Welcome to the Society of Critical Care Medicine, Critical Care Congress, and the Critical Care Congress pre-course. My name is Dr. Paritosh Prasad. I'm the Director of Surgical Critical Care at the University of Rochester, and I'm going to be speaking today about critical care updates for acute liver failure and acute on chronic liver failure. I'm going to begin with, I have no disclosures. A quick overview of what we're going to talk about today, we're going to touch base on some basic definitions between acute liver failure and acute on chronic liver failure. These aren't new or have not changed, but I think they provide a valuable starting point for the discussion. We'll go into the evolving epidemiology around both acute liver failure and acute on chronic liver failure, and then move into advances in management. With respect to acute on chronic liver failure, we'll focus on three major disease processes that complicate acute on chronic liver failure, hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome. We'll move on to acute liver failure and discuss hyperammonemia and intracranial pressure management in those situations, as well as the severe cytokine release syndrome that can follow acute liver failure and some management options on that front. And we'll conclude with questions. So, as I said, we're going to begin with definitions. Acute liver failure and acute on chronic liver failure are distinct pathophysiologic etiologies. Much of their clinical presentation can be quite similar, and their biochemical presentation with respect to laboratory evaluation can be indistinct from each other. But it's very important to understand the distinction between these two disease processes because it severely impacts the course of the patient's care, as well as the types of interventions one would utilize to stabilize in each of those situations. Acute liver failure really is a patient who begins with essentially normal hepatic function. They may have had a history of hepatic injury for other exposures, but ultimately normal hepatic, synthetic, and metabolic capabilities that are then acutely impaired in the context of either an infectious process, vascular process, toxic exposure, etc. Acute on chronic liver failure is deterioration in a patient with a history of or existing liver disease. I modify that because where the confusion often arises in clinical evaluation is patients may not be aware of preceding liver disease and liver damage. They may have cirrhosis physiologically for the preceding several years without clinical symptomatology that has come to the point of ultimate diagnosis. And in that setting, acute on chronic liver failure is really the clinical presentation of a patient with cirrhotic physiology and additional acute decompensation on top of that additional organ systems that are dysfunctional in that state. This is where the timing of onset can get confusing only because what the patient perceives and what's been going on physiologically in the patient may be quite, quite distinct. It is not an uncommon situation where a patient presenting in fairly severe acute on chronic liver failure will either they or more likely their family will adamantly tell you that they were totally healthy and had no medical problems preceding that. The review of prior data, classically imaging, may indicate a longstanding presence of hepatic disease and cirrhosis. Acute liver failure on that front is actually parsed temporally into four subcategories. Probably the most commonly encountered are the hyperacute acute liver failures. This is a classic Tylenol toxicity, though acute hepatitis A and acute hepatitis E virus infection can also create clinical presentations of that degree of acuity. Acute liver failure, that category is the less than one month disease process. This is a wider scale of both infectious and autoimmune physiology as well as some toxic ideologies. Hepatitis B specifically with hepatitis D super infection can create acute onset within the four weeks for acute liver failure and reactivation of certain endogenous reactivation or primary infection with certain human herpes viruses, HSV, CMV and EBV can also create acute liver failure. Amanita's mushroom poisoning is an important ideology, obviously not terribly common, but management does require detoxification and the use of things like milk thistle in that context. And then a slew of autoimmune conditions that would be managed, particularly in the context of autoimmune hepatitis with steroids. So important to delineate ideology because it directly impacts management decisions. The majority of the subacute and late onset acute liver failure are going to be associated drug-induced liver injuries. These can sometimes be the most difficult ideologies to tease out, both because of the subacute nature can go up to about six months and the difficulty in teasing out the history and the association. Chronic liver failure, acute and chronic patients tend to have some exposure or history prior alcohol mediated disease and non-alcoholic steatohepatitis being the two most common ideologies, particularly in the US. Hepatitis C fortunately is a waning ideology in the presence of the new regimens for curative therapy, which are oral can be done outpatient. Chronic hepatitis B, particularly vertical transmission, remains a significant issue globally, particularly in Southeast Asia. And then the autoimmune ideologies of primary sclerosing, cholangitis, and primary biliary cirrhosis are fairly stable in their overall prevalence. Clinical presentation and laboratory evaluation, as I mentioned, can be quite similar. Chronic liver failure patients' cirrhotics will have stigmata, often of cirrhosis that would not be present in the acute liver failure patient. But it is important to recognize that no two cirrhotics present the same. The liver is a complex organ. Depending on where exactly within the hepatic structure primary damage has occurred over time, you can see a wide variety of metabolic and synthetic impairments with respect to coagulopathy, encephalopathy with respect to cholestasis and jaundice. Which I think is one of the reasons why it can sometimes get a little blurry, the distinction between the acute liver failure and the acute and chronic liver failure patients. Again, history is incredibly important in these settings. Acute liver failure patients, primarily, it's a lab finding of severe elevation of AST-ALT that will draw your attention. But the indication that it's a failure state is where you see the dysfunction with respect to encephalopathy, coagulopathy, the development, jaundice, really the indication of the cholestasis. The definition of fulminant acute liver failure really is driven by the encephalopathy component. That is the marker of severe disease, significant risk for morbidity, and particularly for mortality. And that's the indication, if at all possible, to get that patient both stabilized and to a center that has the capability to evaluate, list, and transplant that patient to change their ultimate outcome. As I mentioned, the laboratory evaluation is fairly similar between the two with respect to the markers for synthetic function, coagulopathy, with respect to cholestasis. The thrombocytopenia in chronic liver failure is often driven by splenomygaly and sequestration. It's important to recognize, however, that in acute liver failure, as in any acute systemic multisystem organ failure state, you can see acute onset thrombocytopenia, so that those can't be clearly distinguishing categories between the two. And then from an imaging perspective, it's important to recognize imaging plays a different role in the two disease states. In acute and chronic liver failure, imaging often indicates the chronicity of the liver disease, demonstrating scarring and nodular findings. It's often used in the setting of cirrhosis also to screen for the development of neoplastic consequences. In acute liver failure, the primary reason to utilize the imaging is really to evaluate the vasculature and identify any potentially reversible etiologies of acute liver failure, hepatic vascular thrombosis, which can either be arterial, which can lead to the acute liver failure, or less commonly, portal venous thrombus in a healthy person, which, again, which will create a liver failure state. The acuity will be less, however, than an arterial thrombus. Moving on to the evolving epidemiology, the changes here are predominantly in acute liver failure. It's worth noting that there is a bit of a distinction in resourced environments. The most common etiologies for acute liver failure have generally been toxin-mediated. Tylenol is the leading etiology in the US and in UK and Australia. It's an interesting signal. In China, there's a higher rate of drug-induced liver injury, a wider range of agents in that setting. In low- and middle-income countries, the hepatitis viruses remain significant contributors, hepatitis A, as I mentioned, hepatitis E. And then in environments with limited diagnostic capabilities, not inconsequential rates of unknown etiologies. And again, it's hard to parse what falls within that unknown category. As I said, drug-induced liver injury is often a very difficult diagnosis to make. With respect to acute and chronic liver failure, it's not really so much that there's significant changes in the etiology. It's still very much alcohol and now rising rates of non-alcoholic steatohepatitis-mediated disease. But prevalence of acute and chronic liver failure remains very, very high across the globe, and the mortality associated is pretty significant. So this remains a pretty challenging disease process and one that I suspect all present and are involved in have run into or will run into in their critical care careers. To that end, we'll kind of move on to advances in the management of acute and chronic liver failure. And we're going to start with hepatic encephalopathy. As you all might already have learned across the course of your training, hepatic encephalopathy is a complex interplay of impaired metabolism, toxin clearance in the setting of hepatic dysfunction, the setting of cirrhosis. We classically measure ammonia and look for asterixis, the flapping of the hands. But it's important to recognize that our evolving understanding of hepatic encephalopathy includes a whole slew of altered neurotransmitters, some of which suppress neuroexcitation, some of which increase neuroinhibition. A whole slew of neurotoxins, especially from the gut, that fail to be cleared by hepatic metabolism, all of which ultimately result in reduced brain energy metabolism, impaired blood-brain barrier function, and ultimately lead to the clinical presentation of hepatic encephalopathy. Very common finding, floors, often an ideology to come to the ICU in the setting of inability to protect airway. Management, we talked, there are the Society of Critical Care guidelines for the management of acute liver failure, acute and chronic liver failure that came out in the past year. And no major surprises there, but the one I want to focus on is at the bottom. The nonabsorbable disaccharides, that's your lactulose standard of care, fairly widely utilized. The addition of oral rifaximin, we'll talk a little bit about the data as to where that acts as an adjunct or how that acts as an adjunct. But what I want to zero in on is the addition of using Lola, which is L-ornithine, L-asparaginase. And that's not a newcomer to hepatic encephalopathy management, if you do any of this in the context of urea cycle defects. It's a fairly commonly utilized therapy in pediatric hyperaminemia, but one that's now demonstrating significant benefits in acute and chronic liver failure patients as well in adults. So starting with the nonabsorbable disaccharides, well, this is your lactulose, very nicely done large systematic review and meta-analysis, clearly demonstrating the benefit of using lactulose in the management of overt hepatic encephalopathy across the severity of disease. To the right, you'll see the similar systematic review meta-analysis here of rifaximin. Again, it's important to recognize the rifaximin study is really a study of rifaximin added to lactulose and utilized primarily in the aversion, in the avoidance of the development of hepatic encephalopathy. So lactulose is a management for hepatic encephalopathy, and then rifaximin is an adjunct, which has demonstrated improved control in that context. Where I did want to kind of focus on is L-ornithine, L-asparatate. This is an enteral, well, this is a both intravenous and enteral therapy that modifies ammonia metabolism pathways. And in a very nicely done study back in 2022, it was demonstrated patients receiving IV L-ornithine L-asparatate with clinical presentations of grade three, grade four encephalopathy versus placebo demonstrated significant reduced mortality associated with the IV Lola administration. Looking at this in the context of systematic reviews and meta-analyses, a handful of studies and very clear evidence favoring Lola over placebo. Again, not a head-to-head study of Lola versus lactulose, but demonstrating the clear efficacy of Lola in this context. And the study you see there on your right, that's specifically looking at the ammonia lowering capabilities of Lola. But as we know, hepatic encephalopathy is not purely about ammonia management. And really what you want to think about is the encephalopathy as a whole. And looking in that context, IV Lola, the top Christmas tree plot there, demonstrates the benefit of intravenous Lola compared to placebo with the management of the encephalopathy, of hepatic encephalopathy. Now, in that context, that study, when we look at the cumulative effect, it did touch one. So it's beneficial, though there includes some potentially clinically non-significant findings there. What's intriguing and what's of utility, at least for those of us who practice in the U.S., intravenous Lola is not available in the United States. However, oral Lola is, and the mechanism of activity requires it to act at the gut membrane. And so, and oral should be as effective as intravenous with respect to absorption. And that plays out in a handful of studies that have also been evaluated by systematic review and meta-analysis. That's the category C there, which demonstrate very clear, significant improvement in encephalopathy in patients who received oral L-ornithine L-aspartate, arguably a more clear-cut benefit than intravenous. And this actually led to now addition of Lola in addition to lactulose and rifaximin as our management of severe hepatic encephalopathy in critically ill patients. Moving on to spontaneous bacterial peritonitis as our second complication of acute on chronic liver failure that we're going to discuss. Again, this is a complex interplay of a number of the pathophysiologies associated with cirrhosis. The portal hypertensive physiology leading to the development of acidic fluid. Acidic fluid tends to be hypoprotonemic, low opsonins, impaired immune function. Similarly, the portal hypertension leads to gut edema impairment in the tight junctions of the gut and allowance of bacterial translocation. And then there is evolving data on the dysbiosis of cirrhosis, the modification of the intestinal microecology, all of which leads to increased intestinal bacterial translocation across the mucous membranes into the mesenteric lymph nodes and ultimately into the peritoneal fluid, which is the setup of spontaneous bacterial peritonitis. Here, the guideline update that I wanted to identify and talk a little bit about was the recommendation in the past year for the use of broad spectrum antibiotic agents in the initial management of SPP in critically ill acute on chronic liver patients. Most spontaneous bacterial peritonitis, the recommendation is for third generation cephalosporins like ceftriaxone. And while it's not uncommon for us in the critical care environment to use broader spectrum agents, I think it's important in the evolving space of antimicrobial stewardship to understand why and when we would use broad spectrum agents and what the data is behind that. This is another systematic review looking at bacterial spontaneous bacterial peritonitis, but in the air quotes era of multidrug resistant pathogens, these are studies that pretty much are all the vast majority with the exception of Song et al were in the 2000s. Essentially, they were looking at what was described as nosocomial spontaneous bacterial peritonitis. I draw attention to that only because their definition was spontaneous bacterial peritonitis identified within greater than 48 or 72 hours after admission. A fair number of those, I think there's going to be some overlap with what many of us would call just spontaneous bacterial peritonitis, depending on when the actual diagnosis is ultimately made. And this spans centers in North America, Europe, Southeast Asia. And when we look at the results from this systematic review, what I want to draw your attention to is the frequency with which two categories of pathogens were identified. Now, in this, in this particular paper, the GPB, for those of you in the infectious disease world, GPB, we often think of gram positive, but still I hear it actually means gram positive bacteria. So really what the GPBs are primarily drawing attention to are the presence of gram positives and specifically enterococcus. And the reason it's important to recognize or to identify enterococcus as a pathogen in the context of spontaneous bacterial peritonitis is the classical management with ceftriaxone is not going to reduce, is not going to treat, is not going to manage enterococcus. Enterococcus is not ceftriaxone susceptible. And as you see across these studies and those that reported data on their cultures, anywhere between a third to two thirds of the isolates had enterococcus in these nosocomial spontaneous bacterial peritonitis cases. And again, the description of nosocomial really applied to SVP diagnosed after 48 to 72 hours of clinical presentation, which I would argue is not an inconsequential number of those patients that ultimately present to critical care with spontaneous bacterial peritonitis. The second and within that group of gram positive bacteria, the enterococcus, those that actually went into susceptibility data demonstrated anywhere between a third and a half with degrees of resistance. And as everyone here knows, enterococcus, we worry about the potential for vancomycin resistance, particularly enterococcus fascium. We worry about vancomycin resistance. And in our own environments, we've seen not just vancomycin resistance, but daptomycin resistance beginning to evolve as well. Moving on and looking at the gram negative pathogens, there were actually a significant number, not just of gram negatives, but of multidrug resistant gram negatives. With the rate of multidrug resistant bacteria ranging anywhere between a quarter to three quarters of pathogens and multidrug resistant gram negatives, in particular, ranging anywhere between a third to two thirds of pathogens. In this context, I would make the argument that your better option with respect to empiric management of spontaneous bacterial peritonitis in the setting of a critically ill patient, and particularly one that may have developed their spontaneous bacterial peritonitis more than 48 or 72 hours into their initial hospital stay, is better served with an agent that's going to give you some broad spectrum gram negative coverage, give you some enterococcal coverage. Very much depends on your institutional antimicrobiogram, but we, in our own experience, have found zosyn, piperacillin, tezobactam is a good option in this context, both because of the enterococcal coverage with the piperacillin and the broad spectrum and gram negative coverage with the addition of the beta-lactamase. Obviously, your choice should be driven by your own antimicrobiogram. Moving on and completing the acute on chronic liver failure conversation with hepatorenal syndrome, there's a very nice review of hepatorenal syndrome published in the New England Journal earlier this year. Definitely worth a read for those of you like myself who have a hard time understanding exactly what hepatorenal syndrome is and how to diagnose it. I put this up here. It's a busy slide, but what I wanted to kind of concentrate on is the diagnostic algorithm that's presented on the right. Hepatorenal syndrome remains this combination of, we think, impaired profusion of the kidney in the context of splenic vasodilation, decreased oncotic pressure. There's probably some component of irritation, inflammation from elevated bilirubin and bile salts, all of that coming together with a primary focus on profusion aspect, leading to impaired renal profusion, renal vasoconstriction, decreased renal blood flow and hepatorenal syndrome. With respect to the diagnosis, the flowchart on the right, if you really work it through, it kind of comes down to this. If your patient with cirrhosis presents with acute kidney injury, give them fluid. There's a recommendation in there for using 25% albumin. Do that for about a day. A gram per kilogram is what they include in their algorithm. And if over 24 hours the creatinine is still going up, well, do it again. Give it another day. And if the creatinine is still going up, then after you've pretty much ensured the patient's volume status is repleted, go ahead and check some urine studies. And they recommend fairly strict criteria. I mean, anybody who's ever checked a FINA in a cirrhotic will know they all look like they're pre-renal even when they're not. Primarily due to this splenic vasodilation renal hypoperfusion state. And they purport using a FINA less than 0.1% or a FeREA less than 21%. We don't use a urine albumin, but it's an option as well, less than 44. And in those settings, that kind of leads you to the diagnosis of hepato-renal syndrome. Now, the only reason I kind of go into all of this is the other major advancement in the management of cirrhosis and particularly hepato-renal syndrome in the last year was the groundbreaking data on, in the last couple of years, the groundbreaking data on terlopressin for the management of hepato-renal syndrome. I'm gonna talk about it here. Hopefully those of you who know the arc of this literature know this is not something we should be doing in the intensive care units, but I'll talk about why that is. These were, the confirmed study was a remarkable randomized control trial looking at the use of terlopressin against a standard of care for the management of hepato-renal syndrome. There's not really a clearly defined standard of care essentially. But in this setting, terlopressin was demonstrated to significantly reverse hepato-renal syndrome in patients with hepato-renal syndrome. Not only demonstrated as a primary endpoint, but with respect to its secondary endpoints, need for renal replacement therapy, mortality, significant reductions across the board. Touted as a absolutely phenomenal intervention, led to FDA approval. And of course, those of us who live in the intensive care environment, we see no shortage of acute renal failure in our acute and chronic liver failure patients. It's probably the most common organ system to go down, leading to patients to come into critical care management. What was really, I think, beneficial is within the year of the confirmed study coming out, a analysis of the confirmed data really looking at the different severities of acute and chronic liver failure. The grades one through three, these are the acute liver failure severity classifications. Each grade, the number reflects the number of organ systems in addition to the liver that are impacted. And what this group demonstrated looking at the data from confirmed, this is really a reanalysis of the confirmed data, demonstrated that the significant benefit with respect to reversal of renal failure with turlopressin was only demonstrated in grades one and two acute and chronic liver failure, the less sick patients. Patients with grade three or higher acute and chronic liver failure did not demonstrate a benefit with the administration of turlopressin. More importantly, when you looked at complications in those populations, what you found was that there was a significantly higher rate of renal failure or respiratory failure in patients who had received turlopressin management. And this was something that developed, was not present at the initiation of turlopressin, but developed afterwards. And so you can see that this is across all comers. When you break into that signal of respiratory failure more closely, what you find is that that was primarily driven by the grade three, the more severely ill, acute and chronic liver failure patients. Turlopressin leads to volume over essentially reversing that hypoperfusion at the kidney, but it's associated with marked fluid overload and respiratory failure, particularly in more severely ill liver failure patients. And so turlopressin while approved for use on medical floors is not approved for use in the context of critically ill, acute and chronic liver failure patients with high grade acute and chronic liver failure. And in fact, there's a very significant mortality association as well in those high grade patients with the association of, with respect to the administration of turlopressin. No deaths in the placebo arm for the grade three patients, nine deaths in those that received the turlopressin. So a phenomenal advancement in the management of hepatorenal syndrome, but unfortunately one that is not of clear utility. In fact, as seems to be of significant detriment to our critically ill, acute and chronic liver failure patients. And this is the Kaplan-Meier curve where you can very clearly see the increased mortality associated and sustained over time in the grade three acute and chronic liver failure patients who received turlopressin compared to placebo. So with that, we're gonna move on to advances in the management of acute liver failure. As I mentioned, acute liver failure is much less frequent of a clinical presentation than acute and chronic liver failure. There are many aspects that are similar, but at heart, these are pathophysiologically distinct conditions. One area in which I think that distinction is most significantly highlighted is in the development and how the body manages hyperammonemia. Now, as we discussed earlier, it is a complex interplay, but in the context of acute liver failure, the primary issue is acute loss of a significant percentage of hepatic ammonia clearance, both via the urea cycle and by glutamine synthetase metabolites. So in the context of acute liver failure, the primary issue is acute loss of a significant percentage of hepatic ammonia clearance, both via the urea cycle and by glutamine synthetase metabolites. a clearance mechanism is via glutamine synthetase activity, which is of course limited. In the cerebral circulation, ammonia can activate the NMDA receptor, further activating calcium release and glutamate with a self-amplifying loop that can lead to excitatory activation and ultimately lead to reactive nitrogen and oxygen metabolites, which can lead to mitochondrial dysfunction, dysfunction of volume regulation, and all of these things ultimately lead to astrocyte swelling to cerebral edema. The elevated ammonia impairs tight junctions at the blood-brain barrier, impairs adherence, and ultimately allows breakdown of that blood-brain barrier and the migration of small molecules increased in the circulation in the context of the acute liver injury to penetrate the cerebral circulation and drive excitatory neurocytotoxic clinical presentations that lead to astrocyte swelling and ultimately increase intracranial pressure. Now, while this is not stated as a specific point, a specific recommendation in the guidelines, if you actually read the text of the most recent SCCM acute liver failure, acute and chronic liver failure guidelines, this sentence is right there in the text, continuous renal replacement therapy remains first-line treatment for hyperammonemia and often used in the absence of kidney injury. This is something that is kind of standard of care in our environment with respect to the management of our acute liver failure patients, but I've found in my own practice, and we're a referral center, we're a transplant center, so we often will take transfers from outlying hospitals, the recognition that in acute liver failure, unlike acute and chronic liver failure, in acute liver failure, your primary mechanism for management of the hyperammonemia, which is a primary driver of mortality, is continuous renal replacement therapy, an intervention that's not as widely available across the critical care landscape as one would hope, that recognition is lacking. So I draw it out just so that everyone sees this. If you have an acute liver failure patient and they're moving to a fulminant liver failure patient, you have the encephalopathy, you see an elevated ammonia, you really want to think you need to get CVVH up and running, and if you don't have it available, you really need to make significant efforts to get that patient to a center that does have that capability. The data on this, and I'll highlight a couple of older studies, is a fairly well-recognized capability that, or a fairly well-recognized association between arterial ammonia and the development of intracranial hypertension, which is a significant mortality marker in acute liver failure. This study by Bernal et al. looked at 165 patients with acute liver failure and tracked the frequency with which intracranial hypertension developed and associated with, in the context of specific levels of ammonia, and as you can see, the rate of intracranial hypertension significantly jumps as the ammonia level goes from 100 to 200, and then those above 200, the vast majority, actually developed intracranial hypertension. This is following on work done by Otto Clemmensen et al., who also looked at a smaller population of patients, but specifically looking at ammonia, arterial ammonia, as an indicator or predictor of the development of cerebral herniation in the context of increased intracranial pressure. As you can see, a pretty significant distinction between the two populations, a little bit of overlap, but the ammonia of 150, which is touched upon in the guidelines as an indication for the deployment of intervention, the description of hyperammonemia being above 150, I think is driven by this finding in particular, that it acts as the distinction point between which you kind of end up in patients above 150 who have a high likelihood of developing significant complications, increased intracranial pressure and cerebral herniation that warrant aggressive management if you want to avoid morbidity and mortality. Now, the role of lactulose, you may or may not have heard the old song, lactulose doesn't work well in acute liver failure patients, and it's true if you look at the literature, there really is not a lot of data on the use of lactulose in patients with acute liver failure. Lactulose therapy, when used acutely in a non-cerotic, can be complicated, will often be complicated by the development of ileus, which can be a devastating complication in this context, not only because the patients will aspirate and end up on the ventilator, but especially if you're worried about increased intracranial pressure and herniation, aspiration is the last thing you want to have to deal with. If you really comb the literature, the best you can find, or at least the best I could find, with respect to lactulose in acute liver failure patients was actually an abstract from the Mayo Clinic, and this is two decades ago, essentially demonstrating lactulose did not improve outcome in ALF patients, but the intriguing sort of indication that those that did receive it survived longer than those that not, again, I think highlighting the significant association between hyperaminemia and increased intracranial pressure, increased intracranial pressure and cerebral herniation being the primary drivers of mortality in acute liver failure. So I guess something is better than nothing. I think you have to be very judicious with it with respect to trying to avoid the development of ileus, and again, if anything, only using it as a temporizing agent to get that patient to definitive therapy with continuous venal venous hemofiltration and potentially to a site that has, ideally, to a site that has transplant capabilities for evaluation. The role of CVVH, I think, is highlighted by the Amalfi study. This is an Australian study. It really is more of a descriptive evaluation. So the Australian critical care landscape has a phenomenal research capability, 65 ICUs that collaborate and often address very, very pertinent critical care issues. This, in particular, was a study on the role of continuous renal replacement therapy and its effect on hyperaminemia in acute liver failure patients. These were the 65 centers across Australia. They essentially had data on 36 patients that received CVVH. What they demonstrated over the course of this study was that patients who received CVVH were able to avoid the development of any ammonia greater than 140, again, hearkening back to the data with 140 to 150 being a distinction point, parsing out those that will develop increased cerebral herniation and those that will not. Of those patients across the whole study, eight had levels above 140, and at least once after the first day, only one of them ultimately achieved transplant-free survival. So looking and showing that the CVVH stabilizing and controlling the ammonia, if anything, stabilizes a patient, it doesn't necessarily mean the patient has to go on to transplant. If you can get them through the acute liver injury phase and you can avoid the potential cerebral consequences, it may be a temporizing intervention that ultimately improves outcomes. Now, what we're going to finish up with here is the hard reality that acute liver failure can, in some cases, progress to a completely devastating multi-organ failure state. Now, we often will deal with acute liver failure, especially in the United States, in the context of Tylenol toxicity, if recognized in a timely fashion and managed appropriately with N-acetylcysteine. The vast majority of these patients will do rather well, will not go on to need liver transplant, etc. A subset of them will, and those with acute liver failure that progress to fulminant liver failure, the development of cerebral edema, will often also have pretty profound multi-organ failure, shock state, acute kidney injury. This slide is an image taken from a recent paper describing our best understanding of why this happens. It's pretty much a consequence of cellular death at the liver, release of a whole significant quantity of inflammatory markers, which then activate vascular injury, ultimately leading to cerebral edema, acute kidney injury, cardiac dysfunction, etc. What this particular diagram is showing is that these damage-associated molecular patterns and these inflammatory molecules, the cytokines, if you can potentially mitigate these in the circulation, if you can clear them from the circulation, you can mitigate the development of the end-organ damage, the cerebral edema, acute kidney injury, cardiac dysfunction. It's an interesting concept, and one that actually has had a significant amount of study behind it, and enough that it's actually led to a fairly interesting recommendation in the most recent SCCM guidelines, which is essentially that plasma exchange was recommended for the treatment of hyperammonemia and acute liver failure. Now, obviously, at the same time, this is the same document that says CVVH is the standard of care for hyperammonemia in that setting, but I think what this is getting at is in fulminant liver failure patients who are really getting towards that hyperammonemia that's going to drive towards ingestion to cranial pressure and cerebral herniation, marked by that criteria of that cutoff of 150, recommending where available the use of plasma exchange. It's an interesting thing, something that we don't do, have not done up until this point. We use CVVH on all our acute liver failure patients, something that I thought warranted some further evaluation. So there's two major studies in this space that I want to present. The first is a randomized control trial that was published in the last year. This is done in India, and it's a small study, really looking at 40 patients total. And a couple of things I wanted, these are all acute liver failure patients, fulminant acute liver failure patients, all of them had hepatic encephalopathy, 90% had hepatic encephalopathy grades three to four, 90% of them were intubated, but a third had kidney injury. What I want to draw attention to is the ideology of the liver failure here. The vast majority of these were viral hepatitis that I mentioned in the early part of this talk with respect to the epidemiology. Hep A and Hep E are the more common drivers of acute liver failure in low and middle income countries. So these were viral hepatitis. Those patients that received standard volume plasma exchange, so that's essentially plasma exchange done on a daily basis. When we say standard volume, it has to do with the percent body weight of volume that's replaced. They demonstrated out to 21 days a remarkable increase in 21-day transplant-free survival, roughly a 30% mortality reduction, which is actually shocking in the context of a disease process that with standard medical therapy is a less than 50% survival. Some of the markers that were evaluated, again, cannot directly associate any one of these markers to the improvement in their mortality, but I think those of us who care for these patients know what they die of. A very significant reduction in the INR noted in these patients. Now, again, INR is not the be-all, end-all, but it's a surrogate marker of coagulopathy, and this is a significant reduction in the INR, those receiving the standard volume plasma exchange. The arterial ammonias, again, different units than I'm used to in my own center, but a pretty significant reduction in the circulating serum ammonia, and again, recognizing that association between the serum ammonia and the development of interleukin-2 cranial pressure and cerebral hermeneation. Not surprising, the standard volume plasma exchange patients had improved outcomes. Arterial lactate is a marker of end-organ perfusion, as well as in this context of hepatic clearance, markedly improved over time as well. SOFA scores, a marker of their overall critical illness, end-organ dysfunction, hypoperfusion, vasoplegia, again, statistically improved over the span of the first week. So you can say, okay, well, that's great, very clear improvement, but I don't take care of a lot of hep A patients. I don't take care of a lot of hep B patients. It's a small study. Are we sure this is really, is that enough to justify recommending this if it's available? And this was followed, this actually, this study follows a study published almost, not quite a decade ago, but about seven years ago in the UK. And so this is United Kingdom. This is 180 patients receiving, in this case, high volume plasma exchange, about 15% body volume per day with plasma exchange. In this context, the majority of patients were female. Acute liver failure patients, I didn't draw it out on the prior slides, but they all tend to skew younger 30, 40-year-olds. Etiology-wise, you can see these were almost all hyperacutes. And when you look at the etiology, if you look at the little text at the bottom, the vast majority of these were paracetamol. For those of us here in the US, that's Tylenol acetaminophen. So the vast majority of these are Tylenol drug toxicity patients. Again, high rates of grade 3, 4 encephalopathy, high rates of mechanical ventilation, about a third with shock, over a half on vasopressors, about a half with oliguria. So fairly similar populations, but now we've got data on the acetaminophen patients. And again, we see over the course of that first week of therapy, significant reductions with respect to the INR. Not a major change in the ammonia in this study. In the early phase, there was, but it seems like it stabilized out regardless. Changes in the overall mean arterial pressure with patients receiving high volume of plasma exchange having, on average, higher MAPs. These are still pretty high MAPs in general. And NA here is noradrenaline or levophed. Again, dosing is a little different, different units. But overall, hard to justify the difference between zero. It's really the same number in every unit. So very clear improvement in overall vasoplegia as well in these patients. And when we look at the Kaplan-Meier curves, a pretty significant reduction in mortality in the patients receiving high volume plasma exchange. Roughly, again, about a 30% mortality benefit. Actually, in this case, I apologize. It looks like overall survival was improved by a little over 10% in those treated with high volume versus those with control. The area that I was looking at was the survival to transplant. So ultimately, significant improvements in both drug-induced liver injury, virally mediated acute liver failure with the use of plasma exchange. So why aren't we doing this more frequently? There are centers in the US that are doing this. It's a resource issue. Plasma, Pharesis, plasma exchange, depending on your site, it is not necessarily widely available utilized for very specific indications. The reason I bring this up and the reason I brought it at this talk is so we're in the process actually now of looking at utilizing our existing CVVH machines for plasma exchange. It turns out the CVVH does actually have a filter set that can be used for therapeutic plasma exchange. We're in the process of utilizing that to see if we can create a value, manage the same improvement in stabilization in these acute liver failure patients. This is something hopefully that may be more widely available and may allow for the stabilization of these acute patients, either to allow their livers to recover and improve their overall outcomes or to stabilize them for those that won't achieve hepatic recovery, stabilize them enough for ultimate transfer to an evaluation for transfer to centers that have liver transplant capabilities. With that, I will complete our lecture. Thank you for your time.

Dr. Paritosh Prasad

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