as this pertains to the patients that we're here to discuss the acute on chronic liver failure patients and the acute liver failure patients. So when share 35 was implemented this study by Clara Nicholas and Scott Nyberg looked at the impact of pre and post transplant costs and mortality following the implementation of this share 35 strategy. What they found was that regional sharing for patients with high MELD scores above 35 increased transplants to those patients and was able to actually reduce pre transplant costs in the care of these patients with high MELD scores and as you can see in the graphic the shift from the table on the left with the pre share 35 graphs where the highest number of patients transplanted were more in the MELD 25 to 30 group and a much larger proportion of those compared to the graph on the right showing the shift of the post share 35 to being more towards the MELD of 35 to 40 with a flattening out of the MELDs between 20 and 35. Ray Kim and colleagues looked at the improved post transplant mortality after share 35 for liver transplant and demonstrated in each of these graphs that increased transplant rates, shorter wait list times, reduction in the wait list mortality with fewer organ discards and increased organ offers for patients with MELD 35. So all the high MELD patients including our ACLF patients were receiving more offers and getting more transplants and having a lower wait list mortality. We did see an increase one year post transplant survival especially in the high MELD categories and we did see that although there was a somewhat lower incidence of liver transplants in the lower MELD groups they did not seem to have a worse graft or patient survival and this was despite getting overall less quality organ as we can see on the graphs that they received a higher DRI organs many times in these lower MELD patients but they seem to work and take care of this group of patients. So what about this new ACUITY Circles allocation policy? Well when we look at the data which has only been going on for about four and a half months so far the the data shows to be divided into three groups. The first group is a similar period of time to look at the comparison comparing seasonal changes and liver allocation practices and transplantation practices. So we look at 2019 in February to mid-June for that first era. The second era was the four and a half months immediately prior to the policy change and this is reflective of the new National Liver Review Board in place to standardize all exception scores and to try to have a balanced exception practice across the country which many felt would take care of a lot of the disparity issues by itself. And then finally what happened after the ACUITY Circle allocation system went into place in February 4th of 2020 and and through the mid-June period and see how those groups compared. Unfortunately as you're very familiar the SARS-CoV-2 pandemic came in place and so we have COVID impacting the new allocation about five weeks after it began. And here's what it looks like. This shows the number of liver donors that were recovered in each of these era and showed that in the similar time frame in early 2019 we can see that there is a baseline of number week by week of livers recovered which was fairly similar but a little higher than immediately prior to the onset of our new allocation system. And then again about the same as we saw with the onset of the pandemic with a slight decrease especially due to the high peak of SARS-CoV-2 that we saw during the early March, April and May phase. But miraculously with a lot of work from our OPOs and transplant centers the deceased donors were recovered and were about a thousand livers ahead of where we were at this time last year. If we look at discards which were notoriously purported to be increasing with the new ACUITY Circle allocation we see in fact that the discard rate was just as low as it had been in the previous year before allocation and much improved compared to the immediate four and a half months prior to the allocation we currently have. And similarly the organ utilization was again the same as it had been at this time last year which was better than the four and a half months immediately prior to the new policy. If we look at the number of deceased donor livers transplanted by week we can see again that the ACUITY Circle allocation actually for five weeks was associated with more livers transplanted and this was only impaired from a major way by the pandemic in the in the next two months but then has recovered and we continue to do as many or somewhat more deceased donor transplants than we had last year. If we divide the patients into those that had exceptions and those that did not and we look at our calculated milled patients on the top again these are many of our ACLF patients we can see the majority of organs are going to them with slightly more organs transplanted into calculated milled patients than there was both in both pre cohorts and we see about the same number of HCC exceptions so there's no increase in exception patients being transplanted and somewhat decrease in the non HCC exception patients. If we look at this by UNOS region we can see that many of the regions show similar numbers in transplantation with the increase in livers transplanted in region 9 in region 7 region 5 and region 1 which actually equaled what was done to, in a similar period the previous year. And this, again, is impacted by the pandemic, with slightly decreased numbers in regions two, three, and six. If we look at which patients were getting these livers, you can see that there's not actually much difference in the MELD groupings. Status ones were actually down compared to the two pre-allocation sequences in those groups. And the high MELD patients remained about the same, 15.8%. We can see that the MELDs between 33 and 36 were about the same as they were at this time last year and ahead of where they were immediately, the four-and-a-half months, immediately preceding the allocation strategy. And again, across the board, the numbers are about the same as they were at that time, at this time in 2019. If we look at what happened by distribution on graphics, looking at this map that shows the median score at transplant across the country, what I want to point out is that in this time last year, you can see many extremes on the map, looking at the yellow, which signifies a median MELD of about 18 at transplant. And you can see that on the map is outlined, and the purple showing a median MELD score that's close to 38 on the map. And you can see after the new ACUITY circle allocations, on the right, those yellow and purples disappear, and the colors are homogenizing somewhat. But again, this is pretty early with only four-and-a-half months and a pandemic. This graphic shows the numbers of transplants done before and after the ACUITY circle allocation by center. And you can see how overall they're balanced with some of the centers picking up additional transplants over what they had been doing in the past prior to the allocation system. Those would be the centers to the left and up on the line, and those centers to the right are showing a decrease in the number of transplants, and this balances out the total number of transplants, keeping in mind that we've done more transplants this year than we had previously. Now, how did we do regarding the local, regional, and national distribution? As you know, these were part of the allocation system prior to the ACUITY circle allocation, and therefore, about 60 to 65% of the livers were distributed locally, and then that would leave about 30% going regional and 7 to 5% going national. With ACUITY circle allocation, this was divided into thirds with a third going into local, regional, and national as we currently use. But what the ACUITY circles used is 150 nautical mile circles, and so the majority or a little over 50% of the livers stayed within our new local, which is 150 nautical miles from the donor hospital, and then the 150 to 250 nautical mile circle would accommodate another 17%, and finally, the 250 to 500 nautical mile would accommodate another 27%, leaving 5% going out greater than 500 nautical miles. So, the distribution was still staying within the 150 nautical mile circle for over half of the patients. As we look at the impact of this, it means more travel, but not significantly more travel, as we can see that we're averaging somewhat slightly over 200 nautical miles, where before, we were about 180 nautical miles. So, as we look at the difference, there is more travel, but certainly, it's not as great as one would expect, and as we had modeled. What about waitlist removals for death or too sick to transplant? As we can see from each era, the same period that we would have had in 2019 in the same timeframe was higher than what was seen in the four and a half months immediately prior to acuity circle allocation, but after the acuity circle allocation began, we started to see a drop and continue to see that drop in patients removed from the waitlist for death or being too sick, which shows that we did decrease some of the death rates to some extent afterwards. So, the takeaways I want you to have here is to remember that MELD prioritizes patients for the sickest first. Share 35 is what created the beginning of a broader sharing to focus on higher MELD patients, as well as the status ones, and acuity circle allocation takes over that responsibility, reducing the disparities so that regardless of where a patient lives, they have equal access to these life-saving livers, and moves livers from areas of higher donors to these high MELD patients, increasing utilization, reducing the deaths on the waitlist, and discards. So, we've seen a progress to broader sharing and strategies that enable livers to get to our sickest patients, including the acute and chronic liver failure patients, and this is being done regardless of the residents of our patients. And as the pandemic subsides, I would expect that acuity circle allocation should reduce death rates for these high-risk patients, and thus benefit this group even more. Thank you very much for the privilege of sharing this information with you. I'll look forward to having a discussion to come. Thank you to the ACLF SICK for inviting me to speak today. The title of my talk is, Is There a Role for Palliative Care for the ACLF Patient on the Liver Transplant List? My name is Meena Rokoski, and I'm a transplant hepatologist at Loma Linda University Health. I have a dual appointment in both hepatology as well as palliative care. I run a hepatology palliative care clinic where I provide integrated hepatology and palliative care services for patients with advanced hepatobiliary disease. I've written several papers and presented at national conferences on this topic. I'm also a co-investigator on a multicenter study funded by PCORI called the PAL Liver Study, which is investigating a novel approach of integrating palliative care into subspecialty hepatology clinics. I have no disclosures. So these are my learning objectives. First, I'm gonna discuss what is palliative care. Most of my talk will focus on why palliative care is important and beneficial for listed patients with ACLF, focusing on short-term mortality, uncertainty, and introducing a concept called the organ transplant imperative. I'm also gonna provide some suggestions on how to integrate palliative care into your transplant practice. So what is palliative care and how is it different than hospice? The World Health Organization defines palliative care as an approach that improves the quality of life of patients and their families who are facing problems associated with life-threatening illness. I think we can all agree that ACLF can certainly be a life-threatening illness. In our world of liver transplant, we often think that curative therapies are a separate and independent entity from palliative care. It's black or white, either one or the other. And it's really only appropriate to think about palliative care when curative interventions like transplant are no longer an option. However, this alternate figure shows that these two philosophies of care are not actually dichotomous or divergent. They're actually complementary. As a patient's disease progresses, patients can struggle with readmissions, greater symptom burden, loss of independence, fear of dying. Palliative care can play a larger role to help support the patient and their caregiver until he or she gets a transplant. If at some point a transplant seems unattainable, palliative care can play an even larger role to support the patient and their family as they transition to different goals of care. Now that I've described what palliative care is, I do wanna emphasize what palliative care is not. Palliative care is not end-of-life care. Palliative care can be appropriate at any point in a serious illness and can be provided at the same time as life-prolonging treatment. Importantly, palliative care is also not hospice. Hospice is a form of palliative care that provides care during the last weeks or months of life. You can see from this figure that the blue dot is hospice, and it represents only a small portion of what palliative care services can offer in regards to symptom management for chronic life-limiting illnesses. There are many studies that have shown the benefits of palliative care in patients with advanced liver disease. Palliative care can improve physical symptoms, improve mental health symptoms, improve overall quality of life, and has also been shown to decrease ICU length of stay, hospital costs, and hospital readmissions. So why palliative care for listed patients with ACLF? As you all know, ACLF is associated with significant morbidity and mortality. As the grade of ACLF increases, short-term mortality risk dramatically increases as well. In listed patients with ACLF, the risk of death while waiting for transplant is over 50%, with the most common cause of death overwhelmingly due to the risk of death from acute liver disease. In patients with acute liver disease, the risk of death is over 50%, with the most common cause of death overwhelmingly due to multi-organ system failure, often due to sepsis. Clearly, ACLF in a listed patient is a condition where death could be around the corner. In patients with such severe life-limiting illness, we have the opportunity to make a vast difference in the patient and worried caregiver's quality of life and their quality of life. There's a lot of uncertainty associated with ACLF. This is a patient in the ICU on multiple modalities of life support. Should we transplant an ACLF patient that looks like this? This is a controversial ethical conundrum. An ACLF-3 patient like this has a high weightless mortality. If we are able to get them to transplant, some studies suggest that their post-transplant outcomes seem relatively equivalent to non-ACLF patients, including excellent renal recovery. The concept of medical futility can be defined as pursuing an action with virtual uncertainty of the action actually achieving a predefined objective. So transplant for critically ill ACLF-3 patients is a dynamic balance between the distress and suffering associated with potential medical futility and the curative and joyful satisfaction of saving a life with a successful transplant. Waiting for a transplant in this situation is fraught with uncertainty and suffering. This is an ideal time to request palliative care support for the patient, but more importantly, the caregiver. It would be remiss if I did a talk about ACLF patients and transplant and didn't mention a few important ethics concepts that guide decision-making for both physicians and patients. I'd like to briefly explain a few key terms to help add depth to your understanding of this sensitive topic. Many studies have shown that despite all the high risks that I depicted in the previous slides, palliative care is rarely involved in the care of our liver failure patients. There are several important ethical paradigms that likely contributed to this. Therapeutic inertia is the concept of sticking to our original plan. It is defined as an adherence to a preconceived course of treatment, even in the face of new medical problems or risk. A transplant-related example would be an ACLF-3 patient that remains on multiple pressors, high oxygen settings on the vent, on continuous renal replacement therapy, yet because of the time and resources previously committed by the patient, their family, and even the transplant team, no one wants to waver from the original desire to keep moving forward with transplant. Treatment imperative is defined as a perceived need by providers and patients to provide interventions. As an example, in our listed ACLF patients, we as providers are compelled and driven to offer curative therapy such as transplant. Similarly, patients are inclined to accept them, usually because they don't want to die. Technological imperative is the concept that we as providers feel compelled to use the latest and greatest medical innovation to save our patients. An example in liver transplant would include utilizing all aspects of hospital resources to preserve our patient's transplant candidacy. Next slide. All three of the paradigms set the stage for a concept coined by Santivasi et al called the organ transplant imperative. The organ transplant imperative is the perceived obligation by providers and patients to proceed with transplant and avoid timely palliative care consultations, even in situations where clinical trajectory has worsened. An illustrative example for the listed ACLF3 patient would be commitment to liver transplant at all costs, including all aspects of critical care and medical innovation. Due to a focus on life-saving intervention, palliative care is not consulted until the patient is deemed too sick for transplant. The patient subsequently dies in the ICU with the family left feeling distressed and unprepared. Unfortunately, this is not an uncommon scenario for listed ACLF patients. In this case, there was a high risk of medical futility. Involving palliative care earlier would have allowed the family to have the opportunity to hope for the best, but prepare for the worst. How can we integrate palliative care for listed ACLF patients? Here we have a timeline of a patient that experiences his first acute decompensation on the left and moves through the trajectory of getting listed for transplant, later has several readmissions for liver decompensation while experiencing significant distress and symptom burden, and then ultimately develops ACLF. I propose that we could get palliative care involved upon the first sign of liver failure during his first acute decompensation. However, for some, this is too early of an entry point. Ideally then, palliative care consultation should occur as an integrated part of the liver transplant evaluation process. The patient should be able to see a doctor and receive a medical evaluation as an integrated part of the liver transplant evaluation process. At most institutions, the patient and their caregiver meet several healthcare providers as part of the liver transplant evaluation. For example, they meet social workers, dieticians, financial coordinators, surgeons. If we introduce the palliative care specialty as one of the members of our comprehensive transplant team, it would normalize their role and perhaps dispel the misperception that palliative care is only appropriate when the patient is dying and transplant is no longer an option. In the beginning, when the patient is relatively well, depicted by this high portion of patient health, palliative care can play a supportive role, helping to navigate roadblocks and distress related to the evaluation process. Then, once the patient is listed, we know he'll have several hospital admissions, his mental and physical health will continue to decline as he gets closer to transplant. In this scenario, palliative care can take on a larger role to help manage complex symptoms such as abdominal pain and depression, as well as help with caregiver distress. As this patient gets sicker and is eventually admitted to the ICU with ACLF, the palliative care provider is now a trusted and familiar face that can support the family during this challenging time and facilitate ongoing goals of care discussions. If the patient undergoes successful liver transplant, the palliative care team can celebrate alongside of the patient, family and the transplant team. However, if the patient is no longer transplant eligible, the palliative care provider can guide the discussions and transition to death with dignity. So these are my key takeaway points. Palliative care is an effective multidisciplinary approach to care that focuses on patient and caregiver quality of life. It is not the same as hospice and can be provided at the same time as life prolonging or curative treatments such as transplant. Due to high mortality, as well as potential for uncertainty, suffering and futility, palliative care can greatly benefit listed ACLF patients and their caregivers. Early integration of palliative care during the transplant trajectory is challenging, however, can offer maximal benefits to our patients with ACLF. Thank you very much. And I'm happy to take any questions.

acute onchronic liver failure

liver transplantation

ICU management

shock management

respiratory failure

antimicrobial therapy

encephalopathy treatment

kidney injury

pre-transplant optimization

post-transplant complications

palliative care