Hi there. My name is Konstantin Karvelas. I'm a professor of critical care medicine and hepatology at the University of Alberta in Edmonton, Canada. And on behalf of myself and my program co-chair, Dr. Anna Bank Husu from Baylor and Texas Children's, it is our pleasure to welcome you to the Combined Pediatric Liver Disorders SIG and Acute and Chronic Liver Failure SIG program entitled Management of Acute and Chronic Liver Failure in Adults and Children at the 2021 ASLD liver meeting. We think what we have for you today is a very exciting combined session. It is a four-hour session that we've divided into two parts. The first part will cover definitions of acute and chronic liver failure in both pediatric and adult patients. And then we will proceed to be discussing acute kidney injury in cirrhosis and ACLF and also discussing the management including renal replacement therapy. In the second part of the session, we're going to be talking about other complications of acute and chronic liver failure and then move to the challenging topic of liver transplantation in ACLF in both pediatrics and adults with a special focus on when is it too late to transplant an ACLF patient. One thing that we hoped would add a little bit of variety to this session is that we'll have some challenging cases, both pediatric and adults, one presented by a pediatric fellow and one presented by an adult fellow, which will be thought-provoking for some discussion among our panelists. We're happy to welcome today many internationally renowned speakers in both hepatology and critical care medicine. And we believe that this program today will be of significant value. So we hope you enjoy today's session and look forward to your participation. My thanks to the AASLD SIG for inviting me. These are my disclosures. I have to thank my colleagues Scott Nyberg and Sumita Shrani for use of single slides in this presentation. I'd like you to think of the concept of acute and chronic liver failure within the critical hepatic mass hypothesis, which was expounded more than 50 years ago. According to this hypothesis with rapid loss of liver function, patients reach a stage where hepatic regeneration is not possible and survival is not possible in the absence of liver transplantation. In chronic liver disease with more gradual loss of liver function, patients reach a stage where they have complications like hepatic encephalopathy, but with intensive care can return to baseline. There's an intermediate stage with more rapid loss of liver function, but there's not enough hepatocyte mass to survive, but there's enough hepatocyte mass to regenerate. And if these patients get liver support, they can reach a stage where they can function back in the community. I'd like to think of ACLF as this condition where with liver support, there's enough regeneration taking place and patient can return back to normal. Now, this is not my original concept. In fact, the original description of ACLF is exactly that. So let's look here. The entity of acute and chronic liver failure remains poorly defined. With the emergence of newer liver support strategies, it becomes necessary to define this entity. So basically, ACLF was a condition which I wanted to define as something that would benefit from liver support strategies. A current strategy for the management of liver failure involves supportive therapy for end organs with the hope that liver function would recover if sufficient time for recovery is allowed. Because liver failure, whether acute or acute and chronic, is potentially reversible. The stage is set for application of newer liver support strategies. So essentially, what the authors who described the ACLF were saying was this is a reversible condition with liver support. The required elements for defining a disease, and this is not just for ACLF, it's for defining any disease, needs to be discussed. Why current definitions confuse you, and frankly, why they confuse me. The suggested definition of ACLF, the proposed pathophysiology, and some take-home messages will be part of my talk on defining ACLF and the proposed pathophysiology. Now to characterize a disease, it has to be distinct. So ACLF cannot be acute liver failure, but it should have acute liver failure elements because we call it acute and chronic liver failure. It should not be chronic liver disease, not compensated cirrhosis, not traditional decompensated cirrhosis. The pathophysiology has to be unique. So the pathophysiology of ACLF needs to be defined. It cannot just be inflammation because inflammation occurs in all these other conditions. Is it really cerebral edema in a patient with cirrhosis? That is acute liver failure. That is really unique to patients with cirrhosis. Is there a specific diagnostic sign, symptom, or a test? That is again a requirement. Like for COVID, you've got a specific test. We know the pathophysiology and it's a distinct condition. So is cerebral edema the diagnostic sign or test that we need? And what is the management change that is going to be triggered when we call this ACLF? Is it the need for liver support? So in defining ACLF, there are two purposes here. It should trigger a management change and also it should identify entry points for studies. Remember ACLF like acute and chronic heart failure or acute and chronic renal failure should reflect some degree of reversibility of hepatic function. And liver support may allow return of function. I think most patients find this ACLF in Europe and the U.S. probably have ACLF, but that is accelerated chronic liver failure. They don't have true acute and chronic liver failure. Now, why are these definitions really confusing? This slide is from Sumita Shrani, patients with chronic liver disease, progress to compensated cirrhosis, the onset of ascites, encephalopathy, jaundice, and variceal bleed, and the onset of decompensated cirrhosis. These patients can get critically ill and will die in the absence of liver transplant. They have hepatic and extrahepatic organ failure. So that is these patients' progress from a reversible stage to an irreversible stage. A parcel identifies patients at a reversible stage. However, we do not know exactly how to identify the patient at this stage will rapidly reach a stage of being critically ill. ESL is somewhere more advanced. Many of these patients will have irreversible disease. And AXL essentially identifies patients at the time of irreversibility. Based on this, what is the suggested definition of ACLF? Based on this, what is the suggested definition of ACLF? ACLF is a potentially reversible condition in patients with underlying liver disease, which is chronic or with compensated cirrhosis, usually associated with a precipitating event that may or may not be identified. And these patients have a high risk of three-month mortality in the absence of treatment of the underlying liver disease and precipitating event, liver support, or liver transplantation. So the question is, why three months? So the only precipitating event that can be precisely timed and the patient monitored before and after the precipitating event is surgery. And this is usually carried out only in patients with compensated cirrhosis. So when patients are operated and develop hepatic and extra hepatic failure, that is ACLF. And therefore, post-surgery events are an ideal model to study ACLF. Patients with compensated cirrhosis who undergo surgery have a high risk of mortality, but that risk returns to baseline at three months. And therefore, the timing for the ACLF event, the timing for increased mortality risk should be three months. And that is based on our study here of 762 patients who underwent surgery for cirrhosis. Notice patients with major surgery have a higher risk of mortality, but at 90 days, that risk of mortality returns to baseline and equivalent to that of outpatient controls and patients with compensated cirrhosis who underwent minor surgical procedures like hernia surgery. What is the proposed pathophysiology of ACLF? The normal hepatocyte takes up ammonia and releases urea into the circulation. The normal hepatocyte divides into daughter cells, and that is the regenerative capacity of the liver. When the hepatocyte dies from acute liver injury, ammonia and other waste products cannot be taken up and escape into the circulation. Inflammatory cells are recruited from the extracellular matrix. These inflammatory cells release pro-inflammatory cytokines, which again escape into the circulation. The pro-inflammatory cytokines also inhibit mitosis. So, the end result of liver injury is waste accumulation, systemic inflammation, and impaired hepatic regeneration. And the focus here is going to be on systemic inflammation. The systemic inflammatory response syndrome in cirrhosis on patients with chronic liver disease can be sterile, GI bleed, alcohol-related hepatitis, surgery, or drugs. It is also bacterial infection-related, which causes patients to get septic, second infections, and fungimia. So, at homeostasis, there's a balance between the pro-inflammatory response and the anti-inflammatory response. There's initially immune activation, but several days later, there is immune suppression, and these patients get second infections and multiple organ failure, which leads to death. So, why do organs fail? Organs fail because they get less oxygen. Why do they get less oxygen? Either there's less blood flow, which is related to problems in the vascular endothelium, or because of mitochondrial dysfunction. Let's look at vascular factors first. Within the microcirculation, neutrophils release neutrophil extracellular traps, which lead to thrombosis. The thrombosis is propagated because of a decrease in antithrombin-activated protein C and fibrinolysis. So, the thrombosis is propagated. There's endothelial cell dysfunction, which causes vasodilatation, and there's loss of barrier dysfunction mediated through protease-activated receptor 1, which ultimately results in a decrease in vascular endothelial cadherin and loosening of the tight junctions. On the tissue side, there's release of mitochondrial contents, giving rise to mitochondrial dysfunction and decrease in tissue oxygenation. The thrombosis, vasodilatation, hypertension, and decrease in red cell permeability give rise to tissue hyperperfusion. And the loss of barrier function gives rise to capillary leak and interstitial edema. So, the combination of tissue hyperperfusion and loss of barrier function decreases tissue oxygenation, which then gives rise to organ failure. The organ dysfunction and acute and chronic liver failure, which follows a systemic inflammatory response in the brain, cerebral edema in true ACLF, high-output cardiac failure, acute lung injury, loss of metabolic function in the liver, including cholestasis, adrenal dysfunction, acute kidney injury, and then immunoparesis from bone marrow suppression. Immunoparesis from bone marrow suppression, which contributes to the high risk of sepsis. So, the potential therapeutic targets in these patients are patients with compensated cirrhosis or chronic liver disease following a major insult, yet inflammation mediated multiple organ failure. Patients also get infected, but if we reverse the insult, support the organs, and treat the infection, these patients could potentially return to normal function. So the take-home messages on definitions and proposed pathophysiology of ACLF in adults is ACLF should be restricted to patients with chronic liver disease or compensated cirrhosis since reversibility is a requirement. The optimal definition of ACLF requires better understanding of pathophysiology and that includes probably the presence of cerebral edema. Cerebral organ dysfunction as a diagnostic criteria means diagnosis is probably made too late to impact survival. And standard management is required for international studies if consensus definitions are to be developed. Thank you. I'd like to thank the organizers for the invitation to speak at today's session. The title of my talk is Acute On Chronic Liver Failure in Children, the Scope of the Problem. I have no financial disclosures. Over the next 15 minutes, I'd like to define acute on chronic liver failure in children, characterize triggers and clinical outcomes in children with ACLF, and explore the future of ACLF in the field of pediatric hepatology. Children with chronic liver disease have a variety of different etiologies from biliary atresia to allergy syndrome, autoimmune hepatitis, Wilson's disease, chronic viral hepatitis, among others. They follow a similar spectrum of progression of disease to decompensated cirrhosis characterized by variceal hemorrhage, encephalopathy, ascites, and jaundice, similar to adults. During the course of their illness, a precipitating event may occur from exposure to different medications or toxins, infections with viruses, bacteria, that can lead to the development of acute on chronic liver failure, which in adults is defined as a syndrome in those with chronic liver disease with or without previously diagnosed cirrhosis that's characterized by acute hepatic decompensation and results in liver failure with one or more extra hepatic organ failure, and this ACLF in adults has been associated with increased mortality. Various definitions exist that define ACLF in adults, and these definitions vary not only on their requirement of a diagnosis of chronic liver disease, but also in the number of organ failures and their definitions of organ failure. But despite these differences, ACLF has been associated with high mortality in adults, with 28-day mortality as high as almost 90% in adults who have four to six organ failures. But the big question is how do we define ACLF in children? Can these adult definitions be directly applied to pediatrics, or does a pediatric specific ACLF definition need to be developed? The first step in trying to understand and answer this question is to understand the physiological differences in critically old children as compared to adults. As pediatricians, we take care of children over a vast range of ages from neonates who are several days old to toddlers to adolescents, and many of our patients have a wide range of heights and weights, from infants weighing two to three kilos to adolescents who are adult size. Thus, it's important for us to remember that children are not just small adults. Studies in pediatric sepsis have provided some insight into the physiological differences in multiple organ systems in children. From a cardiovascular standpoint, there are age-specific differences in heart rate, stroke volume, blood pressure, pulmonary and systemic vascular resistance, and these form the basis for many of the age-specific differences in normal values that are seen. Additionally, studies in infants have shown that the infant myocardium has a relatively decreased left ventricular mass in comparison to the adult myocardium, as well as a differential ratio of type 1 and type 3 collagen, leading to the infant heart working at a relatively higher contractile state. Thus, children have a limited ability to increase their stroke volume when they need to increase their cardiac output, thus relying more on heart rate. Additionally, anatomic differences increase susceptibility of children from a respiratory standpoint for acute upper airway obstruction and respiratory failure. Children have a larger head and occiput, a larger tongue, a shorter and smaller narrow trachea, and more prominent adenoid and tonsillar tissue that can contribute to this. Additionally, studies have shown that children have fewer and smaller alveoli that contribute to decreased surface area for gas exchange. And lastly, compared to adults, children have a smaller size of the thorax in comparison to the abdominal compartment and have differences in abdominal compliance. Thus, many children with large volume ascites can experience respiratory distress and respiratory failure. Lastly, the kidney undergoes significant changes during the postnatal period, with GFR reaching adult levels only by approximately two years of age. Serum creatinine is determined by the volume of distribution, which varies greatly throughout childhood, and oftentimes baseline creatinine for our young infants and children is usually around 0.1 to 0.2 mg per deciliter, which is oftentimes the lab variability as well. Therefore, absolute increases in serum creatinine can reflect differing degrees of kidney dysfunction in children as compared to adults. The following table presents the easel-cliff organ failure score, and what I'd like to highlight is the current criteria used in adults to identify kidney failure, specifically looking at the absolute values for creatinine incorporated, as well as the mean arterial pressure parameters used to define circulatory failure. Thus, the big question is, can we apply these directly to children? Bollea et al. in 2018 published an article in the Journal of Hepatology where they suggested the incorporation of pediatric-specific definitions and proposed the pediatric-cliff SOFA score as shown in this table. What I'd like to highlight is that their definitions incorporated systemic systolic blood pressure percentiles for age, as well as creatinine values based on values above the upper limit of normal, and these authors incorporated currently used pediatric definitions for organ dysfunction that were published by Goldstein et al. and used in pediatric critical care centers across the country and the globe. As we think about the pediatric ACLF definition and think about the adult definitions, we should remember that defining organ failure in children should be pediatric-specific, with the goal of this definition identifying children with the highest risk of short-term mortality. Next, I'd like to discuss the currently published literature and present an overview of the triggers and clinical outcome in children with ACLF. The most robust experience in ACLF comes from Asia, with several groups in India and Turkey defining ACLF using the appaisal definition. These authors found a prevalence ranging from around 11% to 47%, and many of the children in their studies had a diagnosis of Wilson's disease, autoimmune hepatitis, and chronic viral hepatitis. Overall mortality ranged 20% to as high as 60% at three months in these cohorts, and many of these children had either an acute viral hepatitis or a flare of an underlying disease triggering the development of ACLF. Two of the authors identified the adult CLIF-SOFA score as being predictive of mortality. When we move to the European experience, I'd like to highlight two studies that defined ACLF using the adult easel-CLIF criteria. A study from the United Kingdom identified ACLF in a cohort of children with biliary atresia with a prevalence of 20%, whereas a multi-center study by Claude et al. identified ACLF in all critically old children with chronic liver disease. Both of these studies had a large proportion of children with biliary atresia and cholestatic jaundice, and similar to the Asian experience, identified children with ACLF as having high mortality. Children in these studies had sepsis as triggering ACLF in almost 50% of the cases. Interestingly, Claude et al. identified the pediatric CLIF-SOFA score that was presented earlier on admission as being associated with 28-day mortality in their cohort. The North American experience in ACLF is also similar to the American experience. And ACLF is also similarly limited. A single center assessed the prevalence of ACLF and characterized ACLF in children using a modified NASL definition that required only one extrahepatic organ failure and identified this in about 30% of their patient cohort. Godfrey et al. utilized a modified easel-CLIF and NASL definition to identify ACLF in children listed for liver transplant in a large UNOS database study and identified a prevalence of 2.5%. Both of these studies had a large percent of children with biliary atresia and once again identified high mortality in these patients with a 90-day mortality from listing in the UNOS database as high as 50, almost 50%. Interestingly, in these studies, admission creatinine as well as listing creatinine was identified as being predictive of not only ACLF development, but also mortality. Similar to studies in adults, as the number of organ failures in children increases, mortality increases. And what I'd like to highlight in figure one is that children who experienced five or six organ failures had a 0% chance of survival. When looking at the number of organ failures, majority of the children in the published studies experienced only one to two organ failures with only a small percentage experiencing three or more organ failures. Lastly, I'd like to highlight the types of organ failures that have been identified in these children. And interestingly, as compared to adults, respiratory failure was identified in many of these studies as being the most common organ failure experienced with as high as 80% of children in a study from Europe experiencing respiratory failure. Kidney failure, on the other hand, was less common with only about 12% of children in a European study requiring dialysis. But the larger question is, what do these organ failures and what impact do they have on mortality? And as presented on this slide, respiratory and renal failure in these children was associated with increased mortality with children having as high as 95% mortality who experienced respiratory failure and 80% in those with renal failure. And as shown in this survival curve, regardless of the degree of renal failure, even those who had stage one or two AKI experience worse survival. Similarly, as this graph shows, having any degree of AKI led to a higher hazards ratio for death and liver transplant in children with ACLF. Lastly, one of the important things that we need as clinicians to help our patients is tools to predict outcome in children who experience ACLF. And as previously mentioned, studies have identified various scores, specifically the pediatric CLIF-SOFA score that was presented earlier as identifying 28-day mortality. And what I'd like to highlight even more from this slide is that when the authors compared the CLIF-SOFA score to the PELD score, the pediatric CLIF-SOFA score had an improved area under the receiver operating curve at identifying mortality in these patients. So, what does this mean for patients with ACLF? Well, it means that the patients with ACLF have a higher chance of having a higher chance in these patients. So, where do we go from here and what is the future of ACLF in children? One of the first steps is understanding what drives ACLF and what is the pathophysiology of ACLF. And this figure summarizes the proposed pathophysiology from adult studies, including the role of systemic inflammation, mitochondrial dysfunction, and tissue hyperperfusion contributing to organ failure. Studies in adults have nicely highlighted that patients with ACLF have higher white blood cell count, CRP values, as well as differences in elevations in not only pro-inflammatory but also anti-inflammatory cytokines. Limited data in children have found similar trends with elevated white blood cell count in children with ACLF, as well as elevated CRP in children with organ failure. So, as we think about the future of ACLF in children, I'd like to begin by proposing a pediatric ACLF definition modeled on what is available in the adult literature. I propose that children with ACLF be defined as a syndrome in those with chronic liver disease with or without previously diagnosed cirrhosis that's characterized by acute decompensation and results in liver failure with one or more extrahepatic organ failures as defined by the pediatric CLIP-SOFA criteria. As we move the field forward, it will be important for us to further characterize systemic inflammation in children with ACLF, further study and develop predictive scores and models for ACLF development and outcome, as well as study and approach targeted therapeutics for ACLF management, with the ultimate goal for us to improve the outcome of children with ACLF. In summary, I would like to highlight a few key takeaways from our presentation today. First, pediatric-specific definitions of organ failure exist in pediatric critical care and should be incorporated into a unified pediatric ACLF definition across studies in order to identify children with the highest risk of mortality. The prevalence of ACLF in the published literature ranges 11 to 47 percent and has been associated with high 28-day and 90-day mortality rates. The presence of respiratory failure, AKI, and renal failure have been shown to impact mortality in these children. Last, further understanding the role of systemic inflammation is needed with potential novel applications and targeted therapeutics in the management of ACLF in children. Thank you for your attention. Good morning, good afternoon, good evening, depending on where you are in the room. Good afternoon, good evening, depending on where you are in listening to this presentation. I'd like to thank the organizers for inviting me to give this talk today on hepatorenal syndrome and AKI and ACLF. Since this session also includes discussion on pediatric liver disorders, I'll try to also address some of the pediatric data on AKI and ACLF, which is not that many. These are my disclosures. If you look at the evolution of AKI and HRS over the last 50 years, for the first 30 years from 1979, really until up to 2010, the only definitions that existed were for hepatorenal syndrome. The initial one was by the Sassari Criteria. This was updated by the International Club of Societies in 1996, then again in 2007. It wasn't really until 2010, and this was published in 2012, when the Acute Dialysis Quality Initiative, the ATCE group, had an international consensus meeting with several members of the International Club of Societies, and for the first time defined AKI in patients with liver disease and also tried to redefine hepatorenal syndrome. This was then slightly updated by the International Club of Societies again in 2015. As I mentioned, again, on the left, you can see this was the ATCE consensus meeting, and the definition, what we had suggested was that AKI in patients with liver disease to be no different from patients without liver disease, and at that time, the AKIN criteria only existed, and you can see we suggested defining it with a 0.3 milligram increase in serum quianin or more than 50 percent from baseline. We also put forth the idea that HRS type 1 should be a form of AKI and type 2 should be a form of CKD. This was then slightly revised by the International Club of Societies about five years after that, and the definition was very similar. By this time, we had the KDGO criteria that had come out, and this staging was based now on the KDGO criteria. As you can see, the urine output criteria was not included in any of these definitions, and it was only the serum quianin definition. Because the definition of AKI was now set forth based on, again, KDGO criteria, the hepatorenal syndrome diagnosis was also slightly revised, and the serum creatinine cut off of 1.5 milligrams per deciliter was now removed. It was based on the ICA AKI criteria, which as I mentioned, was about 50 percent increase in your serum creatinine. The rest of the definition for hepatorenal syndrome stayed input, including the fact that they recommended that there should be no sign of structural kidney disease. However, as many of you know, in this era of increased Nash cirrhosis, a lot of these patients have diabetic kidney disease, and therefore may have underlying kidney injury. They did put a notation that patients who fulfill these criteria will still potentially can have structural damage, and suggested that maybe biomarkers may be important in the future for determining who has hepatorenal syndrome versus ATM. However, as I mentioned, the urine output criteria even though is not included in this definition, this is data from University of Pittsburgh. It's about 3,000 patients, critically ill patients with liver disease in seven of the ICUs at University of Pittsburgh. What they were able to show was that patients who had no AKI criteria based on serum creatinine, but had stage 3 criteria based on urine output, their mortality was actually 22 percent, and that was much higher than if they had no urine output criteria, but serum creatinine criteria of stage 3, which was 13 percent. If patients met both criteria of stage 3 urine output criteria and serum creatinine criteria, their mortality was 48 percent. Again, this is the only data that has come out, but this is large data showing the importance of also the use of urine output criteria in diagnosing AKI in patients with liver disease. This data, these numbers are very similar to critically ill ICU patients who don't have liver disease. A new definition has been put forth to push this a little bit further and to get rid of the term HRS Type 1 or Type 2, and move towards calling it HRS AKI for those who had Type 1. For those who have Type 2 where they have this continuous worsening of renal function, improving, but maybe not to baseline in this slow progression to maybe call it HRS AKD, which is acute kidney disease. These are patients who don't meet the criteria for AKI or they have AKI that has lingered more than seven days, or CKD if it's more than three months. We also have proposed that to include, in addition to the serum creatinine definition of KD, go also including the urine output criteria as defining AKI. What is epidemiology? If the serum creatinine criteria is only taken into account, this is the largest study from Canada, looking at patients who were hospitalized for cirrhosis and they looked at those patients who then went on to develop AKI. You can see about 60 percent of the patients did not develop acute kidney injury, 35 percent did, and from that, the majority were stage 1. As the staging went up, the mortality of these patients went up. Again, this data is very similar to what we see in the general population. What about in patients with ACLF? Well, there's not that much data specifically looking at patients with ACLF, but this is the largest retrospective study, 1,000 patients. About 12 percent had AKI in admissions, 30 percent developed it later on during hospitalization. Again, you can see these numbers are very similar to the Canadian data. For those patients who had AKI, their survival was worse and it didn't make a difference. What they found was whether the patient had ATN or HRS, which most likely these patients had more severe acute kidney injury, their survival was much worse than those who had pre-renal AKI. Depending on what the MELD score, the presence of ascites, sepsis, all of these were independent factors associated with AKI development. Is there a difference between ACLF and acute decompensated cirrhosis? This is a study from China, very small study and 280 patients with hepatitis B related ACLF and hepatitis B related decompensated cirrhosis. On the upper left, you can see that the staging at the time of diagnosis AKI staging was very similar. However, the progression was worse with patients with ACLF. The peak of AKI was more patients with ACLF had stage 3 AKI. The response to trilopressin for those who did have hepatorenal syndrome was worse in patients with ACLF and patients with decompensated cirrhosis tended to respond better to trilopressin. What about pediatrics? The data, there's very few studies out there. This is the first study in 1986 by the University of Pittsburgh by Dr. Starzl. You can see that here, they defined renal failures GFR of less than 20. It's unclear what percentage had underlying chronic kidney disease. But for those who were referred for possible transplant, about seven percent had this GFR less than 20. At the time of transplantation, the prevalence was 10 percent. What about outcomes in pediatric patients with ACLF? You can see here, this was 600 patients. It is from India, about 84 of them had ACLF. The majority were Wilson's and autoimmune hepatitis. From that percentage, about only 20 percent had AKI. It was split between AKI on admission versus hospitalization. The cause was 30 percent was due to HRS, 31 percent sepsis, then there's nephrotoxic agents. The presence of SERS and the bilirubin were independently associated with the presence of AKI. The mortality of those who developed AKI was about 50 percent. What about the treatment of AKI and HRS? Well, nice quote by Benjamin Franklin, an ounce of prevention is worth a pound of cure. The most important thing is trying to prevent these patients from developing AKI, from developing hepatorenal syndrome. It's very similar adults from pediatrics. Again, antibiotic prophylaxis during GI bleed, albumin infusion during large volume paracentesis, avoidance of nephrotoxic agents, minimizing radio contrast. These have all been shown in studies to prevent the development of AKI and HRS. Once the patient has developed acute kidney injury, again, we go through this algorithm, is it pre-renal, renal, and post-renal. But what we struggle a lot with is trying to determine whether the patient has hepatorenal syndrome versus acute tibial necrosis. It's usually not very easy. Initially, between volume depletion and HRS, we can give volume and if they're not responsive, it's thought to be either hepatorenal syndrome or ATN. But again, it becomes important whether or not you use vasoconstrictors or not, and we need to know which patient are we treating with these vasoconstrictors. That's put a lot of interest towards the use of biomarkers. This is from the tribe AKI from Yale. These are studies that were not biopsy proven based on clinicians to determine whether the patient had pre-renal, hepatorenal, ATN. You can see here that NGAL level was highest in those who had ATN, but there was a lot of overlap between the groups. But things that are more available to us like fraction excretion sodium or urine albumin, the diffraction excretion sodium, even though it was less than one percent in ATN, which was very interesting, it was extremely low in patients with hepatorenal syndrome and they looked at urine albumin, which is a marker of glomerular injury, and it was higher in patients with ATN. This is in Paragenesis group in Barcelona. They've also looked at the NGAL in patients with AKI and they saw that day 3, the presence of a level of NGAL of 220 gave an error under the curve of 0.87 in being able to determine whether the patient has HRS versus ATN. This is study from the US cohort trying to replicate what was studied in Barcelona. Very similar results, this is 200 patients. The serum granule was two, and again at a cutoff point of 244, NGAL was able to distinguish ATN from pre-renal. Again, this may become the future of being able to differentiate between these patients because it becomes important regarding treatment. There's really the treatment, there's no treatment for AKI, but the treatment for hepatorenal syndrome. There's been studies showing the use of vasoconstrictors in the US. We have no access to turlopressin. We have norepinephrine and midodrine. But the studies again in the literature, as you can see very few, only one study with midodrine octreotide compared to turlopressin. Most of the studies have been turlopressin compared to norepinephrine or turlopressin compared to albumin. All of these studies really, the studies with turlopressin and norepinephrine for the majority have shown no difference. None of these studies have been able to show survival benefit, but there have been studies showing the use of turlopressin compared to albumin that there was a benefit in the use. This is the latest study that came out in the US. It was a multicenter trial in North America, turlopressin plus albumin compared to albumin. What they showed, there was no difference in survival. However, there was a difference in HRS reversal, 29 percent compared to 15 percent. They had about 40 percent had SIRS and ACLF grading. Again, the majority were ACLF one. But patients who had alcoholic hepatitis, who had a lower serum granule, who had a higher MAP, who had SIRS, they tended to respond a little bit better with the use of turlopressin. Unfortunately, the mortality due to respiratory disorders was significantly higher with turlopressin. The risk for this respiratory failure was higher in patients with ACLF grade 3, higher MELD, hepatic encephalopathy, underlying cardiac or pulmonary disease. For this reason, at this time, the FDA has not approved of the use of turlopressin in the United States. What about patients who have ACLF? Well, turlopressin compared to noradrenaline in this cohort has been shown to be beneficial in terms of reversal of HRS and in terms of actually survival of these patients. What about pediatric group? This is the only study looking at turlopressin use. You can see this was on 17 pediatric patients, seven with HRS. Turlopressin in Europe is used for other causes such as variceal bleed and sepsis. You can see here, the patients who did respond, the mortality with HRS-AKI was about 28 percent. There was some adverse events, but again, the patients who had HRS responded much better compared to those who used turlopressin for other causes, including shock. I'm just going to say a few words because you're going to have another lecture after this whether or not to dialyze or not to dialyze these patients. A lot of them end up on antibiotics, pressors, TPN, again, CRT ventilation of the vasoconstrictors don't work. In high mild regions, again, whether or not to offer dialysis is a difficult decision that we face because if we deny a patient, it's a life-saving treatment, but initiation can cause prolongation of their suffering. This is to show that over the last two decades, this is UNOS data which has shown that the number of patients with MELD over 40 is increasing and this increase is most likely patients have probably ACLF3, they have renal dysfunction, and even though their mortality is quite high on the wait list, once transplanted, these patients do extremely well. Again, suggesting that these patients, even though they are sick, tend to do well and it suggests that maybe the MELD should be uncapped to capture these patients where MELD is more than 40 and allow them to be transplanted on a timely fashion. Thank you for your attention. Hi there. My name is Konstantin Karvelas. I'm a professor of critical care and hepatology at the University of Alberta in Edmonton, and today I'll be discussing the use of renal replacement therapy and extracorporeal liver support and acute on chronic liver failure. I have no relevant disclosures. The main objectives of this presentation will be to understand the indications for renal replacement therapy in ACLF, review the evidence for early renal replacement therapy and interoperative renal replacement therapy in the setting of liver transplant in ACLF, understand the albumin toxin hypothesis, which is the basis of many different extracorporeal liver support devices, differentiate between artificial and bio-artificial devices, and finally, review the evidence of extracorporeal liver support and acute on chronic liver failure with some review of studies in acute liver failure as well. We know that acute kidney injury is common in acute on chronic liver failure, and I highlight the most common causes that have been reviewed in the previous talks. Regarding renal replacement therapy, there are general indications that stand not just for acute on chronic liver failure, but other causes of acute kidney injury and other etiologies. But there are also some things that are specific to ACLF, including lactic acidosis, and potentially hyperammonemia. This is the idea of renal replacement therapy not just being for the kidney, but being in fact blood purification. One question is that there are intermittent modes of renal replacement therapy such as hemodialysis, and there are also continuous low-efficiency modes such as continuous renal replacement therapy or CRRT. Intermittent hemodialysis is generally reserved for hemodynamically stable patients, and this is often not the case for somebody with hepatorenal syndrome. In contrast, continuous renal replacement therapy which is lower efficiency, but over a 24-hour period, can be used in hemodynamically unstable patients and generally minimizes solute shifts, hemodynamic changes, and in the setting of acute liver failure may actually mitigate changes in intracranial pressure. Previously discussed, we know the different stages of acute kidney injury in cirrhosis, which has been validated not only in ACLF, but in the general nephrology and critical care literature. It is important to look at the different stages as this has formed some of the basis for determining what is early renal replacement therapy versus the late initiation of renal replacement therapy. Now, while there has been no studies that have primarily looked at the timing of renal replacement therapy in acute on chronic liver failure, there was the recently large START-AKI study which looked at standard versus accelerated initiation of renal replacement therapy in the general critically ill population, of which approximately 300 patients had evidence of liver disease. As you can see by this Kaplan-Meier curve, there was no difference in outcome whether patients are randomized to starting renal replacement therapy with stage 2 versus stage 3 AKI. In summary, there continues to be a significant amount of equipoise with regards to renal replacement therapy in acute on chronic liver failure, specifically with regards to whether any particular modality is better, whether that's intermittent or continuous, or whether it's hemofiltration versus hemodialysis. What I will say is that really the main thing that it likely depends on is the hemodynamic stability of the patient. For somebody that is reasonably stable and potentially not even in the ICU setting, they can probably tolerate intermittent hemodialysis as opposed to somebody who is hemodynamically unstable on vasopressors where they likely need CRRT. The other thing to consider is also the complexity of the circuit with regards to anticoagulation. If you use a simple circuit like continuous veno-venous hemofiltration, often you can get away with no anticoagulation, where if you use a combined modality like hemodial filtration, you might need to use something like regional anticoagulation with citrate. One of the challenges with that is that patients with liver dysfunction do not metabolize citrate well and can get citrate toxicity. The other question that comes up is the use of renal replacement therapy in the intraoperative setting during liver transplantation. This has been studied prospectively with the use of continuous renal replacement therapy in the recent inception study that we published. This concert diagram really just highlights the cautionary tale of how difficult it is to do a prospective study like this. As you can see, given a large number of patients were screened and only 32 were randomized. Of the 17 patients that were randomized to standard of care, seven of them actually crossed over to receiving intraoperative continuous renal replacement therapy. The bottom line from this study is comparing patients that received standard of care, which could have included preoperative renal replacement therapy versus continuous renal replacement therapy during liver transplant. There was no significant differences in renal outcomes or survival post liver transplant. Also want to highlight there have been studies of intravenous hemodialysis used intraoperatively, but this hasn't been done in a randomized fashion. Given this dearth of literature, really the question of preoperative versus intraoperative renal replacement therapy. One question is that if you can adequately clear a patient before going for liver transplant with preoperative renal replacement therapy, i.e. correcting volume overload, acidosis, and reducing serum potassium levels, it may not be necessary to use intraoperative renal replacement therapy. The One caveat to this is an oliguric patient that has significant metabolic derangement may actually benefit from intraoperative renal support. And with regards to whether it should be intraoperative hemodialysis versus continuous renal replacement therapy in ACLF, that largely depends on institutional experience where you are. I do want to highlight that the use of CRRT has benefits in acute liver failure that we do not see generally in cirrhosis or acute on chronic liver failure. And this largely has to do with the fact of ammonia clearance and the correlation between hyperammonemia and the development of intracranial hypertension in acute liver failure. So I just want to highlight in this study that was published back in 2018, from the US acute liver failure study group, that CRRT was associated with a more rapid decline in serum ammonia levels. And this translated to a significant mortality benefit. So this is one of the contrasts of acute liver failure, where there might be a higher degree of reversibility, as opposed to acute on chronic liver failure. And the fact that patients with ALF are potentially at risk of developing intracranial hypertension or cerebral edema. And essentially, it was found that early CRRT in the ALF population is associated with a significant mortality benefit. Takes us to the to the next stage of complexity, which is albumin dialysis. And I want to talk about the albumin toxin hypothesis. And the idea is that most toxins in liver failure are water insoluble, and that albumin binds toxins that accumulate in liver failure, including peritogens and molecules that cause cholestasis, such as conjugated bilirubin and bile acids, as well as some compounds that exacerbate hepatic encephalopathy. And we know that of studies of albumin and HRS and SVP, that the benefits of albumin exceed what would be expected with a simple volume expander. So the basis of albumin dialysis is that blood is dialyzed against an albumin containing solution across a suitable membrane. The rationale for the use of extracorporeal liver support in ACLF potentially would be the reversal of encephalopathy, improvement of hemodynamics, resolution of hepatorenal syndrome, and most importantly, likely bridge to liver transplant. So the first study of MARS, the molecular absorbent recirculating system, which is the widely most widely studied form of albumin dialysis, was published back in 2007. And the study of Hassenine and colleagues demonstrated in randomized, after a randomized study of 39 patients to MARS in standard medical therapy, versus 31 patients that received standard medical therapy alone, which may have included renal replacement therapy, that the use of MARS therapy was associated with a higher rate of two grade improvement in the West Haven criteria in hepatic encephalopathy in the MARS group compared to standard medical therapy. And this was also associated with improvements in biochemistry. However, this study was not aimed or powered to look at mortality. The largest study to look at survival in acute on chronic liver failure with the MARS system was the RELIEF trial. And the first offer was Rafael Barneiras. And this was published in 2013, which was a multi centered European study. And as you can see, and whether you look at the analysis based on the intention to treat, or the protocol analysis, there was no overall 28 day transplant free survival associated with the use of MARS above standard medical therapy. However, it should be noted in in this study, that there were a large number of patients that did not go on to liver transplant. And I suspect that if this study could be done again, it may have been more fruitful to use as a primary outcome as bridge to transplant rather than spontaneous survival as a large number of these patients likely had a poor prognosis in the absence of transplant. Highlighting this reversibility issue in contrast to the use of MARS and acute on chronic liver failure, there have been some studies that have shown that MARS may have a potential benefit in acute liver failure. And I just highlight this recently published propensity matched study from the US acute liver failure study group, where our team was able to demonstrate after adjusting for significant covariates, that MARS was associated with independently associated with improved 21 day transplant free survival in acute liver failure. And this was even after adjusting for the use of continuous renal replacement therapy. And this once again highlights the difference between acute and acute on chronic liver failure were in the setting where there is potential reversibility. And one example of this is an acetaminophen toxicity, there may be a benefit of albumin dialysis, which has been much more of a challenge to find in patients with acute on chronic liver failure where there may not be this reversibility. The other technology that that was developed at a similar time as the MARS system was Prometheus, which is fractionated plasma separation and absorption, which is a slightly different technology where it's the patient's own plasma that gets cleansed, if you will, over two filters. The study design of the Helios trial is very similar to the relief trial. And similar to the other study, there was no survival benefit at 90 days. And this was also hampered by the same issue that the relief trial had where there were only a small number of patients that underwent liver transplantation. Finally, one system that is probably cheaper than MARS and and Prometheus is simple plasma exchange. Plasma exchange to date has only been studied in acute liver failure. And this was the study by Finn Larson and colleagues that showed that the use of plasma exchange in ALF, similar to MARS, was actually associated with an improvement in transplant free survival. And this was largely seen in patients with acetaminophen induced acute liver failure. We are aware that there is an ongoing plasma exchange study in acute on chronic liver failure, the Apache study, which we look forward to the results of this endeavor. So in summary, the results of extracorporeal liver support in acute on chronic liver failure to date has actually been quite underwhelming. And there hasn't been a study to date that has demonstrated a mortality benefit. However, as mentioned, probably a more appropriate outcome in ACLF would likely be a bridge to liver transplantation. In contrast to this, there are some bio artificial liver support devices, one of them being the ELAD or extracorporeal liver assist device, which is based on a bioreactor with hepatoblastoma cells. The most recent study that was published on this was back in 2018, which was done in the setting of alcoholic hepatitis. And as you can see, similar to the results of both the relief and the helios studies, this was also a negative study that did not show a significant overall benefit. So in summary, regarding the roles of renal replacement therapy and extracorporeal liver support in acute on chronic liver failure. First, renal replacement therapy and specifically CRRT in hemodynamically unstable patients should be considered in ACLF patients with severe AKI as a bridge to liver transplant. However, there are still significant equipoise regarding timing of initiation of renal replacement therapy, whether early or late, meaning stage two or three AKI. Modality, whether that's intermittent hemodialysis versus hemo filtration or continuous mode. And finally, what type of anticoagulation. With regards to the use of pre-transplant or intraoperative replacement therapy, larger studies are required. But generally, the time to consider intraoperative renal replacement therapy is in all of your patients with severe metabolic derangement to bridge them through transplant. Artificial extracorporeal liver support systems have shown some benefit in acute liver failure. We know that early CVBH or CRRT in ALF is associated with improved outcomes in acute liver failure, as is plasma exchange and potentially MARS as well. However, we have not seen the same benefits of these extracorporeal liver support devices and acute on chronic liver failure. Specifically, no study to date has demonstrated an improvement in transplant free survival and acute on chronic liver failure. And future studies should focus on ECLS as a bridge to transplant in ACLF. And I thank you for your time. And I would look forward to your questions at the end of the session. Thank you, everyone. The next part of this session will be an interactive session where we will have a series of case presentations from both adult and pediatric fellows, which we are hoping will stimulate some discussion among our panelists amongst these cases. Our first presentation will be done by Dr. Sarah Wang, who's an adult hepatology fellow at the University of Alberta in Edmonton, Canada. Okay, great. Thanks very much for that introduction, Dr. Cavales. So I will be presenting the first case, which is going to be focused on the management of AKI in the setting of acute on chronic liver failure. So this is a 47 year old gentleman who has been referred to hepatology with a recent diagnosis of decompensated cirrhosis. His cirrhosis is due to alpha one antitrypsin deficiency, which has been proven on biopsy, but that's also been confounded by a history of significant alcohol use. Thankfully, he's been abstinent from his alcohol consumption since his diagnosis of cirrhosis. His course of cirrhosis has been complicated by ascites, for which he's controlled on spironolactone furosemide. He also has evidence of grade two varices on his screening gastroscopy, and he's placed on cravatolol for primary prevention of bleeding. And the plan for him at initial assessment was to get him referred to an addiction specialist and to consider liver transplantation. As you can see, his baseline MELD score is quite high at 25. Unfortunately, one month after his initial assessment, he had to be admitted to hospital with an episode of spontaneous bacterial peritonitis complicated by E. coli bacteremia. This also triggered some new hepatic encephalopathy. His infection encephalopathy was treated appropriately, and after three weeks, he was able to be discharged home. We can see that he did suffer some deterioration in his liver function, and MELD score is now at 28. Since being home, unfortunately, he continues to have clinical deterioration. He's been getting more fatigue, nausea, and progressive anastarka. And so he had to represent himself to the emergency room. Over this course of four weeks, he continues to be absent from alcohol. So now he's about the six-month mark from his last drink. On presentation, he was afebrile. However, his blood pressure was low with sisalic in the 90s and disolic in the 40s. On exam, there's evidence of jaundice, he had ascites, and significant bilateral putoedema. He also continued to have some mild hepatic encephalopathy. So this patient was admitted to hospital for infectious workup, which has turned back negative with no evidence of SVP recurrence. There's negative blood cultures and no other source of infections found, and he's otherwise not accepted clinically. What is concerning now is that he has had significant deterioration in his renal function. We see that he now has hyponatremia with a sodium of 123. His crown is more than double his baseline, and his liver function continues to deteriorate. At this point, the team stopped his diuretics and his Corvetolol and put him on standard treatment, mitodrin, albumin, and octreotide, in the hopes of expanding his intravascular volume and improving vasocirculation to the kidneys. We see that over the course of his admission, he did not respond to this treatment of mitodrin, albumin, and octreotide. By day four, he continues to have significant hyponatremia, and he's developing hyperkalemia, and his crown is now almost five times his baseline. Liver function continues to deteriorate. This is the point where he continues to have low blood pressures, systolic still in the 90s despite mitodrin, and he's becoming aneuric. At this point, the community center gave our center a call. Can we transfer this patient for a liver transplant evaluation, and maybe even dialysis? I think overall, this case brings up a couple of important questions. To summarize, this is a 47-year-old male. He has decompensated cirrhosis from alcohol and alpha-1 antitrypsin deficiency. He's been abstinent from alcohol, but he did develop acute on chronic liver failure with an episode of SVP and E. coli bacteremia. He now has aneuric AKI and is waiting for a liver transplant assessment. So the question regarding this management of his AKI is, should this patient be admitted to the ICU? Which phaser pressure should be used in this scenario? Is there one with the best evidence? And what is the role of continuous renal replacement therapy in the setting of renal failure and acute or chronic liver failure? Is there a role in CRRT as a bridge to transplant? So I will stop the case here for discussions. Thank you. So next, I'd like to introduce Dr. Julia Boster, an instructor in the Department of Pediatrics at the Children's Hospital of Colorado. She recently completed her pediatric transplant hepatology fellowship in July of 2021. And she will be presenting our case of pediatric acute on chronic liver failure for the following case discussion. Thank you so much for having me. I'm excited to present to you guys a case today of an interesting case of acute on chronic liver failure in a pediatric patient. I have no disclosures. This is a five-month-old male with a history of biliary atresia who underwent underwent caci hepatopoietic enterostomy at about two months of age without establishment of good bioflow. In addition to that, he had growth failure despite nasogastric feeds and was listed for a liver transplantation with an exception pelled of 30. He was undergoing a planned admission for initiation of parenteral nutrition and PICC line placement due to ongoing severe malnutrition, despite NG feeds, which were difficult to optimize due to intolerance characterized mostly by vomiting. He was admitted and on hospital day one underwent PICC placement under general anesthesia, which was without complication. However, that evening, he developed progressive irritability and really became truly inconsolable. Labs were obtained during that time period, which demonstrated a rising INR up to 2.2 from a baseline of a normal INR and a normal ammonia at that time. He had a chest x-ray to confirm appropriate location of the PICC line, which did indeed show appropriate location, had an abdominal ultrasound with Doppler, which showed no significant ascites, no abscesses, and patent vasculature, namely a patent portal vein. He had infectious studies done at that time, as well as a CBC, CRP, and procalcitonin, all of which were normal. However, given the unclear trigger for his decompensation was started on broad-spectrum antibiotics with vancomycin and muropenem, and he remained afebrile throughout his hospitalization. He had blood and urine cultures that were all negative and had a series of viral testing, which broadened as his course progressed, but which were all negative, including SARS-CoV-2 testing, respiratory pathogen panel, stool pathogen panel, serum HSV, parvovirus, EDV, CMV, adenovirus, and hepatitis A PCRs, all of which were negative. Additionally, he had a Tylenol level, which was undetectable. He was given vitamin K to ensure that this was not a vitamin K responsive coagulopathy, and his INR did not improve with that. And he was transferred to the ICU for progression of liver failure with concern for worsening mental status and encephalopathy. To compare his labs at baseline to his labs during this hospitalization, pre-admission, he had a total bilirubin that was somewhere between seven to nine milligrams per deciliter, with a direct bilirubin that was around two to four. And his INR was normal prior to this with a creatinine that was low at less than 0.15. On admission to the ICU, you can see that his total and direct bilirubin were around his baseline. However, his INR had gone up to 2.2 and over the course of about 48 hours had climbed to 3.8. And his creatinine had increased slightly to 0.21 milligrams per deciliter. From a neurological standpoint, he had a head CT, which was normal, and he developed grade two encephalopathy characterized by irritability, hyperreflexia, and an EEG which showed diffuse moderate background slowing. His ammonia rose over the course of about two days up to 90 to 120. And that was still true after starting him on oral refaximin. From a renal standpoint, he did have decreased urine output initially and had some fluid overload, however, was nicely responsive to Lasix in terms of both his fluid status and his urine output and was placed on a Bumex drip. He did develop metabolic acidosis in the setting of some aggressive diuresis, however, had no other electrolyte derangements, and the metabolic acidosis improved with transition from loop diuretics to acetazolamide and chlorothiazide. And he maintained good urine output with a urine output over 1 cc per kilo per hour and had a stable to improved fluid status. From a cardiovascular standpoint, he had very mild hypotension, which improved with a low dose dopamine drip, and had an echocardiogram which showed normal biventricular size with some hyperdynamic function. From a respiratory standpoint, he was intubated, but the primary motivator for that was for procedures, namely imaging, but was on really minimal vent settings and was oxygenating and ventilating well. And then finally, from a hematology standpoint, his INR rose to the high threes, as aforementioned, and he had some mild oozing at points of vascular access, so no apparent GI bleeding or pulmonary hemorrhage, but did ooze from vascular access despite getting 20 per kilo of FFP. So based on all of that presentation, he was upgraded from an exception PEL to 32 status 1B listing due to the concern for acute on chronic lipar failure. So I think there are a lot of different discussion points with this case. I think the one bigger picture question is, is this acute on chronic liver failure? And if you say yes to that answer, what is your working definition of acute on chronic liver failure in a pediatric patient? And what about this case makes him qualify for ACLF? And from a renal standpoint, when would you be thinking about starting renal replacement therapy in a patient like this? And how do you make the decision to start CRRT in this type of case? And then to follow that, would you consider any other type of extracorporeal support? Things like plasma exchange or MARS. To remind you, this patient is maintaining appropriate urine output. He's diuretic responsive. He's not yet in renal failure, however, is persistently hyperaminemic and has some ongoing fluid overload and is likely progressing relatively rapidly to liver transplant. And then finally, a question that still eludes us, what was the trigger for his acute decompensation? What do you think pushed this child over into having acute on chronic liver failure? So we'll open it up to discussion now at this point, thank you. Thank you all. My name is Jasmohan Bajaj, and I'm honored to co-moderate this exciting session with Dr. Ng, who is our pediatric hepatologist. I thank Dr. Wang and Dr. Boster for these excellent presentations, and also the other speakers and panelists who will actually be joining us for these discussions. So there are certain cases presented, a question posed for Dr. Wang's case. And my first question to everyone is, should this patient be admitted to the intensive care unit? Maybe Dr. Carvelas can start. This is the adult case. Yes, and something that Dr. Nadeem highlighted was that, fortunately, we don't have terlopresin available in North America, and we get limited benefit with mitogena noctreotides. So generally we take these patients to a monitored setting where we can run intravenous norepinephrine or vasopressin. That would kind of be what we would do. Okay, you did jump to question number two, but that's perfectly fine. We are short of time. So Dr. Nadeem, Dr. Kamath, and everyone else who is on the other panelists, would you want to weigh in on the need for the intensive care unit, which seems pretty obvious in this person. But what about the vasopressor requirement? Yeah, so vasopressor stress is often determined by the comfort of the patient of the ICU physician. I think they would typically go for mitogena noctreotide, but this patient has already been on that. So we would try norepinephrine in this patient. So there was some provocative studies from Stanford also that norepinephrine was given outside the intensive care unit also in these patients. So Dr. Nadeem, do you have any, as a board certified nephrologist, do you have any input as to what would be the reason why one would prefer this short of, this guy is kind of on the borderline. It's not someone who would normally require the ICU beyond this kind of situation. Well, actually, you know, I would actually argue that he does need ICU, not so much for the norepinephrine because if I, I miss his blood pressure, but I think he had anisarka, you know, the rate of rise of creatinine, you know, it's safer to put them in the ICU for CRT for removal of that fluid. Because at the end, if you think they're a transplant candidate, you still want to protect that kidney. So you don't want these like harsh, you know, hemodialysis and fluid removal during dialysis. The issue with the moving them to the ICU only for norepinephrine, you know, at our center, it's impossible to get an ICU bed. It's just becoming very difficult. So to, to, you know, send a patient to the ICU only for HRS norepinephrine is close to impossible. Regarding Ray Kim's study, yes, it was interesting. However, if you look at it, there's what, what they call this floor patient was really not floor patient. It was a step down, step down, even step down, they were monitoring the vitals every 15 minutes, which is not what we do in a step down unit. It was very, very specialized. And even that they had about 25% complications from the use of norepinephrine. So I think it's, you know, not as, you know, step down is usually, you know, one nurse for four patients, you know, but not every 15 minutes of following. So I still think it's going to be very difficult to push that in the U.S., you know, institutions to give norepinephrine even in the step down at this point. So you would give him CRRT? This patient, but from what I remember, the rate of rise of that creatinine and the anisarca it for, for me would be definite because I know the direction that patient's going to go. And the minute they get intubated and fluid overloaded from that, it becomes very difficult to extubate them. And this is kind of a precarious situation because the transplant workup is not completely complete at this stage and they're trying to get there, get it done. So yes, at this point we want this patient conscious, able to do what, because the next shoe to drop is either fluid overload or hepatic encephalopathy, and this is currently only in mind when they can't make their own decisions at that point and give a proper history, it becomes the transplant surgeon's anxiety becomes higher and higher and higher. If I could make a comment, I would say this too, that I think also, you know, at the very least, you know, you can buy yourself time, at least by at least getting them on pressers and pushing up their map because that's the other thing is we'll target a map of 75. I think it's one other thing to know that whether you use Levo or vasopressin or both, it probably doesn't matter. There's no real data to suggest to go one way or the other. And I will say that probably the bigger issue is if you are going to consult ICU on a patient like this, if you do do it too late, and we understand that, that Mitra's point and also in the middle of the pandemic, where there's ICU capacity strain, the problem is that if you were, if you were for somebody already in their creatinine is 4.0, it's very hard to salvage some of these people with vasoconstricting therapies, where maybe if you caught them with with, you know, a creatinine of 2.5 or something, that you might be able to turn this around a little bit earlier, where really at that point, if it's too far gone, you're really heading towards RRT. And if you remember the Wong study, the confirmed trial, at some point of the creatinine ceiling of five or so, I think it was, the early person was no longer affected, given that you kind of like reached that point. So I think this case is perfectly poised for us to actually create a lot of, you know, a path forward. Hopefully this person is a candidate for transplant, because that's where a lot of these things hinge. Are you sure? You know, I'm not absolutely sure this is HRS AKI. This patient has had SBP, has had worsening renal function after that. I did not see the urine sort of parameters, but he may be somewhere in between, but we're never sure. And so the aggressiveness with which we consider CRRT depends on what the diagnosis is and whether they're a transplant candidate. If they're not a transplant candidate, then CRRT becomes sort of less attractive. If it's AKI, even if this is not a transplant candidate, yes, we'd be a little more aggressive with CRRT. So my question to Dean and Nadim, are we sure this is HRS AKI? I guess... Sorry, go ahead. Go ahead, Dean. I think the philosophy of the case is really it was leading a case of HRS that was triggered by SBP, and obviously that was part of the formulation. But really, I think also the idea is twofold, that you have whether this patient is HRS triggered by SBP and now has hypotension, or this is a patient that is hypotensive with septic AKI. Probably them sitting on the ward with a systolic blood pressure of 75 or 80 is probably not a good idea either way. So I think where you could argue is, do I target a MAP of 65 with pressors or a MAP of 75, is really kind of the bigger question. And if we think this is truly HRS AKI, where really the therapy is vasoconstrictive therapy, we'll target the higher mean arterial pressure. And I will say, I'm hoping in the future that if we're lucky enough in the next six months to have turlopressin approved in North America, that potentially a lot of these consults coming forward will be turlopressin failures. So they've tried turlopressin on the floor, rather than a mitodrin and octreotide failure, if you understand what I'm saying. I think Patrick's point is very well taken about needing muddy brown casts and excluding all of those to make sure that we have... We go in with our eyes wide open. If it's not really HRS AKI and we are flogging other things that may not necessarily be directed in the problem. But I think this case is perfectly constructed, although that one month between the SBP and now makes it a little harder for us to even conclude PPCD or something related to the SBP itself. But it's clear that this person is not headed down a good path in the current situation without any critical care. I think, have we reached the 10 minute point for our... Yes. So I hand it over to Dr. N to go over the pediatric questions. Thank you very much, Dr. Bajaj. And I think we'll swing over to the left end of the age spectrum with our five-month-old biliary atresia patient. And I just wanted to ask why our adult speakers who gave excellent talks to please stay poised and we'll ask you guys a couple of questions as well. So I'm going to ask the first question to Dr. Banks-Hussou. How does this five-month-old biliary atresia patient presented by Dr. Boster qualify in your minds as a diagnosis of acute on chronic liver failure? And perhaps I can also get you to draw a mention to your proposed novel definition. Absolutely. So I think the case that was presented by Dr. Boster is a great example of a very common patient that all of us as pediatric hepatologists come across every single day in the ICU. And as mentioned in my talk, we don't really have a standard definition of ACLF in children. But clearly this patient is critically ill. He's intubated on a little bit of dopamine, creatinine is rising. He's experiencing fluid overload, requiring diuretics to maintain adequate urine output. So clearly the patient is critically ill. And I think, you know, as presented the pediatric CLIF SOFA criteria really nicely has adopted a lot of the organ failure criteria specific to children to identify organ failure. And I think if we use that particular table, this patient would qualify based on the fact that they are on a little bit of dopamine. They're mechanically ventilated, although I think Dr. Boster nicely highlighted that the intubation was for procedures and they're in minimal vent settings, which is one of the dilemmas that we often come across in children. And you know, based on the creatinine value, you could potentially say it's one to two times the upper limit of normal. So possibly even based on the information that we have, this patient could qualify based on having three extra hepatic organ failures. And I think, you know, as highlighted, our goal is really to identify children who are at highest risk of mortality. And we know this patient is there already. And that's why even as part of the case and being in the ICU, being intubated already gives him higher priority for transplant as the patient was listed status 1B. Thank you. Dr. Kamath, do you have anything additional to add with regards to this young infant? Yeah, two things. Thank you. So this kid is at high risk of mortality. So that's clear. What we call this is right now probably not changing what we're going to do for this kid. So again, that's where we come into the philosophical issue of definition. We're taking a high risk for mortality. Six organ failure clearly is at high risk for mortality. But if we define ACLF as potentially reversible, then we need two factors in there. Who's at high risk for mortality? So what are the criteria for that? But also who is potentially reversible? I think that has to be factored into the definition and we don't have that as yet. So we can call it whatever we want. It's only an interim definition. In terms of etiology, there is the King's College study from Anil Dhawan on what ACLF as they defined it, but vascular complications are almost in 20% of patients. So when kids deteriorated and you didn't know the cause, they found a vascular event. I'm just wondering whether this child has a vascular event. So that is either they even had hepatic arterial thrombosis, which was not acute, they had venous outflow obstructions. So they thought that contributed, there was small vessel disease equivalent of veno-occlusive disease. So there's something in addition, so I'd consider two additional etiologies in this child for the deterioration. One is it is something vascular or it's considered drugs. We never know about these things, what complementary medicine or something else may have been tried. Those are excellent points. Thank you so much. And I think absolutely, these children all are on polypharmacy and while they may be agents that we're relatively used to, there's definitely always potential contributions. So those are excellent points. But I think the key is actually just being aware of the fact that this child is critically ill and it's more than just a hepatic decompensation and really the mindset of pediatrics is really to move towards supportive therapy. So as we move to the next question, if I can ask Dr. Gengkusu to also comment, what would be your threshold to initiate a renal replacement therapy and are there any potential other options either pre, during or post this sort of in complementary form? Thank you. I think that's an excellent question and one that we always sort of encounter every day in taking care of our patients. At least here at our center, very classic reasons to put a patient on CRT would be fluid overload. And I think from what Dr. Boster presented in this case, this patient was fluid overloaded, but is responding to diuretics. So we would probably, and I would probably recommend continuing to try diuretics if you are able to continue to have adequate urine output and every single day you're net negative and able to improve your fluid overload, especially if it's impacting your ventilatory status. I think, you know, the big question is when should you initiate CRT outside of fluid overload? One of the conditions that also we sort of discuss is hyperammonemia. This patient was having high ammonia levels, but was just on rifaximin therapy and should you consider maximizing oral therapy with lactulose to see if that helps in terms of the hyperammonemia. And I'm curious, you know, that's sort of our perspectives from pediatrics, but I'm curious how the adults would approach this case as well. Dr. Kovalos, I was going to hand the mic over to you. What are your thoughts? I think it's interesting because I, you know, the differentiation between ALF and ACLF is a lot more clean in adults where I think it's a little bit more nebulous in the pediatric population. I think for the, the only thing I will say is, because normally in, you know, in a true ALF patients, things like lactulose and rifaximin don't help you much. This is a very different situation because biliruotrigia, this has been going on for quite some time. One comment I will make is if, if there are concerns about the gut and bowel distention and things like that, then another alternative is also we, like there's no studies in kids, but in adults there have been studies with even just using polyethylene glycol, because you don't get the, you don't get the gut distention. I think also the, the, you know, it's tough to get data in adult populations and it's even more difficult to get, get them in pediatric populations because the, the, the denominator is smaller. So I think it's going to be, it's tougher to come up with a, with a CRT study per se. And also, like I said, it's really this crosstalk where truly where, where CRT probably has its most benefit is if it's probably more of an acute than an acute on chronic and you're looking at both inflammation and hyperammonemia. Right, right. That's great. I might just also extend that comment because the third question Dr. Foster had brought up the question of Mars, and I think that's also perhaps sort of, and would you, do you have any additional comments? Maybe I'll ask Dr. Covellis back. So that's also, and I know that we get a lot of questions about this and so that, you know, truly the best data for extracorporeal support, Mars or plasma exchange has been in the adult ALF population. And as we kind of talked about that, it's been a real gray area in ACLF. One of the criticisms of the ACLF studies is most of them use survival transplant, free survival as the outcome, or perhaps bridge to transplant is also probably a positive outcome, not a negative outcome. And I think you could, if, you know, if I was to design the, the relief trial and the, and the Helios trials, again, I probably would have used bridge to transplant as the primary outcome. You wouldn't put somebody on Mars or, or Prometheus or plasma exchange. If there wasn't the, the out of a transplant, you wouldn't do it for somebody who wasn't a transplant candidate. So I think, you know, we really don't know where the, where the goalposts are in ACLF. You know, where I can say anecdotally where, where things like Mars and plasma exchange help with is, is I agree with hyperammonemia if this is a big issue and also with vasoplegia, if you want to improve somebody's you know, if you're pulling off a whole bunch of cytokines that are contributing to vasodilatory shock. So if that is the setting, you know, you, you could consider it. It's just, I can't give you a, a, you know, a well-done study that's going to show the benefit. Okay. Well, thank you very much. I'm just very incredibly mindful of the time we're two minutes past. So I think actually Dr. Kamath had already nicely kind of gave a couple of clues for the last question about potential contributions. I think that's actually very brilliant. And so I may just actually take the moderator, a co-moderator's prerogative to conclude the session to thank our speakers for four absolutely fantastic talks and really just encourage everyone to come back for part two of this combined pediatric and chronic liver failure stick after the break, have a good day, everyone have a nice break rather we'll see you soon.

Dr. Konstantin Karvelas

management strategies

acute liver failure

chronic liver failure

ASLD liver meeting

liver transplantation

acute on chronic liver failure

ACLF

renal replacement therapy

extracorporeal liver support devices

liver-kidney dysfunction

biliary atresia

pediatric ACLF