All right, first of all, thank you for inviting us to come speak on this not-challenging discussion. But we would love to talk a little bit more today about the difficult decision-making in a pediatric acute liver failure. I want to just bring about three clinical cases quickly first to kind of set the stage for what we're talking about in the first clinical case. These are all patients we've seen in the last six years at our hospital, is an 18-year-old male who presented with fever, jaundice, rash, and diarrhea. He had been on medicines that have been implicated in drug-induced liver injury in the past. He takes occasional alcohol, marijuana, and some recent hallucinogenic mushrooms about a month prior to presentation. And he presented with labs that were greatly abnormal, consistent with acute liver failure. His infectious etiology workup was completely negative, autoimmune was negative, and his liver biopsy that he underwent showed massive hepatic necrosis with concern for toxin-induced liver injury. He became more encephalopathic. A CT scan did show mild cerebral edema, and he was urgently listed as status 1A. He did get an organ off for about 24 hours later. The transplant was really relatively uneventful, but post-transplant, within hours, he had a non-reactive right pupil with worsening edema on CT imaging. He had an ICP monitor placed. The initial ICP was actually greater than 40, and despite many measures, he ended up having uncontrolled ICP elevation. And he had care withdrawn eventually, despite the fact that the liver was in full recovery. In the second clinical case that we saw, about a year after this first case, we had a 15-month-old female who was post-virus, who had jaundice and vomiting, no medicine exposure, no family history of any note. She also was quite jaundiced, had elevated labs, elevated INR. She had labs concerning for autoimmune disease, and was started on high-dose steroids. But despite this, she had worsening mental status. She was intubated to protect her airway. And we quickly consulted neurosurgery, and had an ICP monitor placed for intensive intracranial hypertension management. And she actually was cooled as well, and had CRRT. She was listed as status 1A, and had an uneventful transplant. Her ICP monitor stayed in for about two weeks post-transplant. She had close neurologic monitoring, and eventually full recovery, and has done quite well five years now. And the last case I want to present was happened this past summer, where a two-year-old female presented with jaundice, palmar rash, and a strong family history of autoimmune disease, no real other medicines of note. She was jaundiced, elevated liver numbers consistent with acute liver failure. She was positive for rhino-NRO and adenovirus, and her liver biopsy was kind of a nonspecific liver biopsy. Forty-eight hours after biopsy, she became increasingly encephalopathic, difficult to arouse. She had CT imaging without concern. We transferred her to the ICU. She was listed as a status 1A, and did get an organ offer within 12 hours of being on the list. But we were closely, hour by hour, monitoring her neurologic status, and she showed us a mild improvement. So we continued to watch her for the next eight to 12 hours, and we decided to hold off and not proceed with transplant. And now she's three months later and doing quite well. So these three cases show you that there is this wide spectrum of disease outcomes in a pediatric acute liver failure with and without transplant. I argue the first case probably would have passed away even without transplant, and might have actually bled in his brain prior to us undergoing transplant. But anyhow, you either spontaneously recover with your native liver, you die, or you have transplant. And these patients are continuously moving targets, and really time is of the essence. So these are the things, as we're sitting in the ICU, staring at these patients, discussing these patients, phoning our friends at other institutions, that we're trying to make these decisions in the moment. So I wanted to briefly review with you, because it's the basis of the talk, the PALF study group criteria for pediatric acute liver failure. And that is that there is no evidence of chronic liver disease at presentation. The evidence of liver dysfunction happens within eight weeks of symptom onset. And there's an uncorregulated coagulopathy, even with vitamin K administration. The INR is greater than 1.5 in patients with encephalopathy, or greater than two without encephalopathy. Most of these patients are listed as status 1A. We talked a little bit earlier on acute and chronic liver disease, and those patients are listed as status 1B. But the majority are listed as status 1A, because they have all the factors that meet the criteria for pediatric acute liver failure. So Sahil Kulkarni, who's now currently at St. Louis Children's Hospital, when this analysis was done was at Miami, took a look through the PHIS database at patients who presented with the diagnosis of pediatric acute liver failure in the pretransplant era and the post-transplant era, and looked at the rates of recovery with spontaneous native liver recovery, death, or liver transplantation. So pre-liver transplant, it was very clear, the majority of patients did die when they came in with the diagnosis of pediatric acute liver failure. Post-liver transplant, being available for us, you saw a great increase in the first decade post-liver transplant, showing us that many patients were transplanted for acute liver failure, maybe some that didn't exactly need it at that time. But the death rate has fallen over the decades from 28% to 13% to 4.6% in the four years between 2008 and 2012. The amount of patients surviving with their native liver has also increased over time as well. However, if you look at the SRTR database, in the last 10 years, there really wasn't a significant change of the percentage of patients being listed for pediatric acute liver failure. About 10% to 11% are listed over those 10 years in two different time periods, but 10 years apart. We do know that there is an increasing percentage of patients being listed as status 1A or B, more with a MEL-PEL greater than 35. For a variety of reasons, there are more patients being listed for hepatoblastoma and metabolic, which can account for the status 1B, but also these patients are getting sicker or being listed as sicker patients over time. So I like to look at things like an algorithm and decision-making, and so I created this algorithm for us to kind of go through and walk through over time. So a patient presents to us in the ICU or in the pediatric world, this ward who's previously healthy and just presents with liver failure with the definition I previously told you about. They either spontaneously recover, are listed for liver transplant, or die. Those patients who are listed for liver transplant either are removed from the list because they have spontaneous recovery, are transplanted, or they're died or too sick to be transplanted. And then ultimately, what we're trying to hope for is the best patient and graft outcomes in our patient population. There are two decision points that I think are appropriate to discuss. One is the decision to list, and one is the decision to transplant. And these are very intertwined. I'm going to try to attack the decision to list, and I'm going to have Dr. Doyle work on the decision to transplant during this talk today. So the decision to list, I think that there are some factors that are really important for us to kind of prognosticate here. One is determining the etiology to help with prognosis and also possible therapy for these patients. Two is to assemble your multidisciplinary acute liver failure team to help you over time determine which patients would be the ones best to transplant for the best outcomes. And then also, are there prognostic indicators that help us to predict outcome? So the PALF study group, which is a group of patients that were accumulated over 15 years in about 25 centers in the UK, Canada, and the US, we were part of that group. And they accumulated in the total over 1,000 patients. This is a pie chart showing the final diagnosis of those patients. The large majority are still in the indeterminate category, about 41%. Following that, you see the Tylenol patients who had overdose, metabolic disease, viral disease, and then smaller percentages beyond that. We do have some specific contraindications to transplant. However, these have a little bit of wiggle room in them as well. So severe multisystem mitochondrial disease, not limited to the liver alone, is a contraindication to transplant. Uncontrolled sepsis, especially fungal sepsis, is a contraindication. The hematologic malignancy and irreversible cerebral edema is also a contraindication. But this indeterminate patient population is one that's really interesting because they are more at risk for needing a liver transplant over time. So what was really interesting to see in the PALF study group is that over the time period of 15 years in the different iterations, so there were three phases, P1 and P2, or Phase 1 and Phase 2, and P3 is the last iteration of the patient population through the PALF study group. And over time, using age-specific diagnostic protocols, we were able to reduce the amount of patients that were labeled in this indeterminate, this blue bar group, had gotten smaller over time, which is very important because we just... Having a diagnosis gives you a better control of what may happen with that patient and helps you determine how that patient may do over time. This is the example of the age-specific diagnostic protocols that were used. From this graph, we actually made our own EPIC protocols that we now have, which just self-populate for the age groups. And so you pull up the acute liver failure EPIC list, and our pediatric residents and ICU fellows are able to see what we would typically test for, and they can specifically choose and un-choose those options, and it really has helped over the years. We talked a little bit earlier, actually the first talk of the day was wonderful, about biopsies in pediatric patients with liver failure and what that helps us do. We know from Dr. Chapin and Dr. Alonzo that this actually is very safe and feasible for us to do in our pediatric population with liver failure, and useful for some patients that don't have a diagnosis based on the serum testing and the urine testing that we can do. The transjugular is probably the safest approach in the elevated INR with an outpatient with that. However, most of our IR docs require our patients to have an INR less than two, so we're typically running FFP during a procedure to help them with that. It helps with indeterminate patient population, and you heard earlier today that this dense CD8 positive T cell population that we see on liver biopsies is likely a marker of immune dysregulation and will likely be helpful in the future with maybe some immune modulator therapy if we can use that to help us potentially even treat these patients or treat them differently. There are different prognostic scoring systems that have been used in looking at liver failure patients, especially in the adult population. These have been tried to be utilized in the PALF patient population. None of them have been ideal, and I think a lot of that is because there's an evolving nature of pediatric acute liver failure. So a lot of these scores are used in that time point, your PELD, your MELD, your King's College criteria, the liver injury units, but this is an evolving process that has its ebbs and flows over the first seven to 21 days. There are some specific things like the soluble IL-2 receptor, and if it's very elevated, it's associated with a poor prognosis, either death or transplant. But in the moment, these scoring systems have not been very helpful. On the right, you see the ICU scoring systems that have also been used for looking at mortality and morbidity in the pediatric ICUs and the adult ICUs. But none have been very, very helpful in PALF patients in determining who would benefit most from transplant, which is what we're trying to do. The Pediatric Acute Liver Failure Study Group did use a specific scoring modality trying to look at the patients with indeterminate PALF, and is there a way of prognosticating by putting them into buckets and putting them into subgroups over the days and looking over the first seven days of presentation how that course evolves. So they used something called the growth mixture modeling using an INR, a total bilirubin, and the presence or absence of hepatic encephalopathy and how severe it was. And they divided these patients into five subgroups based on their daily scores of each of these three models. And they were able to divide them pretty clearly into these five subgroups. I highlighted subgroup one and subgroup five, which are the most distinct, of course, but in subgroup one, you can see that the majority of patients did not have either death or liver transplant by 21 days post-enrollment or post-presentation, where the majority of patients in subgroup five did. And so by putting a participant that you're seeing or a patient that you're seeing in the ICU using a scoring modality and how it changes over time, you can maybe at least predict how many would be alive or dead by 21 days or seven days, which may be helpful for prognostication. But the big thing that I want to mention before handing the baton to Dr. Doyle is that really in the ICU, it takes a multidisciplinary team effort to assess and care for the patient with liver failure. It takes your acute liver failure team that you assemble in the ICU with the hepatologist, the transplant surgeon, your intensivist, but it also takes your transplant team and getting them involved sooner rather than later to think about this patient and how we can best treat this patient. I'm going to hand the story over now to Dr. Doyle. Jen, it's fine if you stay up here because we'll have questions afterwards. Oh, sure. Thank you, Dr. Stoll. So I'm just going to talk a little bit more about looking at the neurologic outcomes, how sick is too sick, and what are the other possibilities and alternatives. So we all strongly believe that hepatic encephalopathy monitoring is one of the most important things. We use two scoring systems, one for infants and one for older children. And it's really a paramount responsibility to the team looking after the patients that they scrutinize these scores on a daily basis, if not more frequently. We certainly consider intubation of the patients when they're close to, when they're in stage two or grade two, and obviously when they go into stage three. And this was looked at by the PALS study group also. And so the graph here on the left-hand side of the slide has three groups, and the first group are the patients who had no encephalopathy ever during their course or during the first seven days of enrollment. The second group were patients who developed hepatic encephalopathy during the first seven days of enrollment, and group three were the ones who presented with hepatic encephalopathy. And what we saw from the overall study was that patients who have grade three or grade four hepatic encephalopathy do worse, and in addition, those who progress also are associated with higher mortality. And what's also interesting about this graph is if you look at group three, there are quite a number of patients, about 25 percent of the patients who actually recover despite the fact that they have, that they present with hepatic encephalopathy, but yet they of course have the highest mortality. And then if you look at group one, you can see that while the majority of patients do spontaneously recover, the red bars is the patients who die, so that there are patients who are dying who have never had hepatic encephalopathy. So we can't be, and despite that, listing for transplant in the United States currently requires hepatic encephalopathy as a factor. So we have to keep, we can't scrutinize these patients enough. And this is really hard. This is really, decision-making is really hard. Listing the patient is one thing. We can list the patients, you know, we could list all the patients, but really the decision to transplant is enormously stressful for the whole team, and you know, like we do at our center, load the boat, bring everybody into the decision-making process, because nobody should have to bear the responsibility or the consequences of making the wrong decision. So one of the things that we certainly use, and have used more frequently in our last three cases is ICP monitoring, and we heard mention of it earlier today, and certainly one of the things we worry about is bleeding. But it seems in this study from memory, when it's published, or when it's used, the risk of bleeding is pretty low, and the consequences of even a small bleed are also pretty limited. So some of these other really nice non-invasive measures have also been advocated for. They're definitely not as accurate yet as the more invasive ICP monitoring, but things such as intracranial Doppler was mentioned earlier, and also optic nerve ultrasound definitely have a utility, and of course are much easier to perform in patients who are awake. So how sick is too sick for transplant? Well, we again don't have any criteria. Certainly patients who have active uncontrolled infection and patients who have multisystem organ failure, we're not going to transplant them, it's too late. But patients who have neurocognitive difficulties are the most challenging, and I think once they're intubated and you're managing their ICP, I think deciding when we can't transplant is incredibly difficult, and again, we use our neurosurgical and our neurology colleagues to really help us when we're in this situation. However, the whole picture is a little better. I think when we look at the phase one, two, and three of the PALF study, which is the graph on the left-hand side, we see that we're listing in the gray box less patients, and we're transplanting less patients. So overall, we're doing something right with more patients spontaneously recovering. We put together this graph based on the data from that, looking at the factors that are more likely to lead you to listing, and then most likely to transplant, and so you have a higher chance of being listed if you're male, if you have an indeterminate diagnosis, if you have hepatic encephalopathy, if you're on a ventilator, and if you're on pressors. And that's the blue bar in the graph here, compared to the orange bar, which is not listed. This was a study done by one of our hepatologists and presented here a couple of years ago, and he looked at patients who were listed with acute liver failure on the UNOS wait list, and he showed that if you look in the middle bar on day five, that 50% of the patients at this stage were transplanted, but also of the ones who died, 50% of them had died by day five. The majority of patients had been transplanted by day 10. We heard a little bit about auxiliary liver transplant in the last talk, but I'll just mention a couple of sort of alternatives. It's not really alternatives, because you're still looking at major invasive procedure for the patient, but living donor is certainly a very useful tool for these patients. It's immediately available, and if you decide that you need to transplant, you don't have to worry and stress about waiting on the list for a suitable organ. We can work up a living donor within a 12-hour period, as can any other centre, and it allows the liver to be immediately available. And certainly, studies that have been done looking at living donor show equivocal results to orthotopic liver transplant for this disease, both in adults and children. Alt- or heterotopic auxiliary transplant was sort of initially thought of many years ago, and this is where a piece of a liver would have been taken from a donor and put in heterotopically, so in a different place, usually beneath the left lateral section and sewn onto the cava. But the idea was that you, like auxiliary partial OLT, you'd have a piece of functioning liver, and you'd be able to withdraw immunosuppression. What this has morphed into is this auxiliary partial orthotopic liver transplant, which we just heard about. The nice thing about it is that you can wean off the immunosuppression, but it is associated with complications such as abscess infection and hepatic arterial thrombosis. Having said that, it's more popular in Europe, but it still only comprises of about 2% of all transplants for acute liver failure, and in the States, this study from Cornell and Florida combined is probably the only report from the States, and this is just showing the transplanted graft being big, and then a year later, the native liver has taken over. So in conclusion, we say it's monitoring, take it one day at a time, use every available diagnostic strategy you have, utilize your multidisciplinary team, and load the boat. Monitor closely for presence and for progression of hepatic encephalopathy, but be mindful that just because you do not have encephalopathy does not mean that you're protected from death or for needing a transplant. Consider ICP monitoring in your ventilated patients and certainly the less invasive monitorings in the other patients, and take one day at a time. Thank you. So anyone with questions just come forward to the microphone. Maybe as people are getting organized for questions I'll ask a quick one for Dr. Doyle. You talked about ALF patients and we know that many of them do have circulatory failure and are on pressers. What is your threshold for how much presser support you will tolerate when you take a patient into the OR given that you usually have to escalate during the case? I think it's on a case by case basis for sure. I think if the patient is on three pressers and they're increasing and rising, I think we can't take that patient to the operating room. We need to have them better. I certainly think if they're on a low dose of presser, a single presser, or maybe a low dose, we can't take that patient to the operating room. Yes. Go ahead. Samar Ibrahim from Mayo Clinic. I have a quick question for Dr. Anil Dhawan. It's about these encapsulated hepatocytes that are transplanted through intraperitoneal routes. What's the viability of these hepatocytes? Viability means functionality, you're asking? Yes. Are they functional? Yes. So I didn't show the data, but they have urea genesis from ammonia to urea. They have factor VII production, and they have albumin production. And we have other tests of many other subtypes. So functionality, if you're asking, is very high. Depending on what quality cells you encapsulate, it depends on that. So they have a half-life of a week or something like that? Oh, the half-life is long. So we have up to six months. One patient, when we took the out, they were six months already. We didn't retrieve all of them, but some beads we retrieved, they had a viable cell. So they might be also exerting like more systemic beneficial effect in addition to the maintenance of the hepatocyte per se. Thank you for bringing that because that was the additional main factor for us to put MSCs with hepatocytes is that the exosomes that we think are released into the portal circulation go into the liver. So that's an additional advantage, yes. Thank you. Could I add on to the three best ways of constrictors? So we, we means Royal, we means our transplant colleagues, they do hepatectomy, so they make patient anephatic. So then the vessel, so then we have seen ICP dropping and requirement for vasopressin decreasing. You're taking a gamble because you have all... So, a question for Dr. Dhawan. You know, with respect to the hepatocyte transplantation, do you sort of think that this is something which would be a temporary thing like an auxiliary liver transplant, or would you like it to be, you know, instead of a liver transplant, you're going to be using the hepatocyte transplant? So, I know in King's, you know, initially it was the metabolics and so on that this was being used, and have you used it in the acute liver failure setting, I mean, as a temporary thing and the liver has recovered, as you've seen with auxiliaries? Yes, sorry. So, with the time constraint, I didn't elaborate on eight patients. So, all eight patients were listed for liver transplant. They fulfilled the standard criteria, means everybody INR more than four, and other requirements, bilirubin, etc. So, out of those, they have a predicted mortality, according to our criteria, more than 90%. So, predicted mortality 90%, we had a 50% native liver survival. So, that's a huge benefit, one. Second is, we've avoided a transplant in 50%. So, I think deep inside, I believe, when I made a sarcastic comment that we over-transplant, I think with this technology, we will be reducing that number of over-transplantation. Native liver survival will get better, provided they're supported for a few weeks. I think we need a support for a few weeks only. If they need more than that, then the subacute category, then they will definitely need a liver transplantation. And the immunosuppression is similar to… No. So, sorry. So, again, what I said was, because you're coating them with alginate, which is an inert compound, you don't see immune activation. So, you have to do a lot of tests in the lab, immune activation. Indirect, what happens is, surprisingly, that you get an immune down-regulation. So, alginate somehow down-regulates it. And with MSCs, co-culture, we think MSCs already, as you know, immunomodulatory, they will further down-regulate the immune system. So, we do not need immunosuppression. The point was, no immunosuppression. Okay. Cells put into the peritoneal cavity, and they can detoxify and provide a synthetic function. Okay. Thank you. Yeah? Josh Gramatikopoulos from King's. It's a question for Dr. Stravitz. Can I ask, because there are some similarities you described in terms of the clotting parameters between acute liver failure and cirrhosis. So, in terms of the form of Villebrand, the Adam C13, and everything. So, is it, you know, they're so different conditions, but still, you know, the body reacts in the same way. Are we perhaps looking into the wrong elements here, the wrong clues? The comparison of hemostasis and cirrhotics in ALF is probably not exactly what we should be concerned about. It should be the ACLF versus the ALF patients, because stable cirrhotics, apart from having low platelet count, really generally don't have much coagulopathy. So, there really is not very much information about ACLF and hemostasis in ACLF to compare to the ALF. But generally, cirrhotics have fairly normal rebalanced hemostasis, apart from the fact that they have thrombocytopenia. Yep, but they have raised von Villebrand factor. Yes. You know, the Adam C13. It's not usually nearly to the level of a patient with ACLF or ALF. So, patients with cirrhosis may have 150 or 200% von Villebrand factor. As I showed you, the ALF patients often are five- or six-fold elevated compared to normal controls. So, there are a lot of similarities. I don't know that there's enough information to confidently compare and contrast yet, although there are people working on ACLF, which is really the interesting population, especially because the definition of ACLF really involves coagulopathy, too. And I'm not sure that that's a good part of the European definition, but that's the way it is. Thank you. One last question from Dr. Horslund, and then we're going to conclude the session. So, Anil, that's really great work that you've been doing with that. How are these encapsulated cells oxygenated and perfused, especially when you first put them in? Good question. We haven't tested, so we have some lab data that you do not need. And the peritoneal cavity oxygen saturation, what is there, it's enough. So, that's how we found. So, this is from the animal data, but we haven't tested the oxygen gradient. Islet people have done some work, and they showed that there was an oxygen gradient there. But we think it's because of the peritoneal fluid that's there. Whatever oxygen content is there, that's enough to do the work. But I don't have mechanistic data to show it to you. I want to thank our speakers, my co-moderator, Dr. Squires, and the audience for a really great session today. Look forward to posters about ALF that will be presentations and posters that will be presented throughout the meeting. And I'd like to adjourn the session.

pediatric acute liver failure

liver transplants

auxiliary liver transplants

hepatocyte transplantation

hepatic encephalopathy

multidisciplinary teams

ICD monitoring