Transcript
Speaker: Welcome to Critical Matters, a sound podcast covering a broad range of topics related to the practice of intensive care medicine.
Speaker: Sound 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 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, neurology, peritransplant medicine, infectious disease, gastroenterology considerations.
Speaker: This guideline was released earlier this year and was produced by a panel of 29 members with expertise in aspects of care of the critically ill patient with liver failure and or the methodology of EBM guideline development.
Speaker: We will focus on recommendations for managing of acute and chronic liver failure patients in the general ICU setting.
Speaker: Our guest today is Dr. Rahul Nanshaw.
Speaker: Dr. Nanshaw is a practicing critical care physician with an interest 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. Nanshaw 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 that we will discuss today.
Speaker: In the previous episode of the podcast, we discussed the first part of these guidelines, which focused on the management of cardiovascular, endocrine, hematologic, pulmonary, and renal considerations.
Speaker: That podcast and the paper will be referenced in the show notes.
Speaker: Rahul, welcome back to Critical Matters.
Speaker: Thanks, Sergio.
Speaker: Thanks for having me.
Speaker: Well, as you were saying, acute and chronic liver failure, a very important aspect of daily practice in ICUs all over the country and the world, very common presentation.
Speaker: And we were talking that you had embarked on these guidelines some time ago.
Speaker: We had an opportunity to discuss the first part of the guidelines, and today we're going to discuss the second part of the guidelines that were recently published in Critical Care Medicine.
Speaker: So as a starting point, maybe we can refresh our audience's memory on some of the important definitions.
Speaker: And I wanted you to define acute liver failure, chronic liver failure, and then acute on chronic liver failure.
Speaker: Sure.
Speaker: And again, thanks for having me, Sergio.
Speaker: For the purposes of the guideline, I think we defined acute liver failure.
Speaker: So the definition of acute liver failure was sort of a traditional definition, the onset of synthetic liver dysfunction and hepatic encephalopathy within 26 weeks.
Speaker: weeks of an acute insult to a previously healthy liver.
Speaker: So, you know, that's an important distinction point, I think, between acute liver failure and the and chronic liver failure and acute and chronic liver failure, that acute liver failure refers to an insult and liver dysfunction and hepatic encyclopathy occurring in a previously healthy liver.
Speaker: Now, chronic
Speaker: The chronic liver failure is, and this is something that I think most of us recognize as cirrhosis, if you really have to define it, it's just probably progressive liver dysfunction that lasts more than six months.
Speaker: And acute and chronic liver failure, which is sort of a newer entity and a lot's been sort of...
Speaker: recognized about this entity over the past decade.
Speaker: The definition of acute on chronic liver failure is something acute that happens on acutely decompensated chronic liver disease associated with organ failure, which has a very high short-term mortality.
Speaker: So I think, you know, it's good you ask this question because, you know, there's very distinct entities and, you know, very distinct pathophysiology and some of the management aspects may overlap, but, you know, definitions are important.
Speaker: I agree, and I think it's always a good starting point.
Speaker: Now, you did mention, Rahul, that acute and chronic liver failure is a more novel concept that we're recognizing, yet it has probably been around in our ICUs for some time, and I would say...
Speaker: For most intensivists in general medical and medical surgical ICUs, it might be the more common presentation that we deal with, right, in the ICU at least.
Speaker: Could you give us a little bit more insight into some of the epidemiology and some of the problems that might lead acute and chronic liver failure patients to the ICU?
Speaker: And also if you could comment on some of the misconceptions that intensivists might have about these patients.
Speaker: Yeah, sure, you know, and you're exactly right, Sergio.
Speaker: I think acute and chronic liver failure has been around for as long as intensive care units have been around.
Speaker: I think we've known about this entity, you know, for a long, long time or, you know, or dealt with it in one way, shape, form or the other, but recognizing it and defining it and, you know, and sort of putting definitions around it and some structure around it has occurred previously.
Speaker: And believe it or not, there are three major definitions for acute and chronic liver failure.
Speaker: It's not important to get into what the nuances of the definitions are, but there is an Asia-Pacific definition, there is a European definition, and then there is a North American definition, and they are slightly different.
Speaker: But I think organ failure is what is common amongst all of these definitions.
Speaker: Normally we think of cirrhosis as decompensated cirrhosis in terms of someone has a varicial bleed or someone has large ascites or someone has hepatic encephalopathy.
Speaker: Now you start putting organ failure on top of it, kidney failure and respiratory failure and shock.
Speaker: Those are sort of the hallmarks of acute and chronic liver failure.
Speaker: And so this is a syndrome which is sort of associated with very, very high mortality.
Speaker: The causes of acute and chronic liver failure are many fold.
Speaker: The most common cause of acute and chronic liver failure is an infection that develops in the background of cirrhosis or chronic liver disease.
Speaker: The second most common cause is alcoholic hepatitis or alcohol intake.
Speaker: Probably in the East, viral infections or reactivation of hepatitis B is important.
Speaker: Vericeal bleed is another trigger.
Speaker: So there is some inciting event that leads to acute deterioration of liver function and then organ failure.
Speaker: What is important to note is that I think in about 30% of cases, the cause is never recognized.
Speaker: People just have deterioration of liver function, deterioration of their chronic liver disease, and associated organ failures.
Speaker: I think the misconceptions surrounding acute and chronic liver failure is that I think a lot of intensivists, you know, sort of give up and say that these things have very poor prognosis.
Speaker: Well, that is true.
Speaker: What is also true is that if appropriately managed and given the appropriate ICU support,
Speaker: Up to 20% of people with ACLF-3, that's acute and chronic liver failure, grade 3, which is the severest form of acute and chronic liver failure, can actually reverse their grade or even completely resolve their acute and chronic liver failure.
Speaker: So it's really important that people recognize these early, people recognize the organ failures early, and they support these patients in an appropriate fashion.
Speaker: What is also true is that if you look at one of the most recent studies, controlled for severity of illness, people with acute and chronic liver failure had no worse outcomes than just general ICU patients.
Speaker: And I think the third thing is that I think people should be thinking about referral to a liver transplant center early because these people actually have very high outcomes.
Speaker: mortality within 30 days, especially if you're ACLF grade 2 or ACLF grade 3.
Speaker: And with liver transplantation, you know, people actually do pretty well, but the sort of window for liver transplantation is very, very short and very, very narrow, very high weightless mortality.
Speaker: And so people, you know, should A, recognize this entity early and B, think about, you know, sort of referring to a liver transplantation soon.
Speaker: Center for Liver Transplantation.
Speaker: So I hope that answers your question, Sergio.
Speaker: Absolutely.
Speaker: And I think that these are all important aspects because like you said, the recognition of patients with cirrhosis who are admitted to the ICU with some decompensation or acute problem is very common.
Speaker: And I think the recognition of organ failure in any form would put them in that acute on chronic liver failure category.
Speaker: And like you said, understanding that these patients have a very high mortality, yet it's not futile to care for them.
Speaker: And if we can get them for the proper candidates early to a transplant center, that might actually be not only a life-saving, but might change their trajectory in a very dramatic way.
Speaker: So important for all of us, even when we don't have a transplant,
Speaker: program in our hospital to refer them to the right place.
Speaker: So those, I think, are excellent points for our audience to keep in mind.
Speaker: Now, the genesis, Rahul, for our conversation today, obviously, is the topic of acute and chronic liver failure, and it's really going to be developed around the context of the guidelines that you helped develop.
Speaker: Could you just tell us at a very high level the overview of this guideline process?
Speaker: Yeah, sure.
Speaker: So I think the, you know, firstly, the Society of Critical Care Medicine was kind enough to think that this topic was, you know, was relevant and allowed us to develop these guidelines.
Speaker: So the co-chairs were, which were me and Ram, were actually chosen by the society.
Speaker: After that, we chose panel members that had expertise in a variety of areas, including cardiovascular disease, and each of them had a specific interest in liver disease.
Speaker: And so we had a dietician, we had an APP, we chose people with expertise in ID, with gastroenterology, hepatology, and so on and so forth.
Speaker: And then we divided these experts into various groups for the purposes of this part of the guidelines, which we had four groups.
Speaker: And then in conjunction with the, and each group had a group leader, and in conjunction with the group leader, we formulated questions that we thought would be important to clinicians as well as patients, prioritized some outcomes, and then did a review of the literature.
Speaker: systematic review of the literature and then use the grade process to sort of formulate recommendations and then finally used, you know, the evidence to decision framework to sort of finalize these recommendations for, you know, for the audiences.
Speaker: Perfect.
Speaker: And obviously, there's a lot of recommendations that have come up from the guidelines published in the two separate papers.
Speaker: And we'll have links to all of these in the show notes.
Speaker: But one of the things that I wanted you to explain a little bit is the implications of the strength of recommendation, right?
Speaker: So,
Speaker: There are some that have strong and some that are conditional recommendations.
Speaker: And I think that is worded with a we recommend versus we suggest.
Speaker: What does that mean at the patient, the clinician, and maybe even at more of a society level?
Speaker: Yes, a great question, Sergio.
Speaker: As I mentioned, these recommendations were keeping in line with the grade methodology and the language that is suggested by grades.
Speaker: If something is a strong recommendation, we use the language we recommend.
Speaker: If something is a conditional recommendation, we use the language we suggest.
Speaker: Of course, strong recommendations,
Speaker: I think it has three components to it.
Speaker: It has a patient component, it has a clinician component, and it has, like you said, a society or a policymaker component.
Speaker: And the patient component is that if we recommend, if you are recommending something, then most patients in this situation, in that particular situation, would want what we recommended.
Speaker: And it doesn't mean that all of them would, but the people who would not would be actually a very, very small proportion.
Speaker: From a clinician perspective, when we make a strong recommendation, we are saying that most clinicians would agree that patients should receive what we have recommended.
Speaker: Adherence to this recommendation could be used as a performance, as a quality criterion, or as a performance indicator.
Speaker: And from a policymaker perspective or from a societal perspective, the recommendation could be adapted as a policy in most situations, including the use of performance indicators and so on and so forth.
Speaker: And for very strong recommendations, clearly the benefits outweigh whatever little risks the recommendation has.
Speaker: For a conditional recommendation, it is not as clear.
Speaker: So for a conditional recommendation, I think for patients, a majority of people would probably want the recommendation, but it is possible that quite a few don't.
Speaker: From a clinician perspective, clinicians are, you know, many clinicians would agree that, you know, this is the course of action, but the different choices are likely for different circumstances, and they would say that this recommendation should, you know, be tailored to the individual patient circumstance or perspective, and this should include patient preferences, perhaps not that, you know,
Speaker: recommendations should ever not include patient and, you know, and family values.
Speaker: But I think in conditional recommendations, it's a little more that, you know, we take into account what the patient says, what the family says, and whatnot.
Speaker: And, you know, and we are a little bit more, how should I put it?
Speaker: We are a little bit more iffy about, you know, about it.
Speaker: And from a policymaker perspective, you know, it is hard to make, you know, sort of a performance indicator or it is hard, you know, it is
Speaker: Making a performance indicator surrounding the recommendation would require considerable debate from a variety of stakeholders.
Speaker: And in this sort of conditional recommendation, the clinicians and everyone sort of agrees that perhaps although the benefits may outweigh the benefits, but it is less clearer than a strong recommendation.
Speaker: Perfect.
Speaker: So let's dive into the actual recommendations and talk about how to treat these patients.
Speaker: And I want to start with infectious diseases.
Speaker: So this is one of the most common reasons why patients with acute and chronic liver failure may end up in the ICU or a common occurrence.
Speaker: But another common cause that brings patients to the ICU in this subset is gastrointestinal bleeding or bleeding associated with portal hypertension complications.
Speaker: Could you tell us about the use of antibiotic prophylaxis in these patients?
Speaker: Yeah, I think this is, you know, just to take a step back, Sergio, a lot of recommendations in this guideline were conditional just because, or, you know, there were several areas where we couldn't make recommendations because either the data was indirect or we just didn't have recommendations
Speaker: you know, enough good quality data, you know, for, as you very well know that patients with liver disease are, or at least advanced liver disease are frequently excluded from randomized controlled trials of critically ill patients.
Speaker: So, you know, it is sort of hard to find good quality data in people with
Speaker: with acute liver failure or acute on chronic liver failure, but this was one of the areas where we were able to issue a strong recommendation for antibiotic prophylaxis after gastrointestinal bleeding.
Speaker: And I think, like many of our audience knows, it's common practice to give
Speaker: give antibiotic prophylaxis after GI bleeding.
Speaker: And the reason is that in large meta-analysis, and even when we looked at all of the evidence and did our own meta-analysis, not only was
Speaker: not only was the occurrence of infection, the occurrence of SPP, the occurrence of bacteremia reduced, but even mortality was reduced when you gave antibiotic prophylaxis after GI bleed.
Speaker: The mortality was likely reduced because of the reduction of infections.
Speaker: But we found pretty strong evidence and pretty good evidence that this is one of the things that should always be done.
Speaker: And like you mentioned, this is one of the strong recommendations based on the available evidence.
Speaker: So important for our clinicians to remember, if you admit somebody with an upper GI bleed and they're a chronic liver failure, acute on chronic liver failure, you should start prophylactic antibiotics.
Speaker: And would ceftriaxone be appropriate?
Speaker: Is that kind of what we recommend these days?
Speaker: Perfect.
Speaker: Yeah, yeah, so I think, you know, for prophylaxis of a GI bleed, I think a third generation cephalosporin, cephtriazin would absolutely be appropriate.
Speaker: Cephalopaxime, I think, would be an equally good choice.
Speaker: Perfect.
Speaker: So the other topic that I believe is important in infectious disease in the context of our discussion is obviously SPP, spontaneous bacterial peritonitis, another common reason why patients might end up under our care in acute and chronic liver failure.
Speaker: Before we go into some of the recommendations, Rahul, could you just give us a little bit more of a general overview of SPP, kind of how does it usually present, when we should suspect it, and how do you confirm the diagnosis?
Speaker: You know, obviously, Sergio, if, you know, someone comes in and say, someone with liver disease, and ascites comes in and says, I have abdominal pain and I have a fever and, you know, and things of that nature, it is sort of, yes, you know, they likely have SPP.
Speaker: But in my practice, at least what I have found is that
Speaker: The presentation of SPP is actually so varied that it is probably just, you know, a person comes in sick and they have ascites, it is, you know, probably just very wise to at least get a diagnostic tab and rule out SPP.
Speaker: So the way to, you know, do this is just, you know, send a few cc's of
Speaker: And it does not have to be a therapeutic tap.
Speaker: It's very easily done at the bedside, just a few cc's of fluid sent for cell count and culture.
Speaker: And obviously the diagnosis of SPP rests on finding more than 250 neutrophils.
Speaker: in a sample of the acetic fluid and at the same time starting sort of broad spectrum antibiotics.
Speaker: And so this is such a, I think it is so common and so commonly missed and the presentations are so varied that it can be easily missed.
Speaker: I think it probably behooves us, especially if people are ill and require admission to the ICU, that a diagnostic sort of DAP be done when you don't know what's going on or presentations are less clear or someone presents with confusion or hepatic encyclopathy or things of that nature and you're looking for a trigger, a diagnostic paracentia should be performed.
Speaker: Yeah, I think that's a great point, Rahul, that really very insidious in his presentation and that we should have a super high index of suspicion.
Speaker: Anybody who's presenting with history of chronic liver disease who is critically ill, maybe there's unclear or non-characteristic symptoms, but also important to mention like you mentioned
Speaker: you were talking earlier that somebody might present with a GI bleed and then develop SPP within the hospital.
Speaker: So again, to maintain that level of vigilance, we, we talked, we'll talk about, about, about therapy, but the first recommendation that I think is based really on data that is mostly obtained from non-cirrhotic and non-acute and chronic liver failure patients relates to the timing of antibiotics for SPP and for SPP and septic shock.
Speaker: Any comments there?
Speaker: Yeah.
Speaker: Yeah, I think, you know, again, as you mentioned, there is actually not a whole lot of data that pertains specifically to, at least not prospective randomized control data that, you know, prospective, there have been some retrospective observational studies, but there is nothing that actually pertains specifically to acute liver disease.
Speaker: However, there is so much data from, you know, just general septic shock, general sepsis, and things of that nature, and also knowing that,
Speaker: you know, the patients with liver disease, they have a unique pathophysiology, they are vasodilated at baseline and probably have limited cardiopulmonary reserve, and infections are the major cause of acute on chronic liver failure, and that, you know, as organ failure progresses, like with any other critical illness, you know, short-term mortality actually rises exponentially, so as you go from grade 1 to grade 2 to grade 3 ACLF,
Speaker: there is exponential rise in mortality.
Speaker: I think the timing of antibiotics and the control of infection is so important.
Speaker: And that's why we sort of suggested, of course, the recommendation was
Speaker: conditional and the quality of evidence was low because of a variety of reasons.
Speaker: A, there is no direct evidence.
Speaker: B, the evidence that is there is all retrospective.
Speaker: We had to issue a conditional recommendation.
Speaker: So we did suggest that the appropriate antibiotics are started as soon as possible after recognition and ideally within one hour of onset of shock in critically ill ACLF patients with SVP.
Speaker: And I also think that this also pertains probably, most of the data is for SVP, but we have probably for other infections as well that if you recognize an infection, start antibiotics as soon as possible.
Speaker: And if you have shock, absolutely within one hour.
Speaker: If starting antibiotics as soon as possible, probably, you know, in a lot of cases will prevent either ACLF or the progression of ACLF if you're in ACLF grade one or so on and so forth.
Speaker: And so those are some of the recommendations for, you know, the timing of antibiotics and SVP and septic shock.
Speaker: Perfect.
Speaker: Now, in terms of the timing, obviously, sooner is always better, and that is going to be even more important for critically ill patients in septic shock.
Speaker: What about the choice of antibiotics?
Speaker: So we talked about ceftriaxone as a good prophylactic, and that historically was a starting point for SBP, but my understanding, I'm reading the guidelines, is that maybe we need to think a little bit broader.
Speaker: Can you tell us what the recommendation is today?
Speaker: Yeah, I think we did recommend that we use broad-spectrum antibiotics for the initial management of SVP and that ceftriaxone or a third-generation cephalosporin be reserved for low-risk community-acquired SVP.
Speaker: And so, you know, as you very well know, Sergio, the epidemiology of infections in general have changed with the, you know, use, misuse, overuse of antibiotics and a variety of other factors.
Speaker: And that we more and more, we are dealing with resistant infections, not only in, you know,
Speaker: especially if they are nosocomial healthcare associated or healthcare acquired.
Speaker: But also now in the community, we have been more and more, we have been dealing with resistant infections.
Speaker: And so, you know, our recommendation is probably to, you know, take into account risk factors for resistant infections, A, B, where you acquired the infection, you know, whether you acquired it in the hospital or you acquired it in the community, whether you've been exposed to antibiotics before or not, whether you have other risk factors for multidrug resistant pathogens,
Speaker: and what your local sort of antibiogram, especially if you're in the hospital, what your local microbiological structure looks like before you decide on the choice of antibiotics.
Speaker: And people should be cognizant that there are the prevalence of ESBLs in organisms like MRSA or BRE,
Speaker: is growing in prevalence.
Speaker: And again, like I had mentioned before, these people have little reserve, and infections are the main cause of, and especially SPP, the main cause of one of the main causes of ACLF and progression of ACLF.
Speaker: I think all of these factors should be taken into account.
Speaker: When initiating antibiotic therapy, the choice of third-generation cephalosporin should be reserved for absolutely low-risk patients.
Speaker: Perfect.
Speaker: Another area that applies directly to SPP is the use of albumin.
Speaker: So albumin obviously has been studied and debated as a fluid recitation for sepsis and currently is not part of the standard just based on the available evidence.
Speaker: But your recommendations in the guideline do suggest that or recommend that the use of albumin in SPP specifically has value.
Speaker: Could you tell us a little bit more about that, Rahul, please?
Speaker: Yeah, sure.
Speaker: So, you know, there is a inherent vasodilated and, you know, sort of immune dysfunctional state of cirrhosis.
Speaker: And other than acting as a volume expander, I think albumin has a lot of other immunomodulatory, you know, sort of, and a lot of other effects that are probably beneficial for patients in cirrhosis.
Speaker: And, you
Speaker: And when we looked at the data from, you know, I think there were four randomized controlled trials, of course, you know, the largest of them was published in the New England Journal of Medicine, I think in 1998 now.
Speaker: And all of these four trials, when people were given albumin, you know, it was associated with a reduction in the odds of mortality, in the reduction of renal failure, and, you know, in general, it was found to be very, very beneficial.
Speaker: And we did even in our rationales, we went as far as to say that if once a diagnosis of SPP has been established, you should probably just give albumin just because of the inherent vasodilacted state of liver disease, even if the need for volume resuscitation is not obvious.
Speaker: just to increase the circulating, you know, all of these people have decreased effective arterial circulating volume just to increase that and maybe perhaps even to stave off or prevent people going into acute and chronic liver failure.
Speaker: So again, you know, very important.
Speaker: I think clinicians should recognize, you know, that they should give, as soon as, you know, they diagnose SPP, albumin should be given.
Speaker: What's the recommendation in terms of dosing?
Speaker: So I think the first dose, typical initial dose is one and a half grams.
Speaker: And the first day is one and a half grams per kg of 25% albumin.
Speaker: And that, I think, important to emphasize, Rahul, is not necessarily for flu resuscitation.
Speaker: It's just basically we're treating the SBP with that dose of albumin regardless.
Speaker: Exactly.
Speaker: And would you be more inclined to use albumin as you resuscitate patients with SBP later as well?
Speaker: Yeah, I think, you know, my practice is to give albumin for resuscitation.
Speaker: This is one of the, I think, one of the very few disease states that, you know, I prefer to give 25% albumin for resuscitation.
Speaker: Perfect.
Speaker: What about, you mentioned earlier, the diagnostic parasyntesis to make the diagnosis of SPP.
Speaker: What's the role of a large volume parasyntesis in SPP?
Speaker: And if you could define what a large volume parasyntesis is considered.
Speaker: Sure.
Speaker: I think, so, Sergio, the definition of a large volume SPP is removal of more than four liters of acetic fluid.
Speaker: And, you know, although there is...
Speaker: There is a lot of debate over whether a large volume paracentesis should be performed or should not be performed in people with SPP.
Speaker: As you very well know, large volume paracentesis can induce paracentesis-associated circulatory dysfunction, low blood pressure, shock, and things of that nature, which can eventually lead to renal impairment and worsening of acute and chronic liver failure.
Speaker: we did not actually find any evidence to suggest that this should be performed.
Speaker: So we recommended that it is okay not to perform large-volume paracentesis in patients with SVP unless there was an absolutely compelling reason for it, like intra-abdominal hypertension or things of that nature, but rather to just do a diagnostic paracentesis.
Speaker: And I think that's an important distinction, right?
Speaker: If you have an indication such as you have a documented intra-abdominal hypertension, removing a situs will be therapeutic or will help treat that intra-abdominal hypertension that can also potentiate organ failure such as renal failure.
Speaker: Exactly, Sergeant.
Speaker: Perfect.
Speaker: And the last question or topic that I want to discuss within the SPP category was the use of metodrine and telepresin for SPP.
Speaker: These medications have been utilized for patorenal syndrome, but is this something you would start early or what is the role for metodrine and telepresin in SPP?
Speaker: So Sergio, you know, in short, I think we did not actually find any evidence that in the absence of hepatorenal syndrome, that these medications would, you know, would be helpful.
Speaker: So we actually recommended not to use these medications, either mitodrine or telorepresin, for critically ill patients with ACLF.
Speaker: Now, if people have hepato-renal syndrome, you know, I think that's a different entity and it's a different, you know, that's a totally different sort of animal.
Speaker: And, you know, as you very well know, these vasoconstrictors are sort of the cornerstone of treatment, you know, of that entity.
Speaker: But in the absence of that, they should not be used.
Speaker: Perfect.
Speaker: So let's switch gears and talk about gastroenterology topics.
Speaker: And obviously, these are very relevant to these patients.
Speaker: A lot of admissions to the ICU are related along GI problems in patients with chronic liver disease, developing acute and chronic liver failure.
Speaker: So the first recommendation that I wanted you to give us a little bit more insight is the timing of endoscopy for acute and chronic liver failure ICU patients with known or suspected portal hypertensive bleeding.
Speaker: Yeah, sure.
Speaker: So, you know, interestingly enough, Sergio, there is actually very little data that, you know, guides this recommendation.
Speaker: The American Association for the Study of Liver Diseases recommends that endoscopic evaluation occur no later than 12 hours, you know, of presentation of an acute variceal bleed.
Speaker: And there is a meta-analysis, which is, you know, basically retrospective observational studies and at very high risk of selection bias.
Speaker: But
Speaker: Physiologically, I think early endoscopy, especially in portal hypertensive bleeding, makes a lot of sense, right?
Speaker: So, as you very well know, variceal bleeding is one of the triggers of acute and chronic liver failure.
Speaker: And if you delay endoscopy, you risk hemodynamic instability, more blood transfusions, more portal hypertension, more bleeding.
Speaker: And considering all of these things, considering the physiological effects of early endoscopy and what we would be preventing, we actually said that we recommended that, and this was a best practice statement,
Speaker: And not a, you know, not a strong or conditional recommendation because of, you know, because of what I have told you.
Speaker: And so we recommended that, you know, EGD or endoscopy be performed no later than 12 hours in critically ill patients with ACLF and, you know, who have portal hypertensive bleeding.
Speaker: And like you mentioned, this is a best practice statement, mostly because there was a strong sentiment on the guideline panel that this is important, yet obviously it's something that has not been or may be hard to study in randomized trials, correct?
Speaker: Exactly, exactly, Sergeant.
Speaker: And I think it's an important recommendation because for most of our audience, the intensivists are not doing the endoscopy.
Speaker: So making sure that we're all on the same page in terms of what would be considered a best practice window for these patients to have an intervention, I think 12 hours is obviously valuable, right?
Speaker: You don't have to come right now, but within 12 hours, this patient should be evaluated with endoscopy.
Speaker: Exactly, and especially given the fact that general GI bleeding, most people will say, well, within the first 24 hours is okay, but this is a little different than just general GI bleeds or general upper GI bleeds, where a lot of bleeding, say it's after you give them a proton pump inhibitor, this is not the case with acute portal hypertension, hyperdense like bleeding.
Speaker: Perfect.
Speaker: And you mentioned the PPI, and we obviously use this a lot in non- and liver patients for upper GI bleeds, and there's been demonstrated beneficial effects of using PPIs and decreasing re-bleeding.
Speaker: What's the role of proton inhibitors in portal hypertensive bleeding?
Speaker: You know, again, this was a recommendation where we did have some data, but, you know, at least in liver disease, as you very well know, again, you know, PPIs can have some adverse effects as well, especially dysbiosis, effects on the microbiome, increased risk of SVP and, you know, and sort of hepatic encyclopathy.
Speaker: But we felt that
Speaker: when people had, you know, bleeding, acid suppression was really, really important, especially in any kind, even with portal hypertensive bleeding, because once you, you know, treat portal hypertensive bleeding, you know, creating that, you know, suppressing acid in terms of healing and in terms of, you know, other beneficial effects that were extrapolated from, you know, non-
Speaker: sort of liver disease patient trials were important enough for us to issue a strong recommendation to say that, you know, we should use proton pump inhibitors in patients with portal hypertensive bleeding.
Speaker: Perfect.
Speaker: And what about the use of other medications such as Oxetide or Somatostin analogs in portal hypertensive bleeding?
Speaker: Yeah, again, that's, you know, that's, so there's, so somatostatin and this thing was, you know, this is where we have data with liver disease.
Speaker: You know, obviously, you can use a somatostatin analog or telrepresin.
Speaker: Until recently, telrepresin was not available in the United States.
Speaker: It's just become available.
Speaker: But the, not only, you know,
Speaker: Although the effect on the re-bleeding is a little unclear, but the use of octreotide or somatostatin analogs is actually associated with a mortality benefit in portal hypertensive bleeding after someone has performed banding or sclerotherapy, and this is one of the pharmacological agents which is helpful and should be used, and this is one of the strong recommendations in the document.
Speaker: I'm a big believer in making sure that patients always get treatments that we consider to be standard of care, best practice, or based on evidence.
Speaker: And I always say that for many diseases, the first three or four steps should be the same for everybody.
Speaker: And then you start looking, okay, how do they respond?
Speaker: What's different about this patient?
Speaker: And maybe...
Speaker: go a little bit deeper or do different things.
Speaker: But it sounds from our discussion so far, for the common presentation of a GI bleed in a patient with acute and chronic liver failure, which we presume has a portal hypertensive origin, they should get...
Speaker: prophylactic antibiotic.
Speaker: They should get an endoscopy within the 12 hours of arrival.
Speaker: They should get a PPI and they should probably be treated with octetide or telepression if you have that available.
Speaker: Would that be fair?
Speaker: Yes, that is absolutely true, Sergio.
Speaker: And you've hit the nail on the head.
Speaker: You know, that is exactly like you said, you know, these are standard of care things.
Speaker: And this is something that I do for every patient that presents with a portal hypertensive pain.
Speaker: So once you've implemented all of those and the patient has a re-bleed, what's the next step?
Speaker: Do you re-endoscope or do you talk about tips?
Speaker: I think, you know, practices, so to tell you the truth, real-world practices likely differ from, you know, from place to place.
Speaker: But there is, I think there is, you know, sort of,
Speaker: Pretty good evidence that re-bleeding, if patients re-bleed despite their initial attempt at banding and sclerotherapy and they have received all of the things that we talked about, that strong consideration should be given to TIPS.
Speaker: And, in fact, there is a trial where, although it is very small, that if you do tips early, one-year outcomes in terms of mortality and in terms of recurrence of re-bleeding are much better.
Speaker: than TIPS.
Speaker: So in centers that have the expertise and there are experienced operators, obviously the performance of TIPS requires access to an experienced operator and a center with expertise.
Speaker: If you have those, strong consideration should be given to TIPS.
Speaker: Obviously there are contraindications associated with TIPS, so those have to be kept in mind.
Speaker: However, in cases of re-bleeding, after a good-faith attempt at all of the initial things we talked about to control bleeding, strong consideration should be given to the performance of tips.
Speaker: Perfect.
Speaker: And the last topic I wanted to talk about was neurology.
Speaker: And there's a lot of recommendations regarding hepatic encephalopathy, but what I wanted to start with was if you could differentiate for our clinicians the differences between
Speaker: in broad terms, between hepatic encephalopathy in a patient with acute liver failure and hepatic encephalopathy in patients with acute on chronic liver failure.
Speaker: Yeah, sure.
Speaker: Certainly a very important question and I think very important for the audiences to know.
Speaker: So, you know, as we had mentioned in the, you know, at the start of this podcast, the definitions of acute liver failure.
Speaker: So the acute liver failure, so liver insult occurring in a previously healthy or a normal liver.
Speaker: And, you know, ammonia is central to the development of hepatic encyclopathy.
Speaker: And, you know, so the brain has not, acute liver failure, is not used to elevated ammonia levels.
Speaker: And so, you know, what happens is that, you know, people get encephalopathic very quickly, and they might even develop cerebral edema associated with the encephalopathy because of these high ammonia levels.
Speaker: This does not occur in ACLF.
Speaker: So the entity of hepatic encyclopathy is very different in acute on chronic liver failure as it is in ALF.
Speaker: Secondly, all of the therapies that we use for hepatic encyclopathy and control of hepatic encyclopathy in chronic liver disease or ACLF do not work
Speaker: for ALF.
Speaker: And so the way to control hyperammonemia and ALF is to do plasmapheresis or, you know, or do continuous renal replacement therapy.
Speaker: While, you know, the, while usually the hyper, the hepatic encyclopathy and acute on chronic liver failure is, you know, sort of treated with lactulose and rifaximin and so on and so forth.
Speaker: Hopefully I sort of answer your question about the sort of differences.
Speaker: So the brain, because acute and chronic liver failure develops on pre-existing chronic liver disease, the hepatic encyclopathy is less associated with cerebral edema, usually does not develop, and probably develops less slowly and progresses rather than patients who have acute liver failure.
Speaker: Oh, absolutely.
Speaker: And I think you also mentioned some of the therapeutic differences because the underlying pathophysiology is quite different.
Speaker: So even though we're calling both clinical syndromes, hepatic encephalopathy, the process is very different and what kills patients might be very different.
Speaker: So without going too deep into the acute liver failure, hepatic encephalopathy, two recommendations that I noted that perhaps a little bit different of what was done some time ago, where the one for measuring intracerebral pressure, ICPs, and the use of targeted hypothermia to lower ICP, those seem to be much more...
Speaker: or people were more enthusiastic about them before.
Speaker: But from what I understood, Rahul, the evidence that you looked at doesn't really support any of those.
Speaker: That is exactly right.
Speaker: You know, the evidence doesn't support either the use of ICP monitors or of hypothermia in acute liver failure.
Speaker: And what is very interesting is that as our
Speaker: knowledge of pathophysiology has grown and as our general management of ICU patients has gotten better, the incidence of cerebral edema has actually markedly declined in patients with acute liver failure.
Speaker: So hardly anyone, very few patients actually develop, people might develop hepatic encyclopathy to some degree, but they rarely develop cerebral edema these days.
Speaker: And on the other hand, what was recommended as potential useful therapeutic interventions was, like you mentioned already, the use of plasmapheresis, the use of continuous renal replacement, and also the use of hypertonic saline, correct?
Speaker: Exactly, exactly, Sergeant.
Speaker: So now that we, a little bit more about hepatic encephalopathy and acute and chronic liver failure, if you could just give us kind of like an overview of how to suspect it and some tips and pearls and first-line therapies on this topic, which is very common in the ICU.
Speaker: Yeah, I mean, you know, so...
Speaker: As you said, exceedingly common, Sergio.
Speaker: And, you know, what I say is always look for a trigger for hepatic encyclopathy.
Speaker: Lots of times, as we have talked about before, it is SPP and it can be very subtle.
Speaker: And so, you know, a person presents with SPP and has ascites, you know, make sure you get the diagnostic tap.
Speaker: Make sure you're looking for hypovolemia, make sure you're looking for drugs, make sure you're looking for other things that have happened to cause hypokalemia and whatnot, other things that have precipitated hepatic encyclopathy.
Speaker: The presentation is, again, variable.
Speaker: People can present from anywhere to deep stuporous comas that require intubation and mechanical ventilation because they can't protect their airways.
Speaker: So just mild confusion and a little bit of asterisks.
Speaker: And the classification is actually called West Haven's classification.
Speaker: And what is important for our audience is to count as an organ failure across definitions, whether it is the North American definition or whether it is the European definition.
Speaker: One has to have grade three to grade four values.
Speaker: hepatic encyclopathy.
Speaker: And so one of the most common presentations in people with acute and chronic liver failure or even just decompensated cirrhosis and I think looking for a precipitant, extremely important, removing or treating the precipitant, very important, and again treating the hepatic encyclopathy, very important.
Speaker: Any other comments?
Speaker: I know that there were some recommendations on the use of rifaxamine and polyethylene glycol.
Speaker: Yeah, sure.
Speaker: So I think the cornerstone of management is still non-absorbable disaccharides, and so lactulose remains the cornerstone of management for...
Speaker: for hepatic encephalopathy.
Speaker: I think the addition of rifaximin as an adjunct to lactolose is very important, especially if the hepatic encephalopathy is not resolving.
Speaker: The combination of lactolose and rifaximin seems to work much better and may even have a mortality benefit.
Speaker: Now, the addition of polyethylene glycol, there are, I think, two trials which use polyethylene glycol in place of lactolose.
Speaker: But I would reserve it for people who do not tolerate lactolose or develop some bowel distension or things of that nature.
Speaker: Those are the people I think to give polyethylene glycol to.
Speaker: Remember that we are giving large volumes of polyethylene glycol in people who can't.
Speaker: There's always a risk of aspiration with this, but again, a useful adjunctive therapy if lactose is either not working or people are not tolerating lactose.
Speaker: Perfect.
Speaker: Rahul, first I just want to thank you for spearheading this massive undertaking of really putting together these guidelines.
Speaker: We'll have references to all the papers.
Speaker: I really encourage our audience to read the papers because the...
Speaker: Not only the recommendations are important, but also the discussion of the why and the literature behind them, which also for me was a reminder of how hard it is to perform large randomized trials in a subpopulation on chronic liver failure and acute liver failure patients and how much they're still to be studied in terms of managing these patients, right?
Speaker: You're exactly right, Sergio.
Speaker: I think, and it's surprising, right?
Speaker: We see it so commonly, yet there are so few randomized controlled trials, and there is a lot to be done and a lot to be studied.
Speaker: Is there anything else you want to add to the clinical topic before we move on to the closing part of the podcast, Rahul?
Speaker: Yeah, I think I would just, you know, probably for the audiences, just...
Speaker: maybe remind people that there is, it is always, you know, please be cognizant.
Speaker: Recognition is really important.
Speaker: And then, you know, refer to a center that has transplant capabilities at the right time is really important.
Speaker: Perfect.
Speaker: And you've been on the podcast before, so you know that we like to ask a couple of questions unrelated to the clinical topic to just learn a little bit from the wisdom of our guest.
Speaker: Would that be okay?
Speaker: Of course.
Speaker: So the first question relates to books.
Speaker: Are there any books that have influenced you or struck you recently or gifts or books that you have gifted often to other people?
Speaker: Yeah, so, you know, great question, Sergio.
Speaker: So, you know, I'm a big fan of Daniel Kahneman.
Speaker: And so I think the last time we talked, you know, I said thinking fast and slow has really, you know, had really influenced me.
Speaker: There's a new book of his called Noise.
Speaker: And, you know, which is about why...
Speaker: the same people make different decisions given exactly the same circumstances and what we can do to avoid that.
Speaker: And especially important, for example, in our judiciary systems and especially important in medicine and whatnot.
Speaker: So I think I have found his books to be particularly insightful and particularly very enlightening.
Speaker: And the books that I have gifted the most, and I'm sort of an armchair
Speaker: quantum physicist.
Speaker: And so the book that there is a book by Carlo Rovelli called the seven brief lessons of physics.
Speaker: You know, that's another book that has really influenced me a lot.
Speaker: And that is that is a book that I've gifted the most.
Speaker: And the nice thing of the Reveille book is that it's a short read.
Speaker: So it's a perfect gift.
Speaker: And yeah, we talked about this last time on thinking fast and slow, but I agree.
Speaker: I think Daniel Kahneman, for those who don't know, a Nobel laureate, father of behavioral economics and really of studying how we think, right?
Speaker: And noise is a wonderful read.
Speaker: And like you said, very, very applicable to what we do in medicine on a daily basis.
Speaker: So we will...
Speaker: Definitely link both of these books.
Speaker: I highly recommend it.
Speaker: I've enjoyed both of them and have also gifted Carlo Rovelli books to others.
Speaker: Great.
Speaker: So the second... What's that?
Speaker: You like quantum physics as well, I guess.
Speaker: I do.
Speaker: Okay, very nice.
Speaker: So the other book that I really enjoyed from Carlo Rovelli that's very new is his last, I don't know if it's his last book, but it's a book called Anaximander and really talks about the first great scientist in Greek history.
Speaker: Yeah.
Speaker: And it just shows you, I mean, how much people have evolved in the way they think and just a fascinating, fascinating read.
Speaker: So we'll reference all these in the show notes.
Speaker: Thanks for those recommendations.
Speaker: What do you believe to be true, Rahul, in medicine or life that most other people don't believe or don't behave like they believe?
Speaker: I don't know whether other people don't believe or don't behave like they believe, but I think I...
Speaker: One of the things that, you know, again, it's influenced a lot by Daniel Kahneman and, you know, and people like him is the role of randomness in life and chance in life.
Speaker: I think we discount the role of, you know, randomness in life.
Speaker: And, you know, people sort of tend to think that, you know,
Speaker: there is something special about, you know, a situation when it is all very random.
Speaker: And, you know, as an example, if you take a thousand people and give them a coin and, you know, ask them to toss a coin, you'll probably find one person who tosses 10 heads in a row or 10 tails in a row for that matter of fact.
Speaker: And, you know, that person was like, oh, wow, you know, there is something special when it's just, you know, you're liable to find one person who
Speaker: who sort of, you know, just by chance alone, who tosses 10 heads in a row or 10 tails in a row.
Speaker: And I think it's a great point also to bring back to medicine, right?
Speaker: So especially when you're looking at small numbers, people try to put an explanation to everything.
Speaker: So if all of a sudden they're measuring the ratio to mechanical ventilation, compliance with sepsis bundles, mortality, whatever you want to call it in your ICU, and it goes up,
Speaker: The first thought, or it goes down, the first thought is people attach all sorts of explanations to why that happened.
Speaker: And the most likely reason is that it's just a random finding, right?
Speaker: Yeah, exactly.
Speaker: And so, you know, Sergio, it is so great that you, it's so important that you brought this up.
Speaker: So this reminds me of the...
Speaker: of Tversky and you know, thought about the airline pilots in Israel.
Speaker: I don't know if you sort of read that or not.
Speaker: The regression to the mean, absolutely.
Speaker: Yes, exactly.
Speaker: So what it says, and I always remind people because of the law of small numbers, that if your sepsis numbers look really bad this month, I almost always guarantee that without doing anything, they will look better next month.
Speaker: Exactly.
Speaker: And if they looked very good this month, I can guarantee almost that they will look a little bit worse next month, right?
Speaker: Yes, exactly.
Speaker: Exactly.
Speaker: Perfect.
Speaker: And the last question is just related to what would you want every person listening to our podcast today to know?
Speaker: Do you mind if I read out a quote that I actually read in a...
Speaker: in a book of physical exams.
Speaker: So we used the book of, you know, I trained in India, I went to medical school in India, and we had used a book called Hutchinson's Clinical Methods.
Speaker: And, you know, and this was, this was, the book was, I think it was first published, you know, 100 years ago or so, and has now, and several editions later, you know, it's continued.
Speaker: But,
Speaker: There was a quote in the book by Lord Hutchinson himself, which, you know, has influenced me quite a bit.
Speaker: And so I would like to read that out if that's okay.
Speaker: Please, please.
Speaker: Okay, so the quote said, it's called the Physician's Prayer, and it goes as follows.
Speaker: From inability to let well alone, from too much zeal for the new and contempt for what is old, from putting knowledge before wisdom, science before art, and cleverness before common sense, from treating patients as cases, and from making the cure of the disease more grievous than endurance of the same, good Lord deliver us.
Speaker: I think it's a perfect place to stop.
Speaker: I think very wise words, and I'm a big fan of old books, Rahul.
Speaker: My grandfather used to tell me that old books are always great because only the good ones become old, right?
Speaker: Yeah, exactly.
Speaker: Well, Rahul, always a pleasure to have you back to discuss topics that I know you're very passionate about, but also, like in this case, acute and chronic liver failure, a very relevant topic to our audience and to our practices.
Speaker: I look forward to having you back, and thank you so much for sharing your expertise and your time with us today.
Speaker: Thanks, Rory.
Speaker: Thanks for having me.
Speaker: I really appreciate it.
Speaker: Thank you for listening to Critical Matters, a sound podcast.
Speaker: Make sure to subscribe to Critical Matters on Apple or Google Podcasts and share with your network.
Speaker: Sound's transforming the way critical care is provided in hospitals across the country.
Speaker: To learn more, visit www.soundphysicians.com.
