During this 20-25 minute pre-recorded lecture, Dr. Priya Grewal discusses the topic of ascites, hepatorenal syndrome and spontaneous bacterial peritonitis. This in-depth review will provide an update on this topic for your clinical practice as well as supplement your learning for the ABIM Gastroenterology and Hepatology boards. CME pre-requiste of live Q & A webinar, 8th Annual Mount Sinai Intensive Board Review in Gastroenterology & Hepatology on Oct 13. Uh huh. Hi this is dr pre a grave all welcome to the board review course of september 2020. Um I'm going to be talking about complications of portal hypertension. Mainly a society's spp. Uh And hRS so this is the natural history of liver disease. Uh And we know that any liver disease whether it's viral autoimmune or genetic can lead to a car necessity and chronic liver disease. And for most for the most part people will remain uh in the chronic liver disease and maybe progressed to compensated cirrhosis of the course of 10-15 years. Uh but then any events such as a hemorrhage societies or encephalopathy will then transition them into the d compensated cirrhosis stage. And my focus is really going to be on that area of the natural history of liver disease. The d compensated state of cirrhosis leading to further decompensation as marked by the frankly societies hyponatremia. HRS spp uh eventually leading to multi organ failure and death. Oliver transplant. A lot of this decompensation really relies on worsening portal hypertension. More bacterial translocation leading to systemic information more ways a dilation. And therefore it's sort of a self perpetuating process which leads to further decompensation. So the most common cause of Asides is cirrhosis. So 75% of patients you know with cirrhosis. Their first decompensating event is usually asides and most society stems for cirrhosis though there are some other less common causes like peritoneal malignancy heart failure. TB and a smattering of even rarer causes like pancreatic societies and part carry syndrome. Most of these you know comprise uh make up less than 25% of the causes of societies. So it is a pro prognostic sign. Once you develop a society is less than 50% people are alive for five years. And Once you have refractory societies, the survival drops down to two years. Uh sometimes people with the city's can also have plural effusions in about 10-15% cases, mostly right cited. Um and and it is interesting that sometimes patients will just present with recurrent pleural effusions and not have any asides. And that's purely because the negative inserts, Jurassic pressure pulls the fluid preferentially through the diaphragmatic openings right into the pleural space. So there's no societies in the setting. One would like to see fever John to Spain as a sign of SBP or spontaneous bacterial peritonitis. Uh but sometimes um these symptoms are missing. And as you can see that at least 30-40% of patients with SBP have no signs or symptoms, which is why I always encourage patients appear to the hospital for any reason to undergo a tap. I educate the house stuff about this because that's really the only way to pick up spp um and treated uh treated right away. So let's start with our first case, since this is a board review course. Uh we have a 54 year old woman with alcoholic cirrhosis who presents to the er with abdominal distention, which is worse than usual. Some agitation and and nemesis. She has a past medical history of various of bleeding and developed in breast cancer. She's on the usual meds for cirrhosis. She's lethargic hypertensive tachycardic also has a temperature, no temperature. Um She has some scare electrolysis and muscle wasting also has some by basic crackles. Her abdomen is dance with. The site is mostly uh and she also has two plus oedema. These are her labs. As you can see I would like to point out a few things merely a high white count her plate account. We sort of fits with her level of sickness and portal hypertension. She also has an elevator creating at 1.8 a sodium of 129 An elevated c. 125. And the rest of the labs are sort of in keeping with her presentation. So the next best step in the management should be. Should we scan her belly because we're worried about an acute abdomen. Should she undergo a diagnostic tap? Should be straight away. Start on fluids and antibiotics. Or should we give her like close to wake her up? Um So the answer to that question would be a diagnostic tap. Um And I think the point I want to highlight here is that even though you know she is pretty quickly path like the risk of bleeding remains very low. Um Unless you have really florida key moses on the abdominal ball and you're worried about breeding. You know patients like this can be tapped again, you have to make sure they're not agitated and moving around and restless because that would make the tap more complicated. But short of that, you can actually go ahead and tap these patients because that would give you the diagnosis and once you've tapped the patients, uh this is the results of her food analysis. She has a sag greater than 1.1 her pm encounter. The food is greater than 2 50. She has a lower argument at less than one grandpa desolate and she has a high total protein of greater than two cramps. So all of the presuming that we are making this diagnosis of SPP, all of these support the diagnosis of SPP. Except what would be the exception here. Uh as expected. Or as predicted, it would be the high total protein. Because when you see a high total protein that really reflects um this that this that societies is stemming from either peritoneum tv or from carcinoma ketosis. Because that's where the saG is low. But the total protein is high and if the saG is high but the total protein is high that goes with cardiac aside. So this is a nice little algorithm which you can go over at leisure later on, uh showing the differentiation between a low sag and a high sag. The sag is basically the gradient between between the serum and the uh societies are women. So, you know, you take the serum albumin subtract the city's argument and the difference between the two gives you the sag. Um So if you have a high sag you're thinking more about liver disease and cardiac disease. If you have a low side you're thinking about peritoneal disease. And then the high protein really points towards either cardiac or again malignancy or Tv. So now that we have the initial sag results on this patient. We also know that how fluid shows that she has a high P. M. And count of 5600 and the gram stain as well as the culture is negative. So what would be the next thing to do for this lady? Would you give her I. V. Antibiotics? Give her ivy albumin whole direct X. Hole. Not a law or two and I'll be on her. So so you can do all of those things but you would rather not do an L. B. P. In this patient because we have a lady who's sort of chemo dynamically unstable. You don't want to shift her fluid around too much. So you would definitely start antibiotics emergent lee. You would give her all women you would hold all other medicines that can cause your blood pressure to go down further which includes diuretics and beta blockers. But an L. B. P. S. Probably not warranted given that that that could worsen how human dynamics and potentially you know precipitate about syndrome. So this is another table. Just showing us all the different possibilities of SPP. The classic one is where you have more than 250 cells and culture positive which is the classic spp which you should definitely treat. You can also have a high cell count of greater than 250 but a negative culture which is usually what we see in practice. But this uh this sort of culture negative nutraceutical side is also requires antibiotic treatment. You can also have a low Celcom but a positive culture that is called amona microbial bacteria sides. And again this situation some of these patients will progress to SPP has a similar mortality of SPP and should be treated the same if you have a lot of different bacteria growing. That usually reflects a little cooperation and peritonitis. Um and um I think that you know if you really have secondary peritonitis you should be getting imaging to rule out a diverticulitis or appendicitis. It is causing you know such high PMS and uh and you know a positive culture. Um So contrary to what we see in hospitalized patients, the instance of SCP and our patients is actually very low. It is in the range of 1 to 3% because these are generally 1 to 3.5% which is it is generally because patients are um much healthier when they are outpatients and predominantly these people have staph and strep growing out of the aesthetic floor in contrast to the gram negative flora that we see in the inpatient setting. And then most of these ultrasound guided Acidic taps really have a low incidence of bleeding less than 1%. Even in the setting of neuropathy. You should try to get the patient to act within six hours and start antibiotics immediately. And I do encouraged how staff to be trained in paris and pieces and to have supervision when they're in the early years as an intern should be watched by a resident or resident. You know in some instances needs to be watched by a fellow because we have seen more bleeding when um you know in these very sick patients uh you really should I say it a good pocket and do the para synthesis in a safe way. So uh you know I do I do recommend that there is supervision for you know medical students and interns who are going ahead and doing these parents para synthesis are not very sick. You know, transplant listed patients. So this is the flora and as you can see it has changed a little bit from From say you know the latter part of the 1900. So from 1971 to 2000 it was mostly mostly equalised uh and ram negatives. But after 2000 almost 65% of the isolates that actually gram positive including quite negative staff and then tear a caucus and this is attributed primarily to increase the number of procedures. Were doing putting lines in these patients, the chronic antibiotic use um And when you have a hospitalized patient develops spp you really have to be mindful that this may actually be a drug resistant bacteria as an equal I. E. S. P. L. Or Klebsiella. And it should be treated appropriately. Sometimes it can be more so obviously. So the first step in treatment is antibiotics you can go with usually um We start with self tracks on if they're allergic to penicillin, you can use legal fluxus in if you have a nosocomial spp, you really should be starting with Wilson and banco. Uh And if you suspect chiari then uh desolate is the drug of choice or dr mason. Um If you have an spl specie s room then you should be with my panel. And while all women is usually given on the first day and the and the third day um there is a role of if you have a short of a shortage of albumin, you can actually give it to people who are sicker as uh as shown by the high bilirubin, high B and and high create and you can reserve it for those people. So people who are generally Have close to normal believable renal function can get away without albumen. Um but in most instances we would lean towards giving abdomen on day one and day three and secondary profile access has to be started before the you know at the time when the patient is getting discharged either with no flocks of Backstrom for several. Uh And the and the references for all of those antibiotics are in this are in the slide. If you suspect your secondary peritonitis you should get a city uh And you should really suspected when you have a high white count multiple organisms, a low glucose. The psychology is usually not helpful unless a desperate oral carcinoma, carcinoma, ketosis where it is very sensitive hi say 1 25. Which was another thing that we saw in this lady's presentation can just resolve from distention of the peritoneum. Uh And as a missile material cells come under pressure. They produce a 1 25. If you're suspecting TV then you know the yield of the culture is very low. It's less than 50%. And you should really rely on PCR uh you know biopsy in the peritoneum and we talked about bacteria. It's already So renal dysfunction is a very poor prognostic sign in patients with spp. If there's no renal insufficiency, the chance of death is quite small. However progressive renal insufficiency is marked by 100% more And based on this. Uh this is a very old publication but a very valid one at the same time. The use of antibiotics is mainly the story. The use of albumin is merely relying on decreasing the renal dysfunction. That comes with spp from 32% to 10%. And therefore corresponding improvement in hospital mortality from 27% of 10 and also a benefit at three month mortality. So that is the basis on which we combine antibiotics with argument for the treatment of SPP. It is purely to prevent hepatic Mendelson's. So going on with our patient, she undergoes treatment for SPP and she improves um and on discharge, has a decent blood pressure and heart rate. And we're going to resume all of her medicines except so we definitely put on SPP profile access I think you know given her blood pressure being good we can put her back on her feet a blocker so we can probably assume a load or some diabetics that can be di traded up as an outpatient. And then she came on a P. P. I. And the question is whether she should resume her P. P. I. And I think the point I'm trying to make here is that P. P. I. S. Are given sort of inadvertently to patients with end stage liver disease. You know, they believe they get a P. P. I. They stay on it for a few weeks and uh you guys have definitely been linked with an increased risk of infection in patients with cirrhosis. This was a consortium, the non north american consortium for the study of end stage liver disease looking at 188 patients and following them for 66 months and there was a 45 uh infection risk. And you know, some of the predictors of infection was. Again, people had An odds ratio of 2.72. So that's something that is preventable. And we should definitely try to hold them if there is no strong indication to be. The other predictors were obviously if you wanna speak with profile axis, which increases, which tells you that you are at increased risk of infection to begin with. The recurrence of SCP at one year after you've had about is very high and it's almost in the range of 75%. And it also is a company is a very low one year survival of 88%. And for that reason we have enough data to support the use of North frocks season as a secondary profile access in patients with SPP. We also have data to support the rule of uh no fluxus in in primary prevention of spp, especially in very sick people who have a protein less than 1.5. Uh some real dysfunction, hyponatremia and a child Pugh score greater than nine or billy greater than three. So in that group of patients, you know, you can actually put them on a flux is in with an improvement Uh in a decreased risk of B as well as a decreased risk of hepatic renal syndrome. So this is a study looking at 35 patients in each arm. Again, showing benefit of relaxation and primary prevention of SPP. And also this showed almost a statistically significant survival. As far as beat up blockers are concerned, there are multiple studies that have shown that their detriment and advanced cirrhosis and at least one study that shows that they are beneficial and advanced cirrhosis. Uh so briefly, this was a study looking at 151 patients with a meld of 18 who are undergoing Mbps periodically and being given an agreement and the ones who wouldn't beta blockers had a law of survival. Uh five months. The meetings of all those five months versus 20 months in patients who are not on beta blockers suggesting that beta blockers in this very sick, advanced advanced be compensated sort of suspicions was actually um and this was another study looking at a similar, a similar situation, but it was retrospective. And here the patients had had their first part of SPP and then went on to either have, you know, take beyond beta blockers are not being beat up lockers. And clearly the transplant free survival Rate was better in the patients who were not non selective beta particles. And this was particularly true in patients who had a low systolic blood pressure of less than 82, even the incidence of HRS was less. Um it was 8% versus 24% in patients who were not only beta blockers versus those who were on non selective beta blockers. Again, something to think about. But in a study looking at a listed patients. So we're going to undergo a transplant. It almost seemed like the patients who were non selective beta blockers had a lower incidence of death on the transplant list and also were more likely to get transport. So there are pros and cons on both sides. My personal data that is if somebody's hypertensive I would probably on this side I would probably hold the beta blockers. And this is supported by this nice window hypothesis which tells you that as you progress from early cirrhosis to be compensated cirrhosis and then end stage cirrhosis cirrhosis. Uh there are certain Hema dynamic changes that take place. So you know, while the cardiac reverse cardiac reserve tends to go down, there is an increase in the sympathetic nervous system and the reigning angiotensin. Aldo siren system activity. Uh this increase is paralleled by an increase in rut bacterial translocation. So as we go towards the right side of the spectrum, you can see that, you know, the cardiac reserve continues to fall and you know giving patients peter blockers at this stage is probably going to make the hemo dynamics worse and probably pushed them into HRS. So when I see this patient with refractory asides and low blood pressure. I tend to hold the beta blockers. So moving on to our case do we have a 68 year old man with nash diabetes, he's getting L. V. P. S. A. Big two weeks. He has larger side is a mama. He has a dina. His labs are not bad. His believes 1.4 saw him as a law. He's on some cardiac maths, Some maps for diabetes. He's on diuretics. His portal vein is closed off and his Echo shows up pulmonary artery pressure of 55 mm of mercury. So we have a guy with the sides and multiple comorbidities. And the question is, how do we manage his societies? So the next best step for his refractory societies is so he's getting tapped and you have this presentation that we just saw uh is a right heart cath versus doing a tips on him versus increasing his diabetics or doing an indwelling catheter which I would reserve for people who are very sick as a palliative approach. So there was some clues in his history suggesting that he actually may have, you know, some hi peer pressures and that a lot of the societies may actually be stunning from heart disease. The right answer to this question, whenever you see that high peer pressures to do right hard caps and investigate whether this gentleman has brought about a hypertension, which is a major goals of the societies. And if he has that, then the tips would really push him into heart failure and not do any good for his society. So I think the right heart cat is probably the best way to go. There was also a certain uh certain implications that he had bought events from bosses. But we know that now that is a relative contraindications for tips. We are actually a center where we can do a tips even in patients with what events from bosses. Uh but the definite contraindications for tips is uncontrolled PSC Just a heart failure Singapore. We have pretension high male greater than 18 if you have obviously some on durability, obstruction or multiple hepatic cysts. So he undergoes a tips as his right heart cat doesn't show put up on my hypertension. It just shows fluid overload. So he's diaries over the next few days and undergoes attempts. But after the tips he becomes short of breath and he has increased abdominal distention. And you can see he's hypertensive, very tacky Codec. Obviously looking very sick and lethargic. His lap short, nice dropping his hemoglobin. The rest of his numbers are sort of a little worse but close baseline. So the most likely explanation for this rapid deterioration of the after tips in his situation is sepsis is that liver failure tips tips occlusion or him a peritoneum. Uh Answer is really him or peritoneum because we have that drop in H and H and you know just how he looks. So these are some of the complications of tips which are all real complications. So before you, you know, put a patient to this procedure, you really have to think about all these complications and make sure that you know the benefit of the tips out Korea is the risk which includes breeding uh you know different kinds of fistulas that can form between the bottle green and bile dogs. You can have you know pot of beans from bosses. And we actually have a gentleman admitted right now on ourselves who has a tip side as as we call it. Which is an infection of the tips. And and and and the patients actually listed for transplant and awaiting one because there's no way declared that infection and it's hard to take out the tips. You can also put patients into heart failure and uh worsening uh incivility. So moving on to our final case, this is a young man with alcoholic cirrhosis who's been binging on alcohol recently. He's also using and sets for hangovers. Comes in with lethargy societies. He has small amount of urine. He's joined us lethargic and his labs really look like that. Or typical alka patient, high liver enzymes. Hi billy Rubin hi creating um and then he has a urine analysis which shows that his casts are not present. There's no protein. And his His final is less than one. So the most likely explanation for his A. K. I. Is that A. T. M. Is that HRS is a pre renal Mesopotamia or interstitial nephritis. Right answer to that question is extremely salty means until you rule out Um dehydration. Everything else is not. You cannot diagnose the rest of the situations. So the fact that he's not in shock makes 80 and unlikely. And even though the urine studies look like H. R. S. I think before you come to that diagnosis you really have to make that you resuscitate these patients well. Um and this patient, he got a fluid challenge over the next 24 hours. He held his diuretics but his tracking continued to rise. I think now I think most of us can guess that what is going on with him is he's actually a true HRS patient because his creatinine is going up significantly in spite of uh repeating all his fluid loss. So now the next best step in his management. Do you start him on ways oppressors like dr tied and middle train do you start to really present you give him the toxic violent predniSONE arena replacement therapy. And just to point out this the pen Toxie file and there was just a small group of patients that we tried that was it was tried on that is the article that's reflected at the bottom of that page and you know, we don't use it anymore. So in the current day all we have. Mhm. There is a new definition for HRS previously we talked just about the rise in serum creating but now we use a new definition though. The studies on each others have all been done with the old definition which is uh which is what is based the confirmed trial is based on the new definition is basically HRS a key i where we define HRS by an increase in serum correcting by 0.3. Um all um an increase in serum correcting by 50% from baseline in 48 hours. Um And anything outside of each other is considered non each other Broadly. These are the distinctions between Hrs and 80 in which most of us are familiar with. Um And this is the design of the confirmed trial that is that has been presented to the FDA. And uh based on this trial we await FDA approval for telepresence. So basically patients were With Hrs were randomized attorney personal placebo and 2-1 ratio that were given aggregate at the same time. Initial dose was one mg might be every six hours. Uh and it was increased to two mg. If they're creating did not decrease by 30% from the baseline value on day four. And along with the early president both arms got As you can see we had a big 90 day mortality in both arms. Just sick. These patients work. The baseline demographics reflect that most of these patients are at least 40% had alcoholic hepatitis. They had a mouse code of 33 at baseline. Most of them were young believable enough. Uh Um this is what happened at the end of the study which showed a reversal in almost 30% patients losses. 15.8 and the patients in the placebo arm. Um and I think this is one of the slides that's crucial showing us that the reversal really happens much better if your serum cracking is less than three. Which is why I'm hoping that once the drug gets approved, we don't wait till the serum cracklings are higher because it doesn't really work very well. Um It also leads to a decreased need for dialysis, post liver transplant. And as you can see patients who want to re present required replacement therapy only 19% of the time versus nearly half of them requiring replacement in the uh one of the things that the FDA is very concerned about is the respiratory failure which seems to be higher in the only person I am compared to the placebo arm. But I think this uh you know goes back to the hypothesis to the path of physiology. Most people with HRS do have, you know, cardiac psoriatic cardiomyopathy. Uh and therefore it has to be used very cautiously in patients who already have respiratory problems of your overlord. Because once you add the vessel constriction elements, some of these patients can go into worsening respiratory distress and respiratory failures. I think that's something that you have to remember. Um And therefore that this is the this is the document that was presented to the FADA on July 15 and the FADA came back with certain, you know, certain problems. And some of the problems will you know, if we lower these patients melt, you know, does it take it take them further away from transplant and if so then I'll be doing them any good. There was also this concern about increased substance and respiratory failure in the treatment arm. But overall the respiratory failure risk remains very low. It's less than 1%. And therefore I think when the drug does get approved it will come with a warning to be used cautiously in patients with multi organ failure which is defined as a cLF create three where you have three or more organ failures and patients with preexisting respiratory issues on patients with very high male score. They were also concerned that you know, a lot of the patients in both arms had alcoholic hepatitis and they were concerned that these patients don't have cirrhosis. But we do know the majority of the patients with alcoholic hepatitis do have underlying cirrhosis. And then the last question was is HRS reversal really a valid endpoint. Um and I think uh even though it doesn't really translate into survival advantage, I think it's the best we have at this point. And once the drug is approved, obviously we will look at these patients after transparency if the outcomes are better than those who um who were not on who were not on early present because if you put a patient on dialysis, you're not really changing the underlying parts of physiology that is struggling HRS. So these patients actually continue to be at high risk for infection. They continue to have portal hypertension, that higher risk for breathing and being in the ICU longer and probably not making it to transport. So I think all and all for now. If dirty person does get approved, I would quite quite willingly. And this is just the last slide. I guess we will tackle questions in october. Thank you for listening to me.