All right, good afternoon, everybody. Hopefully we're slowly working through our glutamate and we'll start waking up. The coffee I think will happen after, unfortunately. All right, so we're gonna get started. I'm gonna talk a little bit about updates for the management of acute liver failure, as well as acute on chronic liver failure. I'm gonna try and focus on changes in the management and updates in the literature over the last two years or so, just to get a sense of where everybody's at to start with, how many people take care of or have taken care of acute on chronic liver failure, patients with cirrhosis? Everybody, acute liver failure. Anybody with some acute liver failure? A large number, perfect. So this works really well, because I'm gonna focus on the new things. I'm not gonna go through some of the basics. So you can go ahead and click, or let's see, there we go. All right, have no pertinent disclosures. And so we're gonna touch base on some basic definitions, some quick changes to epidemiology, and then we're gonna take it first as acute on chronic liver failure, work through some of the basic, some of the major complications there and some of the new components of management. And then we're gonna finish with acute liver failure. So definition-wise, it's always worth drawing this distinction, this does come up every now and again. Acute on chronic is what most of us are used to dealing with in general. These are patients with known cirrhosis. They have a longstanding history of liver disease, and then they have an additional organ failure on top of that, that's the acute on chronic component. They've usually had liver disease for more than six months. In that context, in the most common ideologies currently that people deal with are lanic cirrhosis, that's the tying them two together, it's lanic, no, is alcoholic liver disease, and then non-alcoholic fatty liver disease. Hep C is still present, but on the drop now, hopefully should not be an issue in the next decade or so with the treatments available for hepatitis C, and then we've got some of the other ideologies. Acute liver failure, on the other hand, we often deal with the hyperacute and acute forms that tends to be our drug-induced liver injury, particularly acetaminophen. I'll talk a little bit about some other ideologies that one might run into in other parts of the world. Hepatitis A and E are examples of that. And the acute liver failures can be broken down based on onset. We tend to deal in general in our developed environment with the more acute forms, but there are subacute and late-onset forms that can present a month, two months into the present, three months into the presentation. When we see those more subacute forms, those are the less common drug-induced liver injuries, and we won't touch on too much of that. All right. There's a distinction in how patients present. Patients who present with acute on chronic liver failure, they have that known history of cirrhosis, and they can have the complications of that. The classic, the one that often we deal with is variceal bleeding. Not gonna go into a lot of details because we've already talked a lot about bleeding and coagulation management. We'll talk a little bit about infection in that population, encephalopathy management, et cetera. With respect to acute liver failure patients, the definition of fulminant liver failure is really driven by that encephalopathy, that loss in mental status, and we'll often see varying degrees of coagulation, dysfunction, and cholestasis with the jaundice. You guys know how to diagnose it. You don't even know labs and imaging. All right. Epidemiology-wise, it is intriguing that for a long time, there has been a distinction in the resourced world. What we tend to deal with is more drug-induced liver injury and toxin-induced liver injury, things like alcohol and Tylenol in reverse order, with the viral ideologies being more prevalent in less resourced environments. That is changing to some extent, and we have seen higher rates of some of the drug-induced ideologies throughout the world these days, though to remember, we still have a not inconsequential amount of acute hep A in the pediatric population in some environments. Acute on chronic liver failure, unfortunately, is becoming more and more prevalent, alcohol in particular, and then the non-alcoholic forms due to metabolic syndrome and non-alcoholic fatty liver disease, and it carries a pretty significant mortality, and we're seeing a shift in liver transplantation away from the classic hep C and alcohol into some of the more non-alcoholic fatty liver disease presentations, and they still have pretty significant mortality associated with them. So let's jump into acute on chronic liver failure, and we'll start on hepatic encephalopathy. Very, very common indication for hospitalization in the chronic liver failure patient. Obviously, everything is not driven by ammonia alone. My hepatologists are very quick to tell us we don't just worry about ammonia, and really, it is a multifactorial disease process in which the liver in its impaired state, in its cirrhotic state, has significant reduction in its metabolic clearance of a number of metabolites, and particularly the protein synthesis pathway. That ultimately does result in elevation in ammonia levels, which impact glutamate transition to glutamine, and that ultimately results in inflammatory reactions in the brain and impairment in the blood-brain barrier, and can ultimately lead to edema. Not a common issue in the acute on chronic liver failure patient. Acute on chronic liver failure patients, they've been pre-gaming for a while. They often, when you see them at the ammonia of 90 or 100, 150, as in this case, they may even be having a conversation with you. That is vastly different than the acute liver failure patient, and we'll talk about that in a second, and that might be what throws people off on the answer to the question there, because the vast majority of management, when it comes to acute on chronic liver failure associated hepatic encephalopathy, is lactulose. That's what we use in these patients. Now, is that the most effective thing? Well, we'll talk about that, but the non-absorbable disaccharides, lactulose, that is the recommendation for the management of hepatic encephalopathy and ACLF. And the two things I want to touch on for the purposes of this talk are the new recommendations around the adjunctive addition of rifaximin, and more importantly, the additional use of Lola, which is L-ornithine L-asparaginase. These are now guideline supported. These are SCCM guidelines that came out earlier. I think it was last year, actually. But the data behind it's sort of intriguing. I'm going to show a couple of meta-analyses, and the fun thing with these is they switch which side the placebo's on, so you'll have to follow along just for giggles. But on the far right, the non-absorbables, not surprisingly, everybody is pretty comfortable with lactulose works pretty well when it comes to acute on chronic liver failure patients with hepatic encephalopathy. No shortage of studies, significant reduction in, well, significant reversal in management of hepatic encephalopathy in that setting. The addition of rifaximin, it's worth noting, rifaximin is not a replacement of lactulose, neither is Lola. These are adjunctive therapies that one can add on. For the longest time, it's primarily been used as an outpatient therapy, and it works reasonably well when it added to lactulose in that context. There's a slew of studies now that have led to meta-analyses that have really shown in overt hepatic encephalopathy and in minimal forms, it really does reduce the overall rate of that clinical presentation on encephalopathy, not just reduction of pneumonia, but the clinical presentation. So it's worth kind of adding on. Easier for us to do in the hospital than it is for people to continue outside of the hospital. Anybody who's taking care of these patients when they leave, insurance immediately says, hey, no, we don't need the rifaximin, we'll readmit you tomorrow, it'll be fine, don't worry. All right, now Lola, my new favorite addition to management. So I'm a very weird intensivist for a lot of different reasons, but I'm also a pediatrician as well as being an adult doctor. And if you deal with some of the metabolic etiology, some of the congenital metabolic dysfunctions that lead to hyperammonemia, the use of L-ornithine, L-asparaginase has been standard practice in the management of a number of urea cycle defects for a long time. It's expensive as all hell and it's hard to get in small quantities because that's for pediatrics, so then the pediatric pharmacists get mad at us because we used up the whole pediatric hospital supply. But now there are a number of studies, randomized controlled trial that I'm going to show here that actually showed a significant reduction in mortality when you use Lola in addition to Lactulose in severe hepatic encephalopathy. Interestingly enough, this study was actually done outside of the US and the study used predominantly intravenous L-ornithine L-asparaginase, that's not available in the US. But if you look through some of the recent meta-analyses, large systematic reviews and meta-analyses, you see not only do you see a reduction in ammonia when you use IV Lola in addition to Lactulose, you see that same level of effect with oral Lola as well. And interestingly enough, you can actually get pharmaceutical grade Lola on Amazon. That's actually how we do it. Listen, you figure it out, make it work. Interestingly enough, it not only reduces the ammonia, but in the clinical presentation, the hepatic encephalopathy, the altermental status, you see that same effect. In fact, you see it stronger with P-O Lola than you do with intravenous. And so that P-O Lola really does seem to be a nice adjunct to your Lactulose. And where this is really helpful to my mind is when I'm managing a cirrhotic, some of these folks, you got to give them almost two liters of diarrhea with the Lactulose to get that ammonia to where they can be awake and not intubated. They don't like that. The electrolytes go funky, my nephrologists get mad at me, it's all kinds of things. So the Lola doesn't create that, it doesn't create that same degree of osmotic diarrhea with the management of hyperammonemia. So a nice trick to help optimize your management there. We're going to jump forward to spontaneous bacterial peritonitis. The other thing that makes me a word intensivist is I'm actually an infectious disease doctor. And you can ask why in God's name is an infectious disease doctor who runs a surgical ICU talking to you about liver patients. We're a big liver transplant center. And so we're a surgical ICU, but part of being an aggressive liver transplant center, we admit every single critically ill cirrhotic to the surgical ICU so that we can manage them and figure out who is a good candidate for a liver transplant, who's not. So spontaneous bacterial peritonitis, near and dear to my heart. I'm not going to read that slide to you, but ultimately spontaneous bacterial peritonitis is a posse bacillary process, right? So you get edema in the context of your portal hypertension, gut edema, loss of a little bit of that tight junction physiology, bacteria get across into the mesenteric lymph nodes and then into your situs fluid. Situs fluid is another name for culture media. It's essentially low immune, high nutrient fluid. And it doesn't take a lot of bacteria before you get into a lot of trouble with spontaneous bacterial peritonitis. That's great. You all know how to manage it. What do you do? You give them ceftriaxone, high five, everybody's done. Now, unfortunately, not surprisingly, drug resistance is marching on and ceftriaxone is really not necessarily the best option for the critically ill patient with spontaneous bacterial peritonitis any longer. The guideline recommendation that came out was now broad spectrum antibiotics for the initial management of SBP. And this is something that I'll be honest, it's been there for about a year. I still see very frequently any decompensating cirrhotic where my ED has been awesome enough to go and get that para right out of the gate because they got the procedure done, we're good. It's SBP, immediately they're on ceftriaxone. What am I missing when I do that? So I'm not going to go through all the different studies. This was specifically a large retrospective review or a systematic review of the nosocomial spontaneous bacterial peritonitis patients. So these are patients who were in hospital for more than 48 or 72 hours at the time of diagnosis of their spontaneous bacterial peritonitis. So it is a little different than that patient that just shows up in the ED. What's really interesting, it was a representation of a number of, I would say, resourced ICUs across the globe, South Korea, Spain, Canada, China, Germany, Italy. And really what I want to draw attention to here is the relative frequency with which non-standard enteric pathogens, not your simple E. coli, not your simple Klebsiella was identified. You had a number of gram-positive, and they say here bacilli, it's a little fudge if you want to look at the actual microbiology. That was entrococcus, they were not bacilli, they were gram-positive cocci. But a not inconsequential number of enterococcus popping up in these samples. And I don't know how many of you are running to this in your own practice, but enterococcus is kind of turning into a big problem in abdominal sepsis in particular, particularly due to marching drug resistance. Not inconsequential amount of multi-drug resistant enterococcus as well in a couple of these studies, about a third and a half in some. And that's generally going to be your VRE. We're beginning to run into not just VRE, but we're starting to see VNDRE, so daptomycin-resistant, vancomycin-resistant enterococcus, which is very entertaining when they're all serotics and they're played like cancer already in the 20s, so in these, it's not much fun. And then not an inconsequential number of multi-drug resistant gram-negatives as well. And so often what we'll do in this setting is if you have that severely ill serotic with SPP, that patient who develops SPP in the hospital and comes to the ICU, at the very least, reaching to something like zosyn, because it's going to give you that enterococcal coverage, as opposed to if you're a shop that predominantly runs things like vanccefepime or vancmero, you're not going to get your enterococcal coverage as well with that. The zosyn's going to give you that enterococcal coverage. You're hoping you get there with the vanco, but that's not a drug that often gets to level very quickly, depending on how you're dosing it. We're going to jump over to hepatorenal syndrome. This is a very busy slide. I just put it up there mostly to draw attention to how awesome that table is with the little arrows everywhere. All that really says is this, if you have cirrhosis and acute kidney injury, and you're worried it might be hepatorenal, give them volume. If the creatinine is still going up, give them some more volume. And at least in cirrhosis and in liver disease, we do not shy away from our albumin. We love our albumin. Albumin is wonderful for serotics. So this is where you're going to give that salt-poor 25% albumin. You give it, creatinine is still going up, give it again. So this is one day of resuscitation, creatinine going up, another day of resuscitation. That seems to be the primary sort of like, okay, now I'm in my hepatorenal syndrome category. I've resuscitated, they're intravascular. Serotics in general are volume up, right? They're total body volume up, but they're often intravascular volume down when they come in critically ill. And you can check your urine studies. Every cirrhotic, no matter how volume up, always looks like they're dry because of their splenic vasodilation. They're kind of hyper perfusing that kidney. And that leads you down to the ultimate diagnosis of hepatorenal syndrome. Big deal for the pharmaceutical companies, turlopressin, right? So vasopressin, bad. Vast trial, oh, no, we don't like vasopressin. No, turlopressin is the new one. It's now, you know, not generic. So, hey, we love this one. Turlopressin came out for hepatorenal syndrome. Gangbusters drug. Does wonderful as long as your patient's not that sick, right? So works out beautifully for those grade one and two. So if you all remember the acute liver function grade, acute on chronic liver failure grade is essentially the number of organ systems in addition to liver that have failed. So if you're a one or a two, hey, good, you're fine. We give you the turlopressin, that's the purple group. Everything goes well, everybody's happy. The problem is, so you reverse your hepatorenal syndrome. Not so great in the grade threes. What's more worrisome, and now the difference between the green and the gray is now at the start and at the end, is the rate of liver failure or the rate of respiratory failure that developed with the turlopressin that was used to reverse the splenic vasodilation, perfuse those kidneys. All of a sudden they're seeing a signal of respiratory failure. And when you look and see who was having the respiratory failure, the purple is the one and twos, the gray is the threes, people who are grade threes. Anybody who's a grade three, anybody who's in an ICU, you do not give turlopressin to reverse hepatorenal syndrome because they get severe volume overload, respiratory failure, and mortality. So if in the rare situation, so there's your death at 30 days, not a subtle finding. Now, might you have that grade one, two liver failure patient with hepatorenal syndrome who hops into your ICU for another reason? Maybe, just be really, really careful about the use of turlopressin in the critically ill patient. There's a very, very strong signal of volume overload, respiratory failure, and mortality in that population. All right, and that's your rock curves there. All right, so that's our run through acute on chronic liver failure. I'm gonna try and make our plan everybody happy. So I'm gonna try and do it in 25 minutes. So we're gonna jump onto acute liver failure. Acute liver failure is a vastly different beast than acute on chronic liver failure. We see a lot less of it in general. Hopefully it's reversible with the appropriate management, depending on the ideology, but it's also one where if you can stabilize the patient and they're not reversing, there is a significant opportunity to save that patient if you can get them to a transplant center, right? Acute liver failure patients in particular, you have a double duty. One is to figure out how to reverse it. And if you can't reverse it, stabilize it and figure out how to get them to a transplant center. Because acute liver failure patients, unlike acute on chronic who are waiting on the list and like getting a spot based on their MELD, acute liver failure patients jump to the top of the list and we can get them transplanted very quickly. It's a life-saving intervention in that context. Hyperamine and acute liver failure patients are not just inexperienced acute on chronic liver failure patients. They are a vastly different physiology and they are exceptionally unforgiving in general when it comes to that. One just quick caveat, I jumped over it when we talked about ideology. I do wanna put a random plugin because I think this is actually one of the benefits of society meetings. Ideologies for acute liver failure, often Tylenol in specific environments, hepatitis A, hepatitis C. In our own shop, we have diagnosed acute liver failure secondary to herpes simplex virus in otherwise healthy patients. About, I've got two diagnoses just in the last couple of months. It is a hard diagnosis as hell to make because you either have to get that acute liver failure patients stabilized enough to get a liver biopsy while we're sorting them out for transplant, or you have to think ahead and send off your herpes simplex virus viral load. So the PCR, which for most centers is gonna be a three to five day turnaround time. The only reason I put that plug out there, it's in the case report level. So there's probably about 15 to 30 of these cases out there. The fact that we've seen two or three in the span of six months is weird. And it's partly because we've started looking now. And so I think it's worth thinking about primarily because it is a treatable ideology. You have acyclovir. So slap that acyclovir on and go hunting for it. Acyclovir is fairly benign in these categories. You're gonna be resuscitating. The kidneys are gonna be injured for another reason. Take it from an ID doc. It's worth looking for that. But just something to throw out there. Hyperammonemia. In the acute liver failure patient, the thing you have to worry about is these patients do not tolerate the inflammatory cascade that drives from this. This is not solely that the liver is not processing protein and you're developing ammonia. There's a whole cytokine release inflammatory cascade happening due to the liver damage. You're having significant inflammation and leakiness of that blood-brain barrier. And the risk of increased intracranial pressure in these patients is incredibly high. The pathway of sort of ammonia converting to glutamate causing inflammatory cascade, astrocyte swelling. So not only do you have cerebral edema due to sort of that blood-brain barrier breakdown, but you have inflammation in the neural cells themselves. And this is the primary mechanism by which, or one of the primary mechanisms by which acute liver failure patients have mortality. They develop cerebral edema and they herniate. Now, in that setting, the standard of care, the best intervention to reduce hyperammonemia is going to be continuous veno-venous hematofiltration. And the primary reason that we mentioned this, and it's worth knowing this, acute liver failure patients do not generally like lactulose, right? So lactulose is wonderful in acute on chronic liver failure patients, but in an acute liver failure patients, your chances of giving that patient an ileus is, it's not that you can't use it. You can certainly try a little bit of lactulose, but you very easily can shut down their GI tract. And now you're in trouble if you're trying to manage that hyperammonemia and they jump very quickly. These guys will get hyperammonemic and cerebral edema very, very quickly. When we look at the clearance of ammonia when we use CVVH. So one, you know, here it's the association of encephalopathy and ammonia in the acute liver failure patients. As they, unlike the chronic liver failure patients, they're not going to tolerate 100, 150, 200. Once you start getting in that range, you're going to have significant issues with cerebral herniation. To the right there is a study specifically looking at the development of cerebral herniation in patients with acute liver failure and looking at the range of ammonias. Roughly around 150 is where that break happens in that population. And so the most recent guidelines in the acute liver failure patient, when your ammonia has got 150, you really want to start thinking about CVVH to clear that ammonia. Now, I would argue you want to think about it a little sooner. CVVH works very quickly for ammonia. It doesn't work like that though. When I did go hunting for lactulose in the acute liver failure patient, there's very little literature on that population. In fact, this is essentially just a snippet out of case presentations, poster presentations at a prior GI conference. And essentially it may have a little bit of benefit, might buy you a little bit of time, but it's not going to get you there kind of thing. Studies of renal replacement therapy on hyperammonemia. We can thank our colleagues in Australia. They have the phenomenal Australian research network across I think something like 17 ICUs. This was really not so much to my mind. They didn't really, there's not a randomized controlled trial. This wasn't comparing CVVH to not CVVH. This really just showed their experience and how they're able to clear ammonia in patients who are receiving CVVH. And it's a pretty impressive reduction in hyperammonemia. So patients who got up to that 150 range within the span of a few days easily could keep them below that. And in doing so, they were able to kind of give a pretty significant liver transplant free survival in those with acute liver failure who had that ammonia level up to 140. So along those lines, the injury in the context of acute liver failure is not just that the liver is not working. It's a profound hyperinflammatory cascade. And that inflammation leads to not just the cerebral edema, you have end organ damage and you have pretty profound coagulation dysfunction that is not solely reduction in the production of coagulation compounds from the liver. It's actually a consumptive process, the development of a pretty significant DIC. And so the thing I'm going to finish on now is really what I found the most interesting recommendation out of the most recent guidelines and some of the literature around that, which is the use of therapeutic plasma exchange in the management of acute liver failure patients and the impact on outcomes. So this is now from the SCCM this past year's guidelines. When available, plasma exchange in critically ill acute liver failure patients that develop hyperammonemia. Now it's not just for the management of hyperammonemia, but they kind of use that as their cutoff for those that are that severe. Just a show of hands, how many people who have taken care of acute liver failure patients, how many have placed them on plasma exchange? That's what I thought, right? So we've got one. This is actually something I think is worth considering and thinking about and I'll show you the literature on it. It's now made its way into the recommendations. The primary limitation is the availability to my mind of plasma exchange, right? That's often a limited resource, but I'm going to touch on that at the end as well. All right, so the first study I'm going to present here is the use of a standard volume plasma exchange in acute liver failure. These patients were, this one is the, let's see. Yes, this is the Indian study. Can you go back one slide? So this was done in Southeast Asia, in general young population, not uncommon when we're talking about acute liver failure. These were generally young patients. They all had grade three, four hepatic encephalopathy. They were all intubated. They, about half of them had acute kidney injury, about all of them had SERS physiology. The predominant mechanism here was hep A and hep E. The reason I've draw that out, one of the big questions around using plasma exchange has been about the immune dysfunction initiated by that, the risk of that in somebody who's got, let's say, a viral infection. These were predominantly viral infection patients. And interestingly enough, 21-day transplant-free survival was significantly improved in patients who received the plasma exchange therapy. And not only did you have improved survival, but a lot of the parameters with respect to what we consider decompensated liver failure were significantly resolved. So you look here, this is just looking at the INR over the span of the first seven days and those that were receiving the plasma exchange. Now again, often what you're running the plasma exchange against is FFP, so yeah, you're correcting it externally. But then if you look at things like the ammonia, significant reduction. Look at the overall lactate, significant reduction. If we use that as a marker of endorgan perfusion, look at the overall SOFA scores, marked reductions. That study didn't look at the presser requirements, but the next one I'm going to show you is done in a more resourced environment. This is, I think, a UK study. Slightly older population, and not surprised, by about a decade. Similar degree of severity. You've got grade three and four hepatic encephalopathy making up the vast majority of these patients, a lot of them being on mechanical ventilation, a lot of them on vasopressors, so similarly sick. The vast majority of these were paracetamol, acetaminophen toxicity patients, so difference in that environment. And similarly, in those that received, this was high volume plasma exchange as opposed to standard volume plasma exchange, a marked reduction in the hyperammonemia, a marked reduction in the INR, a marked reduction in, so stabilization of the overall map didn't really look different between the two. But when you look at the administration of the, that's noradrenaline, because this is across the pond, and they use their micrograms per kilogram per minute, so marked reduction in the amount of pressure requirement these patients required, and again, a increase in transplant-free survival. So in the specifically acute liver failure patient who is decompensating despite your management, so you're doing your standard NAC for your acetaminophen overdose, you're trying to manage, if there's a viral ideology you can manage, and it's responsive to therapy, fine, most of those are not responsive to therapy. In those patients who are continuing to decompensate, there does seem to be a potential role for the use of plasma exchange. Now, how do we get around the fact that you kind of have to have access to a bunch of pharesis to be able to do that? Our institution, we're a coordinate care center, we've got two dedicated surgical ICUs, three dedicated medical ICUs, a trauma ICU, a cardiac surgical ICU, a neuro ICU, we have a freestanding cancer hospital, we've got four pharesis machines and one nurse to run the four pharesis machines, and you're not going to do that anytime between nine, the only options are between 9 a.m. and I think 3 p.m. on a Monday through Friday, unless it happens to be the third week of the, it's not something you can deploy in a critically ill patient all the time. In fact, we have a very hard time doing it for the liver failure patients. Interestingly enough, it appears that there may be a way to do pharesis using your standard CVVH setup. We're looking into it. Anybody who's doing it, I would love to talk to. That may be the next iteration of this, because if we can do pharesis using the CVVH machines, from a resource perspective, our ICU nurses run the, they're the ones who are doing the CVVH machines. And we have a lot more of those machines than we have pharesis machines. So something to kind of leave you on as a interesting next steps. But with that, thank you very much. Thank you.

acute liver failure

acute on chronic liver failure

management strategies

organ failure

complications

therapeutic plasma exchange