Transcript
Speaker: Welcome to Critical Matters, a sound critical care podcast covering a broad range of topics related to the practice of intensive care medicine.
Speaker: Sound Critical Care provides comprehensive critical care programs to hospitals across the country.
Speaker: To learn more about our programs and career opportunities, visit www.soundphysicians.com.
Speaker: And now, your host, Dr. Sergio Zanotti.
Speaker: Patients with acute
Speaker: and acute on chronic liver failure are at high risk of developing critical illness.
Speaker: The unique pathophysiology of liver disease related to critical illness presents a series of challenges to clinicians.
Speaker: In today's episode of the podcast, we will discuss highlights of the guidelines for the management of adult acute and acute on chronic liver failure in the ICU, cardiovascular, endocrine, hematologic, pulmonary, and renal considerations.
Speaker: This guideline was released earlier this year and was produced by a panel of 29 members
Speaker: with expertise in aspects of care of the critically ill patient with liver failure and or the methodology for evidence-based medicine guideline development.
Speaker: We will focus on recommendations for management of acute and chronic liver failure patients in the general ICU setting.
Speaker: Our guest is Dr. Rahul Nanchal.
Speaker: Dr. Nanchal is a practicing critical care physician with an interest and expertise in liver disease.
Speaker: He is a professor in the division of pulmonary and critical care medicine at the Medical College of Wisconsin in Milwaukee.
Speaker: Dr. Nancho is a recognized clinician educator and has a long list of publications.
Speaker: He is the lead author and co-chair of the guideline for the management of adult acute and acute on chronic liver failure in the ICU.
Speaker: This is the guideline we'll be discussing today.
Speaker: Rahul, welcome to Critical Matters.
Speaker: Thanks, Sergio.
Speaker: Thanks for having me.
Speaker: I really appreciate it.
Speaker: So we talked about doing this podcast back in February at SECM, and obviously a lot has happened since then.
Speaker: but I'm happy that we're finally getting you to do this.
Speaker: And I know that right now in your institution, in your state, you are very busy with COVID.
Speaker: So I really appreciate you taking the time to talk about a non-COVID issue, which I think might be refreshing for both us and our audience.
Speaker: No worries, Sergio.
Speaker: I'm happy to talk about something different than COVID for once.
Speaker: I would like to start with some basic definitions to put things in context, Rahul.
Speaker: And maybe if you could just define very succinctly and from a general clinical perspective,
Speaker: What do we mean by acute liver failure, chronic liver failure, and acute on chronic liver failure?
Speaker: Okay.
Speaker: So, you know, so great question.
Speaker: So acute liver failure is, you know, basically liver dysfunction that occurs in a normal liver.
Speaker: So that's important.
Speaker: So, you know, the liver is normal.
Speaker: And, you know, there is an insult such as maybe Tylenol, maybe a virus, you know, maybe something else.
Speaker: and the liver fails.
Speaker: And what I mean by the liver failing is that the synthetic function of the liver is affected and there is development of hepatic encyclopathy.
Speaker: Now, if the development of hepatic encyclopathy is within about 24 to 26 weeks of the initial insult to the liver, that is termed as acute liver failure.
Speaker: Now, the important thing is
Speaker: that the insult occurs again, like I said, in a pre-existing normal liver.
Speaker: So the liver is normal.
Speaker: So that's acute liver failure.
Speaker: So chronic liver failure is this sort of process that sort of destroys liver cells and there is regeneration and eventually fibrosis and the eventual manifestation is cirrhosis.
Speaker: So that is chronic liver failure.
Speaker: And the hepatic encephalopathy that sets in, you know, in chronic liver failure is way beyond the 26, 28 weeks of acute liver failure.
Speaker: And it is sort of a, you know, a slow process, you know, that affects the livers.
Speaker: Usually it takes many, many months and, you know, even years to develop.
Speaker: Acute on chronic liver failure is a little more controversial topic.
Speaker: We have known about this.
Speaker: I think the entity was first described in the earlier part of the decade.
Speaker: And there are still controversies surrounding it.
Speaker: And the definitions are still a little bit controversial because there are groups that have come out with, there are at least four groups that have come out with
Speaker: with sort of their own definitions.
Speaker: But very simply, acute on chronic liver failure occurs in the context of pre-existing liver disease.
Speaker: So it occurs in the context of chronic liver disease.
Speaker: There is an accused superimposed insult that leads to organ failure.
Speaker: So chronic liver disease, acute insult and organ failure
Speaker: That is the basic definition of acute on chronic liver failure.
Speaker: And I think the, again, the cardinal manifestations of the three cardinal things that happen in acute on chronic liver failure is this intense inflammatory response syndrome as a result of, you know, some inciting event and the various organ failures.
Speaker: It's important to emphasize.
Speaker: Absolutely, Brahu.
Speaker: And I think it's important to emphasize that for most of our listeners who work in ICUs,
Speaker: it's the acute and chronic liver failure patient that they encounter on a regular basis.
Speaker: That's the most common encounter in the ICU where they come with primary liver problems causing the organ failure or some other critical illness that impacts the liver.
Speaker: And that's what we're going to talk about today in more detail.
Speaker: Yeah, absolutely.
Speaker: So the acute liver failure is actually a, you know, sort of a very rare disease.
Speaker: It is not very common and one could even call it an awful disease.
Speaker: In terms of acute and chronic liver failure, Rahul, could you give us a little bit of a context of some, you talked about the definition and how there's varying definition, but gave us an overall idea of what we mean by that.
Speaker: But what are some of the problems in these patients that ultimately lead to an ICU admission?
Speaker: And what are some, perhaps, some of the common mistakes in management or misconceptions that intensivists might have related to these patients?
Speaker: You know, I think there are a couple of things that I would like to emphasize.
Speaker: So first of all, there is, you know, something happens.
Speaker: It could be either a hepatic insult or an extra hepatic insult.
Speaker: So a hepatic insult is someone with preexisting liver disease took a bunch of alcohol and so, you know, and that's a, you know, sort of a hepatic result or for some reason got ischemia of the liver.
Speaker: You know, again, that's a hepatic insult.
Speaker: More commonly, people get a UTI or SVP, some sort of infection or a GI bleed, and that sort of sets off a cascade of events that leads to severe inflammation and then leads to organ failure.
Speaker: So one of the things is that once these organ failures start occurring, it is very, very essential that we recognize
Speaker: we recognize the entity because sometimes it's elusive.
Speaker: So for example, if you look at the European Consortium or EASL or the European Association for Study of Liver Diseases where this entity was sort of the acute and chronic liver failure was first described, in that cohort, the most important, the most common organ to fail was the kidney.
Speaker: Now, you know, how do we measure kidney function by, you know, usually people do it by measuring creatinine and we
Speaker: All of us know that in liver disease, there is less hepatic production of creatinine, which is the precursor of creatinine.
Speaker: The liver mass, the muscle mass is decreased.
Speaker: There is malnourishment problems.
Speaker: And so usually creatinines are not very high.
Speaker: And so someone might look at a creatinine of 0.6 or 0.7 and say, hey, oh, that's normal.
Speaker: and sort of not realize that their baseline creatinine is 0.3 and the creatinine is actually doubled and their GFR is halved.
Speaker: And right there is a recognition problem.
Speaker: And so that's one of the things that needs to occur very expeditiously because
Speaker: again, the longer you leave someone without treatment, the worse the outcome is.
Speaker: The second part of this is that the insult that there should be a search, a thorough search for the insult that is leading to acute and chronic liver failure because it is important to treat that.
Speaker: So again, if you looked at the European cohort, there were about 22% of patients were admitted with acute and chronic liver failure, but
Speaker: about 10% of people actually developed it short time, 24, 48 hours into the hospital.
Speaker: And that was likely because someone missed SVP or someone missed UTI or something of that nature that was leading to decompensation or leading to sort of organ failures and acute and chronic liver failure.
Speaker: So that's really important.
Speaker: And the third thing that I would like to emphasize is that this is
Speaker: recoverable, you know, so an insult happens, people get into organ failure, but it doesn't like you get into organ failure, you can't recover.
Speaker: I mean, you know, you can't, the many of these cases are recoverable and, you know, and you get back to sort of, you know, you have this downward spiral and then you get back to where you were at baseline.
Speaker: And, and so prognostication should not occur right at day one when the organ failures are, or you diagnose acute on chronic liver failure.
Speaker: Actually prognostication is much better if you do it, you know,
Speaker: a week after all of this occurs.
Speaker: So I think those are some of the important things that we need to realize.
Speaker: And I think the fourth thing for places that don't have liver transplant centers is early referral to centers that do do liver transplantation.
Speaker: Because there is more and more sort of data emerging that traditional scores like the MELD score or the MELD sodium score sort of underestimate the risk of mortality for these people with acute on chronic liver failure because of all of their organ failures and so on and so forth.
Speaker: So what I'm hearing, Rahul, is a lot of important aspects that maybe the general intensivist who's not really
Speaker: involved with acute liver failure and acute and chronic liver failure might overlook and might lead to almost like a circular thinking that leads to a nihilistic approach and a self-fulfilling prophecy that we don't recognize early organ failure.
Speaker: We don't look aggressively for the cause of that acute and chronic liver failure.
Speaker: That leads us to believe that there's nothing we really can do for these patients.
Speaker: We prognosticate too early and at the end we really are doing a great disservice to these patients
Speaker: by either not treating aggressively their acute organ failure that can be reverted or by not giving them the appropriate referral and evaluation for perhaps more definitive therapy like a liver transplant.
Speaker: Exactly, Sergio.
Speaker: Excellent.
Speaker: Like I said at the beginning, we're going to focus a lot around the document that you co-chaired with the guidelines committee.
Speaker: But before we dive into the management recommendations, perhaps you could give us a list, very general brief,
Speaker: high-level overview of the guideline process, but also I'm very interested in if you could just clarify for everybody to understand what's the difference between the strength of recommendation between a strong recommendation and a conditional recommendation from the perspective of the clinician, the patient, and maybe even policy makers.
Speaker: Oh, yeah, yeah, sure.
Speaker: I think, you know, that is the, that is a fantastic question, Sergio.
Speaker: And that's probably, you know, something that we tried to clarify in the document.
Speaker: And hopefully, you know, talking to you, you know, on the podcast, this is something that, you know, I can spend a few minutes on and sort of clarify.
Speaker: So the overall process was, you know,
Speaker: We proposed a topic.
Speaker: I think my co-chairs and I were really interested in developing some sort of document or guidelines that would be of benefit to the general leadership, especially people in community hospitals and people who see liver disease on a regular basis.
Speaker: And we pitched the idea to SCCM who were interested as well and
Speaker: and then we were appointed chairs.
Speaker: And then we selected our committee and since liver failure sort of affected the organ of the body, we thought it was important that we not only selected people who were experts in liver disease, but we selected people who were experts in, for example, the cardiovascular system or the renal system so that we sort of had a combination of people who were
Speaker: experts in liver disease and experts in their field to formulate the best questions and the best recommendations.
Speaker: And then we selected a few methodologists from the guide group from Canada and our methodology chair was, as you know, Walid Al-Hazani.
Speaker: He was just a wonderful, wonderful person.
Speaker: And after we had gotten the panel together, we sort of divided the panel into nine groups by organ system and then appointed a leader for each of these nine groups and then asked the group to develop questions that they thought were really important to answer.
Speaker: And we asked them to develop questions in the PICO format, which is population intervention
Speaker: control and outcome.
Speaker: And these are sort of one should sort of really try and develop questions in this format because this is the final scientific method of sort of developing a question that then you can look up evidence and sort of try and answer the question.
Speaker: After we had developed the question and sort of decided on what were priority outcomes, we enlisted the help of a librarian here at the Medical College of Wisconsin where I am.
Speaker: literature searches and we searched several databases for relevant papers to the question, went through, and we went through the process of selecting the papers, selecting articles that were pertinent.
Speaker: And after we had selected articles that were pertinent,
Speaker: pertinent, we sort of abstracted their data, did a risk of bias assessment, summarized the evidence.
Speaker: This was all with the help of our methodologists.
Speaker: The evidence was summarized using general meta-analytic techniques.
Speaker: And I don't think we need to get into what those meta-analytic techniques were, but I do want to sort of get into a little bit about how we formulated our recommendations.
Speaker: So for the formulation of a recommendation, we use something called the grade process.
Speaker: Now the grade process is the grading of recommendations, assessment, development, and evaluation.
Speaker: And this approach involves principles that are guided by assessment of the quality of evidence, which is rated from high to very low.
Speaker: Okay, and it is the quality of evidence that actually determines what the strength of our recommendations is, along with some of the other things that I will describe.
Speaker: So the quality of evidence is based on six domains.
Speaker: The six domains are risk of bias, inconsistency, indirectness, imprecision, publication bias, and I think there are some other criteria.
Speaker: And again, the panel members worked very, very closely with the methodologist
Speaker: on sort of the grade process and the development of recommendations.
Speaker: After we use something called an evidence to decision framework, after we had sort of rated the evidence to go from quality of evidence to the final recommendation.
Speaker: Okay.
Speaker: And we graded our recommendations as strong or
Speaker: Conditional, okay.
Speaker: And if it was a strong recommendation, we use the language we recommend.
Speaker: If it was a conditional recommendation, we use the language we suggest.
Speaker: Okay, a strong recommendation is something that we favor.
Speaker: So it is in favor of the intervention or not in favor of the intervention, but it reflects desirable effects of adherence.
Speaker: And it reflects that the effects, the desirable effects clearly outweigh
Speaker: the undesirable effect.
Speaker: Okay.
Speaker: And that it would, that this recommendation would be acceptable for most patients and that it would be acceptable for most clinicians and they would use it in most situations.
Speaker: But Sergio, it's important to remember that a strong recommendation does not imply standard of care.
Speaker: It really doesn't mean that, you know, if you're making a strong recommendation, you absolutely have to follow it to the T and it is standard of care.
Speaker: There are circumstances where you want, you may want to deviate from the recommendation.
Speaker: A conditional recommendation reflects that if you adhere to it,
Speaker: that the desirable effects probably may outweigh the undesirable effects, but the confidence in our recommendation is diminished because either the quality of evidence is not good enough or that the risks and benefits are more closely balanced than they should be.
Speaker: And then we anticipate that while the recommendation is relevant in most patient settings, but it is really heavily going to be influenced by clinical circumstances and the individual situation and personalization
Speaker: of this to the individual patient.
Speaker: And strong recommendations, and we never make a strong recommendation if the quality of evidence is low.
Speaker: Now, as it relates to clinicians, I think you had asked a question of how it relates to, how this relates to clinicians, how it relates to policy makers and how it,
Speaker: relates to patients, which are all our stakeholders.
Speaker: So for patients, strong recommendations, most patients we believe would want, if we make a strong recommendation, they would want the intervention.
Speaker: For the same, for patients, we make a conditional recommendation, the majority of them would probably want it, but many would not.
Speaker: For clinicians, it's the same thing.
Speaker: Most clinicians, we make up for strong recommendations, there's enough evidence that most, and the strength of the evidence is good enough that most individuals would recommend the course of action.
Speaker: In conditional recommendations, there are different choices.
Speaker: Like I had explained, it's probably dictated by clinical circumstance.
Speaker: For policy makers, strong recommendations can be adapted as policy in most situations.
Speaker: For conditional recommendations, there will be substantial debate and there has to be involvement of many stakeholders for policy makers before they make a determination of whether to adopt the what is recommended or not.
Speaker: I'm sorry, this was sort of a long-winded answer, but I think it was sort of important to clarify how people should... We got a lot of questions saying, well, how could you say this?
Speaker: And we were like, well, we said it,
Speaker: it is a conditional recommendation.
Speaker: And we did say that there was very low quality of evidence, which means that you guys are free to do what you want depending on clinical circumstances.
Speaker: From my perspective, I think this is a very valuable discussion, obviously, because it gives the context of what we're going to discuss.
Speaker: But also, as somebody who works with a large number of programs, my approach would be that strong recommendations
Speaker: are things that we likely should be making sure that we do the majority of the time.
Speaker: So let's focus on making sure that when there's strong recommendations, that we are providing that to the majority of our patients, that we have processes to ensure that.
Speaker: Meaning that it's not 100%, but it should be kind of what we do on a regular basis.
Speaker: And it's focused on what defines the floor of treatment.
Speaker: Conditional, like you said, are going to be much more applicable.
Speaker: to the clinician, the patient's preferences, and the exact situation, right?
Speaker: So they're good to know, but again, like you said, as of where we stand right now with the evidence, these are suggestions, things that we should be thinking about, but not necessarily doing on a regular basis.
Speaker: And to that event, it seems that you have six, I think there's six strong recommendations, and we'll emphasize those at the end, but also the majority of the recommendations are gonna be conditional because
Speaker: And not only we don't have tremendous amount of studies for all these questions, but it's also hard to find questions that are answered in trials, specifically looking at acute on chronic liver failure patients, correct?
Speaker: Yeah, so that's correct, Sergio.
Speaker: And that was, so the document had a lot of questions and most of them were conditional recommendations for exactly the reasons that you've described.
Speaker: A, it is very hard to find randomized controlled trials just on,
Speaker: patients with liver failure or acute liver failure for that matter.
Speaker: And then the evidence becomes indirect because then you're, so for example, there is evidence from sepsis, but a lot of those trials excluded patients with liver failure.
Speaker: So now the number of people who were included with liver failure was really small.
Speaker: And so now you're left with indirect evidence and you're left scratching your head as to whether this is applicable to these patients or not.
Speaker: And while you think that physiologically this may be applicable, you really can't make a strong recommendation.
Speaker: And now we realize that there may be situations where you may have to sort of think about doing it, but also individualize it to the clinical circumstance and to the patient that you're treating.
Speaker: Excellent.
Speaker: With that out of the way, let's dive into the management recommendations.
Speaker: And I would like to start with cardiovascular considerations.
Speaker: Sure.
Speaker: Tell us a little bit about fluid resuscitation and the role of hydroxyethyl starch, gelatin solutions, and albumin.
Speaker: Okay, so let me talk about the one that is easier first, which is the hydroxylthyl starch and gelatins, and then maybe we can talk about, you know, we can sort of talk about albumin.
Speaker: And I would like to get your thoughts on this as well, Sergio, since I like the style of podcast, which is very, you know, very conversational.
Speaker: So, you know, so it was, you know, although there were not, there are,
Speaker: So again, randomized controlled trials comparing resuscitation fluids.
Speaker: Now we are talking about people in shock, right?
Speaker: So we are talking about, okay, there's someone in shock or someone who's hyperbolemic, and now we are thinking about what best resuscitation fluid to give a patient.
Speaker: So randomized controlled trials of resuscitation fluids in acute liver failure or acute on chronic liver failure are actually absent.
Speaker: So there is nothing that, there is no randomized controlled trial of dealing with liver.
Speaker: And if you look at the randomized controlled trials of the cessation fluids in general, many trials, again, like we had discussed, had liver failure as a exclusion or had incredibly low numbers of people that had liver failure.
Speaker: Having said that, if you look at meta-analyses of really large trials, we are pretty certain that hydroxyethyl starch
Speaker: is probably harmful.
Speaker: And so we sort of issued a strong recommendation saying that, you know, we probably shouldn't be sure, you know, it is liver disease, but I think the renal failure effects of, for example, you know, hydroxythyl starch in someone who already
Speaker: is predisposed to acute kidney injury, you know, from just from the basic pathophysiology and hepatorenal syndrome, it's probably not a good idea to give them hydroxyethyl starch.
Speaker: So that was, I don't think there was a lot of debate and that was, I think, an easy one for the group saying, yes, you know, we should recommend against the use of hydroxyethyl starch.
Speaker: And similarly for gelatin's, although the quality of evidence is not, you know, not as good as hydroxyethyl starch, you know, I think we said, you know, a conditional recommendation that, you know, we suggest that we don't use
Speaker: for the initial resuscitation of these patients.
Speaker: Now, albumin was a little bit more controversial.
Speaker: And so I think the panel problem, I'll describe to you what went through the panel's mind when they were issuing this recommendation.
Speaker: So we know that if albumin is used for SBP, it is helpful.
Speaker: You know all that was not compared to you know, it was compared to nothing but you know, but regardless it was you know, it was helpful We know that if it is used for post paracentesis circulatory dysfunction it is helpful Okay, we also know that albumin has You know albumin metabolism and the levels of albumin and you know the quality of albumin is a
Speaker: affected in liver disease in the sense that the albumin molecule is sort of oxidized and things of that nature.
Speaker: It is not, its properties are changed and that albumin also has other physiological effects just other than just volume expansion, especially in liver disease.
Speaker: And there is some evidence to that.
Speaker: And then there was a meta-analysis have not shown any evidence
Speaker: although the meta-analyses have in general, critically ill patients have not shown benefits of albumin to crystalloid patients, for example, in sepsis.
Speaker: But the ALBIOS trial, which did show that the mortality of albumin replacement, if the level was less than three was sort of decreased.
Speaker: and if the patient's at septic shock.
Speaker: And so when we combined the beneficial, the physiological beneficial effects of albumin and the effects in post-parasynthesis circulatory dysfunction and in the effects of SBP, we made a conditional recommendation saying that you should consider the
Speaker: use of albumin in patients as initial resuscitation fluid in patients with ALF or ACLF, especially when the serum albumin is low.
Speaker: Now, again, we did acknowledge that there was
Speaker: the evidence was indirect and therefore very low quality and it wasn't conditional recommendation.
Speaker: But I think the panel sort of felt that given all of this, all of the physiological beneficial effects of albumin, especially in liver disease and some states where it is helpful that the guidance of perhaps it should be considered in the correct circumstance should be sort of issued.
Speaker: So that was our rationale of
Speaker: sort of making this recommendation.
Speaker: From my perspective, the way I've always looked at fluids in presentation has been that we initially have accepted that crystalloids and colloids, like albumin specifically, were perhaps, and there was not a superiority between them.
Speaker: However, albumin might be more expensive.
Speaker: Now we've evolved to believe that within crystalloids,
Speaker: balanced solutions are probably better than unbalanced solutions or just, I mean, normal saline.
Speaker: So we move to those balanced solutions.
Speaker: But I've always felt, like you said, that within a lot of these trials, there's been signals towards the liver patients.
Speaker: And the way I approach it at the bedside is it's a conditional, let's say, approach in terms that in some patients I would consider it, especially in liver patients.
Speaker: I think that's the best patient to consider it as part of the resuscitation.
Speaker: but it's part of another regimen of fluid.
Speaker: And like you said, maybe further data might give us more clear instructions on what's the best role of it.
Speaker: But like you said, I would say that from a clinical practice perspective, I have used albumin in patients with liver disease who've been resuscitated.
Speaker: It's not the only fluid I use, and for many of the reasons that you had mentioned.
Speaker: So that's kind of the way I look at it right now.
Speaker: Yeah, I think, you know, on Twitter, especially on Twitter, we got a lot of comments about, you know, making this recommendation.
Speaker: And while, you know, while I understand, I understand the lack of evidence, Sergio, I think in clinical practice in a lot of places, I do actually, like you have mentioned, see people, you know, reach for albumin as a resuscitation fluid if it is someone who has underlying liver dysfunction.
Speaker: And I would say people confuse sometimes.
Speaker: It's not a lack of evidence.
Speaker: There's a lack of direct randomized trial evidence.
Speaker: But like you said, there's other areas that when we try to put the available evidence together, suggest that there might be a possibility and we know that it's not harmful.
Speaker: So when you take that into consideration for some patients, it might be appropriate, but we definitely would love to see better data.
Speaker: to maybe delineate the use of albumin in these patients in a much more precise way.
Speaker: You're right.
Speaker: I think, you know, and that's one of the things that this, probably this document highlights is that this is a fertile area for research.
Speaker: You know, there are not a whole lot of, you know, high quality randomized controlled trials and it isn't uncommon to see these patients.
Speaker: And so, you know, you
Speaker: there is opportunity to design great, well-controlled, randomized trials to test a lot of these hypotheses.
Speaker: Once we're done with fluids, we usually, if we still have issues, we will, like you said, go and grab a vasopressor.
Speaker: Can you share with us what is the vasopressor of choice and what are some recommendations that the panel made specifically around vasopressors?
Speaker: Yeah, so we had, I think, like in all
Speaker: probably in many of the shock states, the two burning questions are what should the first line vasopressor be?
Speaker: And after that, should you, I think the big question that comes up is, should you add vasopressin to any of these types of things?
Speaker: to the first line vasopressor agent.
Speaker: And so we recommended that the first line vasopressor in either acute liver failure or ACLF in people who remained hypertensive despite adequate fluid resuscitation or in people who were hypertensive and fluid resuscitation, but they had profound hypertension and fluid resuscitation was still ongoing.
Speaker: we recommended that norepinephrine be utilized as the first-line vasopressor.
Speaker: Now, there was a specific reason for this.
Speaker: Again, I want to emphasize again, like you said, there is no direct randomized control, high-quality data in liver failure.
Speaker: However, there is data in a distributed physiology state
Speaker: which is sepsis and at baseline, the liver disease patients have the same sort of distributed physiology because they're vasodilated, there is arterial underfilling.
Speaker: And so we sort of extrapolated the data that is available for other vasodilated states, specifically sepsis.
Speaker: and applied it physiologically to the patients with liver disease.
Speaker: And therefore, this recommendation was a strong recommendation.
Speaker: And we said we sort of downgraded the evidence because they were no, and made it moderate quality because there were, again, it was, there was not direct applicability or there were no direct randomized control trials in liver disease.
Speaker: But again, we extrapolated, like I said, we extrapolated from the severe sepsis guidelines and sort of said that norepinephrine should be the first line vasopressor or we extrapolated from severe sepsis and said, okay, or sepsis and said norepinephrine should be the first line vasopressor.
Speaker: Now, we were, we didn't recommend, we specifically did not recommend epinephrine because
Speaker: uh epinephrine probably likely increases lactate production in in skeletal muscle and there are already impairments of you know when people with liver disease there's already an impairment of lactate clearance and uh a this we don't know what effects will have this will happen and this also may impair the the utility of uh you know you sort of utilizing lactate clearance as a to guide therapy and so uh
Speaker: know and so so we didn't you know we didn't recommend that and we you know obviously there is a you know dopamine you know no one uses uses that anymore and so so we were left with sort of recommending uh vasopressin as the first sorry not epinephrine as the first line vasopressor and in terms of uh vasopressin again uh no randomized controlled trials uh but we did say that you could use
Speaker: low-dose recommendation, and this was, again, a conditional recommendation with low-quality evidence in people who remained hypotensive despite fluid resuscitation and despite the addition of vasopressin.
Speaker: And now, the addition of vasopressin has to be sort of, I think, balanced with the risk of increased
Speaker: digital ischemia.
Speaker: And the liver specific data are very little.
Speaker: There is not very much out there.
Speaker: But there was in the meta-analysis, there was a study that included cirrhotic patients.
Speaker: I just want to emphasize that
Speaker: The definitions of acute and chronic liver failure just came about in the last seven or eight years.
Speaker: And so, and this was an older trial that looked at cirrhotic patients and cirrhosis is sort of different from acute on chronic liver failure.
Speaker: But there was one study that was, that included cirrhotic patients and the digital ischemia rates in that study were more with vasopressin, but the, uh,
Speaker: But again, so when you use vasopressin, you just have to be careful that there is a study out in cirrhotics that had more digital ischemia with vasopressin.
Speaker: Excellent.
Speaker: I think it's worth emphasizing that from the cardiovascular recommendations, we already hit on two strong recommendations.
Speaker: One against the use of hydroxyethyl starch as an initial fluid recitation.
Speaker: And the second one is the recommendation of using norepinephrine as the first line basal pressure in patients with acute and chronic liver failure or acute liver failure, who despite fluid are still hypotensive.
Speaker: With that, I would like to move on to hematology, Rahul.
Speaker: I think that this is obviously a fascinating area within liver disease.
Speaker: And I think it's also an area where there's a lot of misconceptions.
Speaker: And clinicians in general
Speaker: feel that the risk of bleeding is higher than the risk of thrombotic complications in these patients.
Speaker: And perhaps that is not exactly true.
Speaker: Furthermore, clinicians tend to rely too much, I think, or over-rely on the INR in these patients.
Speaker: And I would like to hear your thoughts on, in general, the assessment of bleeding and thrombosis risk in these patients and also in the assessment of bleeding risk specifically for procedures.
Speaker: Sure.
Speaker: So great question, you know, Sergio.
Speaker: This is one of my favorite things to talk about because I think in the past decade and a half, the advances that have been made in the understanding of bleeding and coagulation in, you know, especially in cirrhosis and chronic liver disease have been remarkable.
Speaker: They have been just fascinating.
Speaker: And so, you know, initially even two decades ago, even when I was, you know, sort of training in residency, we used to measure these INR, all these people with liver disease used to come in and they, you know, they need a line or an arterial line or something of that nature.
Speaker: And everyone used to measure the INR or the prothorban time and say, oh, the INR is elevated.
Speaker: Why don't you give FFP and bring the INR down to below a certain number and then you can do this procedure safely.
Speaker: And that was the misconception.
Speaker: And what people did not realize is that the INR is a...
Speaker: sort of this test was developed specifically and only for vitamin K antagonists.
Speaker: It was not developed for people who have endogenous states where INRs are elevated and PTs are elevated.
Speaker: And what we have learned over, and very brief, what we have learned over the past several years in studying coagulation profiles of many of these cirrhotic patients,
Speaker: and many of the patients with liver failure is that there is this concept of rebalanced hemostasis.
Speaker: That whether you look at platelet function, whether you look at the coagulation cascade, or whether you look at fibrinolysis, that there are defects in both, you know,
Speaker: things that, so for example, if you take platelets, there are things that cirrhosis is associated with thrombocytopenia and liver failure is also associated with thrombocytopenia.
Speaker: So you would say, well, the ability to form a clot has decreased because there is thrombocytopenia.
Speaker: But on the other hand, the liver failure is also associated with increased factor eight.
Speaker: increase one willibrand factor.
Speaker: And so it makes the platelet actually more sticky to collagen.
Speaker: And similarly, if you look at the coagulation cascade, there are defects in two factors, two, seven, nine, 10, one, I think factor one, factor 11.
Speaker: However, levels of factor eight are increased and concomitantly there is a decrease in some of the anticoagulant proteins such as protein C and protein S.
Speaker: And it is same for the fibrinoidetic pathway.
Speaker: And so in some, in many instances, this rebalanced hemostasis leads to a state where many serotics are actually even pro-thrombotic.
Speaker: They're not anti-coagulation.
Speaker: Although this concept of auto-anticoagulation is being dispelled and
Speaker: and people with liver failure actually may very well be pro-thrombotic and, you know, need, and that's why, you know, you see a lot of them develop portal vein thrombosis and, you know, and so on and so forth.
Speaker: And so what we have learned is that the use of INR and PT to assess for the risk of bleeding is actually not the correct way to, you know, to assess who would be,
Speaker: who's at risk of bleeding and who is not.
Speaker: Although there is just one trial and maybe we'll talk about it, but probably a correct way, a more valuable way of assessing sort of the entire coagulation profile of a patient is to use viscoelastic testing, something
Speaker: either tag which is thomboelastography or rotem, which are sort of not very different.
Speaker: It's basically a needle in a cup.
Speaker: In one test, the needle rotates, in another test, the cup rotates.
Speaker: But they are probably better tests to measure, to assess bleeding and thrombotic risks, rather than traditional factors such as the INR or the PT or even just a
Speaker: you know, just a normal or just a usual platelet count.
Speaker: And along these lines, Rahul, like you mentioned, it's the new development or the better understanding now of a way to really assess this dynamic situation that you described in liver disease with either Rotem or thromboelastography over using our usual parameters, such as INR and platelet.
Speaker: You made a strong recommendation for using this type of testing
Speaker: in assessing the risk of bleeding in patients who are undergoing procedures and surgery, correct?
Speaker: Yes.
Speaker: So that was based on one randomized controlled trial.
Speaker: It was an open-label randomized controlled trial of 60 patients in cirrhosis who were scheduled to undergo invasive procedure.
Speaker: And the blood transfusion was triggered by, you know, either by TEGS or by standard of care.
Speaker: It was guided by either the INR or the patient count.
Speaker: And what really happened was that it resulted in many fewer patients being transfused.
Speaker: So, you know, only if you looked at the platelet count or the INR, 100% of the patients were transfused.
Speaker: If you did this by a tag, only 16.7% or 16 or 17% of these patients were transfused.
Speaker: And there was no one, there was just one out of 60 people had bleeding.
Speaker: And that was the person who got, you know, who received a transfusion, who had a FFP transfusion before a, you know, before a paracentesis and was actually a local, probably a local mechanical complication and nothing to do with the, you know, to the, with the systemic state of what the INR was or what the coagulation profile was.
Speaker: From a practical perspective, what I've seen is that clinicians,
Speaker: over-rely or over-utilize the INR, assuming that there's a high risk and they probably over-treat patients, which can have its own set of complications, not only adding cost to care, but can be associated with complications.
Speaker: So from what you're telling me, for most of the procedures that we would do in an ICU, like paracentesis in these patients or putting in a central line or putting in an A line, even maybe sometimes a thoracentesis, the INR probably is not a great thing to look at.
Speaker: And the majority of these patients probably can have these procedures very safely without transfusions.
Speaker: Is that correct?
Speaker: That is exactly correct.
Speaker: And paradoxically, if you do transfuse someone FFP, you may increase the portal pressure and end up with a GI bleed.
Speaker: Which obviously defeats the whole purpose.
Speaker: You also made a very strong recommendation, or a strong recommendation, I should say, against the use of novel platelet stimulating factors such as a
Speaker: Eltramopab.
Speaker: And can you make some comments on that?
Speaker: Yeah, sure.
Speaker: So, you know, again, that was based on a trial of, again, people who were scheduled to, I think, undergo procedures in about two weeks in chronic liver disease.
Speaker: And they were given, you know, all of them had thomocytopenia.
Speaker: And these people had received
Speaker: which is a thrombopoietin agonist.
Speaker: And while the platelet counts went up, so did the thrombotic complications, and especially the portal venous system.
Speaker: And this actually emphasizes the fact where, although you may have a low platelet count, if you truly look at how these platelets adhere to collagen,
Speaker: in many people, they actually have more adherence to collagen, even though the platelet count is low, they actually adhere to collagen much better because of increased factor eight, one valibrance factor and things of that nature.
Speaker: And so this trial probably indirectly sort of corroborates that hypothesis.
Speaker: And that's why you made a strong recommendation saying, and the trial that I'm talking about actually was stopped early because of these portal venous thrombotic complications.
Speaker: And so therefore we had actually issued a strong recommendation against use of these agents prior to surgery or procedures.
Speaker: And again, this goes back to the explosion of knowledge that has occurred in terms of the coagulopathy and assessment of bleeding risk in patients with liver disease.
Speaker: Excellent.
Speaker: The other topic that you mentioned, which I think is very relevant to our daily clinical practice, relates to hemoglobin targets.
Speaker: We have moved in the critical care world from a very aggressive threshold of transfusing people to keep their hemoglobins above 10 to really tolerating the most critically ill patients, a hemoglobin of seven or above.
Speaker: Could you comment on the conclusion that the guidelines came to this topic?
Speaker: Yeah, so the conclusion that the guidelines came to the topic and this was a general sort of, okay, what should be the hemoglobin target in critically ill people for like any other general, particularly ill patient, what should be the hemoglobin target in people with ACLF and ALF?
Speaker: And again, we sort of said the transfusion target should be seven milligrams per deciliter and restrictive transfusion like we do in general critical care.
Speaker: And this was sort of based on, you know, as you very well know, you know, general critical care trials, like you have mentioned, the first one was the CRIC trial, you know, which was the first one to show that, you know, a target of seven is,
Speaker: is no worse than a target of nine, especially.
Speaker: And if you do target higher hemoglobins, you end up with more complications related to the transfusion.
Speaker: And if you sort of stratify those, so all of those for cirrhosis,
Speaker: And it's the same thing, restrictive transfusion is not significantly different to a liberal transfusion.
Speaker: And there is some data in the post-liver transplant world where red blood cell transfusions are an independent predictor of mortality.
Speaker: Erythropoietin levels are already sort of increased in people with cirrhosis.
Speaker: And it sort of correlates to the degree of
Speaker: of portal hypertension, but there is not a, again, our data latch from a study of patients that are solely for acute liver failure and, you know, or ACLF.
Speaker: And so the, you know, the recommendation was conditional, you know, taking into account that, you know, you, in the liver disease population where there are many, many other
Speaker: many other factors that may influence your decision making, you may want to, you know, sort of weigh in those other factors before you decide on hemopromatology.
Speaker: Excellent.
Speaker: And the final topic I wanted to touch on the hematologic front relates to DVT treatment and prophylaxis.
Speaker: As we mentioned earlier, Rahul, I think there's a common misconception about a high INR, meaning that these patients, if anything, are just
Speaker: prone to bleeding and that they're protected from thrombotic complications.
Speaker: But what we see clinically is that thrombotic complications, where it be portal vein thrombosis or other deep vein thrombosis, are actually more common or very common in these patients.
Speaker: Could you give us a little bit of an overview of how we should prophylax and treat these patients?
Speaker: And what are your thoughts on this topic?
Speaker: Yeah, I think, you know, again,
Speaker: when you grade the quality of evidence in terms of, so when we formulate these recommendations, you know, we follow a very strict grade process and, you know, and we rate the quality of evidence.
Speaker: And then, you know, if the quality of evidence in many of these things are downgraded, if the trial is not randomized control, if it's an observational study or if it is indirect evidence, there are lots of things that sort of downgrade the evidence.
Speaker: And so, so the evidence we found was not, you know, although there is, there is, there are all of these mechanistic insights available,
Speaker: The evidence that we found is not high quality.
Speaker: So we can't, you know, so we issued a conditional recommendation, but my thoughts are that many cirrhotics paradoxically are actually pro-thrombotic and they should absolutely receive pharmacological DVT prophylaxis if able, over pneumatic stocking or over mechanical DVT prophylaxis.
Speaker: And especially if they're hospitalized.
Speaker: And understanding that there might be circumstances that you're not able to give pharmacological DBT prophylaxis.
Speaker: This is a big misconception, Sergio, because even in my place where I work, if you look out on the floors with these people who are admitted, they are often not receiving DBT prophylaxis because their INR is two or two and a half.
Speaker: And people don't realize that even with the INR of two, two and a half, they are actually pro-thrombotic and not auto-anticoagulated and should absolutely be receiving pharmacological DBT prophylaxis.
Speaker: Again, an important point that we have to emphasize because it's something that we commonly see in clinical practice.
Speaker: And I think it relates to those misconceptions we have about liver patients and not fully understanding the pathophysiology involved with these hospitalized patients.
Speaker: Exactly.
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