So, our last talk will be given by our esteemed colleague, Dr. Jody Olson, who is an associate professor of medicine at the Mayo Clinic in Rochester. He is a critical care physician and hepatologist, and he's going to be talking to us about the challenges around liver transplantation, particularly in acute on chronic liver failure. Thank you very much, Dean, and thank you, everyone, for being here this afternoon. My objectives today are to review general considerations for transplant program risk acceptance. I really want to help demystify how transplant decisions are made in transplant programs sort of based on what kind of risk a program can take. I'll review to do transplant for advanced ACLF patients, hope to be able to discuss some considerations for when a patient may be considered too sick for transplantation, and lastly, I'll review the importance of the intensivist in the transplant process for critically ill patients with multisystem organ failure and ACLF. So take home from this slide, this was a study performed in Europe from the CLIF Consortium, and if you look at one thing, notice that patients with high-grade ACLF, those with ACLF grade two and three, have an extremely high 90-day mortality rate, which oftentimes is 100% in many cases. Patients who demonstrate progressive organ dysfunction over time obviously have worse outcomes, but just remember this as we talk about high-grade ACLF as we go forward in this talk. These patients have very, very high short-term mortality. So what are risk considerations for transplant programs? How do we understand how programs can assess risk and make decisions about what kind of patients they can transplant? Obviously any time we're making a transplant decision, the first and foremost decision we're making is what is best for the patient, but there are a lot of other things that go into these conversations as well. Patient transplant programs are required to maintain certain outcome percentages, and they need this to maintain program certification from government agencies. Remember that insurance and payers also look at center outcomes when they're deciding whether they're going to allow for transplant to be performed at certain centers. And lastly, we're using a very limited resource. If you remember from Dr. Subramanian's talk, there's a significant degree of discordance between the number of people who need a liver transplant and the number of organs available. We have a duty to make sure that we're using these organs appropriately. If you're not familiar with this and you work in a transplant program, you need to understand the SRTR. The SRTR is the Scientific Registry of Transplant Recipients, and this is currently housed in Minneapolis, Minnesota through the Chronic Disease Research Group at Hennepin County Medical Center. This is an entity that's under contract from Health Resources and Services Administration, or HRSA. In fact, all transplant is under this umbrella. So OPTN, UNOS, these are all subcontractors that are provided these contracts under HRSA. The SRTR provides analytic support to the Department of Health and Human Services and to the Organ Procurement and Transplant Network that helps with policy formulation. They look at system performance metrics, and they also perform economic analyses. If you go to the SRTR, and we're required to tell patients about the SRTR, this is the data that they see whenever they look up a transplant program. So this is Mayo Clinic data, and you can see that the three main measures that are reported on this page are survival on the wait list, patient survival once they've been listed for transplant, the speed at which they'll get an organ from a deceased to donor, and this is, of course, the most important metric that improves survival while patients are on the wait list. And lastly, this is one-year graft survival, so the number of patients that are alive with a functioning graft one year after transplant. And to understand this a little bit more, these numbers and these outcome statistics are measured on an 18-month sort of rolling assessment. And you can see, when you look at any center, you can see how many transplants they're doing in one year. So in Mayo Clinic in Rochester, about 114 transplants with nine living donors. And the graft survival data is from a 2.5-year period. This data that I pulled on January 3rd was from January 1st, 2020, to June 30th, 2022. And this looked at survival in 230 patients who were transplanted at our program. These are the other two Mayo Clinic programs, so this is Mayo Clinic Arizona doing about 245 transplants a year, and Mayo Clinic Florida at 144. And you can see that this is a large denominator for these programs. And so when you're looking at graft survival and or patient survival, you can see that when you have a large denominator, these centers are able to take on more risk. I'm going to show you some other centers. This is from the same time period, but now you're looking at programs that are having some outcome problems. So in this program, survival on the wait list is poor. One-year graft survival also poor. This is actually a reasonably-sized center doing 134 transplants a year. This denominator was 276 patients. But you can see that if you're a decision maker at this center and you're already having some outcome trouble, you may be very risk-averse to taking on a high-risk patient for transplantation. I highlighted two other programs that are small, so this is a program doing 18 transplants per year. The denominator for their outcomes is 58. They have really good wait list survival and really good graft survival. But again, when your denominator is 58, you're going to be a little bit careful in the kind of patients you're taking on. Look again at another program, small number of transplants, bad outcomes. This center is going to be, again, pretty risk-averse to taking on high-risk transplant patients in their center because they're already in trouble. And if this continues, they may be under review, and they may lose accreditation. So when you're talking about outcome risk assessment in a transplant program, you can see that this is very individualized to specific transplant centers. Key factors in making the decisions are volume and current outcome assessments. And additional influences that are very important are center experience. This is both surgical and center experience overall. Do you have good multidisciplinary teams that can take on complexity? Are you a living donor program? Data has consistently shown us that the more living donors you do, the better your outcomes. The number is 20. So programs that have done more than 20 programs have better outcomes. More recent data suggests that if you need to at least do five per year to maintain these good outcomes. Do you have multi-organ transplant experience? Are your program accomplished in heart, livers, heart, lungs, lungs, and other organs, et cetera? And specific considerations for certain types of diseases, for example, cholangiocarcinoma is a pretty risky transplant endeavor because these patients have a high risk of recurrence and therefore a high risk of post-transplant mortality. Colorectal cancer metastasis is an emerging area for liver transplant as well. This was a study performed in Europe, and it looked at vast disparity in how patients with high-grade ACLF were being considered for transplantation. So this was looking at patients who presented to the intensive care unit with high-grade ACLF3, and it looks at a couple different groups. Those who presented to the ICU not listed for transplantation, that was the largest number in the study at 318, and also patients who had been previously evaluated and listed prior to ICU admission. They then looked at the number of patients who were listed or not listed, and ultimately those who were transplanted or not. These are the centers, the center data from the centers that were evaluated in Europe. You can see that if you look across the centers, most of the centers are doing a fair number of transplants. But when you look over in the far right column at the number of patients who are being evaluated and ultimately listed for transplantation with ACLF3, you can see a significant disparity. So some centers, for example, this one was listing 70% of their patients with ACLF3. Other centers are listing zero. And this is really not dependent on the program size. So even larger programs are still being very risk-averse in some circumstances. Again, looking at the percentage of patients who were listed for ACLF3 or listed for transplant with ACLF3, you can see that, again, some centers are listing a large number. And again, it's not dependent on the size of the program. So this small program with 81 transplants performed over the study period listed 80% of their ACLF3 patients. This is a larger center with 185 transplants done over the same time period. They listed zero patients for ACLF3. Not surprising. There's statistically significant improvement in survival in patients who were seen and evaluated with ACLF3 at a high-listing center versus a low-listing center. Remember that in anything you look at, when you have advanced grade decompensation, the only thing that's really going to make a long-term difference in your survival is transplantation. In this study, the only thing that was statistically different in the assessment of who was eligible for transplantation and who was not was based on the assessment of illness severity. So between high-listing and low-listing centers, this was the variable that was deemed. This was the only one that reached statistical significance. They agree on things like addiction. They agree on comorbidities. They agree on things like infection. But there's a significant amount of discordance between what is too sick for transplantation. What happens if you transplant a patient with ACLF3? Well, they don't do as well as patients with lower-grade ACLF. But again, this is five-year patient survival in patients transplanted with ACLF3. It's still at almost 70%, which is not bad. Again, when you think back to slide number one, remembering that many of these patients are absolutely not going to survive without transplant, most people would agree that this is an acceptable level of survival post-transplant. It's statistically different than those with lower-grade ACLF. But again, it's not all that bad, considering. So when is a patient too sick for transplant? Well, this might depend on who you ask. So this was a study using the Delphi method, where they asked a group of transplant surgeons, intensivists, and hepatologists what they deemed too risky for transplant. And you can see that overall, most people agree on things like number of organ failures, respiratory failure, circulatory failure, things that are most concerning. But there's some differences between what certain providers deem as too risky. So there were statistical differences in providers who felt that cerebral failure was a barrier to transplantation, with surgeons being much more concerned about this than hepatologists who recognize that encephalopathy is going to go away after transplantation. Interestingly, hepatologists were much more concerned about renal failure than were intensivists. But again, this sort of depends on who you ask. And this, again, I think highlights the importance of a multidisciplinary team to help make really good decisions about when is transplant feasible and when is it too risky in patients with high-grade organ failures. What are some of the tools that can be used pre-transplant to risk stratify patients for poor outcomes after transplant? So an additional study looked at these four variables to arrive with a score in patients who were being evaluated for transplantation with ACLF grade 3, arterial lactate greater than or less than 4, mechanical ventilation, yes or no, with a low PF ratio, age 53, and leukocyte counts. And we can see that if you got a score of greater than 2, outcomes were marginal at best for patients that didn't do well with this. So again, you see things that are sort of recurrent themes in who may be too risky for transplant. Respiratory failure is something that comes up over and over again. Again, in the CLIF Consortium trial, not a single patient was transplanted with high-grade ACLF if they had respiratory failure and a low PF ratio. This was a study that was performed here in the United States, actually, it's a multi-center study looking at ACLF 3 patients transplanted on mechanical ventilation. There was a decreased one-year survival as compared to patients without mechanical ventilation. But again, the overall survival is not unreasonable in this patient population. I think, again, this is important to really have a multidisciplinary team where you're looking at these patients carefully, because not all organ failures are created equal. So let's look at two different patients with respiratory failure. This is a 45-year-old female with PSC-related liver disease, actively listed for transplant, had a PF ratio of less than 200, and presented with progressive respiratory symptoms that had been significantly worse over the last 10 days. Patient was diagnosed with MSSA bacteremia. This is a representative slice from her CT scan, and yes, this is a lung window. You can see there's almost no normal lung parenchyma. In addition, she had evidence of cerebral emboli as well. Would you transplant this patient? I think everybody would agree, absolutely not. But let's contrast this patient also with severe respiratory failure. So this is a 68-year-old female with MASH cirrhosis. She's admitted to the hospital with progressive kidney injury, and because of her kidney injury, was resuscitated aggressively with 25% albumin in the setting of hepatorenal syndrome. No prior history of respiratory disease. Developed an acute onset of respiratory failure with frothy pulmonary edema. The PF ratio was low. Thirty minutes after she gets put in the intensive care unit, she receives an organ offer for transplantation. Would you transplant this patient? The answer for me was yes, we did. We dialyzed her. We got rid of the fluid overload. She did well. She had a short stay in the ICU, went home, and has never been readmitted to the hospital. So both patients with respiratory failure, clearly two striking different presentations. And I think with a thoughtful approach, you can make a rational decision about which one of these patients is safe to transplant and which one may not. Are there absolute contraindications to transplant? Yes, I think there are a few. One of these is severe pulmonary hypertension. If you have portal pulmonary hypertension, there are exception criteria, and these are sort of the numbers that are used to help determine whether you can be transplanted safely. If you have a mean pulmonary artery pressure of less than 35, you can probably proceed to transplant without a lot of difficulty. If your mean pulmonary artery pressure is between 35 and 45, but you have a low PVR, OK to proceed. Between 35 and 45 and your PVR is greater than 240, we would not recommend transplantation. In fact, you no longer can keep your MELD exception if these are your numbers. And Mayo Clinic data again demonstrated in patients who were transplanted with mean pulmonary artery pressures of 50 millimeters of mercury or greater, they had 100% post-transplant mortality rate. Refractory shock, so people in multiple pressors that cannot be weaned off, probably a hard contraindication to transplantation. Probable, we won't transplant people in our center if their EF is less than 45% unless we're considering them for combined heart-liver transplant. Joint ventricular dysfunction, also a relative if not absolute contraindication for transplantation. Post-transplant, livers do not do well if they have significant congestion. Again, relative mechanical ventilation, if you're intubated only for hepatic encephalopathy or if you have something that's clearly reversible, would not be a barrier for us considering transplant. Somebody with severe ARDS, I think you really need to think hard about this. There are certain infections that are absolute contraindications, disseminated fungal infections or a bacterial infection with an uncontrolled source. So for example, bad infective endocarditis, no contraindication or maybe a relative contraindication to those people who have a controlled source of infection. So somebody with PSC and infected bile ducts, no problem. The infection is going to leave with the liver. Bacterial peritonitis, which is not uncommon. We're probably going to consider transplantation in this situation unless it's with a very resistant organism. Lastly, I'll say a couple of words about the role of the intensivist in ACLF3 and transplant. It's my strong opinion that intensivists need to be an integral part of the multidisciplinary team when you're making difficult transplant decisions. Ideally, intensivists can help assess risk, those organ failures which are likely to improve after transplant, cerebral failure due to encephalopathy, that's going to go away after transplantation. Organ failures or complications which are not likely to improve after transplant, severe respiratory failure from something that's not going to easily go away, ARDS, central nervous system issues that are not hepatic encephalopathy, helping clarify that is very important. And I think you can also provide a significant amount of input regarding the overall trajectory to the patient. So if people are on a trajectory of getting better, I think that tells us that we can likely move forward with transplantation. Take home messages, transplantation is the only tool which results in durable, improved long-term outcomes for patients with advanced ACLF. Transplantation is probably underutilized in critically ill ACLF, and we see that in certain studies there's gross disparity in how patients with ACLF3 are treated. The intensivist should be a key member in assisting with difficult transplant decisions in critically ill patients. And I think for you, if you're working in a transplant center, you need to know a little bit about what your transplant center is doing. So if you're a large volume center, you should have expectations that you can take on more risk. Conversely, if you're in a center that's not doing a lot of transplants, this is going to help you maybe guide your team in making good decisions. There's still a lack of consensus on when a transplant patient is too sick to be considered for surgery. Again, it's really guided by what the center is able to do and the center experience. So knowing what that is can help you inform the team. Thank you for your time and attention.

liver transplantation

acute-on-chronic liver failure

transplant eligibility

program risk

multidisciplinary assessment