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This is the fifth episode of SCCM’s Current Concepts Series, in which authors unveil exclusive insights into the 2024 Current Concepts course. Diane C. McLaughlin, DNP, AGACNP-BC, CCRN, FCCM, is joined by Paritosh Prasad, BA, BS, MBA, MD, to discuss the management of acute and acute-on-chronic liver failure.
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Transcript:
Dr. McLaughlin: Hello and welcome to the Society of Critical Care Medicine Podcast. I’m your host, Diane McLaughlin. Today we’re joined by Paritosh Prasad in the fifth episode of our multipart series discussing the Current Concepts course and text. Get ready to dive into each chapter as we chat with the authors, providing an exclusive sneak peek into their expertise in the course content.
Dr. Paritosh Prasad is director of surgical intensive care in the Divisions of Transplant Surgery, Infectious Disease, and Pulmonary and Critical Care Medicine at the University of Rochester Medical Center. Welcome. Before we start, do you have any disclosures to report?
Dr. Prasad: No disclosures, thank you.
Dr. McLaughlin: All right, excellent. Your chapter is the chapter on acute liver failure and acute-on-chronic liver failure. For people who don’t know, can you explain, what’s the difference between acute liver failure and acute-on-chronic liver failure?
Dr. Prasad: Absolutely. It’s quite interesting because, while it’s the same organ and many of the presentations in acute liver failure and acute-on-chronic liver failure are somewhat similar, they are vastly different disease entities in how we have to manage them. Acute liver failure is really an individual who has normal liver function and presents with severe acute injury to the liver, usually less than 26 weeks of duration. Acute liver failure has a couple different types. Hyperacute, that’s the kind that most people are used to in clinical practice, which is the Tylenol overdose, the acetaminophen overdose. In less-resourced environments, that’s going to be more of an acute viral hepatitis, like an acute hepatitis A or hepatitis E.
Then as we move a little bit further down the time course from hyperacute, you can see acute hepatitis, which is on the order of a couple of weeks, and that’s your standard hepatitis viruses like hep B, hep D in certain environments with patients who’ve got baseline hep B. Some of the less common presentations of the endogenous human herpesvirus are HSV or CMV. Mushroom poisoning is a classic one.
Then there are more subacute forms. That’s really where you’re getting into the, a little bit beyond one month or so of a kind of percolating illness that comes to a head. Those are almost always non-Tylenol-associated drug injuries. These are patients who really, their physiology hasn’t prepared for it, it hasn’t worked its way up to dealing with organ dysfunction, so they tend to have all of the things we expect in chronic liver failure but acutely and they’re not able to compensate for it.
That’s in stark contrast to your acute-on-chronic liver failure. Those are patients who, by definition, have chronic liver failure or cirrhosis, commonly due to either alcoholic injured liver, Laënnec cirrhosis, or a slew of other conditions. One of the more common ones these days is nonalcoholic steatohepatitis.
Those patients with underlying chronic liver disease with cirrhosis, when they have an acute exacerbation, acute injury on top of that, that’s considered acute-on-chronic liver failure. That’s really the majority of what I would imagine most providers taking care of decompensated liver failure patients, in the U.S. in particular, see on a regular basis. They see a lot more of the acute-on-chronic liver failure than they do the acute liver failure.
We’ll talk about some of the presentations, but they’re very similar. Again, these patients have had a chance to kind of work their way up to it. Their bodies have not become cirrhotic acutely. They’ve had time to develop it so their compensatory mechanisms are better developed. They tolerate some of those disease consequences better than the acute liver failure patients.
Dr. McLaughlin: Knowing that most of what we’re going to see is acute-on-chronic, how common really is chronic liver disease at this point?
Dr. Prasad: Unfortunately, it’s kind of a growing disease process. The primary mechanisms by which we see cirrhosis, chronic liver disease, particularly in the resourced environment, are due to toxin exposure, with alcohol being the leading toxin in that context. Unfortunately, rates of alcohol use and abuse have not decreased. The pandemic, I think, unfortunately, threw some fuel on that fire. The second most common cause of chronic liver disease really is metabolic disease in the context of hypercholesterolemia, obesity. This is the nonalcoholic steatohepatitis, the fatty liver disease, which unfortunately is a growing cause of not just hepatitis, but that progresses into cirrhosis.
The more viral etiologies, things like chronic hepatitis B and then hepatitis C, those are still fairly common in some environments. Hepatitis B, chronic hepatitis B, is still a very common etiology in the less-resourced parts of the world. It’s being replaced by alcoholic liver disease and by steatohepatitis-mediated liver disease as we see in the resourced parts of the world. So, unfortunately, they’re disease processes that are on the rise worldwide at this point.
Dr. McLaughlin: I was once told that, in terms of lab findings that might help differentiate, chronic liver patients typically have thrombocytopenia and acute doesn’t. Is that true? Are there any other lab findings that might tip you in one direction or the other?
Dr. Prasad: I’d be careful with that. It is absolutely true that patients who have chronic liver disease often have thrombocytopenia in the context of their splenomegaly. They have sort of reticular endothelial sequestration of those platelets. The problem is, depending on the kind of acute liver failure you’re talking about, and it’s the severity of the acute liver failure and its specific etiology, you can see quite a bit of acute-onset thrombocytopenia in those situations as well.
Now, if you have access to laboratory data that dates back, let’s say, a couple of months, somebody who’s in your medical records system and you can look back, you might be able to distinguish between an acute drop in platelets and a kind of long-standing thrombocytopenia. But one of the tricky things about the laboratory evaluation is because its body responses are similar, though there’s a compensation in the chronic, in the really severe acute forms of acute liver failure, they will develop many of the same ultimate consequences with time. They’ll develop the same coagulopathy, thrombocytopenia, as they slip into more of a DIC picture. You’ll see the same changes in the LFTs and bilirubins.
There is a little distinction one can make with respect to the transaminases, AST and ALT. Classically, in a chronic liver disease patient, they’ve had sort of progressive fibrosis, bridging fibrosis of the liver damage that ultimately means they don’t generally have a lot of healthy hepatocytes to spill when they take injury. So they don’t usually present with extremely highly elevated AST and ALT. They can; it just depends on where they are with respect to the degree of their cirrhosis, but on average, they tend to be lower.
Acute liver failure patients, on the other hand, tend to have a large volume of healthy hepatocytes that are acutely being injured, so they can spill really high levels of AST, ALT. That’s one of the things that might be an indicator one way or the other.
Dr. McLaughlin: I see. This is interesting. It’s great being the host of this because I get to ask questions that I’m personally interested in, but we’ll broaden it out for everybody, which is this series of the Current Concepts text. What is new in our understanding of both these disease processes?
Dr. Prasad: Oh, there’s a lot of really interesting updates to our management that I think are extremely exciting. To sort of jump a little bit to the end, the thing that excites me the most, honestly, when I look particularly at acute liver failure, acute liver failure, as I said, is not the most common, but it’s often the one that so much depends on the critical care provider and the critical care resources recognizing the disease and intervening because acute liver failure can be profoundly morbid and mortal in often young and otherwise pretty healthy individuals.
If you can recognize the etiology, make the diagnosis, many of these conditions are manageable. If the damage is so severe that you progress to really fulminant liver failure, it really is on the intensive care provider to make that identification, that recognition, and try to get that patient stabilized and to a transplant center because these patients can do incredibly well with a liver transplant. You can, not only save their life, but you give them back a whole life essentially.
One of the biggest updates in Current Concepts is really the recognition of the role of plasma exchange in acute liver failure. This is something that has been studied over the last couple of decades. It’s been gaining ground and, just in the last year and a half, has now really come into enough of its own that it’s found its way even into the SCCM guidelines with respect to management of severe hepatic encephalopathy, etc. This is essentially the use of plasma exchange in acute liver failure.
As I said, these patients generally have a large volume of healthy hepatocytes that are significantly injured. That large volume of healthy tissue that’s dying releases a slew of cytokines and inflammatory markers that trigger an incredible systemic inflammatory response that results not only in that liver failure with the coagulopathy and the development of hepatic encephalopathy, with the elevated ammonia and the consequences, which we can talk about in a second, about cerebral inflammation and edema. But the patients go into disseminated intravascular coagulopathy and hemodynamic instability with vasoplegia.
All of that, really, in the studies that have been done recently, both in the UK and in southeast Asia, has really demonstrated a remarkable degree of stabilization by using plasma exchange, essentially on a very sort of superficial level, just cleaning away those evil humors that are leading to that decompensation. Now that buys time either for the process to run its course and if the damage to the patient’s liver is not so severe then they can recover.
Remember, the liver is the one organ in the body that actually has the capability to regenerate to some extent or, if it acts as a bridge to get that patient to a transplant center and to get a new organ in that patient, it can really be an incredible game changer. The reason I mentioned the studies both from the UK and from southeast Asia, from India, the two studies both looked at the use of plasma exchange in a randomized control approach and showed mortality reduction with use in transplant-free survival.
But they looked at slightly different populations, which was so important in this. All of these studies, these two studies were done in acute liver failure patients. But the one in the UK really looked at the kind of acute liver failure that we’re sort of used to in the context of resourced environments, which is classically acetaminophen toxicity. It showed real benefit in the setting of acute liver failure due to acetaminophen toxicity.
In the study done in India, the vast majority of the patients were patients with acute viral hepatitis, which is also a very common cause, depending on the environment you’re looking at. It showed the same significant stabilization and transplant-free survival. That’s really important because, when we think about plasma exchange and plasmapheresis, these are interventions that often we’ve raised an eyebrow and wondered about if they’re safe and feasible in the context of infection, particularly viral infection. These really showed that they were safe and beneficial. It’s something that we’re really looking into.
The availability of pheresis for this acute intervention is a hard thing to pull off in your intensive care unit, depending on your resources. But now there are actually approaches where the machines we use for continuous venovenous hemofiltration, if your ICU has access to CVVH, there are setups where you can use that CVVH machine to actually do plasma exchange, so it sort of expands that capability to stabilize these patients so that you can hopefully get them to a place where either they can be evaluated and taken to transplant to save their lives or stabilized so that we can see if the liver actually recovers with transplant-free survival.
Dr. McLaughlin: What would the trigger be to consider plasmapheresis in a patient with acute liver failure?
Dr. Prasad: The plasma exchange trigger really is when you’re talking about fulminant liver failure. The definition of fulminant liver failure in someone who has acute liver failure is really when they develop encephalopathy. This is, I think, a great example of the distinction between acute liver failure and acute-on-chronic liver failure.
Most of us who’ve taken care of patients with cirrhosis have taken care of patients who present with hepatic encephalopathy. We know that, when the liver is diseased, you have cirrhosis; the ability to metabolize a whole slew of breakdown products of metabolism are impaired. That results not solely in the elevation of ammonia, but the ammonia is a sort of a surrogate marker for these products that inflame the cerebral circulation, blood-brain barrier, cause dysfunction from a neurologic perspective, lead to encephalopathy.
It’s a very, very common consequence of cirrhosis, hepatic encephalopathy, and it’s classically, in the chronic form, managed with drugs like lactulose, essentially therapeutic diarrhea to keep the ammonia under control. We’re all pretty used to those patients coming in with their altered mental status, elevated ammonia, they get the lactulose, the ammonia comes down, and they’re not too much the worse for wear from it.
In the acute liver failure patient, however, that patient has not had any time physiologically to compensate or prepare for the consequences of those metabolites, that ammonia, etc. Arguably, in the context of acute liver failure, as I said, there’s those healthy cells that are releasing all these cytokines and cytotoxins, there’s a much more inflammatory cascade in the brain.
What we see in acute liver failure patients is, with similar levels of hyperammonemia and similar degrees of hepatic encephalopathy, the acute liver failure patient is much more likely to develop increased intracranial pressure and cerebral edema, putting them at profound risk for herniation and severe morbidity mortality.
So when we see that altered mental status in the acute liver failure patient, that’s your indication that you’re dealing with fulminant liver failure. The criteria set out by SCCM in their recent guidelines, the second, part 2 essentially, of their guidelines for the management of acute and acute-on-chronic liver failure, identified an ammonia of about 150 as the indication to intervene.
A close read of the literature would sort of indicate that that 150 is, I would say, when you look at the literature, that’s the lowest ammonia at which you’re going to start seeing hard cerebral edema. But in a patient who’s an acute-on-chronic liver failure, when you look at these studies, the error bars are wider than just 150. And the delta, the speed at which those ammonias rise, is actually pretty remarkable. So if you have that patient whose mental status is deteriorating in the setting of acute liver failure, to me, that’s the indication to start thinking about whether you’re going to use CVVH solely to control the ammonia and get them to control it.
That’s actually something that came out of the studies in Australia, they really showed the efficacy of continuous venovenous hemofiltration for clearing ammonia. It’s arguably more effective than things like lactulose, particularly in the setting of acute liver failure. Acute liver failure patients, unlike those acute-on-chronics, they don’t tolerate, they don’t respond as well to drugs like lactulose or common therapies for hyperammonemia. So, CVVH triggered at about 150, and if you have that patient who’s showing those signs of fulminant liver failure, and on top of it developing disseminated intravascular coagulopathy and vasoplegia, really going down that cytokine storm decompensation standpoint, that’s where I would deploy the plasma exchange.
Dr. McLaughlin: Then I’ve heard about liver dialysis or MARS, do you have recommendations regarding that or consideration for that?
Dr. Prasad: Absolutely. MARS therapy has been around for a little while. It’s still being evaluated, it has a much bigger role in toxin clearance, and particularly in the clearance of management of hyperammonemia and hepatic encephalopathy, but it’s not clear that it’s really adding a whole lot above, say, continuous venovenous hemofiltration in that context.
If you’ll look at the guidelines in the literature, it’s not really clear that in, air quotes, liver dialysis takes the place of your standard CVVH for the management of hepatic encephalopathy in the acute liver failure patient. It hasn’t demonstrated the same DIC management stabilization and vasoplegic stabilization that plasma exchange has. So, at present, really, the guidelines in our own practice kind of focus on CVVH for hepatic encephalopathy in these acute liver failure patients, and if they’ve got the concurrent DIC vasoplegia decompensation aspect, that’s where we look at plasma exchange. So not really a space for the hepatic dialysis aspect just yet.
Dr. McLaughlin: Then when you talk about hyperammonemia and cerebral edema, this is one of the areas I’m very interested in. I remember when we used to consult neurosurgery, they’d look at us like we had three heads. That was a time that we were considering putting in EVDs for monitoring in these patients. What are we doing now for neuromonitoring?
Dr. Prasad: Yeah, certainly the world has changed a little bit on that front. Obviously, and you can kind of understand a little bit where the neurosurgeons get a little worried about the possibility of invasive monitoring in these patients, they’re almost always marked by some degree of coagulopathy, thrombocytopenia and, not surprisingly, the studies that really looked at invasive intracranial pressure monitoring in patients with acute liver failure marked a pretty significant complication rate, particularly with respect to bleeding complications. So, these days, there’s really not a big push to use invasive intracranial pressure monitoring.
Now, there are noninvasive approaches one can use that have become more prevalent, I think, both in patients with acute liver failure, but outside of that, just in the general evaluation of patients with increased intracranial pressure, bedside ultrasound modalities, looking at optic nerve dilation, for example, as one of them.
But at this point, really where we sort of focus is that acute, rapid resolution of the hyperammonemia. If you do see signs of increased intracranial pressure, either by noninvasive monitoring or clinical signs that are concerning for impending herniation, there is actually a recent study that looks at intervention, interestingly, looking at 3% saline versus mannitol, and two of the therapies at our disposal for the management of acute increased intracranial hypertension.
Interestingly, that study done in acute liver failure patients didn’t really show a significant difference with respect to the initial efficacy of 3% normal saline versus mannitol. But what they saw, which I think is instructive to our, or at least my, clinical practice, is the patients who received mannitol had a roughly 30% rate of recurrent increased intracranial pressure, clinical signs and symptoms of impending herniation, whereas the patients who received the 3% sodium chloride did not. So it sort of favors the use of the hypertonic there. So, really, from a monitoring perspective, we’re moving more to those noninvasive modalities. There are some studies looking at transcranial Doppler, if that’s something that’s available to you in your practice setting. I’m a big fan of the optic nerve ultrasound.
Dr. McLaughlin: How do you see the management of these liver conditions evolving in the next five to 10 years?
Dr. Prasad: I think one of the really amazing signals that we’ve seen is that, whether you’re talking about acute liver failure or you’re talking about acute-on-chronic liver failure, in that subset of patients that has such severe injury that, despite optimal medical stabilization and care progressed to fulminant liver failure, liver transplant is providing absolutely phenomenal long-term survival rates for both acute liver failure and acute-on-chronic liver failure patients.
One of the biggest take-home messages when it comes to management of these acute hepatic failure states is, if the patient is deteriorating despite the best support that you have, it is really important to look at trying to get them to a transplant center for additional support and potential lifesaving transplantation. That remains, unfortunately, a limited resource available, but there have been some really remarkable steps in the direction of xenotransplantation.
The next decade is actually going to, I think, on that front, be really, really remarkable. I think that’s a space to just really watch very closely. I think the other thing that really the SCCM guidelines, I think, highlight, these conditions, if you think back maybe 20 years ago, if you had somebody come in with acute-on-chronic liver failure and three or four organ systems down, that was a pretty terminal condition that wasn’t something that people thought we really had a lot of things we could do to stabilize and get you out of the intensive care unit, even for evaluation for things like transplant.
We’ve really made remarkable, remarkable progress on that front. If you look at the management of hepatic encephalopathy, yeah, we use lactulose, but now we’ve added new tools to our armamentarium for managing hyperammonemia in acute-on-chronic patients. We use rifaximin and a new addition just in the last year or two, L-ornithine L-asparaginase, or LOLA, a very, very effective additive to lactulose, doesn’t worsen patient’s diarrhea, increases the speed and degree of hyperammonemic control.
Enough studies at this point to have multiple meta-analyses published showing its efficacy when it’s added above and beyond just lactulose, both in the intravenous form, which is available in Europe, and here in the U.S. with the oral form; the oral form has actually been shown to be more effective. So we’ve added layer upon layer of therapy if we look even to one of the most dreaded complications of cirrhosis of acute-on-chronic liver failure, which is hepatorenal syndrome.
I don’t know about you, but when I was first taught about hepatorenal syndrome, it was really parsed into two categories, one that just rapidly progressed and the patient wasn’t going to make it, and one that might respond to our cobbled-together therapy of midodrine and octreotide and albumin. Just in the last year and a half, a phenomenal study in the New England Journal looking at the deployment of terlipressin in the management of hepatorenal syndrome showing that really incredible reversal of hepatorenal syndrome in up to 30% of cases.
One really big caveat, and the reason I mention that, it is a huge reason to be optimistic about the care of these chronically ill patients, but it is not a modality that one can use in the intensive care unit. The reason to draw attention to that is, when you look at the terlipressin studies for hepatorenal syndrome, while it had a remarkable reduction in mortality and an incredible reversal of hepatorenal syndrome in any patient, in patients who had ACLF scores of 3 or higher. ACLF score is essentially the number of organ systems that are down in a patient with acute-on-chronic liver failure, the primary complication was actually the development of acute respiratory failure.
There was actually a higher rate of mortality when patients received terlipressin with those acute-on-chronic liver failure scores of 3 or higher if they received terlipressin. Most centers will not allow the use of terlipressin in patients who are in the ICU for that reason. So I would say it’s not just about being in the ICU, it’s really how many organ systems are down and primarily how volume overloaded is the patient. If you’ve got hepatorenal syndrome and your patient’s volume overloaded, you definitely want to avoid that intervention.
We’re learning a lot. We’ve got new tools in our armamentarium. These are diseases that legitimately a decade, two decades ago, were almost like a death sentence. Now we really do have the arrows in the quiver to be able to reverse the tide a little bit, buy some stabilization, buy some time, and either get the patient well enough to get out of the ICU to really be evaluated for the next steps.
Hopefully that’s not something where they need to go to transplant, but something where they can reverse what it is that led them there, whether it’s programs for abstinence from alcohol, whether it’s dietary changes and metabolic medications to manage hypercholesterolemia, etc., whether it’s any number of therapies for the other conditions that lead to chronic liver disease, a number of the autoimmune conditions. Again, that liver is the organ that if you catch it soon enough and turn it around quick enough, there is a potential for it to kind of gain some ground back.
I think it’s gone from a critical care perspective, it’s gone from a disease process that was pretty bleak back in the day to one that now there’s a great deal of potential optimism and you can really make a big difference in these patients. It takes a lot of critical care effort and it takes a lot of resources and it takes a lot of awareness and dedication from the field care teams, but it’s also one where there’s just so much potential for benefit for the patient.
Dr. McLaughlin: Well, it’s been really interesting talking to you. Thanks for being here, Tosh. I think it’s really exciting to see what’s going to happen over the next few years, seeing how much has changed and how much growth there’s been in the last few. Any other final comments?
Dr. Prasad: No. I appreciate the opportunity to have the conversatio n and I agree completely. I think it is a remarkable opportunity we all have to get to practice critical care and to continue to grow with how our understanding of disease evolves. It’s just really remarkable to be a part of it.
Dr. McLaughlin: Great. With that, this concludes another episode of the Society of Critical Care Medicine Podcast. For more on Current Concepts, please listen to the series, and don’t forget, if you’re listening on your favorite podcast app and you liked what you heard, consider rating and leaving a review. For the Society of Critical Care Medicine Podcast, I’m Diane McLaughlin. Thank you.
Announcer: This educational activity is supported by the SCCM Current Concepts Committee. Diane C. McLaughlin, DNP, AGACNP-BC, CCRN, FCCM, is a neurocritical care nurse practitioner at University of Florida Health Jacksonville. She is active within SCCM, serving on both the APP Resource and Ultrasound committees, and is a social media ambassador for SCCM.
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