Thank you very much. It's a real pleasure to speak to all of you today on this interesting and cutting-edge topic. So we're going to be speaking about current challenges with managing cirrhosis and multi-organ failure, leading into a discussion of hepatorenal syndrome and its management. So my name is Dean Karvelas. I'm a professor of... Can you hear me or you can't? We're good? How about that? Is that better? Okay. All right. So my name is Dean Karvelas. I'm a professor of critical care and hepatology at the University of Alberta in Edmonton, Canada. And I'll be doing the first talk. And this talk will be on current challenges with management of cirrhosis and multi-organ failure. So just to remind us, I know that we come from a variety of different backgrounds clinically here, that generally when we're talking about decompensated cirrhosis, we're talking about scarring or fibrosis of the liver, which leads to complications related to portal hypertension. And with decompensated cirrhosis, there are many different complications, including hepatic encephalopathy, acute kidney injury, of which one subtype is hepatorenal syndrome, which we'll be talking about in more detail in the second two talks, variceal bleeding, spontaneous bacterial peritonitis, etc. So to take it a step further, when we talk about the term acute on chronic liver failure, really the simplest way to think about this is a patient with cirrhosis with multi-organ failure. While there are a few different definitions, whether you're from Asia or different parts of the world, really the simplest way to think about this, and I kind of put this combined European-American consensus definition, that really it's a patient with decompensated cirrhosis that due to some superimposed injury or complication or precipitating event leads to multi-organ failure, generally defined with an increased mortality at 3 months. So there are a couple of well-defined pathophysiological processes, so the classic being that you've got complications of cirrhosis, and then what are these precipitating events? It can be alcoholic hepatitis, it can be infection, it can be drug-induced liver injury, and this can then lead to this ACLF phenomenon leading to multi-organ failure, which in a very predictable way in many patients can lead to death. So when we talk about kind of this multi-organ dysfunction syndrome, as mentioned, there are a variety of different precipitating events, and I will briefly kind of go over the different organ failures while my other two colleagues will focus specifically on AKI. So these patients can develop circulatory failure, acute lung injury, both hepatic and GI dysfunction, and eventually this can lead to bone marrow suppression and myocardial dysfunction. So, as mentioned, there are these different definitions of ACLF which come from different parts of the world, and one of the reasons for this is that if you're in Southeast Asia, for example, there's a large population of patients with chronic hepatitis B, where in places like Europe and North America we tend to see more fatty liver and alcohol-induced liver disease. For the purposes of this talk and the next talks, primarily we're going to be using the easel cliff definition, which is the one in the middle, which is based loosely on the SOFA score, which looks at six different organ failures. So, looking at the literature in terms of the most common triggers of ACLF, you're going to see that the canonic study was based from Richard Moreau and the Cliff group in Europe, and then the second group is from Asia, and you can see that probably one of the most common precipitants of this is bacterial infection, most likely second most common being in North American European populations, kind of alcohol as a precipitant, where as you can see in Southeast Asia, hepatitis B exacerbation or reactivation tends to be one of the most common precipitants. So, where the Cliff definition of ACLF came from, and this is the canonic study that was published back in 2013, what they did is they looked at 1,343 hospitalized patients with decompensated cirrhosis, and then followed them of which eventually, 415 of them developed multi-organ failure or acute on chronic liver failure. And based on this, they were able to derive these different definitions of grades of acute on chronic liver failure, and the simplest way to remember this is that this loosely relates to the number of, we mentioned there are six defined organ failures, the number of organs that fail. The only thing that I would mention is that to be defined as ACLF grade 1, for example, if you came in with respiratory failure, generally you would either need some mild AKI or some mild hepatic encephalopathy as well. Once you get to ACLF grade 2, it's two or more organ failures, and then ACLF 3, it's three or more. And you can see here fairly clearly that you get this stepwise increase in mortality to the point that when you're an ACLF 3 patient with three or more organ failures, you have a 28 day mortality of almost 80%. So in terms of what are the most common organ failures, and part of the reason why we're focusing on AKI today is that when you look at the canonic data, single AKI is a very common precipitant of organ dysfunction, and it does portend a detriment to survival at the end of hospital stay. So why as an intensivist will you be consulted on these patients for management? Generally it's these four things. It would be for management of circulatory failure, for vasopressor support, respiratory management, so either airway protection for hepatic encephalopathy or treatment of acute lung injury with mechanical ventilation, hematological support, and then renal support, whether that's vasoconstricting therapies initially to support the kidneys or with renal replacement therapy. So just to give you a background in terms of some of the baseline circulatory abnormalities that occur in cirrhosis is that cirrhosis is characterized by a hyperdynamic state, and this is based on the fact that you have portal hypertension and hepatocellular dysfunction with portal systemic shunting, and what this means is that there are vasodilatory molecules such as nitric oxide, for example, which due to a lack of clearance and an increase in shunting into the systemic circulation can lead to both splanchnic and systemic vasodilatation, effectively decreasing your systemic vascular resistance, and initially a patient is able to compensate by increasing their cardiac output, and if you were to do bedside echocardiography on most of these patients, they will be hyperdynamic, but this can generally only go so far, and as this progresses, you end up getting relative arterial hypovolemia, which leads to activation of other neurohormonal pathways such as the renin-angiotensin system and the sympathetic nervous system. So that's why quite often when you get called to assess a cirrhosis patient that's heading into ACLF on the ward is they tend to be hypotensive and they tend to be hyponatremic even before they develop acute kidney injury. And this is just showing this graphically here that you can see on this as you get progressive decompensation and a decrease in the systemic vascular resistance. This is a diagram from Vicente Arroyo. You see that really only up to a point can you compensate by increasing or maintaining your arterial blood volume. So in terms of how we assess volume status in these patients, which is very challenging because often patients with cirrhosis and ACLF tend to have a lot of third space fluids such as ascites or peripheral edema. And I will say that one of the advents of more widespread use of bedside echocardiography has also been very valuable in these patients as well. First of all, for assessment of filling, looking at the inferior vena cava, but also you get information on both left-sided cardiac function but also right-sided cardiac function and things like portal pulmonary hypertension. And these tend to be kind of the predominant things that most people are using these days. If you're from Europe, things like thermodilution techniques tend to be a little bit more common and as you can see here, these are some of the parameters that are used. One thing to mention just with other, as we know from the general critical care literature that we're learning more and more that volume overload can have adverse impacts on many different organ systems in the body. And what we find quite often is that when we get consulted on these patients on the floor because certainly in a hypotensive patient with cirrhosis with AKI, often your options really on the floor are crystalloid, albumin, mitadrine, and octreotide. So it's very easy for these patients to get fluid overloaded despite being hypotensive. And we just want to highlight again that fluids and albumin are a drug and these are things that are not necessarily without harm if used inappropriately. And one other thing to be aware of is intra-abdominal hypertension with tense societies that can exacerbate AKI. Another kind of cautionary tale that leads to this is the whole idea of monitoring the serum albumin. And this was a very interesting study from Alistair O'Brien's group that they published in the New England Journal where they looked at this idea of transfusing patients' albumin to a target blood value of 30 grams per liter versus standard of care. And what they found was that there was no significant difference in the primary composite endpoint or mortality primarily in these patients. What the bigger concern was was that these albumin infusions actually led to more complications and in particular one of them was pulmonary edema or respiratory complications from volume overload. And you'll see this kind of as a tie-in to some of the other discussions that are going to be coming from the next two lectures. So in terms of kind of basic management of shock and ACLF, this is based on both the SCCM guideline and also on the upcoming AASLD guideline that will be coming out. Just to remember to perform early baseline assessment of volume and perfusion status and cardiovascular function. Resuscitation of shock, one thing I always mention is that people sometimes can be reticent to give crystalloid to these patients because of this concern of third spacing of fluid. But in many cases, these patients need to be resuscitated like any other patient with septic shock. Specifically for the use of albumin, the kind of level one evidence is primarily in the setting of spontaneous bacterial peritonitis in HRS and following large volume paracentesis, but generally not as a primary resuscitation fluid. These are constricting therapies, often this is when they're in your unit. First line of choice is still norepinephrine, obviously we're going to hear a little bit more specifically in the setting of AKI about turlopressin today and particularly its potential role outside of the ICU. In the absence of AKI, probably a map of 65 is reasonable, however we target a higher map because of this relative arterial hypovolemia and decrease in systemic vascular resistance that we tend to see in hepatorenal syndrome patients with ACLF. And the final item is to remember to rule out adrenal insufficiency as this tends to be often undiagnosed in ACLF and cirrhosis patients. So why are cirrhosis patients so suspect to sepsis as it tends to be one of the biggest precipitants of ACLF and also one of the biggest precipitants of mortality? It essentially also relates to this portal systemic shunting phenomenon. We know that patients in cirrhosis will often lose these tight gap junctions that they get in the bowel, leading to bacterial translocation. Because of portal systemic shunting, a lot of these pathogens evade the natural defenses of the reticuloendothelial system and the specialized macrophages in the liver, such as your Kupfer cells, and you end up getting this seeding of bacteria in sterile areas such as the blood, leading to bacteremia, or in peritoneal fluid, which leads to SBP. One thing, as we know with the different iterations of the surviving sepsis guideline, that while some things have changed, it isn't necessarily that much different specifically when looking at ACLF, where I just kind of highlight with study that early appropriate antibiotics is still probably the most important thing that we can do. This is an older study from a sub-study of Anand Kumar's CATS database that looks specifically at septic shock and SBP, where each hour and delay of appropriate antimicrobial therapy led to an increased mortality of almost 1.9 times. Looking now specifically at some of the non-renal respiratory failures, when we talk about non-renal organ failures, acute lung injury in ACLF tends to have etiologies that are specific to cirrhosis and liver disease, such as hepatic hydrothorax, hepatopulmonary syndrome, and alpha-1 antitrypsin deficiency that can lead to cirrhosis. And then there are the non-specific things, such as pneumonia, thromboembolic disease, pulmonary edema, and atelectasis. Ventilating a patient with ACLF, once again, a lot of this is borrowed from the general critical care literature, but I would highlight one thing, is that ACLF patients tend to be very fluid sensitive, so the challenge with running a high PEEP strategy is often you can hinder venous return or decrease return to the right heart, which can lead to hypotension. So that's really one thing to kind of remember, and one of the challenges that we often deal with where we talk about the frailest organ system is sometimes the therapy that's the best for your AKI may be complicating your respiratory dysfunction, potentially whether that is to give volume or refrain from giving volume. Just to talk briefly about variceal bleeding, one thing to mention is that the severity of the underlying liver disease, particularly in ACLF, likely has a bigger impact on outcome as opposed to what the endoscopist sees with the gastroscope. I just kind of show you here the different blood supply for right and left-sided variceal bleeding, so esophageal varices tend to come off of the left gastric vein, and they tend to be superficial, and they tend to be using banding techniques, where gastric varices tend to be more subucosal, coming off the short gastric splenic vein and posterior gastric vein, which often need to be glued because they're too deep to be banded effectively. One thing to mention, there's going to be a lot of discussion of turlopressin in acute kidney injury today. Turlopressin has also been demonstrated to improve outcome in variceal bleeding, independent of endoscopy. Octreotide, which is what most of us are using at the moment, is associated with improved outcomes in combination with endoscopy, which is generally what we do, but in itself, as a primary drug therapy, hasn't shown a mortality benefit on its own. Most of you are probably familiar with TIPS, or transjugular intrapartic portosystemic shunting, where you create a communication through the liver from the portal vein to the hepatic vein. If it's done early, it can be associated with improved outcomes. The challenge is that most patients with ACLF and multi-organ failure are often too far gone to have a TIPS procedure, as it will lead to exacerbation of their multi-organ failure. Really, the setting that often it's done in is kind of in the salvage or rescue setting with a massive bleed. Similar to the general critical care population, there is specific data in patients with cirrhosis that shows a transfusion trigger of 7 grams per deciliter as the appropriate trigger. When looking at prognosis, just highlighting again, this will look similar in some ways to the SOFA score from Jean-Louis Vansau in the 90s, where you've got hepatic, renal, neurologic, coagulation, circulatory, and respiratory failure. What you see highlighted in blue is what's kind of been defined by the CLIF group as an organ failure. What they've done to kind of take it a step further is created a nomogram, and this is something you can get online and use an app with the CLIF ACLF score, where they took these individual organ failures and then put in an equation, age and white count, giving you a score between 0 and 100, which is able to give you a prognosis. Just to highlight that, this is data that was derived from North American Europe outside of the original CLIF study that showed that once you're getting a CLIF ACLF score of 70, you're looking at a 90-day mortality of almost 90%. Very clearly, if transplant isn't in the cards, then this is something that may help you in terms of making an informed decision about whether to either proceed with life support or to initiate life support. Now, this all seems fairly depressing. However, it should be highlighted from that same study that about 40% of patients, once they go into the ICU and we can support them, improve by at least one ACLF grade or organ failure. So there are people we can certainly challenge or improve, and in the setting potentially that you might also be able to bridge these patients to transplant.

cirrhosis

multi-organ failure

hepatorenal syndrome

decompensated cirrhosis

portal hypertension