Hello, everybody. Thank you for being here. This is the second part of our combined ACLF SIG session. So today, we're going to have four more speakers. And we'll do the same thing as we did in the morning. We'll have to present in an hour and a half. And then we'll open up questions at around 12.15. And then we will have our business meeting at 12.30. We're having a small technical issue here with our first presentation. So give us one second. So our first speaker today is going to talk about kidney failure in ACLF. Dr. Mitra Nadeem, who was supposed to give this talk, is out sick. And so we are fortunate to have Dr. Francois Nourand from Hôpital Bigeon in Clichy in Paris, who's also a well-known expert in this topic. So please, Chouth, thank you. So sorry for the inconvenience. I will try. I will do my best to be at the level of Dr. Mitra Nadeem. So we are talking today about, I have no disclosures, about acute and chronic liver failure and the kidney. First, you see that there are different definitions of acute and chronic liver disease, European, which is relatively ancient now, which is called the easel cliff criteria, an Asian definition, and a North American definition. And in all those definitions, there are criteria to define AKI. And in all these definitions, the definition of AKI is different. The most simple is the North American one, which is RRT versus no RRT. It is simple and pragmatic. And in all the definitions of ACLF, the kidney function is mentioned except in the Asian Pacific definition, which only takes into account liver failure and ascites and encephalopathy, but no kidney function. So it's sometimes difficult to compare different publications coming from different areas. So let's go to the definition of AKI. We tried to change the definition of AKI in cirrhosis to stick with the CATEGO recommendation and the nephrologist's world. And now there is agreement that AKI is defined by an increase in the serum creatinine by 0.3 milligram per deciliter within 48 hours, or an increase by 50% in serum creatinine by seven days. Urine output was deliberately not included in the definitions because cirrhotic patients are known to have low urine output at baseline. And urine output can be modified by diuretics. But we restored urinary output in the latest definition based on the finding that it has a strong impact on the outcome. And the next step is to identify within patients with AKI in cirrhosis those who have hepatorenal syndrome, termed HRS-AKI, because HRS-AKI corresponds to a phenotype which is specific of cirrhosis with ascites, portal hypertension, increased asplenic volume, and decreased central volume with an activation of the renin-endotoxin aldosterone system and kidney vasoconstriction. So there is also a definition of AKI, a diagnosis of cirrhosis and ascites, a diagnosis of AKI according to the criteria that we have mentioned, no response to two consecutive days of diuretic withdrawal and a plasma volume expansion with albumin, an absence of shock. This is important because in patients with shock, the issue is not the asplenic vasoconstrictor but treatment of shock. And patients with HRS-AKI can have associated conditions, including ATN. So in patients with acute and chronic liver failure, we can see different profiles, different phenotypes of impaired kidney function. First, we have patients with normal kidney function at the baseline, an increasing number of patients with CKD. And either in patients with normal kidney, they can develop AKI or HRS-AKI, a very uncommon form, which was termed HRS type 2, which is a more chronic form. And patients with baseline CKD, of course, can also develop AKI superimposed to CKD or HRS-AKI. And it's important, again, to identify patients with AKI because they should be treated with asplenic vasoconstrictor, which is specific of this condition. So it's important to recognize AKI and CKD in patients with ACLF in the pre-transplant setting because there are interactions between the kidney function and the MELD score. HRS diagnosis and treatment, drug dosing, RRT initiation and liver transplantation versus simultaneous liver and kidney transplantation. It is also important in the post-transplant setting for CNI minimization or renal preservation strategies. So the first important point is that serum creatinine is misleading in cirrhosis. It tends to overestimate glomerular filtration rate. You can see here an example of three patients, one to three, with their respective serum creatinine level, 0.89, 0.66, 3.21. Serum creatinine is bounded for two to one in these two patients for calculation. And we know that based on several series that patients with normal serum creatinine can have a markedly decreased glomerular filtration rate. So you can see here patients will have a value of one, but with very different GFR, 91 versus 34. And here are patients with high creatinine level and a low GFR. The important point is that these two patients with a similar GFR will have very different MELD score, 30 in one patient versus 13 in the other one, which makes that there is some sort of injustice when you use serum creatinine alone. And these two patients with some creatinine of one all have the same MELD score while the GFR is very different. The second point is bilirubin, because there is an interaction between bilirubin and any method to determine serum creatinine concentration. You can see here a single patient with different methods to measure serum creatinine. And the higher the bilirubin level, the higher the fluctuations in serum creatinine level. With one method here, you can have GFR of 221 and creatinine level of 146. And with another method, creatinine of 228, which makes a big difference. So bilirubin is a confounding factor. Now, all the equations to evaluate EGFR in patients with cirrhosis are also biased. One of the best one is the GRAIL equation. And the mortality predicted by this model in comparative EGFR has been evaluated in a large population of patients. MELD-GRAIL-NA was the better predictor of observed mortality at higher scores. You can see here observed mortality, predicted mortality with the MELD-GRAIL score, and predicted mortality with the MELD-NA, which is underestimated again. Now, we go back to these different phenotypes of patients. In ACLF, some patients have a septic shock requiring norepinephrine. Of course, there is no place for a splenic vasoconstrictor. So we will not talk about HRS in this HRSA-KA in this population. The important population is here, because this patient should receive splenic vasoconstrictor. And the best one is telepressin. So we have now several control studies showing the superiority of telepressin over placebo. And this is one of the latest one, comparing telepressin to placebo with a higher rate of response, which is a reversal of HRS here in the telepressin group versus the placebo group. The problem is that in this study, a null definition of HRSA-KA was used with a high level of serum creatinine. And we know from other studies that the higher the creatinine at baseline, the lower the rate of reversal of hepatorenal syndrome, 50% for patients with serum creatinine below 3% compared to only 10% in patients with baseline creatinine over 5%. So how to differentiate HRSA-KA for ATN? There is no miracle-matic tool. FENA can be one of these tools. You can see here differences in the FENA in patients with pre-renal azothema, patients with HRS, which have a lower value, and patients with ATN. So this is a way, but there is a significant overlap between the different groups. NGAL, which is a marker of tubular cell injury, is another attractive biomarker, because NGAL is significantly higher in patients with a diagnosis of acute tubular necrosis as compared to patients with a diagnosis of HRSA-KA. And this is true at day one, and still true at day three. And the threshold value has been determined to differentiate patients with ATN versus patients with HRSA-KA. The same results have been observed in US population here. You can see on the top in blue patients with a diagnosis of ATN versus patients with HRSA-KA who have higher levels of urinary NGAL, and a cutoff value which is very close to that which has been observed in Europe. So NGAL is interesting, but in all of these studies, the diagnosis of ATN was based on clinical data. There was no biopsy data, of course, because in these patients, biopsy is really impractical. There was a significant overlap between HRSA-KA and ATN, which can be observed in this figure. And it's probably due to the fact that the patients with HRSA-KA and ATN represent a continuum rather than two distinct entities. It is plausible that patients with a prolonged HRSA-KA and kidney hypoxia develop, in the end, acute tubular necrosis. So it is questionable to decide telepression versus no telepression based on these biomarkers. Next, the issue of renal replacement therapy. It's a complex decision which is based on biochemical values, the onset of symptoms and manifestation on cephalopathy, fluid overload, and also transplant candidacy. So this is a typical scenario in the ICU. You have a patient with ACLF and a high MEL score. Should we dialyze? Should we not dialyze? Should we use ventilation, antibiotics, vasopressor? This is a daily discussion that we have in the units. We have a number of studies focusing on when to initiate renal replacement therapy in the general ICU population, generally negative. But the problem is that the proportion of patients with liver disease in these studies was very small, for example, 11% only in one of the latest studies in the field. So we have a recommendation. And we did recommendation during a multidisciplinary, following a multidisciplinary workshop a few years ago and recommended that RRT should be considered even in non-oliguric patients if the daily fluid balance cannot be maintained as even or negative, because it is very difficult to obtain volume depletion in these patients with diuretic alone. And the second point is that RRT should be anticipated in patients with sometimes mild metabolic changes because of the risk of encephalopathy. So my take-home message is AKI is common in ACLF. And serum creatinine and GFR are as misleading as you have seen, as both of them tend to overestimate to GFR. Early identification of HRS-AKI is an important point, because in this group, telopressin is justified. Biomarkers are not perfect, and you always have to think about the phenotype of the patient. The earlier, the better for introduction of telopressin. And telopressin should not be considered as a cure, but rather as a bridge to transplantation, because if the patients are not transplanted, the prognosis is very poor. Renal replacement therapy trial is justified in candidates for transplantation in patients with fluid overload, because they are poorly responsive to diuretics, and patients with metabolic changes, because metabolic changes can trigger encephalopathy. And AKI is not a contraindication for transplantation. It's ACLF. Even if we do not have good markers for reversibility with liver transplantation alone, and we always have to think about underlying CKD, which precludes renal recovery after liver transplantation alone. And here is a group of experts who met a few months ago in San Diego on behalf of the ICA, International Club of Scientists at AITCHI for the kidney, and representatives of hepatology, nephrology, critical care, and surgeons also, to try to redefine the diagnostic criteria for AKI in cirrhosis, and to make recommendations for the management of these patients. And I hope that the manuscript, we are in the process of finalizing the manuscript, and I hope that it will be published in the end of this year or next year. Thank you for your attention. Thank you. Thank you. We'll hold questions to the end, and we'll have a panel discussion at the conclusion of our talks. Next, we'd like to welcome Dr. Jackie O'Leary from the University of Texas Southwestern to speak on sepsis and septic shock in acute and chronic liver failure. Thank you. Wonderful, wonderful. Thank you very much for this opportunity to present to you today on septic shock in acute and chronic liver failure. The definition of sepsis actually did change in 2016. And sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. And septic shock is when sepsis is present with a lactate in the serum of greater than or equal to 2 millimoles per liter and a presser required to keep the mean arterial pressure greater than or equal to 65. And the SOFA score is often used to evaluate it. And then we'll go to my next slide. And the most common cause of ACLF is infection. And meta-analysis does show that patients with cirrhosis who develop an infection have a fourfold increased risk for death if they develop an infection. When we look specifically at the mechanism that underlies ACLF, there are numerous factors that are upregulated as well as downregulated. And we can't measure most of those. But ultimately, overall, bioenergetic failure and systemic inflammation underlie ACLF. And so it would be nice to be able to have a simple and easy tool to look at both the bioenergetic failure and the systemic inflammation. And so at this time, we're sort of stuck with lactate. And in our patients with cirrhosis who develop a requirement for admission, MELD lactate does definitely predict inpatient risk for mortality better than other MELD scores. And when the lactate goes from 1 to 7, as a matter of fact, the risk for death increases by almost fourfold. And that is because lactate level is a combination of two factors. Number one, production, and in this case, would be from underperfusion, most often from septic shock, combined with the need for elimination, which is going to be dependent on liver function. And so that is why this is so helpful. When looking at another lab test that might be clinically applicable in ACLF, we have a recent study, of which there's actually more than one, looking at the role of CRP. And in 170 patients with acute decompensation that were hospitalized, the two predictors of whether they would later go on to develop ACLF were CRP and the CLIF C-Acute Decompensation score. And CRP is really a crude marker of systemic inflammation, which is inexpensive and widely available, but certainly doesn't tell you about what's causing that. So looking at a little bit more of a granular level, in Naxled, we looked at 602 admitted patients without ACLF on admission and did serometabolomics. 15% of the patients later went on to develop ACLF. And independent predictors of ACLF development were, in fact, a lower level of endopropionic acid, which is a stabilizer of the intestinal barrier, decreased microbial metabolites of phenylalanine and tyrosine, which promote local immunity, and decreased levels of phospholipid moieties, which do improve the integrity of the cell membrane, which essentially tells us that the patients that went on to develop ACLF, most often from sepsis, were all a setup for bacterial translocation, chronic inflammation, and infection. So infection is an integral part of sepsis and septic shock. And that is why all admitted patients with cirrhosis do require a full infectious workup the minute they hit the door, which should include two sets of blood cultures, urinalysis, urine culture, chest x-ray, a timely paracentesis, an inoculation of that fluid at the bedside. And then in patients where you do suspect infection in a higher rate, or those with GI bleeding, they need to receive their IV antibiotics in a very timely fashion. And you're going to choose those based on the type of infection, severity of infection, local resistance patterns, and mode of acquisition. And we're going to try very hard to decrease the risk for nosocomial infections by avoiding PPIs when not absolutely indicated, and Foley catheters when not absolutely necessary. Because once infection starts, it can become out of control and develop sepsis, which is when fluid resuscitation is often required. And this data comes out of the non-cirrhotic literature. But in 23 trials in over 14,000 patients, the best fluid resuscitation that can be utilized to improve mortality was balanced crystalloid. When we turn our attention in sepsis to patients with cirrhosis, 5% IV albumin was compared to saline in an open-labeled trial of 154 patients. And there was improvement in hypotension reversal in the albumin group at one hour, as well as improved one-week survival. So this can be used as well. But in another trial of IV albumin versus plasmolyte in sepsis in patients with cirrhosis with a primary endpoint of a mean arterial pressure greater than 65 at three hours, 20% albumin was superior by almost threefold at achieving that endpoint, as well as a more rapid normalization of arterial lactate. But IV albumin patients did have to discontinue therapy for adverse events in almost a quarter of patients. So then we turn our attention to the dose. So IV albumin was dosed at 0.5 to 1 gram per kilo over three hours. Certainly in Texas, that would be a lot. And plasmolyte was less. And overall, there were no differences in mortality. We all are probably familiar with the data looking at IV albumin for decompensated cirrhosis to prevent new infection, AKA our death, and 3 to 15 days after treatment where there was no difference in this outcome. However, there was an increased risk for pulmonary edema. So when we use IV albumin, do remember, not everybody needs IV albumin. The dose definitely matters. And too much is definitely harmful. And when doing trials, this study endpoint was incredibly difficult to meet. But there may be additional benefits to IV albumin that we hadn't thought of before. And that is, there's this interesting article that came out in RATS. And I don't often present on that to a clinical audience. But cardiac function and fluid challenge did matter. And these cirrhotic rats who had ascites and received a fluid challenge actually had improvement in cardiac function if they received albumin, which was not found in patients sorry, rats who received saline. And there are no rat patients in my house. Or starch. And so I think that we need to potentially focus a little bit more on cardiac function in the patients with septic shock. And so in conclusion on IV albumin, IV albumin has several beneficial effects beyond oncotic pressure. But we need the Goldilocks approach when administering IV albumin. Because too little may be problematic. But certainly too much is also problematic as well. So in volume management and septic shock, we do need to make sure that we have a baseline volume status, intravascular, not necessarily extravascular. Probably a bit more attention on cardiac function, as so many of our cirrhotic patients have mass old and diastolic dysfunction and potentially cardiac complications, even of cirrhosis. And then assess early fluid responsiveness and then reassess. Our cirrhotic patients in decompensated disease are hyperdynamic with lower SVR and increased cardiac output. And so POCUS may be of greater utility in ICU management over time. So fast volume resuscitation is needed, followed by reassessment. And this can and should be done with ideally balanced crystalloids with or without IV albumin, in addition to stopping diuretics and non-selective beta blockers. And then determining whether the target mean arterial pressure has been achieved. So in conclusion about volume management, timely fluid resuscitation and septic shock is essential when we're looking at a patient who is at high risk for ACLF. It's essential when intravascular volume depletion is determined, balanced crystalloid is the fluid of choice. And IV albumin in moderate but not large doses can be used. When that is insufficient to achieve renal function improvement and mean arterial pressure, pressor support is required. And we certainly know that patients who have a higher mean arterial pressure at baseline are at lower risk for ACLF. That it has any impact on outcome. And norepinephrine is the vasopressor of choice in patients with ACLF. In this non-serotic trial, looking at what they called permissive hypotension, which is essentially what everybody is walking around in clinic in, which is the arterial pressure of 60 to 65 versus usual care, which was the ability of the intensivist to adjust the pressors to what they thought was required. There was no overall difference in outcomes. There was a randomized trial of 150 patients with cirrhosis and sepsis randomized to different mean arterial pressure goals of 60 to 65 versus 80 to 85. And there was overall no change in mortality. However, there was an improvement in the reversal of renal function in those with AKI. So therefore, I concluded that 60 to 65 would be the goal unless renal improvement is necessary or not happening. And then, ideally, set it a bit higher at 70 to 75. In a prospective open-label trial of sepsis randomized patients to terlipressin and norepinephrine versus norepinephrine alone, the combination at 12 hours did require less norepinephrine dose. The serum lactate level was lower. Urine output was higher. And the total duration of pressors was less. But there was no overall survival advantage. This is an incredibly small trial. But terlipressin does lower the heart rate. So certainly, it's something to consider in patients getting too tachycardic on norepinephrine. But it is an interesting approach that could have further study. Do remember adrenal insufficiency in our patients who are in the intensive care unit. And adrenal insufficiency in a single center prospective trial was very prevalent as relative adrenal insufficiency. As a matter of fact, about half of patients had this. And patients with relative adrenal insufficiency were at higher risk for sepsis as well as the development of ACLF. However, in another single center study looking at 75 patients with cirrhosis and septic shock, even more, 3 quarters had relative adrenal insufficiency. About half did receive hydrocortisone. And hydrocortisone did decrease the vasopressor dose and improve shock reversal. But there was no overall change in 28-day mortality. There was an increase in shock relapse and an increase in GI bleeding. So I think, in general, relative adrenal insufficiency is incredibly common in patients with cirrhosis, especially those in septic shock. But at this time, until we have further data, we need to administer treatment for adrenal insufficiency only in those with refractory hypotension. But certainly do remember that as an important factor. Coagulation also needs to be assessed in patients with septic shock. Could I have water, please? I'm sorry. Thank you. And coagulation in cirrhosis is a bit more complicated. So in stable cirrhosis, you get rebalanced coagulation. In acute decompensation, you have hypercoagulability. And in ACLF, it depends. So ultimately, we all need to be using viscoelastography to better determine where our patient is in the spectrum of hypercoagulability to hypocoagulability. Especially in septic shock, patients can be hypocoagulable. And that actually portends an increase in mortality if that is found. Transfusion of products is never necessary in the absence of bleeding or a procedure. But certainly, many patients are receiving transfusions that are not necessary. So we do not need to transfuse for the procedures of paracentesis, thoracentesis, banding, or even diagnostic endoscopy. Transfusions in bleeding may be needed, but should be based on viscoelastography. And we should never be using FFP because of the volume, the anticoagulants that are given, and the sensitization to HLA antibodies, to HLA antigens that occurs. In contrast, cryoprecipitate and four-factor prothrombin complex concentrate should be utilized. And just a moment on what I see as the next frontier, and that would be looking at genetic factors. So RACE and ACLF was recently published on in a prospective evaluation of almost 1,300 non-electively admitted patients to 44 hospitals in Latin America, a third of which developed ACLF. And one of the big risk factors was, in fact, Native American versus European ancestry. And ultimately, in the future, hopefully we'll understand the genetic causes of who is more predisposed to ACLF than others. But what I'm most interested in is why and when do pathobionts transition from friend to foe? And this is a recent Nature paper looking at the bacterial transition of Pseudomonas aeruginosa. And so when Pseudomonas aeruginosa is in a low-oxygen environment, it produces mRNA from a gene called SICK-X. When that occurs, ubiquitin production dramatically increases. And this is like Xanax for Pseudomonas. It chills out in a biofilm of chronic colonization and does not invade the organism. However, when oxygen goes up, SICK-X goes down. Ubiquitin production is abated. And then it can frolic around, invade, and cause havoc throughout the organism. So certainly a potential area to target in the future. In summary, plopped for septic shock and ACLF prompt fluid resuscitation is needed with balanced crystalloid and the Goldilocks approach to IV albumin. When presses are needed, norepinephrine is the first choice. And you consider terlipressin in addition in tachycardic patients on norepinephrine and HRS-AKI. And generally, the goal map is greater than or equal to 65, but do follow the kidney function as it may need to be higher. Relative adrenal insufficiency is common and certainly think about it in refractory shock. Serotic cardiomyopathy is probably underappreciated and POCUS may be helpful. And coagulation should be assessed with viscoelastography. Patients with cirrhosis do develop infections with or without sepsis, with or without ACLF. And I think the future is looking at those host and pathogen features that contribute to this. Thank you so much. Thank you, Jackie, for this wonderful presentation. I now have the honor to present Dr. Patricia Pringle-Bloom, who will be talking to us about neurological failure in ACLF. All right. Thank you very much for the invitation. And wonderful to see so many people in the audience today. All right. So here are my disclosures. Neither are relevant to this talk. ACLF is characterized by multiple organ failures, as depicted on the left side of this figure. While the grading systems for ACLF vary from organization to organization, one thing they all have in common is that grade three or four hepatic encephalopathy all count as an organ failure. So today, I'll be talking about identifying and treating neurologic failure in ACLF. Even in the context of other organs failing, having hepatic encephalopathy has a poor prognosis. The NASL-D cohort analyzed over 1,500 patients hospitalized with cirrhosis and found that HE severity was significantly associated with death, even when controlling for age, white blood cell count, meld, shock, dialysis, ventilation, and many other factors. So encephalopathy really carries with it a very poor prognosis. And then you add ACLF to that, and that makes it an even more poor prognosis. In an analysis from the Canonic Study, ACLF with HE had higher mortality than HE alone. So really, the combination of encephalopathy and ACLF is truly a particularly poor prognosis. The development of encephalopathy in ACLF is multifactorial. There are multiple biological pathways involved. First, of course, there is high gut ammonia production. And there is diminished metabolism of ammonia due to dysfunctional urea cycle. Then because of portosystemic shunting, there is more ammonia that is able to reach the brain. And ammonia has many different effects on the brain, including increasing GABA production and diminishing neurological activity. And then as Dr. O'Leary was just sharing with us, there is certainly severe hyperinflammatory state seen in ACLF, perhaps in part due to bacterial translocation. So lipopolysaccharide is present on the surface of gram-negative bacteria. And this activates toll-like receptor 4, which initiates an inflammatory cascade in cytokines. And this makes the blood-brain barrier leakier to toxins, including ammonia. And there are also microbe-mediated metabolites that influence the intestinal barrier and contribute to ACLF. And for example, short-chain fatty acids are an important nutritional source for enterocytes. And if these are diminished, which they appear to be in ACLF, that can contribute to leaky gut. So hepatic encephalopathy is the primary cause of neurological failure in ACLF. But it is not the only cause. There is certainly a large differential, including alcohol intoxication or withdrawal, opiate intoxication or other drugs, delirium, electrolyte abnormalities, medications, like for example, psychiatric drugs, which are in large part metabolized by the liver or kidneys and may have metabolites building up when both of those organs are dysfunctional. And I'll just quickly mention the recently published ACORN trial in JAMA, which compared cefepime and peptazo in adults hospitalized with acute infection. And there were many patients with cirrhosis in this trial. And they did find that cefepime was associated with a small increase in delirium as compared to peptazo. And this is, of course, a medication that we're commonly using in our patients with cirrhosis. So how do we differentiate encephalopathy from these other causes of neurologic failure in ACLF? It still truly is a clinical diagnosis. We can look to the physical exam. We usually in encephalopathy see asterixis and disorientation. We can use various serologies or blood tests to look for the presence of toxins. We can, if there's a focal neurological deficit, do brain imaging. But really, it remains a clinical diagnosis. The West Haven criteria gives us a scoring system for the severity of encephalopathy, but doesn't truly help us distinguish and tease apart each of these other possible etiologies. So now I'll move into talking about the management strategies of neurologic failure in ACLF. And the first is to treat the trigger if you can. Only in one third of the cases of ACLF, we really don't know what the trigger is. Second, hepatic encephalopathy is not an absolute contraindication to TIPS if there is variceal bleeding. Especially variceal bleeding is what is prompting the ACLF. Third, consider fluids. Because fluids are dehydration, I should say, is a possible trigger for encephalopathy. And fluids can help to resolve that encephalopathy. And I will address the rest of these points on their own slide. So lactulose and rifaximin should be empirically started or continued in patients with neurological failure and ACLF. And this can be concurrent to ruling out other causes. If a patient has a grade three or four hepatic encephalopathy, they're severely confused and at risk for aspiration. So ideally lactulose should be administered rectally or via nasogastric tube until a patient can safely take lactulose orally. There is often an instinct to flood our patients with lactulose, I think when they're, you know, when we're seeing them incredibly sedated in ICU, but there is a possible harmful consequence to that. We can induce diarrhea, which then dehydrates our patients, causes electrolyte dysfunction, and that can actually prompt more encephalopathy or delirium. Lactulose also can cause ileus. So be cautious if your patient is starting to have a more distended abdomen and not passing bowel movements. It may not just be ascites in their belly, they may be developing ileus and that has been associated with lactulose before. Now, when have you ever managed a straightforward ACLF patient? You know, they always, you're worried about the sedation, they're encephalopathic, confused, but then perhaps they have acute or chronic pain, or you're trying to sedate them for a procedure or for intubation. And so you're struggling between their sedation, but also, you know, their somnolence and keeping them comfortable, but trying to not make them more encephalopathic. So one of the ways to manage that tug and pull is with close monitoring of pain and their neurologic status. That's, of course, easier said than done and often requires a lot of close nursing care. But with this close monitoring, you can hope to not overshoot your management too far in one direction or the other. Consider small, short boluses of sedatives as opposed to infusions. Again, easier said than done and requires a bit more nursing, close nursing care. Avoid opiates and benzodiazepines as possible as those can provoke encephalopathy or constipation. Caution with hepatic and renally metabolized drugs, like for example, gabapentin and many psychiatric medications. Those medications are often being used in the outpatient setting for these patients and then just sort of get continued when they're admitted. So be cautious as their liver function and renal function is worsening. Metabolites of these drugs could be building up and contributing to encephalopathy. And the recently published ACG guidelines for ACLF say, in hospitalized patients with ACLF, we suggest the use of short-acting dexmedetomidine for sedation as compared to other available agents. And to my knowledge, there isn't any specific data about dexmedetomidine in cirrhosis or ACLF, but this is an appropriate sedative to be using in a short-term or long-term setting in the ICU. There are two large robust randomized trials using dexmedetomidine in the ICU for sedation, and they were non-inferior to midazolam and propofol in terms of sedation endpoints and also in terms of safety and time to extubation. However, very few patients with liver disease were enrolled in those studies. So this still is an area that requires further exploration in our specific context, and just be mindful that this drug can cause hypotension, hypertension, and bradycardia. Airway management is, of course, a really key tenant of care in an ACLF patient with neurologic failure. We still, to this day, are using Glasgow Coma Scale. A score of eight or lower is usually an indication for endotracheal intubation, and that's because it is highly correlated with a risk of aspiration. So when the GCS is eight or lower, there's a much higher risk of aspiration, and this is, of course, true in our context as well. When you have an encephalopathic patient who has a Glasgow Coma Scale eight or lower, really consider prompt intubation. ACLF is associated with a high risk of death, and liver transplantation decreases that risk. However, some of our patients may be too sick to be rescued by transplant. I recommend for ACLF patients with HE to begin planning and considering that possibility of transplant early, because, of course, brain failure introduces some complexities around the evaluation. Not being able to speak to your patient about transplant makes it a bit more complicated. We also need early goal of care discussions and honest discussion around futility if that's not an option. So the next speaker is going to address this in more detail, but liver transplant in ACLF and brain failure is not always futile. The Belly and Colleagues study found in over 200 patients with brain failure in ACLF that ACLF did not predict death, or sorry, the brain failure with ACLF did not predict death after transplant when controlling for other factors. The, again, the ACG guidelines coming in here, they say in patients with cirrhosis in ACLF who continue to require mechanical ventilation because of brain-related conditions despite optimal therapy, we suggest against listing for transplant. And I do agree with this. This population of patients who are dependent on the vents despite optimal therapy, these are not the patients who are getting routinely transplanted. They weren't in that belly cohort to my understanding. So this does make sense that there are some people who are in fact too sick to move forward with transplant. And then now in my last few minutes here, I'm just gonna discuss some therapies under active investigation. So we know that gut microbial composition and function is altered in advancing cirrhosis and ACLF. And this well-known study showed decreasing species richness with advancing severity of liver disease all the way down to the lowest category there of ACLF. Others have found similar results, including lower short-chain fatty acid producers like lacnose, Bracea, and ACLF. And again, short-chain fatty acids, very important to the energy of enterocytes and intestinal barrier health. So fecal microbiota transplant, or FMT, may correct some of this altered microbiota and replace some of the beneficial taxa. Several groups are actively studying FMT in liver disease. And I'll give a shout out to Dr. Karen Thompson's group at Aarhus University in Denmark. They are actively trialing FMT in hospitalized patients with cirrhosis and acute decompensation, many of whom have ACLF. I know they're trying to enroll over 200 patients and are well into enrolling. So soon enough, we will have more data on the safety and efficacy of FMT in this really sick population. I'll briefly mention MARS, which is an extracorporeal albumin dialysis system used to extract protein-balanced substances from blood, like, for example, ammonium. This seminal trial on MARS for ACLF, the relief trial, found no survival benefit with MARS, but did see a trend in improvement of hepatic encephalopathy. A more recent meta-analysis did suggest a possible survival benefit for high-intensity MARS, but we're still not quite ready for primetime routine clinical use. Given the role of heightened immune activation in ACLF, immunomodulators have been widely considered as a possible therapy for good reason. We know that the hyperimmune response is a huge contributor to the pathogenesis of ACLF. This analysis of blood samples from patients with acute decompensation in ACLF showed that albumin infusions reversed some of the plasma-mediated immune dysfunction. But then, as has already been described in the last talk, the entire trial, unfortunately, really didn't show us a benefit more than standard of care in cirrhosis patients hospitalized with acute decompensation. So still, given the significant role of immune dysfunction in ACLF, immune modulation is and should be an ongoing area of investigation. In the famous HELP trial, Dr. Rahimi, who I see here, took patients hospitalized with overt encephalopathy and randomized them to lactulose versus PEG. The headline from this trial was that polyethylene glycol, or PEG, led to more rapid resolution of hepatic encephalopathy than lactulose. It's still not totally clear to me how PEG works. You know, lactulose does so many things to the microbiome. It mediates more short-chain fatty acid production and so forth, and PEG doesn't do that. So, you know, it should help clear out constipation, which might trigger encephalopathy. Also, everyone in the study did receive lactulose from the start and could receive lactulose after PEG, and there was a much higher volume of PEG given. So we're still not ready to say that PEG replaces lactulose or is superior, but I certainly do use it in my patients where they're still not having bowel movements despite lactulose. So some closing thoughts here. We should be employing multiple strategies to treat neurologic failure in ACLF all at once. These patients are critically ill and require multiple simultaneous attempts at treating the encephalopathy, and we know it has a very poor prognosis, so we need to attempt to aggressively treat it. And these critically ill patients don't have a lot of time for us to try things serially. Ideally, we could closely monitor these patients, their sedation, pain, airway. The future therapies under investigation that I have a lot of optimism about include those that are microbiome-targeted, immunomodulators, and possibly some sort of liver dialysis. So we need to tackle multiple biological pathways at once. It may not just be one therapy, but multimodal therapies that target the microbiome and immune system and ammonia, perhaps, all together. And perhaps this is an opportunity in the future for personalized medicine where we identify what a specific patient's problem is and try to target that with our therapies. So thank you very much for listening, and I'll welcome any questions at the end. Thank you. Thank you, Dr. Bloom. Next, we'll hear from Dr. Dean Karvelas from the University of Alberta to speak on bridging the ACLF patient through to liver transplantation. Is that you? Yeah, that's me. Thank you very much. And I wanna highlight that the presentation I'm gonna give is gonna build on some of the themes that you've heard in the previous presentations. So I don't have any disclosures. So the main things I wanted to cover in this presentation is to talk about critical care management of specific organ failures, particularly from the ICU perspective, and I know that you've heard some of this already in the previous talks. We'll talk a little bit about ventilation strategies, talk in a little bit more detail about specific renal replacement strategies. There are a lot of questions with equipoise, and also briefly look at post-transplant outcomes in ACLF and talk about prognostic scores, not only looking at post-transplant outcomes, but also weightless mortality. We've seen now in several studies, but the Sentinel study that Vinay Sundaram and Rajiv Jalan published in 2019 demonstrated that the MELD score, which doesn't account for extra hepatic or renal organ failure, in particular cases may actually underestimate mortality, particularly in those patients with ACLF and a low MELD score. So this kind of gave us the impetus to start looking at more kind of global scoring systems, and as you can see, the CLIF-ACLF score, for example, built on a score like the SOFA score, which looks at six different organ failures. So kind of starting, I know that you've heard quite a bit already about septic shock. When looking at circulatory failure, one of the biggest things that's changed with regards to our management in the critical care unit is the use of dynamic techniques like point-of-care ultrasound or bedside echocardiography, and it gives us a lot of, in well-trained hands, it gives a lot of information, not only looking at left ventricular and right ventricular function, we can get assessments of pulmonary pressures, we can also get assessments of responsiveness to fluid, so it can guide our resuscitation. The other thing to mention, that point-of-care ultrasound, not only is just cardiac ultrasound, but you can also do lung ultrasound and look for things such as pleural effusions. And because of the more widespread use of bedside point-of-care ultrasound in many different critical care environments, we've kind of shifted to this in a way from using traditional central venous pressure monitoring or things like thermodilution techniques. And just to emphasize again what Dr. O'Leary presented in her presentation, that generally we perform early and often assessments of volume and perfusion status in ACLF patients to assess their filling and their cardiac function. One of the challenges when you look at the studies is that we know that there are problems with starches and gelatins. Normal saline has an issue with hyperchloremic acidosis, and there's only been a couple of studies that have looked at albumin and balanced crystalloids per se, but I would echo what Dr. O'Leary said, that really we favor the use of balanced crystalloids as the bulk of your resuscitation fluid with the proviso that you can use albumin in specific circumstances. And really one of the concerns is over-transfusion with albumin. Also, norepinephrine is our first-line vasopressor, and there is work to be done looking at second-line therapies. Currently we're in places where turlopressin hasn't been improved. We're using vasopressin, but there is the possibility of using turlopressin as a second-line vasoconstricting agent, particularly in the patient that has acute kidney injury. And as mentioned before, while we target a map of 65 in cirrhosis ACLF patients with shock similar to the surviving sepsis guidelines, there is more and more evidence to demonstrate that in particular in patients where you are trying to improve renal function or they have HRS physiology, that targeting a higher mean arterial pressure, certainly at least above 75, is preferable. And as mentioned before, certainly in patients with refractory shock, often we will employ empiric hydrocortisone therapy. And in many cases, you may not necessarily have time to do a stimulation test or do anything above just ordering a random cortisone level. Highlighting as well that unfortunately, while we don't have a lot of other direct therapeutics besides antibiotics and septic shock, one of the important things to emphasize is early and appropriate antimicrobial therapy. And I always kind of highlight this because the sepsis six-pack that we used to have, we don't have activated protein C anymore. There's a lot of controversy around the use of steroids and septic shock, that really we're left with early appropriate antimicrobial therapy, frequent assessments of volume status, and resuscitation to specific perfusion targets, whether that be echo or lactate or otherwise. To mention when looking at causes of respiratory failure in ACLF, and this can be a real challenging one because often this might be your make or break decision, I'm sorry, with regards to proceeding with liver transplant. There are, we know there are causes of acute lung injury that are specific to cirrhosis. And there also are non-specific causes that we see in general critically ill patients, including pneumonia, thromboembolic disease, acute lung injury, pulmonary edema, et cetera. Now, we don't have a specific literature for mechanical ventilation of ACLF patients specifically. So unfortunately, we left with borrowing literature from the general critical care population. We once again mentioned the lung protective strategy. This has been around for some time. And the idea here is that you wanna prevent barotrauma by lowering your driving pressure, but also prevent lung atelectasis and improve recruitment by maintaining a higher baseline positive end expiratory pressure. The only challenge with this strategy in an ACLF patient is when they can be very fluid dependent. Using a high positive end expiratory pressure, for example, using a PEEP level of 12 or 14 can sometimes decrease venous return and cause hypotension. So obviously we do this with caution. And just to build on some of the themes that Dr. Bloom presented with regards to patients with altered mental status, it is true that, well, hepatic encephalopathy is common. Generally, if it's their first presentation, we will work them up for other causes of delirium. And one of the biggest challenges obviously can be somebody with alcohol induced hepatitis, where is it alcohol withdrawal or is it HE? And I would concur that we will intubate generally with the GCS of less than nine for airway protection. And we will consider empiric therapy, well, trying to discern if it's HE or a different cause. And I will say that the point made about lactulose and ileus is a very important one. And in some cases, one of the big concerns you run into is intra-abdominal hypertension or intra-abdominal compartment syndrome, where a distended abdomen can cause problems with ventilation and tidal volume and also with acute kidney injury. So we will use PEG as a second line treatment. And as mentioned before, while we don't have a lot of guidelines on how to dose this, generally we'll dose it in the same way where we'll give it often 17 grams once or twice a day to target two to four loose bowel movements. Also important to mention that using sedating medications with short half-lives, the practical reality is that propofol is cheap. Dexmedetomidine is more expensive. Generally how it's used in most centers is that in somebody that likely will be intubated for some time, you'll likely use propofol. Dexmedetomidine has the advantage in somebody that may be intubated short-term. And also if you extubate somebody with ongoing delirium or agitation, you can run them on dexmedetomidine even without a breathing tube. So in a patient that may be difficult to manage, you can continue it even once they're awake and alert. But certainly the bradycardia, particularly when you initiate or start dexmedetomidine has to be considered. We find the use of ammonia at least upfront is important in terms of potentially, if the ammonia is rock solid normal at 20, then we know that it's likely another cause of altered mental status. Generally if it's elevated, it doesn't tend to correlate with the grade of HE and it's not something that we order repeatedly. We talked about timing of renal replacement therapy and there's a few important caveats. This is the START-AKI study that Dr. Durand was referring to. It's important to note that in a patient without cirrhosis that comes in with AKI in the setting of septic shock, really the goal here or what you're looking at is potentially renal recovery in somebody that likely will walk out of the hospital. And one of the challenges with this study and what's come out in subsequent studies is that we might actually be potentially doing patients a disservice by starting CRRT or RRT too early and might be actually impacting negatively potential renal recovery. It's a little bit of a different situation in a patient with ACLF, and as mentioned, it was only in the STARDATE study, there was only about 11 percent of patients that had chronic liver disease. Unfortunately, in looking in that data, it's been difficult to identify if they truly had cirrhosis or not. But I think one of the secondary points that came out of this that's probably more important is what they demonstrated was probably a continuous modality or the use of CRRT in a critically ill hemodynamically unstable patient may be advantageous to hemodialysis. And this likely reflects the mass majority of patients with ACLF. It's actually very challenging to put them on intermittent hemodialysis. So what most centers would advocate is potentially considering using a continuous modality. Beyond that, the other thing you need to think about is if you need any kind of circuit anticoagulation, whether, you know, generally we'll start without anticoagulation, we'll just use saline. In some cases where you have a hypercoagulable phenotype in these patients, potentially may clot the filter, you might consider using citrate over the short-term citrate regional anticoagulation. This leads into another question of heading into liver transplant. Are you better off clearing somebody very aggressively pre-transplant or running renal replacement therapy during the intraoperative period? As you can understand, you have an ACLF patient that's critically ill. Are they going to be able to deal with the metabolic demands of transplant, including the lactic acidosis from the antipatic phase or the hyperkalemia when you reperfuse the graft and a significant amount of blood products that are often required? I'll mention having been involved in a prospective pilot study with this, this is a very challenging question to answer because there were a lot of confounding factors. And just to kind of highlight the inception study that was done in our institution was a negative study, but one of the confounding factors is a large number of patients crossed over from the standard of care and received intraoperative renal replacement therapy. And more recently, you can see that there has been a systematic review that has looked at all at other controlled studies and where they weren't necessarily randomized. And at this point, there isn't a study that's demonstrated a mortality benefit with intraoperative CRRT or intraoperative renal replacement therapy more generally. So this kind of comes back to personalized medicine, right patient, right indication, right outcome. Certainly if you have somebody who's oliguric, it will be very difficult to get them through a transplant. And those are the patients that certainly we consider for intraoperative CRRT. In those patients that are making some urine, the question becomes, if I can aggressively bring, you know, dry them out or bring down their potassium prior to transplant, that might be considered as well. As you're probably aware of, in terms of the studies of looking at extracorporeal or artificial liver support in ACLF in particular, the studies to date have been quite underwhelming. And the challenge is that we know that ACLF patients carry a high mortality. And that's essentially been the story of Mars, of Prometheus. And we are obviously looking forward to the results of the Apache study with plasma exchange. Certainly most of these studies have demonstrated improvement in biochemistry and also improvement in encephalopathy in several cases. But really what we're looking for in future studies of liver support are studies that are looking at a primary endpoint of bridge to transplant, because we know that the natural history of these patients in the absence of transplant in many cases is quite poor. Finally, when looking at outcomes with transplant, I want to highlight two key points that it's not just the post-transplant survival that we're interested in, but also weightless mortality, which is probably a more important metric. And I'll highlight this older study now from 2013, where we looked at ACLF patients that were transplanted at five different Canadian centers. And when we looked at outcomes in the 198 patients that received a transplant, we couldn't actually find a discriminatory cutoff by, in those times it was the SOFA score, which was loosely reflecting the number of organ failures between those that were alive and a dead post-transplant. But there was a significant difference between those patients that received a graft and those that died on the wait list. And what I always kind of highlight is the counterfactual that, you know, we don't know how those patients on the wait list would have done with an organ. But many of these patients were actually delisted as a human decision. We felt that they were too sick to transplant. And in some ways, the fact that we don't see a difference in this other group here probably implies that we're making good clinical decisions at the bedside, that we're declining the worst of the worst. This study also demonstrated that the Tulavath study that looked at UNOS, which, and I think it's very important to inform families, that with an increasing number of organ failures, the vast majority of ACLF patients, certainly with four or more organ failures, don't actually make it to transplant. And as you can see here, the 30-day mortality on the wait list was almost 100 percent. So when you look at data like this that shows reasonably acceptable outcomes in patients, certainly with ACLF and ACLF3, with three or more organ failures, it is obviously there's a significant selection bias. It's probably a small proportion of patients that actually went on to get a transplant. In some senses, that is a good thing. It means that we're making sound clinical decisions. And this is being made at multiple different transplant centers. And I highlight again, that's why it's so challenging just to look at post-transplant outcomes in isolation to try to come up with futility criteria. One thing to note, though, is that certainly those patients that come in with ACLF, as highlighted by this study from Vinay Sundaram that was published in 2020, is those patients that come in with ACLF3 and with organ support in the ICU, if they improve down to a grade one or two, they tend to follow the trajectory of those patients that came in with a lesser severity of ACLF. So it highlights the importance of ICU management pre-transplant in potentially improving outcomes. But I just want to mention as well that transplant in general in ACLF is a high-risk business. Generally, these patients, certainly once you get to the ACLF3s, have a significant demand of resource allocation post-transplant, longer ICU stays and hospital stays, higher proportion requiring renal replacement therapy, and a higher rate of readmission. So we're aware that there is the CHANT study that's ongoing. But I will also mention this score that was derived through the model consortium and the brainchild of Vinay Sundaram, who unfortunately is no longer with us. But it just kind of highlights that when we make decisions for transplant, we have to look at potentially, you know, the probability of getting you to a transplant, you know, what you're potentially looking at after transplant, along with the post-transplant survival or mortality at a year. And some of the examples that came up in the SALT score and is in this predictive tool included higher age, higher burden of multi-organ failure, particularly respiratory failure or multiple pressors, and other factors like BMI and diabetes. So in summary, consult ICU early for the ACLF patient who is potentially transplantable. As mentioned, for volume status in ACLF, use dynamic tools such as point-of-care ultrasound. Consider PEG in ACLF patients with hepatic encephalopathy and ileus. Renal replacement therapy in ACLF, continuous modes may be preferable due to hemodynamic instability and potentially beneficial if you believe the follow-up study of the START-AKI trial. With regards to preoperative or intraoperative renal replacement therapy, consider intraoperative renal replacement therapy, particularly in those patients that are aneuric. Transplant in ACLF is resource incentive. We have good published outcomes, but just remember there is a significant selection bias that is probably a good thing. And finally, weightless mortality is an important outcome and should be considered in the decision to proceed for liver transplant listing in ACLF. And finally, just a gentle plug that after two years of work, and I noticed that several of our co-authors are in this audience, the ASLD practice guidance on ACLF and the management of critically ill patients with cirrhosis finally came out last week, and it is now online on the ASLD website. Thank you very much. Okay, well, thank you to all the speakers. I want to invite the presenters up to the podium, and we're now open for questions. We're going to have about 10 minutes of questions, so please come up to the microphone if anybody has any questions for the speakers. Okay, while we wait, well, first of all, I want to thank everybody for these wonderful presentations. I thought the jokes were amazing. I do want to begin with a question for Dr. – oh, you have a question? Please go ahead. Hey, how are you doing? Jim Crismale from Mount Sinai in New York. For Dr. Karavellas, so, you know, the – as you mentioned, sort of assessment of volume status is very difficult in these patients, and, you know, oftentimes we're left guessing we have someone who's anisarchic, but are they, you know, intravascularly dry? What – if you had to choose one sort of relatively easy to implement non-invasive test that we could use, for example, in terms of POCUS exams that we could train our fellows on, that we could train the medical house staff on, what do you think is the best sort of method, and how do you approach that just on a floor patient who you're seeing not necessarily in the ICU? Yeah, that's a very good question, and the one good thing is in a lot of internal medicine training programs now, there's more and more adoptions of point-of-care ultrasound teams, and I know that part of it is actually just getting your hands on a machine. Probably the one thing that is the most important, that is probably the most reproducible is the inferior vena cava diameter with compressibility, so generally the one thing we'll look at is it less than two centimeters, and do you get greater than 50% respiratory variability? That's probably the one that's the easiest to do, because a lot of the other factors, as you said, it's operator-dependent, and you need to do kind of enough scans to be kind of competent with those skills. Great. Thank you so much. I have a question for Dr. Francois and Durand. So this is a relationship to the use of urinary biomarkers for a TZDEPART ATN in HRS, which is a significant clinical problem we have in practice. So we've used it, we've used urinary NGAL, although it's not commercially available. I don't know if you have any experience with it in trying to tease apart ATN and HRS. No, we do not use urinary NGALs, and we do not really have other biomarkers that we use, so it's based on clinical judgment, mainly. Okay, so you're still using FINA and clinical judgment. The problem, there are two opinions. First one is that HRS and ATN are two different entities, definitely different. And my position is that it's rather a continuum, so it's not surprising that there is an overlap between the biomarkers, because at some degree of progression, there is tubular cell ischemia or necrosis, so it's not surprising that you have biomarkers of injury in patients who have a profile of functional HRSA-KI, for instance. Okay, thank you. Do you have any questions? So speaking about POCUS, we have a lot of POCUS training programs for our house staff for medicine, but not necessarily in GI and hepatology, and one of the things we've been talking about recently is even renal POCUS in looking at congestive nephropathy and trying to tease out ATN versus HRS. Could you speak a little bit to how you, or Dean or Dr. Duran, talk a little bit about how that might impact the field? So I think it's an interesting question. I think the problem is that certainly when you're looking at renal Doppler, you're getting more and more, it's more technical, and it's probably, you need more and more expertise. So I can say having gone through a training program for a mid-career intensivist that, you know, once again for the basic skills you generally can acquire, you know, certainly with getting your peristernal long and short axis of a heart, you can get that fairly quickly. But a lot of these things are fairly nuanced, and I think you'd have to really focus on it. And probably it's, like for example in our institution, that's actually being done by our ultrasound lead with our nephrology team. So the nephrologists are actually interested in this as well. But like you said, I think it just once again, do you have a kind of a site champion with expertise that's willing to set up a program, because it's a lot of work. And then also the question becomes, how do you check, you know, competence and that you're getting, you know, quality control for reliable information? Good. Jackie, quick question. In relation to albumin, which I agree that we perhaps are giving too much of it, and that one of the problems that people get into pulmonary edema is perhaps the dose and the priming. Do you have any specific recommendations on how to, you know, avoid pulmonary edema in these patients? And what is your recommended dose of albumin if you have to use it? So generally I use albumin for, when it's indicated. So of course for post-parasitosis circulatory dysfunction, six to eight grams per liter that you remove. And then of course do remember that we don't necessarily need it if you're removing less than five liters in a patient without ACLF, but in ACLF patients we do have data that shows they get post-parasitosis circulatory dysfunction even if you remove less than five liters. So I am replacing it there as well. However, when I'm giving it for AKI or HRS-AKI, I generally give it as 25 grams IVT-ID, so smaller doses spread out, but then check the serum albumin level every day. And so when it gets towards three, I'll either stop or go to once daily 25 grams, but more likely stop. And then, yes. That's perhaps an adequate dose without having to go up to 40 grams a day, and also the way you infuse it. So if you just let it infuse over 10 grams or 20 grams over one to two hours, it's not the same as just stripping it. So that has an impact perhaps as well. Dean, do you want to say something? Oh, and Francois. Oh, actually Francois, do you want to go first? I think, you know, it's a really good point because, you know, nobody is arguing with level one indications, but certainly what we found in our institution is there's been an albumin creep in terms of using albumin in non-kind of level one indications. As we can, you know, we're learning more and more that organ volume overload has impacts on many different organ systems. And I think we're just kind of seeing this now with a lot of the albumin trials that came out. So for example, our hospital has actually initiated an albumin de-adoption protocol where if somebody orders it on the electronic medical record, a checklist comes up and says that, you know, these are the class one indications. Are you sure? You can still order it. But obviously, you're going to have to go through that thought process. And I think that's just one thing too, Eilidh, but... Francois? Well, this is an important discussion that we had during the last meeting because in the classical definition of HRSA-KI, there is a need for absence of a response to 24, 48 hours of albumin infusion and volume expansion. But the problem is that not all patients who have HRSA-KI at presentation are volume depleted. Some patients have a normal blood volume, central blood volume, or even are overloaded. So I think it is very important to have an assessment of fluid status with POCUS or echocardiography at the time of initial management. And we thought it was not mandatory to systematically infuse albumin because there is a risk of development of pulmonary edema in this patient. In other words, no patient with HRSA-KI need a fluid challenge before starting telepressing, I think. Thank you. And finally, Dr. Blum, do you have any information on any other therapies for encephalopathy that are used in other countries like Lola? And I know you don't have experience here, but some countries do have it approved and used it. So what is your opinion on that? Apologies for my American-specific context there. But yeah, so there are, of course, these other ammonia-lowering strategies, OPA, Lola. You know, with Lola in particular, there have been many randomized trials and meta-analyses. It's been used in kind of various severities of HE with different effect. And the data is mixed, I'd say, and kind of it seems perhaps depends on the quality of the study done, but also the specific context it was used in. I don't have any problems with it. I think it may indeed be effective, and there are certain analyses that show that. But I haven't been astounded by a lot of the data I've seen. And then OPA just, of course, recently had the recently published, you know, not superior to placebo effect. So yeah, I don't think I left much out. Okay. Well, thank you. Do you have any other comments? Christina? I have one other question. So if we could go back to albumin creep for a second. In terms of post-liver transplant management, especially for someone who has acute on chronic liver failure heading into transplant, we see a lot of 5% albumin use on the post-transplant side. I'm not aware of data supporting necessarily its benefit in the post-transplant setting. Could you, anyone care to speculate on what the role might be for albumin post-transplant for ACLF? That's a difficult question. This is more opinion than evidence. I think there isn't a great amount of, the assumption is with post-transplant that over a period of time that you're going to correct a lot of these neurohormonal pathways that have been going on for some time. I find it quite often on the floor under the surgical care that we tend to end up using this. I don't know if you find the same. I'm not aware of any literature and I can't really think of a good argument to use it at that point. Often I'm trying to kind of DC albumin and kind of reassess how people need to be resuscitated if necessary, even at that point or not. But the only thing I can think of is if somebody has a large volume of fluid coming out of their JP drains and if it's truly still ascites, in some cases we will kind of say, okay, we can make a justification for giving a volume of albumin in terms of what we're losing with your Jackson-Pratt drain. But that's the only thing I can really think of. Okay. Well, this concludes the session. I want to thank the speakers for their wonderful lectures and we have like five minutes and we will convene for the SIG business meeting of the ACLF group, whoever wants to participate. So we'll be starting shortly. Thank you.

acute-on-chronic liver failure

ACLF criteria

kidney dysfunction

sepsis

septic shock

neurologic failure

infection impact on ACLF

hepatic encephalopathy

kidney transplantation

liver transplantation

post-transplant care

FMT and MARS therapies