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Pretransplant Management of Multiorgan Failure in ACLF/Cirrhosis
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I'm Victor. I'm an intensivist and hepatologist out of Calgary in Canada. And I'll be talking about the preoperative management of multi-organ failure in acute on chronic liver failure. I don't have any disclosures. In terms of the objectives for my part of the talk, we will define acute on chronic liver failure, describe the management of different organ system failures in ACLF, and then also describe prognostication in ACLF. So to start with, in terms of defining acute on chronic liver failure, it's when an acute precipitating event occurs in a patient with underlying chronic liver disease, with or without cirrhosis that leads to rapid onset of multi-organ failure and clinical deterioration. There's no consensus right now in terms of the diagnosis or definition of ACLF, and several different society organizations have come up with slightly different definitions. But the most commonly used one is the Eazle-Cliff definition, which divides ACLF into three grades based on the type and number of organ failures that are present, up to six organ system failures. There's also the North American Consortium definition, which stratifies patients according to the number of organ failures, and they list up to four organ failures. And then there's also the American Association for the Study of Liver Diseases, which requires the presence of liver failure, along with at least one extrahepatic organ failure. So regarding the Cliff ACLF definition, the organ failures are defined based on the Cliff SOFA score. So the values highlighted in red define the organ system failure. So it's broken down into, again, six organ systems. And so liver failure is defined as a bilirubin of greater than 12 milligrams per deciliter. Renal failure is having a keratinin of 2 milligrams per deciliter or more. Inflammation failure is having at least grade 3 hepatic encephalopathy. Coagulation failure is an INR of 2.5 or more. Circulatory failure is anyone requiring press or support. And then respiratory failure is having a PF ratio that's 200 or less. So now we'll just go into some organ-specific managements in ACLF. So starting with hepatic encephalopathy, this occurs in up to 45% of patients with cirrhosis. Results in impaired cognition, confusion, and decreased level of consciousness. Common precipitants include infection, GI bleeding, acute kidney injury, sedating medications, and constipation. It's important to recognize that when a patient develops hepatic encephalopathy, their mortality goes to greater than 50%. We grade the severity of hepatic encephalopathy based on the West Haven grading system where grade 0 is no encephalopathy. Grade 1 is some alterations in behavior, mild confusion, disordered sleep, and then all the way to grade 4, which is essentially coma. For management of hepatic encephalopathy, as intensivists, the first thing we always need to do is assessment of the airway and breathing, as tracheal intubation and mechanical ventilation may be required for airway protection, especially in patients with high-grade encephalopathy. We also need to identify and treat the precipitating factors. And for specific treatment of the encephalopathy, the first-line therapy is non-absorbable disaccharides in the form of lactulose, which can be given orally via an NG tube or rectally in patients who are not currently intubated and who have higher-grade encephalopathy. And glycol can be used as an alternative. And rifaximin, which is a non-absorbable antibiotic, is often added as adjunct therapy in patients with refractory encephalopathy. And then there's also other therapies like L-ornithine, L-aspartate. And it's also important to remember to try and avoid sedatives in these patients, especially benzodiazepines. Neurofailure is also a fear of complication in ACLF. And acute kidney injury occurs in 50% of hospitalized serotics. And Dr. Olson did a fantastic job of going through the revised criteria for AKI. Risk factors for development of AKI include GI bleeding, infection, particularly SBP, large-volume paracentesis without adequate volume replacement, and alcoholic hepatitis. In terms of general treatment of renal failure, again, you want to treat potential precipitating factors, discontinue and avoid nephrotoxin medications, and also, most importantly, to optimize fluid status. So if someone is requiring volume resuscitation, then crystalloids is the preferred fluid, and preferably balanced solutions as first-line therapy. However, volume status, again, is very important to determine. And if patients are volume overloaded, then you, again, want to discontinue fluids and initiate diuretic therapy. Again, hepato-renal syndrome is what a lot of people think of when patients with liver disease develop AKI. And again, it's a very specific form of AKI. And the diagnostic criteria include patients who have cirrhosis anesthetes, the presence of AKI according to the ICA-AKI criteria, absence of shock, no response to diuretic withdrawal and plasma volume expansion with albumin for 24 hours, and no current or recent use of nephrotoxic drugs, and no macroscopic signs of structural kidney injury or damage. In terms of specific management for hepato-renal syndrome, so we recommend albumin use. But again, the mainstay here is initiation of vasoconstrictor therapy. And to initiate vasoconstrictor therapy earlier on in the course of the illness, as opposed to waiting until patients are volume overloaded after getting tons of albumin, or their creatinine has gone significantly higher. Terlepressin is the agent of choice. It's the most widely studied medication for the treatment of HRS. All studies have shown terlepressin with albumin reverses HRS compared with placebo and albumin. And particularly for patients in the ICU with HRS, these patients were more likely to achieve renal improvement and shorter ICU lengths of stay with terlepressin compared to placebo. With that being said, you do have to be mindful of certain adverse effects and potential side effects of terlepressin, which includes angina, arrhythmias, digital ischemia, and respiratory compromise in the form of pulmonary edema. If you don't have access to terlepressin, norepinephrine can be used as well in lieu of terlepressin. And studies have shown non-inferiority with norepinephrine compared to terlepressin. In terms of the dosages, so terlepressin can be given as an IV bolus or an infusion. And with terlepressin, you want to increase the dose every 24 hours if serum creatinine has not decreased by 25%. And with norepinephrine, as you all know, it's given as an infusion. And you want to increase the dose every four hours if the MAP has not increased by 10 millimeters of mercury or more. And with hepatorenal syndrome, the goal is to increase the MAP overall by at least 10 up to a maximum of about 80 to 85. When you do start patients on vasoconstrictors for HRS, it's important to recognize how long to keep them on it and when to stop vasoconstrictor therapy. So stopping points would include if the serum creatinine returns to within 0.3 milligrams per deciliter of their baseline, if you encounter any serious adverse reactions, if there's no improvement in serum creatinine after 48 to 72 hours, and potentially for up to four days with maximal tolerated doses. If patients are initiated on renal replacement therapy, total duration of therapy has been 14 days, or if they undergo liver transplantation. And again, some of these patients may require start of renal replacement therapy. At this time, there's no data to really suggest what the optimal timing of initiation of renal replacement therapy is in ACLF patients. There's no benefit from preemptive initiation. Continuous renal replacement therapy is preferred in hemodynamically unstable patients. And renal replacement therapy can be used as a bridge to liver transplantation. So in terms of data around the best modality and the timing of initiation of renal replacement therapy, we kind of take what was shown in the START-AKI trial. So this graph on the left is just showing from the START-AKI trial that accelerated renal replacement therapy, START, did not provide any mortality benefit or survival benefit compared to starting renal replacement therapy when standard criteria is met. The other figure here was a post hoc analysis showing CRRT versus intermittent hemodialysis in critically ill patients who required renal replacement therapy. As you can see here, CRRT resulted in lower rates of death or renal replacement therapy dependence compared to intermittent hemodialysis. When patients are on continuous renal replacement therapy, they often will require some form of anticoagulation, mainly to preserve filter life. And it's either in the form of systemic anticoagulation or more commonly regional citrate anticoagulation. And previous recommendations were to avoid any form of anticoagulation in patients with liver failure due to the potential increased risk of bleeding. However, recent evidence suggests that regional citrate anticoagulation may actually be safe. So this systematic review and meta-analysis looked at the use of regional citrate anticoagulation in patients with liver failure, and their pooled rate of bleeding was about 6%. More recently, a randomized control trial was done in patients with liver failure, comparing citrate versus no anticoagulation in patients undergoing CRRT. And what they found was that in the citrate group, unsurprisingly, the filter life was prolonged and there was less filter failure. But at the same time, there was no difference in rates of bleeding between the two groups. Moving on to respiratory failure. When patients with cirrhosis and ACLF develop respiratory failure, there's etiologies that are specific to cirrhosis, such as hepatic hydrothorax, hepato-pulmonary syndrome, portal pulmonary hypertension, and alpha-1 antitrypsin deficiency, or etiologies that are not specific to cirrhosis, so pneumonia, PE, pulmonary edema, ARDS, and atelectasis. So again, in terms of treating respiratory failure, you want to treat the underlying precipitant, utilize high-flow nasal cannula for patients with acute hypoxemic respiratory failure, and monitor their respiratory status closely. You utilize non-invasive ventilation for exacerbations of COPD and acute cardiogenic pulmonary edema. Invasive mechanical ventilation may be required in patients who develop acute lung injury or ARDS. And the ventilation strategy is very similar to any other patient with ARDS. So low tidal volumes, low plateau pressures, low PEEP strategy for mild ARDS, and then consider a higher PEEP strategy for moderate to severe ARDS. Cirrhotics also have baseline hyperdynamic circulation with low systemic vascular resistance, and they may also develop cardiomyopathy. And when cirrhotics develop ACLF, they often have a systemic inflammatory response syndrome, which worsens systemic vascular resistance and reduces end-organ perfusion. So what you want to do is, again, do a baseline assessment of volume status, cardiac function, and fluid responsiveness. You want accurate monitoring of hemodynamics and circulatory status. Judicious use of intravascular volume resuscitation with balanced crystalloids and potentially albumin. Target a MAP of 65. Use vasoactive agents when required using norepinephrine as first line and vasopressin as second line. And if you have access to terlipressin, terlipressin may also be used in lieu of vasopressin. And then consider hydrocortisone for refractory shock, similar to really any other septic shock patient. And so there's been a few studies looking at what the optimal MAP is in patients with cirrhosis and shock, and particularly cirrhosis and septic shock. And so this was a randomized control trial looking at targeting a higher MAP, so a MAP of 80 to 85 versus a lower MAP, 60 to 65. And what they found was that there was no difference in 28-day mortality. The higher MAP group did have decreased incidence of hypotension during dialysis, but they also had more adverse events versus the lower MAP group had higher incidence of hypotension during dialysis, unsurprisingly, but fewer adverse events. And then in terms of the type of fluid to use in patients with cirrhosis and shock, and particularly sepsis-induced hypotension, there was a recent randomized control trial looking at comparing albumin to plasmalate. And so the albumin group had faster achievement of MAP over 65, faster decline in arterial lactate, reduced need for dialysis, and also if they did need dialysis, longer time until initiation of dialysis. But survival was comparable, and again, with albumin as seen in other studies, there was higher incidence of pulmonary complications, particularly pulmonary edema. So if you are going to use albumin, you just have to be aware of the potential adverse events mainly in the form of respiratory compromise. Prognostication is very important in patients with ACLF, especially if they end up in the ICU. And the most commonly used scoring system we use is the CLIF-ACLF score, which takes into account the types of organ failure and the number of organ failure along with the patient's age and white blood cell count. And several studies have been done looking at the prognostic value of the CLIF-C-ACLF score. This study by Carvalis and colleagues found that as your CLIF-C-ACLF score goes up, your mortality goes up. And particularly with patients who have an ACLF score of greater than 70 at day one or day three post-ICU admission, their mortality rates were 90% at 90 days. And in that same study, what they found was that ACLF is quite dynamic and the severity of ACLF can change in the first couple of days during an ICU admission. So what they found was that 40% of patients improved their ACLF by at least one grade at day three post-admission, 48% had no change, and 12% unfortunately deteriorated by at least one ACLF grade. And as your day three ACLF grade increases, your mortality at 28 days and 90 days also increases. However, if you are able to improve these patients' grade of ACLF at day three post-ICU admission, especially if they came in with grade three ACLF, they had improved 90-day mortality. And then another study by Engelman and colleagues found that if a patient with an ACLF score of greater than 70 at 48 hours post-ICU admission, they had a 28-day mortality of 100%. And sometimes liver transplantation may be the only option for these patients. There is always questions around, you know, how sick is this patient and are they too sick to tolerate and undergo a liver transplant? This study, so I just wanted to highlight this study, which looked at patients undergoing liver transplantation and at the time stratifying them based on the number of organ failures from zero organ failures all the way up to five or six organ failures. And what they found was that even in patients who had five or six organ failures, their one-year post-liver transplant survival was still greater than 80%, which is still pretty remarkable considering that without a transplant, these patients would all universally have passed away. So I think the take-home here is assess these patients early for transplant, and even if they have multi-organ failure, they may still benefit from liver transplantation. And so in conclusion, ACLF is a distinct entity that involves multi-organ failure in patients with chronic liver disease. Organ-specific treatment options are available for critically ill patients. Prognosis without liver transplant is poor in patients with high-grade ACLF and high ACLF scores. And liver transplantation improves survival and has good outcomes even in high-grade ACLF. And with that, I will hand it over to Dr. Subramanian for his part of the talk.
Video Summary
Victor, an intensivist and hepatologist from Calgary, Canada, discusses the preoperative management of multi-organ failure in acute on chronic liver failure (ACLF). ACLF is characterized by an acute event in patients with chronic liver disease leading to rapid multi-organ failure. There are diverse definitions of ACLF, but the most common one, Eazle-Cliff, categorizes it into three grades based on organ failures. The talk addresses key aspects of managing organ failures like hepatic encephalopathy, renal failure, and respiratory failure. Hepatic encephalopathy requires airway management and lactulose treatment, while hepatorenal syndrome is treated with albumin and vasoconstrictors. For respiratory failure, underlying causes must be treated, and appropriate ventilation strategies applied. Prognostication involves using the CLIF-C-ACLF score, with higher scores indicating increased mortality. Liver transplantation remains a vital option, even for patients with severe multi-organ failures, showing significant post-transplant survival improvement.
Keywords
ACLF
multi-organ failure
hepatic encephalopathy
hepatorenal syndrome
CLIF-C-ACLF score
liver transplantation
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