SCCM Resource Library-Managing Multiorgan Disease in Acute-On-Chronic Liver Failure: Improving Critical Care Management of the HRS/AKI Patient

Video Transcription

discussing the management of multi-organ disease and acute on chronic liver failure. And by way of introduction, my name is Konstantin Karvelis.  I'm a professor of critical care medicine and hepatology at the University of Alberta in Edmonton, Canada. And I have the pleasure to be joined today by Professor Ram Subramanian,  who's a professor of critical care and hepatology, as well as the head of transplant at Emory University School of Medicine in Atlanta. And also by Professor Jody Olson,  who's an associate professor of internal medicine and surgery who practices critical care medicine and hepatology at the University of Kansas.  So there's going to be three talks today, one focusing on current challenges in management of cirrhosis and multi-organ failure or acute on chronic liver failure.  One will discuss the identification of acute kidney injury and specifically hepato-remal syndrome in patients with cirrhosis. And a third talk, which will focus on the management.  So to start off, I'll be discussing the current challenges with managing cirrhosis and multi-organ failure or otherwise known as acute on chronic liver failure.  These are my disclosures.  Just as a way of context, when we discuss decompensated cirrhosis, we're discussing patients that have a scarred or fibrotic liver,  which classically manifests with portal hypertension. This leads to many multi-system complications that we're aware of, classically hepatic encephalopathy  due to a lack of a detoxification function of the liver,  acute kidney injury and specifically hepato-remal syndrome, which we'll discuss further today. You can get portal hypertension with variceal bleeding  and ascites, which can be complicated by spontaneous bacterial peritonitis.  So taking this a step further where intensive care providers get involved is generally when these patients develop multi-organ failure and need multi-organ support.  And classically we call this acute on chronic liver failure. And while there are a few different definitions, really the way to think about it  is a patient with decompensation in liver function in a cirrhotic patient, either due to a superimposed injury or some kind of precipitating factor  culminating in multi-organ dysfunction with a high mortality.  Now, there is kind of a, well, there is some debate there. There is a theory of kind of a classic progression from chronic liver disease and cirrhosis.  And specifically some of these precipitating events include could be alcoholic hepatitis, a superimposed drug-induced liver injury,  or ischemia leading to acute on chronic liver failure, leading to multi-organ dysfunction. In some cases, patients can develop sepsis and septic shock  and in severe cases leading to death.  And now there is kind of a, within this context of ACLF, there are different subtypes.  And it generally goes along the spectrum of how severe the patient's liver disease is before they develop multi-organ failure. And classically, we talk about patients  with chronic liver disease that may have fibrosis of the liver, but not necessarily complications of portal hypertension.  Patients that may develop complicated stated cirrhosis and then may develop decompensation. We classically define this as jaundice or ascites,  variceal bleeding, herpetic encephalopathy.  And as mentioned before, that you can develop in theory ACLF in a patient even with chronic liver disease or compensated cirrhosis. And we classically call this type A or type B,  but more often than not, the people that we tend to see in the ICU setting with ACLF are truly the type C ACLF patients that have decompensated cirrhosis.  So generally multi-organ failure can occur from a diverse set of precipitating events and generally tends to follow through a predictable pathway.  So you can get hemodynamic alterations, you can develop acute lung injury such as, or in severe cases, acute respiratory distress syndrome.  You can develop progressive hepatic dysfunction or jaundice and severe cholestasis. You can develop an ileus or gut dysfunction. You can develop acute kidney injury.  You can develop brain failure or severe hepatic encephalopathy.  And eventually can actually develop bone marrow suppression as one of the reasons why these patients are at a high risk of developing bacterial translocation,  sepsis and septic shock.  So just so you're aware, there are some subtle differences in definitions of ACLF from different parts of the world. And part of the reason for this is it probably reflects  slightly different patient populations. So if you go to countries in Southeast Asia where probably the most common cause of cirrhosis and multi-organ failure is hepatitis B,  there is a continuum of patients with viral hepatitis. In contrast, if you go to places like Europe and North America where the more common causes  of cirrhosis and eventually ending up with acute on chronic liver failure, it's predominantly alcohol, fatty liver and in previous generations, hepatitis C. We tend to focus more  on the kind of organ failure definitions, which is very similar to the SOFA score that we're all kind of familiar with within the critical care literature.  And classically we talk about six predefined organ failures, hepatic, renal, neurologic, coagulation or hematologic, circulatory and respiratory.  So in terms of looking, what are the triggers that most commonly push patients from decompensated cirrhosis to acute on chronic liver failure  with multi-organ dysfunction often in the ICU? The most common cause of this classically is bacterial infection. It's almost a third of patients.  The second most common cause would actually be in the setting of alcoholic cirrhosis or alcoholic hepatitis. It's actually active alcohol use within the past three months.  So when looking at the European CLIF definition of acute on chronic liver failure, and I find that in some ways this, as a critical care provider, because it's kind of an evolution  based on the previous critical care SOFA score definition, it's something that as a context is fairly easy to understand.  The grade of organ failure or the number of organ failures essentially was based on a large study called the Canonic Study that was published in Gastro back in 2013.  And this was a study of over 1,343 hospitalized cirrhotic patients with decompensation of which 415 developed organ failure and as such acute on chronic liver failure.  And what this group of investigators were able to demonstrate nicely, and the simplest way to think about this is that ACLF grade one, two, and three  is one, two, or three or more organ failures, is that once you develop three or more organ failures, your 28 day mortality in the absence of a liver transplant was almost 80%.  Interestingly to know as well is that when looking at patients with ACLF at some of the most common causes of organ failure, acute kidney injury tends to be  one of the most common causes of organ failure in the ACLF population in the Canonic Study and almost 15% of patients that had solitary organ failure or ACLF grade one.  So in terms of intensivists, the main thing that we're called on doing for the management of acute on chronic liver failure primarily is circulatory support with vasopressors,  respiratory management with mechanical ventilation or non-invasive, hematologic support for resuscitation, for example, for a large bleed,  and renal support, which can be either in the form of vasoconstricting therapies, which we'll talk further about in the setting of hepatorenal syndrome  or later on potentially renal replacement therapy.  One of the other things to note is that there are circulatory abnormalities in patients with cirrhosis, which we see even more exacerbated and acute on chronic liver failure.  And because of this scarred cirrhotic liver with portal hypertension, you get portal systemic shunting with decreased clearance of vasodilatory molecules such as nitric oxide,  which leads to both splanchnic and systemic vasodilatation, which initially leads to a decrease in systemic vascular resistance, which a cirrhotic patient initially can compensate  by increasing their cardiac output. So essentially most of these patients have a hyperdynamic physiology, but eventually you're left with a form of relative arterial hypovolemia,  which leads to upregulation in the renin angiotensin system and the sympathetic nervous system and antidiuretic hormone, which in some cases will lead initially to hyponatremia,  which we see in very advanced liver failure and then eventually hepatorenal syndrome. This has just showed more schematically that initially that you get this hyperdynamic state  despite the decrease in systemic vascular resistance, but eventually you end up at a point where you can only increase your cardiac output so much.  And this is where you get these deleterious pathways that lead to hyponatremia and HRS.  So how do we assess volume status and cardiac output, which tends to be a big challenge in patients with cirrhosis and acute on chronic liver failure?  One of the benefits of bedside echocardiography is that we can get real-time assessment, even in the patient that may have a lot of ascites or third spacing of volume.  And the benefit of bedside echo is that we can assess both left and right ventricular function, and we can also look at fluid responsiveness.  We can look at things like inferior vena cava compressibility to see if despite the fact that a patient might have ascites, they might be intravascularly deplete.  There are other techniques that we use that are kind of falling out of favor, like central venous pressure monitoring. And depending on certain parts of the world,  people use thermodilution techniques like PICO and Litco, which are more popular in Europe. And then there are blood markers such as lactate,  which still have significant importance.  So generally for the management of shock,  and this is outside of the setting of hepatorenal syndrome, which we'll talk further, similar to other critically ill patients, generally our first line therapy in the ICU  still tends to be norepinephrine with vasopressin or turlopressin being second line. It's a little bit different if the primary issue is acute kidney injury, where it's different.  We'll target a mean arterial pressure of 65  in patients without acute kidney injury, but generally with AKI, we'll target a higher map to perfuse the kidneys of 75. And often it's important to rule out  relative adrenal insufficiency in these patients and those patients that might need hydrocortisone.  As mentioned before, sepsis and septic shock bacteremia tends to be one of the leading triggers of ACLF. And there are many reasons for this.  We know that in cirrhotic patients and patients with ACLF, you get increased intestinal bacterial overgrowth and you lose the tight gap junctions in the gut.  So you get more bacterial translocation. And because of portal systemic shunting of, you end up with bacteria in sterile environments. So bacteria that are generally dealt  through the reticuloendothelial system with the natural killer cells and Kupfer cell and macrophages will end up in these sterile environments like peritoneal fluid or in the blood  leading to bacteremia and spontaneous bacterial peritonitis.  And we know that certainly bacteremia and specifically spontaneous bacterial peritonitis when associated with septic shock  portends a significantly worse outcome in ACLF and cirrhotic patients. And this study that was from the large, it was a subpopulation of a large sepsis cats database  demonstrated that overall survival was only about 20%.  And this was in non-transplant candidates where probably what was more important is that early antibiotics is probably the most important thing you can do. And each hour in delay  and appropriate antimicrobial therapy was associated with an increased rate of mortality by almost 1.8 times. So speed is definitely life.  Looking at acute lung injury, there are respiratory complications that are specific to cirrhosis such as a hepatic hypothorax, hepato-pulmonary syndrome  and portal pulmonary hypertension.  And then there are nonspecific things that we see in other patients as well, such as pneumonia, pulmonary embolus, pulmonary edema and anelectasis.  Just to mention that we tend to ventilate patients with acute or chronic liver failure and acute lung injury in a similar fashion to general critical care patients  that we tend to use a lung protective strategy. The only thing I would qualify that is a little bit different is we tend to be a little bit more judicious with PEEP  because high PEEP is sometimes associated with decreased venous return and can exacerbate hypotension in patients with ACLF.  Looking at bleeding,  as variceal bleeding is a common reason why patients with ACLF will end up in the ICU. Just one thing to note that there are, there's what we call left-sided portal hypertension,  which leads to esophageal varices that can bleed, which generally come off of the left gastric vein. And then, sorry, this is right-sided portal hypertension.  And then there's what we call left-sided or sinistral portal hypertension, which usually comes off of the short gastric vein and the splenic vein, which leads to gastric varices,  which are a little bit different because as opposed to banding these often, we need to glue them.  In terms of the management, one thing to remember is that in terms of outcome, it has more to do with the severity of liver failure  as opposed to about the endoscopies with the scope. Furthermore, turloparesin, which we'll talk about further in the setting of hepatorenal syndrome,  has actually been associated with improvements in control of bleeding and decreased mortality, as we're still waiting for approval by the FDA. Currently, we use octreotide.  Early tips is interesting, or the transjugular interhepatic portosystemic shunt, which essentially you're creating an extra communication between the portal and the hepatic vein,  has been associated in the secondary prophylaxis setting to be associated with decreased one-year mortality. And similar to the general critical care population,  we use a transfusion trigger of seven.  Finally, I just want to mention that just because patients with cirrhosis and ACLF may have an elevated INR, it doesn't necessarily imply only a risk of bleeding.  These patients can actually be hypercoagulable, and it should be remembered that while patients have deficiencies in procoagulant factors like factors 2, 5, 7, 9, and 10,  they also have deficiencies in anticoagulant factors like protein C, protein S, and antithrombin 3. And furthermore, while they may have low platelets,  they also have decreased levels of ADAMTS-13 leading to larger von Willebrand's factors. So one simple way to think about this is generally the bleeding risk goes up  with a platelet count of less than 50 and a fibrinogen of less than 1.5.  Once again, this is just looking at the CLIF ACLF score. And as you can see, similar to the SOFA score, we've got our six organ failures.  And on their website, they also have a nomogram, which kind of stratifies you from zero to 100, which also includes age and white count.  And it's interesting to note that when you use this score, that once you get a CLIF ACLF score of greater than 70, you end up with a 28-day mortality of almost 90%.  And while this all does seem somewhat, that's in the absence of transplant,  while this all does seem somewhat depressing, it should be noted that ACLF is dynamic. And we as intensive care physicians have a lot to play.  And that from the same study that I just showed you, that once we resuscitate these patients and get involved, almost 40% of these patients improved by at least one organ failure.  And this might be in the setting of either getting them back to the ward or potentially bridging them to a transplant.  So I thank you very much for your time and we'll proceed to the next talk, which is entitled Algorithm-Based Identification of Hepato-Renal Syndrome, a.k.a. NACLF.  Hello, everybody.  And just to follow up from Dr. Karagolis' talk, so he covered some of the multiple organ system failure with an ACLF. And I'll just zoom into the kidney aspect  and Dr. Olson will follow up  with the therapeutic aspects of HRS.  So,  just a disclosure slide with respect to this presentation. So from an outline standpoint,  number one, we'll go over the different potential ideologies of AKI in the context of ACLF and the prognostic value of these ideologies  as we deal with them in the ICU.  And then I wanna move on to talking about how the diagnostic criteria for HRS have evolved, have luckily evolved in the right direction with respect to diagnosis and therapy.  And then we'll move on to the current published guidelines for the diagnostic evaluation of AKI in decomstitutory cirrhosis.  We'll talk both about the European guidelines and also to the recently published US guidelines.  And then I want to move on to a brief word about the potential role of or the evolving role of biomarkers in the diagnostic evaluation of AKI. It's ROSIS.  And finally, we'll conclude with talking about an important evolving concept of the implications of chronic kidney disease related to the evaluation of AKI in this context.  So let's start with the different ideologies of AKI and their prognostic value in the setting of the ACLF patient in the ICU.  So as you think about AKI in general critical care, you have the usual suspects. You will have prerenal azithemia, you'll have hepatorenal syndrome, which we'll do a deeper  dive into, and then ATM. So these are the usual sort of short list of differential diagnosis.  But just to add on to this, especially in the context of ACLF, interabdominal hypertension,  especially from tense societies, can have renal consequences with regard to, in particular, the renal vasculature compression.  And then another sort of example of a specific ideology that can be of significance is bio-cancer nephropathy, especially in the setting of coelistasemia, cholecystic liver disease.  And so this is just a snapshot of all the potential ideologies of AKI in the typical  ACLF, class T-compensatory serotic patient. And I think one important take-home message for the audience is that AKI in ACLF can be multifactorial.  So you can have two existing ideologies that can coexist at the same time, and this further  complicates matters with regard to diagnostic and therapeutic management of such a complex patient.  Moving on to prevalence and causes of AKI, just looking at the published data, this is a summary table that over the years sort of maps out all that has been described.  And as you can take a glance at this table, what you're seeing is that there is, as you look at column three, you see a wide range of reported incidents.  I think this is a function of what was the definition of AKI used, especially as it has evolved over time, and the patient population studied, and especially as we've been trying  to define ACLF better. The other thing to notice, especially as you look at the more recent studies, and I'll  use my, so just to draw your attention to the last column, and you can see the HRS percentages  sort of higher, is that as we have redefined HRS AKI based on KDGO guidelines, and I'll share with you the older definition and the newer definition that is more in alignment  with KDGO, you can anticipate that there will be an increased recognition of HRS AKI in this patient population, which will be of benefit from a diagnostic, and importantly  as Dr. Olson will elaborate on from a therapeutic standpoint. So moving on to the prognostic importance of these different forms of etiologies, and  this will, you'll find this similar to what we see in general critical care. So just a couple of published studies that I'll share with you, and so this is one study  that as you look at the different etiologies of AKI, you can see that survival worsens as you head from sort of hypovolemia-induced preadrenal azotemia down to hepatorenal syndrome.  And just to give you some specifics on this study, HRS was independently associated with a higher 90-day mortality compared to other etiologies of AKI.  Similar pattern, another study that gives you a very similar profile, that as you progress,  if you will, or change the etiology from hypovolemia to sort of an infection slash sort of septic AKI to HRS, again, survival worsens as you head towards HRS AKI.  And this model, similarly, and they model HRS and infection together in this multivariable analysis, the odds ratio was for mortality increased as you headed towards HRS.  So just to summarize, this slide is a couple of examples of studies amongst many others that are shown that highlight the high mortality associated with HRS phenotype of AKI, and  therefore it emphasizes and underlines the importance of accurate early diagnosis, and more importantly, early therapy, as Dr. Olson will talk about.  All right, so now let me switch gears and talk about how diagnostic criteria have evolved over the years in the context of HRS AKI.  And just to give you a snapshot of this sort of summary slide from a review article that summarizes well, the old name, and this is back in the 1990s, there was HRS type 1, and  the newer name, this process started in about 2015, and is now almost becoming standard of care, if you will, is now the redefinition of this disease process to HRS AKI.  And let me just highlight a couple of important sort of differences. So here, as you look at this, the previous definition required a creatinine greater than  2.5, and as you can tell, this could, as critical care providers, you can see that this could be, create a lot of missed opportunities for early recognition and timely treatment  of HRS, of AKI in particular. So luckily, we have now in the hepatology community learned from the critical care community  that incorporated the clinical guidelines in such a way that now the redefinition acknowledges  that a serum, an increase in serum creatinine as little as 0.3 within 48 hours is clinically important.  And so that has been the one big change as we have become wise in the liver community to incorporate clinical guidelines into the definition of AKI management in the ICU.  I won't belabor the other bullet points, but basically, they summarize ruling out other  forms of potential AKI ideologies, in particular, pulmonary nephritis and other intrinsic diseases.  So, just to summarize this slide, I think this newer definition and terminology highlights the important switch regarding discarding the previous definition adopting AKI concepts  related to care to go guidelines that we are all familiar with in general critical care. All right, so now let me move on to staging of HRS-AKI, and again, this mirrors what we  do in general critical care with regard to staging AKI in general. So just to recap on this, we define stage one as an increase in serum creatinine greater  than 0.3 milligrams per deciliter, or an increase in serum creatinine greater than 1.24, so less than two-fold from baseline.  Just to draw your attention to what is also a sub-definition of stage 1A versus stage 1B, and this is basically based on the serum creatinine value, and I'll share with you  some data that actually underlines the importance of making this distinction, especially in the European guidelines, where stage 1B is greater than 1.5 milligrams per deciliter.  And then, very similar to the care to go guidelines, stage 2 is a slightly higher increase, so  this is at least when you double the baseline creatinine to a max of three-fold, and then  stage 3 is greater than three-fold from baseline, or an absolute serum creatinine greater than four, or importantly, the initiation of renal replacement therapy.  And then, one important sort of caveat, if you will, to this current staging, and I would  contrast this with what we do in general critical care, is that urine output has not been included in the current staging criteria.  I think Dr. Olson will elaborate on this in his slides as well. I think this is one potential limitation of the current state of the staging.  And this, I think, post-editorial, I hope this is revisited in the future guidelines and redefinitions.  And then, just to briefly allude to one study that Dr. Olson will be elaborating on, this is a study from the University of Pittsburgh Critical Care Group, published a few years  ago, that does show that if you incorporate urine output, as we do in general critical care, with regard to the staging of AKI, that provides additional value with regarding earlier  diagnosis, defunding severity, and importantly, affecting prognosis. So moving on to prognostic utility, this has been validated.  These stages of AKI have been validated with regard to predicting prognosis in the ACLF patient.  And just to give you a couple of examples here, this study, again, as you can see, as your stage of AKI worsens, that translates to a worsening prognosis.  Interestingly, and I've made the distinction between stage 1A versus 1B, again, that's less than 1.5, greater than 1.5.  You can see that that does make a difference with regard to prognosis in this patient cohort.  And a very similar other study, this is shared with you, again, looking at the hazard ratio of 90-day mortality based on stage of AKI.  And I just want to draw your attention again to 1A and 1B, that a CRAN greater than 1.5 does make a difference even within stage 1 AKI.  So, and I just want to share this with you as we move on to the next slide, because this has, this concept of distinguishing stage 1A and 1B has been incorporated into the European  guidelines of management. So based on all of that, what are the current guidelines for diagnostic evaluation?  And so this is a snapshot of the ESIL or the European Association for the Study of Liver Disease Algorithms.  So just to walk you through this, the top box is when you have a creatinine increase greater than 0.3, and what this algorithm does is risk stratifies by taking them to  stage 1A AKI, which is creatinine less than 1.5. And here it's more of a conservative watchful waiting, if you will.  So you have close monitoring, elimination of risk factors such as nephrotoxic drugs, anti-stage diuretics, treat any potential coexisting infections, and then if the patient  is hypovolemic, then plasmodium expansion. And so this part of the left side of the diagram is more of a conservative management, and  then if there's a potential resolution or if there's progression, then you go to the right side of the diagram. On the right side is stage 1B, stage 2, and stage 3.  So this is a creatinine greater than 1.5 here. In addition to what we did on the left side of the diagram, here is where the current  guidelines based on evidence suggest volume expansion with albumin, and it's one gram per kilogram for a 48-hour duration.  And then just walking down this side of the deck, you can have potential resolution just with volume expansion, which would suggest a pre-related tinea state or etiology.  And if you have AKI that's not responsive to that albumin challenge, then you start invoking ATN versus HRS-AKI.  And then based on further diagnostics such as urinalysis and urine microscopy, you can rule out ATN and then move towards making a definitive diagnosis of HRS-AKI.  And then you will hear more from Dr. Olson regarding subsequent therapy once you have a diagnosis of HRS-AKI. So just to mention, this is the European guidelines.  Recently we had some of the American guidelines, the American Society, ASLD, the liver community  published these guidelines just to bring to your attention that in that specific guideline they did not differentiate between stage 1A and 1B.  They have bucketed both those categories into stage 1 on the left side of the diagram. Just to make you aware of the subtle difference between the U.S. guidelines and the European  guidelines with regard to stage 1 AKI management. Switching gears again, let me just briefly share with you sort of the potential evolving  role of biomarkers in the diagnostic evaluation of HRS-AKI and just to share with you one particular study. This was published in 2014 by Belcher et al.  But just to draw your attention to the potential growing interest in EMGAL, urinary EMGAL in particular.  And as you can see, there are a few biomarkers, urinary biomarkers, that are studied here  including IL-18, Kym1, and liver fatty acid binding protein. But I just want to draw your attention specifically to urinary EMGAL.  This is one of many studies that is now shining light on the potential role of EMGAL in differentiating ATN from HRS and thereby guiding subsequent therapy.  So I would just stay tuned regarding further data regarding the potential application of urinary EMGAL in the context of HRS-AKI in ACLF.  And then finally, concluding this part of the talk, let me just briefly conclude with the CKD etiologies in cirrhosis and how they can potentially affect diagnosis and management  for HRS-AKI.  So as you think about the differential diagnosis of CKD in the setting of cirrhosis, as you  all aware, there's an epidemic of NASH-induced cirrhosis in the U.S. and in the Western world.  And so one sort of correlation with that is, or association with that, is diabetic nephropathy,  which can increase the prevalence of underlying CKD in that patient who is presenting with acute kidney injury.  There is a second, another etiology, we haven't had time to talk about it, but that is HRS-CKD  in contrast to HRS-AKI, and this is defined as an EGFR less than 60 for greater than three months.  And so this is a physiology that can exist in a patient with chronic portal hypertension that can contribute to the coexistence of CKD in this patient population.  And other rare examples would be alcohol, liver disease, and associated IgA nephropathy. And then finally, another example is patients with viral hepatitis, like hepatitis B and  hepatitis C, can be associated with MBGN that can cause intrinsic kidney disease. So just to give you a sort of an idea of potential underlying CKD etiologies that can exist in  this patient population, I want to draw your specific attention to diabetic nephropathy and CKD associated with that in the setting of the NASH.  So as you can imagine, the presence of underlying CKD in this patient population can further  complicate the diagnostic evaluation of HRS-AKI, and importantly have implications regarding further management, including the need for renal placement therapy and the consideration  potentially for combined liver-kidney transplantation. So just to summarize my talk, number one is that in the setting of AKI and in cirrhosis  and ACLF, that process can have multiple etiologies that can coexist and contribute simultaneously to renal dysfunction that will affect diagnosis and therapy.  Another important take-home message is that the definition of HRS-AKI has luckily evolved to incorporate the general principles of AKI management and diagnosis that we are  all familiar with in general critical care, and that has really helped us with regard to earlier diagnosis and therapy.  I've shared with you the revised clinical practice guidelines that are aimed at optimizing and importantly standardizing management of HRS-AKI and also the subtle difference between  the European guidelines and the American guidelines. We briefly spoke about the potential role of emerging biomarkers, in particular uranium  gal, and then finally the importance of assessing for underlying CKD, especially in the growing  presence of NASH, as it can complicate diagnosis and therapy in the setting of HRS-AKI.  I'll now turn it over to Dr. Olson. Thank you to the organizers for inviting me to speak with you today with a section that  I'll be covering today will be evidence-based vasoconstrictor therapy and monitoring of patients with hepatorenal syndrome type acute kidney injury in the intensive care unit.  I do serve as a consultant for Malincroft as they continue to navigate FDA approval of trilopressin.  Dr. Sumanian went through the algorithm for management of acute kidney injury and cirrhosis and I've recaptured these slides both from the EASL and the American Association Study  of European Association for the Study of the Liver. And I want to talk about these algorithms in the context of the intensive care unit.  As we think about the diagnosis of hepatorenal syndrome, this really remains a diagnosis of exclusion.  As Dr. Carvelis highlighted, patients with ACLF presenting to the intensive care unit oftentimes have multisystem organ failure.  In both of the typical protocols looking at hepatorenal syndrome, they talk about withdrawal of diuretics and expanding with albumin and observing the patient for two days.  But in the intensive care unit, when patients are presenting with multisystem organ failure, oftentimes we're going to be more aggressively addressing these issues and taking a more  aggressive approach right upon presentation. This is where vasopressors and albumin may come into play slightly before the two-day  observation period when we have a high index of suspicion of hepatorenal syndrome in our patient population. This is the ASLD practice guideline.  As we saw before, there is no differentiation between acute kidney injury stage 1A and stage  1B, though there are clear implications for this differentiation in stages that have been identified in previous studies from the European group.  But again, we're making a diagnosis of exclusion after ruling out other causes of acute kidney  injury and then moving to vasoconstrictor therapy and albumin when we believe that hepatorenal syndrome is the central diagnosis.  When hepatorenal syndrome type acute kidney injury is the presumed etiology of kidney dysfunction, both the ASLD and ESL practice guidelines are very similar in their approach.  The treatment remains vasoconstrictor drugs in combination with albumin. The preferred drug in both practice guidelines is terlopressin, where available, administered  either as an IV bolus or by continuous IV infusion. In settings where terlopressin may not be available, predominantly in the United States  and Canada, norepinephrine should be considered. And if neither can be administered, for example, patients who may be outside of the intensive  care unit, therapy with mitadrine plus octreotide may be used. However, the efficacy is very low with this combination of therapies.  Thinking about critical illness in patients in the ICU, this pooled analysis from Dr. Velez and others demonstrated that an increase in mean arterial blood pressure is strongly  associated with a decrease in serum creatinine in patients with presumed hepatorenal syndrome.  In this slide on the right, representing only randomized control trials, you can see that the seven-day change in serum creatinine is mirrored by the seven-day increase in mean  arterial blood pressure. With increasing mean arterial blood pressure, there's a more pronounced reversal of elevated serum creatinine.  The study also highlighted that in certain patients, depending on their baseline creatinine  presentation, you can estimate a mean arterial blood pressure increase, which would be required to achieve a normalization of serum creatinine.  When we talk about vasopressors, which ones are available for treatment of hepatorenal syndrome, we've talked a lot about trilopressin.  And for providers in North America, the United States and Canada, where this is not available, you may not be aware of this drug.  Trilopressin is a synthetic vasopressin analog that has a selectively higher affinity for V1-type receptors, which are predominantly located in the smooth muscle cells of the  arterial circulation and the splanchnic vasculature.  Utilization of trilopressin reduces splanchnic blood inflow and thus decreases portal pressures,  redistributes part of the intravascular volume to central circulation, thereby increasing effective circulating volume.  Published literature to date provides evidence that trilopressin improves renal function in patients with hepatorenal syndrome type 1.  I'm using this term because many of the studies still utilize this definition of hepatorenal syndrome in the patient recruitment.  Trilopressin remains the standard of care for this condition, wherever the drug is available.  When we talk about the evidence basis for usage of trilopressin at this time, we looked at three major studies that have been carried out over the last several years, starting  with the OT0104 study. This study was a multinational study carried out in centers between the United States, Germany, and Russia.  It provided additional supportive evidence of the efficacy of trilopressin and the effectiveness of trilopressin.  This was followed between 2010 and 2013 in centers in the United States and Canada. This was the reverse study enrolling 196 patients.  In the most recently published confirmed study, a pivotal trial evaluating efficacy and safety of trilopressin in hepatorenal syndrome.  Again, this was carried out in North America and completed enrolling in 2019, with the data being published in the New England Journal of Medicine in 2021.  The primary efficacy endpoints of phase three studies, looking at comparing between the studies, the definition for enrollment and identifying patients with hepatorenal syndrome  has actually been the same across studies utilizing the old hepatorenal syndrome one definition.  Serum creatinine requirements for definition reversal required the serum creatinine level  to fall to less than 1.5 milligrams per deciliter and measured at least on two different values at differing time points. In the OT0401 study, this was at 48 hours.  Same in the reverse trial, and in the confirmed trial, verified HRS reversal required at least two documented serum creatinines less than 1.5 milligrams per deciliter, at least two  hours apart. And sustained clinical requirements required live without renal replacement therapy at  greater than 10 days and confirm, and without dialysis or hepatorenal central recurrence at day 14 at the OT0104 study, 0401.  In the reverse study, achieving confirmed hepatorenal syndrome reversal with Turlopressin improved survival.  And in this specific study, in this specific slide, we look at reversal versus non-reversal in the Turlopressin arm.  And you can see that there was a statistically significant improvement in 90-day survival in patients who achieved reversal of hepatorenal syndrome in the Turlopressin arm.  This effect was lost and did not maintain statistical significance in the placebo arm, remembering both arms received albumin in the study.  The confirmed study, which was the North American randomized controlled trial of Turlopressin plus albumin for the treatment of hepatorenal syndrome type 1, was designed as follows.  Patients received one milligram of Turlopressin intravenously every six hours by bolus infusion or placebo plus albumin, which was given to both arms.  The study drug dosage increased to two milligrams every six hours if the serum creatinine had  decreased, but not by greater than 30% baseline value on day four. And the albumin administration guidelines were as recommended from the International  Club of Societies, one gram per kilogram on day one to a maximum of 100 grams,  followed by 20 to 40 grams per day thereafter as clinically indicated.  In the confirmed study, the results were fairly impressive, again demonstrating verified HRS reversal. This was compared to the placebo arm.  Approximately 30% of patients achieved verified HRS reversal compared to just 16% in the placebo arm.  And when you look at simple HRS reversal with the fall of serum creatinine to less than 1.5 at any time during therapy, this effect was even more pronounced with 36% of patients  in the treatment arm having a reversal versus 16.8% in the placebo arm.  In the confirmed study, additional data also demonstrated that there was a decrease in the amount of patients who required renal replacement therapy through 90 days of follow-up.  This did not maintain statistical significance completely through day 90, but it did demonstrate  a decrease in the requirement for renal replacement therapy in patients treated with Turlopressin as compared to placebo.  And there was a statistically significant decrease in the percentage of patients who required renal replacement therapy after liver transplant in the group of patients who underwent  liver transplantation.  This also translated into shorter times in the intensive care unit as well.  In pooled analysis of the duration of HRS reversal in patients treated with Turlopressin, we can also see a significant benefit in the patients who had sustained reversal after  being treated with Turlopressin as compared to placebo.  In the intensive care unit, we have choices for vasopressors, and is one pressor particularly  better than any other, and the treatment of hepatorenal syndrome, and this is a question of ongoing study.  In one open-label randomized control trial looking at specifically patients with hepatorenal syndrome type acute kidney injury in the acute on chronic liver failure population,  this study demonstrated that as compared to Turlopressin, as compared to norepinephrine, Turlopressin actually had improved outcomes and improved survival, which was statistically  significant at day 28, suggesting that Turlopressin may be superior to norepinephrine for management  of hepatorenal syndrome in patients specifically with acute on chronic liver failure in earlier stages of ACLF, as I will elaborate on later on in this presentation.  Other studies looking at comparative treatments for management of hepatorenal syndrome have consistently demonstrated superiority to Turlopressin over placebo, and as superior to  treatment with Midotrin plus Octreotide. Again, in meta-analyses looking at Turlopressin versus norepinephrine, with the exception  of the previous study that I showed you, there's no significant difference between treatment outcomes in patients receiving Turlopressin versus norepinephrine in the ICU.  However, there are some other important considerations when thinking about Turlopressin versus norepinephrine.  This includes, importantly, the route of administration. Norepinephrine typically requires central line insertion and ICU-level monitoring,  though there has been one recently published study looking at usage of norepinephrine outside of the ICU for hepatorenal syndrome, as a study performed in California demonstrating  that this was acceptable.  But overall, Turlopressin has an important distinction from norepinephrine in that it may be given by bolus infusion due to its duration of action, and this can be administered  by a peripheral line allowing for non-ICU use, and this is very important for minimizing a transfer to the ICU for patients who are experiencing hepatorenal syndrome.  There will likely be significant cost considerations.  Certainly, managing a patient outside of the ICU will decrease overall patient costs, but Turlopressin is likely to be significantly more expensive than norepinephrine, at least  in the United States and Canada.  When thinking about management of hepatorenal syndrome-type acute kidney injury in the ICU, I want to mention a few things about timing and special considerations, specifically  some of the safety data that has emerged in the Turlopressin trials.  As Dr. Subramanian alluded to previously, I think this is very important for an ICU audience to see this data.  The liver guidelines typically have excluded urine output as a screening tool for patients  identifying patients with acute kidney injury. However, this study looking at over 3,000 patients in the intensive care units in Pittsburgh  identified that serum creatinine is important, but urine output measurement is also critically important for early identification of patients with evolving acute kidney injury.  This slide demonstrates that patients who have either stage three acute kidney injury as identified by serum creatinine measurement with normal urine output versus urine output,  which is stage three by the Kidego guidelines, and serum creatinine measurements, which would be stage zero, demonstrate similar outcomes when you look at age-adjusted survival over  a year.  Patients who have the worst outcomes are those who have both stage three acute kidney injury as manifested by both serum creatinine and urine output measurements.  Again, the study looked at 3,458 patients with chronic liver disease in the intensive care unit.  And another important finding from the study was that when using urine output criteria alone to identify acute kidney injury, there were 1,281 patients were found to have stage  two to three acute kidney injury that were not identified when using serum creatinine criteria alone.  And as a reminder, these are the Kidego urine output criteria for identifying stage one through stage three kidney dysfunction.  A few words about some adverse events, which were identified during the most recent confirmed trial.  And there was an increase in significant adverse events in the treatment arm treated with trilopresin.  Specifically, we identified two signals, one for respiratory failure and for sepsis.  And this deserves some additional commentary.  When this was further analyzed as a function of the data, which was available from the confirmed trial, we could see that there were some specific patient populations that were  much more likely to develop serious adverse events. And some of this follows a logical pathway.  Patients with serum creatinine greater than five milligrams per deciliter were unlikely to benefit from trilopresin administration.  Similarly, patients with ACLF grade three and remembering back from the beginning when  Dr. Carvelis outlined these patients, these are the patients with multi system organ dysfunction of at least three organ systems.  And again, patients with clear evidence of vascular congestion or central volume pulmonary, excuse me, volume overload or pulmonary edema.  And in these specific patient groups, the benefit of using trilopresin was low and the risk for significant adverse events was higher.  So when thinking about vasopressor choice, certainly there needs to be careful thought applied to the identification of patients who will benefit from the usage of trilopresin.  Again, usage in patients with serum creatinine less than five and lower grade ACLF grade zero through two are the ones who are most likely to demonstrate benefit.  Again, when you look at long term outcomes from patients with ACLF grade three, the overall outcome from this group of patients is poor at 90 days as compared to patients who have  ACLF grade zero to two. Similarly, patients who have baseline serum creatinine greater than five have overall  worse outcomes, but certainly they have a higher mortality and higher rate of significant adverse events when treated with trilopresin.  So what is the basis for some of the increased adverse events that were identified in this trial?  Likely there's a component to the albumin administration, which is being administered to these patients.  And to elaborate on this, I will highlight the entire trial. This was a study which was also recently published in the New England Journal of Medicine  looking at albumin administration in hospitalized patients with cirrhosis. In this particular study, the entire trial was targeting a serum albumin of three grams  per deciliter or greater in decompensated cirrhotic patients who had a serum albumin level of less than three grams per deciliter at enrollment with repeated daily infusions  of concentrated albumin. And this was as contrasted to the standard of care. The question was whether routine administration of albumin to raise the serum albumin level  to a specific threshold would decrease the incidence of infection, kidney dysfunction, and death.  This was a randomized multi-center open label parallel group trial involving hospitalized patients with decompensated cirrhosis with albumin levels less than 30 grams per liter  or three grams per deciliter enrollment. And patients were randomly assigned to receive either targeted 20% albumin solution for 14  days or until discharge versus the standard of care. This study used a composite primary endpoint.  And you can see that there was no significant difference in outcomes between the albumin  group versus the standard of care group across different time points and looking at different components of the primary composite endpoint.  However, in patients hospitalized with decompensated cirrhosis, albumin infusions used to increase  the albumin level to a targeted three grams per deciliter or more was not beneficial to beneficial as compared to the current standard of care in this study, which was carried out  in the United Kingdom. However, there were more severe and more life-threatening serious adverse events, especially  pulmonary edema and fluid overload in the albumin group as compared to the standard of care group.  So this highlights some of the considerations that if you're using albumin plus trilopresin, which may be utilized to help determine who may benefit from these therapies and in whom  caution may be warranted. One of the questions that we're always faced with when having conversations about acute  kidney injury in the intensive care unit and the cirrhotic patient population is when should renal replacement therapy be used?  The easel practice guidelines state that this should likely be considered on a case-by-case  basis, initiate if there's a reversible cause of liver failure, and when patients are listed for liver transplantation.  I think it's certainly my belief that listing for liver transplantation should not be the only requisite for consideration of renal replacement therapy in patients with acute  kidney injury and cirrhosis. The statement from a U.S. consensus meeting in which both Drs. Karvelis, Dr. Subramanian, and myself participated in issued the following statement.  We recommend that in patients with evidence of worsening acute kidney injury, worsening fluid overload with greater than 10% total body weight increased despite diuretic therapy  or worsening acid-base status, then renal replacement therapy should be initiated. I agree that it's likely should be considered on a case-by-case basis, and in patients who  have worsening of multisystem organ failure, as Dr. Karvelis has clearly demonstrated in published studies, patients with progressive organ system  dysfunction and patients with very high ACLF, CLIF-ACLF scores are not likely to benefit from renal replacement therapy, and clearly studies have demonstrated that this does not  change long-term survival.  Definitive therapy for hepatorenal syndrome remains liver transplantation. Timely transplantation is indicated for optimal recovery of renal function.  Patients who have persistent acute kidney injury should be considered for simultaneous liver kidney transplantation.  In the United States, persistent acute kidney injury is defined by OPTN as follows, including  one or both for at least the last six weeks, patients being on dialysis at least once every  seven days, or calculated creatinine clearance or GFR of less than 25 milliliters per minute at least once every seven days.  In this situation, patients may be considered for simultaneous liver kidney transplantation.  There's still several unresolved questions. What is the appropriate dosage duration of albumin, and are there certain stopping points? Should this be based on a serum albumin level?  Should it be based on patient weight?  We're seeing more and more obese patients in our ICU populations, and how should we adjust albumin doses?  What are maximum dose limitations for albumin?  Should patients with suspected hepatorenal syndrome be moved to the intensive care unit more rapidly for norepinephrine treatment in situations where terlopresin may not be  administered, recognizing that mitigrin and noctreotide are really not very effective at all and are only slightly better than placebo?  And again, when should we be utilizing renal replacement therapy in these patients?  Hiccum points for my section include that acute kidney injury type hepatorenal syndrome carries a very worrisome prognosis.  You should always be thinking about hepatorenal syndrome early in cirrhotic patients who have ascites and develop acute kidney injury.  Increasing the mean arterial blood pressure is critical for management in the ICU. We should be aggressive utilizing vasopressors where appropriate.  Urine output is a powerful predictor of acute kidney injury in cirrhotic patients, and in the ICU, this should probably be combined into your assessment for evaluating patients  for acute kidney injury. At the end of the day, transplantation remains the only definitive treatment for hepatorenal syndrome.  We utilize other treatments in an effort to buy patients time for recovery, especially when they have ACLF from a defined cause, such as GI bleeding or infection.  An aggressive treatment for hepatorenal syndrome is absolutely necessary for the best outcomes for this patient population.  Thank you for your time and attention.  Thank you, Jody.  We've got about two minutes left to the audience. If you want to pose any questions through the chat, feel free.  I just have one question I'm just going to pose to both Ram and Jody.  Do you think there's an opportunity, or depending on the setup of your hospital, to improve the care of patients with HRS in the ward setting, in particular with turlopressin,  and moving us, or do you think that there are significant challenges with regards to monitoring in your own hospital setting?  I'd just be kind of curious to know the individual setups that you would have to deal with in Kansas and Atlanta. I'm very optimistic that we would be able to utilize this.  I think COVID's actually helped us in two ways. One, it helped us identify patients that needed to be managed outside of the ICU and needed closer monitoring.  So this allows us for very, you know, we've clearly been able to demonstrate that we can monitor oxygenation very easily on floor patients.  And this is clearly a very unmet need.  COVID also highlighted that the shortage of ICU bed availability is a big issue.  So being able to effectively manage out-of-renal syndrome outside of the ICU, I think, is going to be critically important.  We have not traditionally moved patients, you know, simply for initiation of norepinephrine,  and I think we probably are under-treating these patients where we can only use mitotriotide.  Just to follow up on that, at our center, it's probably a bit of a moving target,  and just as far as the comfort with which initially, if we deploy a drug like toliparacin, would it be initially on the ICU setting, and then once everybody gains more comfort  with it, then we'll be more comfortable transitioning care to the non-ICU floor.  So as I think about our center, that may be a potential scenario. I guess just to take it a step further, I think you showed some interesting data about  the challenges of kind of looking into these perceived kind of pulmonary complications that came out of the trial, where really it may potentially be reflecting actually a  fluid management issue.  And we might be a little bit constricted by saying that, you know, if you're an ACLF grade three, but technically you don't have fluid overload, you might still potentially benefit  from toliparacin.  Yeah, I agree with that. Just the other point I think is with the revised criteria, as we know in the confirmed trial,  the creatinine activities are greater than 2.25 for enrollment. But as we appreciate and apply clinical guidelines to HRSA-KI, we now have the option to retreat  earlier, which would also be beneficial because now you're dealing with a patient who may  not be in worsening oliguria, and therefore having a baseline sort of increased intravascular volume state that increases the risk of respiratory insufficiency.  Yeah, I completely agree.  Maybe just to take that a step further, just a question from the audience. I'll start this with Ram.  When looking at the definitions of HRSA-KI, do you think that the rigid diagnoses are perhaps counterproductive?  Would a more fluid use of information such as N-Gal, FINA, point-of-care ultrasound be more useful in forming volume and treatment decisions in the ICU?  No, I think that is, especially when I think about point-of-care ultrasound, I think that's going to be very beneficial as you assess volume status in these patients.  And with regard to specifically HRSA-KI management status, I totally agree with  that specific point raised in that question.  I think urinary LDL has always been interesting even outside the HRSA-KI setting and general AKI as well.  It's about trying to see how practical it is as you create or as you strive for practical guidelines.  And then the FINA data is interesting. I think a lot of the folks in the audience may know that if you have an extremely low  FINA, that may help you distinguish between HRSA-KI and prenatal azothemia. The data is a bit noisy, but there is opportunity to explore that as well.  But I think POCUS will have a very important role, as we do in general care as well, but in particular, as we manage fluid management in HRSA-KI.  All right.  I think this draws this wonderful session to a close. I want to thank again the organizers for helping us put on this wonderful session. And on behalf of myself, Drs.  Olson and Subramanian, we really thank all of you in the audience for your participation today.  And we hope you enjoy the rest of the Congress. Thank you.

Video Summary

The session discussed the management of multi-organ disease and acute on chronic liver failure. The speakers highlighted the challenges in managing cirrhosis and multi-organ failure, such as hepatic encephalopathy, acute kidney injury, and portal hypertension. They emphasized the importance of early diagnosis and treatment of acute kidney injury in cirrhotic patients, particularly in the ICU setting. The use of bedside echocardiography was discussed as a tool to assess volume status and cardiac output in these patients. The speakers also discussed the diagnosis and management of hepatorenal syndrome, noting that it is a diagnosis of exclusion and highlighting the importance of vasoconstrictor therapy and albumin administration. They discussed the use of trilocylin as a preferred vasoconstrictor and the potential challenges in using it in the ward setting. They also noted the importance of urine output as a predictor of acute kidney injury in these patients and the need to consider renal replacement therapy on a case-by-case basis. Overall, the session provided valuable insights into the management of multi-organ disease and acute on chronic liver failure, highlighting the importance of early diagnosis and treatment and the challenges in managing these complex patients.

Asset Subtitle

Pulmonary, GI and Nutrition, Renal, 2022

Asset Caption

This session is for critical care medicine professionals involved in managing multiorgan failure arising as a consequence of acute-on-chronic liver failure (ACLF), including hepatorenal syndrome/acute kidney injury (HRS/AKI), and the risks of acute respiratory distress syndrome (ARDS) in patients undergoing albumin revolumization.

Learning Objectives:
-Discuss the terms cirrhosis, decompensation, and acute-on-chronic liver failure (ACLF), as well as their clinical significance and risk to patient mortality
-Review current evidence for the whole-patient management of multiorgan failure arising from ACLF, including risks to renal and respiratory function
-Apply evidence-based fluid management protocols to revolumize patients with ascites following large-volume paracentesis in AKI patients to establish a diagnosis of HRS/AKI, while mitigating risks from fluid overload
-Intervene with proactive evidence-based vasoconstrictor therapy for patients who meet diagnostic criteria for HRS/AKI based on American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) algorithms
-Monitor patients with cirrhosis, ascites, and HRS/AKI for treatment-emergent adverse events that may worsen prognosis

This program is supported by an education grant from Mallinckrodt

Meta Tag

Content Type Presentation

Knowledge Area Pulmonary

Knowledge Area Renal

Knowledge Area GI and Nutrition

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Tag Acute Respiratory Distress Syndrome ARDS

Tag Liver

Tag Renal

Tag Updates and Future Directions

Year 2022

Keywords

multi-organ disease

acute on chronic liver failure

cirrhosis

hepatic encephalopathy

acute kidney injury

portal hypertension

early diagnosis

bedside echocardiography

hepatorenal syndrome

renal replacement therapy

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