I would like to welcome everyone back to Part 2 of the Joint Pediatric Liver Disorders and ACLF-SIG Program on the Management of ACLF in Adults and Children. This part will focus on ACLF beyond the kidney and onto transplantation. Our first talk will be by Dr. Desai on the Management of Cardiovascular Complications in ACLF and the Role of Serotic Cardiomyopathy. Good evening, everybody. Thank you for this opportunity to present Management of Cardiovascular Complications of ACLF and particularly the Role of Serotic Cardiomyopathy. I want to thank the ASLD and the moderators for allowing me to happen. I'm Dr. Desai. I work at Baylor College of Medicine, Texas Children's Hospital, and I'm a pediatric intensivist with a keen interest in critical care hepatopathy. The agenda for today is to define serotic cardiomyopathy, introduce this disease in pediatrics, tell you what it means in children, the impact of serotic cardiomyopathy on peritransplant and management in children, then explain somewhat the molecular mechanisms, the data gleaned from animal models and clinical findings, and then discuss some treatment options. So I always start this with a case which I was involved as a fellow, a third-year fellow, and there was a kid with biliary atresia who was listed for transplant. She was in state liver disease. She came to the ICU with gram-negative sepsis and fever and hypertension, and despite giving the appropriate things, the fluids, the inotropes, the child continued to have poor cardiac contractility, low heart rate, and hypertension, and she died within a few hours of survival despite doing everything we know what to do. That baffled us. Our question was, it was quite evident to us, was inappropriate cardiovascular response to endotoxemia led to that patient's death. So the question we had was, did this child have what they called an adult, a serotic cardiomyopathy? That was a question. At the same time, we also wanted to find out, was there something that serotic liver did that restricted the cardiac function of this child? At the same time, in 2005, Dr. Lee and all from Calgary, they met and World Congress came up with a consensus definition on serotic cardiomyopathy, and mind you, it's in adults, and they said it's a chronic cardiac dysfunction in cirrhosis characterized by blunted response to stress, diastolic dysfunction, and electrophysiologic abnormality in absence of other known disease in adults. So this was the other definition. Recently, this is as of 2020, Manny Izzi and his team and the consortium came up with this again, an adult definition, where they modified some of those old 2005 criteria and came up with systolic dysfunction, which were echo findings of global strain and LV ejection fraction, diastolic dysfunction based on TDI images, and certain other supportive criteria where you have abnormal response to inotropes, you prolong QT interval, heavy heart, or serum biomarkers. We wanted to find out, our questions were, does this exist in pediatrics? These were all other definitions. Does it exist in pediatrics is number one. And number two question we had was, can we identify an easy echocardiographic metric to define this disease? So in 2011, Dr. Saul Carpenter was my mentor. He's a ASLD member. He suggested to me to look into biliary atresia as a population. And at that time, we found out that children with biliary atresia listed for transplantation had almost 63% of abnormalities in echocardiography before transplant. And that abnormal echoes were associated with increased length of hospital stay. In fact, if you look here, the ICU hospital and total hospital length of stays were higher than those who had abnormal echoes going into liver transplant surgery. And we also looked at a particular metric called left ventricular mass index. It's just left ventricular mass index with height. And we found out that LVMI actually correlated with all the badness that happened after surgery. We then in 2019 came up with more number of ends with biliary atresia. And we could then conclusively say that patients who had cirrhotic cardiomyopathy going into surgery had increased perioperative mortality, increased adverse events, increased risk of mechanical ventilation and tracheostomy, increased need for dialysis, and increased need for inotropic support and multi-organ dysfunction syndrome. So a bad heart affected the lungs, the kidneys, and overall outcome in the children. We also came up with the metric, which I told you earlier, LVMI, that's left ventricular mass index. LV mass is calculated easily on the echocardiogram. And we divided by height, raised to 2.7. That's how we indexed it to the child. And we found out that higher the LVMI, more the problem with the child post-transplant. If you look here, pre-transplant mortality was higher. Post-transplant mortality was higher if you had a high LVMI. We also found out through statistics that LVMI above 95, that was the optimal cutoff, was a better predictor of perioperative mortality and morbidity than even L-scoring. So we found out that this particular metric might be able to tell us how a child will do surrounding the operative period. We also showed that in children with biliary atresia, there was a gradual increase of LVMI, that the hearts became thicker as you approach transplant. And then they started resolving after transplant. This has been shown in adults too, that cirrhotic cardiomyopathy resolves after transplant. Even in our autopsy findings, when we looked at histology of all the children who died, we found out here that same child whose autopsy had a yellow heart, and we found out that right ventricle and left ventricle both were thickened, if you see here, that thickening in the lower panel. And there was a substantial finding of endomyocardial fibrosis in these children, which was surprising to us. We found out that cirrhotic children had higher weights on autopsy, heart weights, than non-cirrhotic components, all those who died after transplant. We also found out here, which was surprising, that fibrosis was present in the cirrhotic patients, and there was no fibrosis in the non-cirrhotic children with liver failure who died after transplant. So those who were non-cirrhotic did not have any evidence of fibrosis in cardiac autopsy. So there was some correlation between cirrhosis and liver fibrosis and heart fibrosis, at least on autopsy. So our working hypothesis was that cirrhosis leads to certain things that happen in the heart, which, when stressed, stress could be infection, inotropes, a major surgery like liver transplant that leads to cardiac failure. This was our working hypothesis. After data gleaned from in vivo, in vitro, and ex vivo mouse models, we're finding out a lot of things can contribute to cirrhotic cardiomyopathy, channelopathy, your potassium and your calcium channels are abnormal, you have desensitization of beta adrenergic receptors, you have enhanced cannabinoid receptors, you have increased activity of musculinic receptors, and internally, through CAMP mechanisms, you can have abnormal systolic and abnormal diastolic dysfunction. Circulating neuromediators like hemoxygenase, carbon monoxide, nitric oxide, and bile acids, they all can cause and induce cirrhotic cardiomyopathy. We then, you know, what is commonly known as cirrhosis causes malnutrition, inflammation, circulating mediators, total hypertension, all this can cause heart to adapt and fail. Our focus was on bile acids. Why? Because bile acids is one metabolite which can be manipulated or modulated, and maybe we can find a treatment for cirrhotic cardiomyopathy right now. The only treatment for cirrhotic cardiomyopathy is a liver transplant. And ironically, presence of cirrhotic cardiomyopathy gives you bad outcomes after liver transplant. So the treatment itself should be something. So what we thought that we could have a good treatment so that a child is capable of getting a liver and having a good post-operative course. So we focused on bile acids. And the concept we called colicardia, bile acid myocardial interaction as colicardia. And we found out that in an article published in 2018 with my colleague Sai Anand, we actually found out that bile acids can decrease a nuclear receptor called PUC1 alpha, which affects metabolism. And that changed metabolism of the heart. The abnormal metabolism of the heart is what we call colicardia. You remove the bile acids, and in that mouse model, we use cholesterol to decrease the amount of bile acid load. And that replenished the PUC1 alpha, and that caused resolution of cardiomyopathy. So here we found out that modulating bile acids, either by bile acid raisins, bile acid inhibitors, or by actually removing bile acids from the system, you might be able to help the heart and help the cardiovascular damage that happens. So the question is, we did it in mice, but is it even relevant at BestSite? Do we see bile acid myocardial interaction actually while taking care of patients? And this is unpublished. But what we found out is in children with biliary atresia who have high bile acid levels to look that those who have modest amount of increase, and on the right side is those who have marked pathologic elevations, you find that the LVMI, which I was talking about, was higher in those who had bile acid levels above 150 micromolar per liter in their circulating blood. The odds of having abnormal LVMI, if you had bile acid levels above 150 micromolars, was around 17. That's a high odds. We also found out that as bile acids increased, the left ventricular mass increased in children on echocardiography. Also, if you plotted bile acid and LVMI together, we had a good area under the curve suggesting that there was a good correlation between bile acids and left ventricular mass index, suggesting that bile acid concentration in the circulating body of a child can be causing the cardiac problems. And changing the bile acid levels or concentration or modulating it might be beneficial in management. So I'm coming back to the same case of biliary atresia. If that child were to come now in 2021 to our unit in the liver ICU at Texas Children's Hospital, of course, we are going to do supportive care, airway, breathing, circulation, infection control, and nutrition. But in addition, we will do blood purification, which is we will remove all the toxic mediators circulating by using total plasma exchange. We use albumin dialysis in the form of MARS and then CRRT, which is high-flux continuous dialysis. And that is what we call hybrid extracorporeal therapy. The hybrid extracorporeal therapy includes, on your left is the CRRT machine. In the center is the MARS machine. And on the right is the total plasma exchange machine. This together, what happens is MARS, what it does is it takes blood from the child. It first clears off the water-bound toxins, then goes to charcoal, clears off the protein-bound toxins, and then recharges the albumin. That's why it's called the recirculation system. This takes away the water-soluble and the protein-bound toxins, ammonia, the bile acids, everything. And we have found that as more beneficial. Our indications for putting the children on extracorporeal liver support is hepatic encephalopathy, multi-organ failure with liver failure, and need for inotropes and primary or delayed graft non-function. This paper was published by Dr. Arikan and us in Pediatric Critical Care. This is where we described our experience in hybrid extracorporeal therapies. As I said, we do CRRT, we do plasma exchange, and we do albumin-related dialysis all at the same time. We call it hybrid extracorporeal support. And we found out that we reported a cohort of 22. We found out that we had a pretty good success. 77% survived overall, 85% were listed, and 100% had 90-day post-transplant survival. So in conclusion, cirrhotic cardiomyopathy is also a pediatric disease. Thick and heavy heart is there at baseline. Stress leads to heart failure and multi-organ dysfunction. It resolves after liver transplant, but ironically, it also impairs outcomes after liver transplant. Bile acids could be potential targets for manipulation and treatment, and removing toxic vasodilators through any mean possible, plasma exchange, albumin dialysis, blood purification may help attenuate cardiovascular collapse. I want to thank the patients, the families, my liver ICU team, and specifically my boss, Dr. Shekhar Demian, Dr. Goss, who is a liver transplant surgeon, Dr. Schneider, who is the chief of GI, and Dr. Leung, who is the chief of pathology. Thank you all. Hello and good afternoon. My name is Eric Liana, and I'm a neurointensivist at Northwestern University in Chicago. I was invited to speak about the neurointensivist's perspective on protecting the brain during ACLS. Here are my disclosures. Since my segment is only 15 minutes, I won't be able to cover the complex pathophysiology of acute brain dysfunction during ACLS. However, I'd like to cover some foundational concepts of brain protection and the practice of neurocritical care as they are relevant to the ACLS population. The dogma that neurologic dysfunction from encephalopathy is completely reversible and without long-term consequences has been challenged in the last 10 to 15 years. In mixed medical and surgical ICU populations, experiencing even moderate encephalopathy is associated with long-lasting cognitive dysfunction and impaired quality of life. The young are not protected from this effect, and some studies suggest that well over a quarter of patients who experience encephalopathy have long-term cognitive dysfunction on par with moderate severity traumatic brain injury, and the dose of encephalopathy predicts greater severity of cognitive dysfunction. Our group recently described that encephalopathy in hospitalized COVID-19 patients was associated with a detrimental impact on functional outcome nearly as ponent as the need for mechanical ventilation. This long-term effect of encephalopathy likely extends to patients with liver disease. Hepatic encephalopathy is associated with increased mortality, and hepatic encephalopathy appears to be a factor in worse cognitive outcome after transplant. Relevant to encephalopathy and liver disease, data from stroke and traumatic brain injury suggest that cerebral edema is a mechanism of secondary brain injury that could contribute to this increased mortality and long-term morbidity. Cerebral edema was first widely recognized as a possibility in ACLF in the late 1990s. Using ICP elevation as the criteria, cerebral edema was felt to be rare in ACLF at about 5%. However, quantitative imaging studies in patients with cirrhosis have suggested that cerebral edema is likely more common. Quantitative water maps have illustrated a consistent increase in white matter and basal ganglia water content corresponding with encephalopathy severity. Quantifying cerebral edema in critically ill patients is challenging and an area in need of further research. However, using serial CT-based volumetric measurements, our group at Northwestern has suggested that cerebral edema evolution and corresponding neurologic exam changes appear typically similar in ALF and ACLF patients. In about two-thirds of our ACLF patients, there was evidence of cerebral edema progression with corresponding neurologic exam deterioration during the first 24 hours of hospitalization. And about one quarter of ACLF patients appeared to be admitted with cerebral edema that improved over the first 24 hours of hospitalization. So, why is elevated ICP a poor means to identify cerebral edema? The Monroe-Kelley Doctrine states that the cranium has a fixed volume composed of brain, blood, cerebral spinal fluid, or CSF, and sometimes pathologic masses. Increased volume of any of those components is accompanied by an increase in pressure. However, the simplified version of the Monroe-Kelley doctrine doesn't address the element of intracranial compliance that we see in practice. As the volume of the intracranial compartments increase, there is an ability to displace CSF from the skull and then an ability to compress vascular structures. These processes act as a reservoir of cerebral compliance that effectively buffers intracranial pressure increases. Once those buffers are exhausted, then we observe exponential increases in intracranial pressure. As a result, intracranial pressure volume curves allow for cerebral edema to develop for quite some time before it can be detected as an increase in intracranial pressure. The resulting low sensitivity of ICP monitoring for cerebral edema is magnified in elderly patients and patients with chronic medical diseases whose compliance curves are right-shifted. The insensitivity of ICP monitoring for the underlying disease severity may help explain why intracranial pressure monitoring has been unable to demonstrate a clear mortality benefit, either in acute liver failure or in traumatic brain injury. This, of course, begs the question of how to best evaluate cerebral edema clinically. Our group at Northwestern feels that a high index of clinical suspicion and detailed serial neurologic exams is likely the most sensitive method available in routine clinical practice. Serial neuroimaging can provide additional guidance. In particularly challenging cases, we apply volumetric assessment to the serial neuroimaging. In traumatic brain injury, the approach of serial neurologic exams and supplemental imaging perform similarly to management with an ICP monitor. There are a variety of additional techniques that have been described to evaluate ICP, but none are a standard of care. Optic nerve sheath ultrasound is a widely discussed option. Unfortunately, a recent NIH funded study in traumatic brain injury suggested that this technique required much more extensive training than is typically available in practice before clinicians are able to make reliable measurements. Furthermore, it seems that the traditional cutoff for elevated ICP of 5.5 millimeters likely is too nonspecific to be clinically useful. Another technique that can be used is transcranial Doppler. In cases of cerebral edema, cerebrovascular resistance can increase as a result of brain compression. This manifests as a high resistance waveform that can be improved with the use of cerebral edema directed therapies. Automated pupillometry to quantify pupil reactivity is likely a useful tool in select patients. However, it's hard to imagine that this technology isn't confounded in cases where sedative exposure is less than judicious. In cases with high suspicion for cerebral edema, brief therapeutic trials of hyperosmolar therapy may provide clarity. These trials are predicated on the notion that increasing serum osmolality acutely will shift water out of the brain and reduce cerebral edema. In the most impressive cases, ALF and ACLF patients can awaken from coma during the course of this trial. Regardless, a positive trial really should have a response that is quantifiable by a change on the Glasgow Coma Scale. I should note that a therapeutic trial of hyperosmolar therapy is not the same as instituting prophylactic hyperosmolar therapy. A recent trial in TBI showed no benefit of prophylactic hyperosmolar therapy in TBI patient outcomes. A study in ACLF patients did demonstrate that hypertonic saline infusion to maintain a serum sodium of 145-155 milliequivalents per liter improved ICP. However, the authors commented that their findings might only apply to those on renal replacement therapy and could be due to the benefit of buffering osmotic shifts related to dialysis. In fact, there's reason to believe that premature institution of hyperosmolar therapy could be detrimental in patients whose edema hasn't progressed to the point of needing relief of brain swelling. The classic medical school teaching is that hyperosmolar therapy requires intact blood-brain barrier. Unfortunately, our understanding of how hyperosmolar therapy actually reduces brain volume is incomplete. The simplest evidence of this comes from animal models demonstrating that hyperosmolar therapy actually disrupts the integrity of the blood-brain barrier. In fact, this is leveraged in neuro-oncology to increase the penetration of chemotherapeutic agents into the brain. Animal models have actually demonstrated increased bilirubin content in the brain after hyperosmolar boluses. Relevant to liver failure, bilirubin can activate brain microglia and contribute to cerebral edema through neuroinflammation. In support of the hypothesis that hyperosmolar therapy could increase exposure of the brain to toxic substances, our group recently reported that elevated hospital admission serum osmolality was an independent and proportionate predictor of encephalopathy severity and liver failure. In neurocritical care, attention to osmolality is a core component of routine practice. This is because when the brain is injured, its ability to respond to stress, including osmotic shifts, is impaired. Acute decline in osmolality is a well-described exacerbating factor for cerebral edema. Our Northwestern group investigated this principle on ALF and ACLF patients. As we would expect from the literature on other ideologies of brain injury, acute reductions in serum osmolality during either ALF or ACLF were both strongly and linearly associated with brain swelling. This osmolality decline was also strongly associated with neurologic exam deterioration. Note that our study measured osmolality and not effective or active osmolites. This is because osmolites that are inactive in the body, because they can freely flow across cell membranes in the muscles and viscera are restricted in their movement across the blood-brain barrier, and therefore become active osmolites for the brain. Outside of sodium, urea is likely the osmolite of most relevance to the liver failure population. Urea must be actively transported across the blood-brain barrier. The impact of rapid urea clearance on brain swelling has been appreciated since the 1960s and is seen most often in the setting of renal replacement therapy. Our cirrhotic patients may be particularly prone to brain swelling exacerbated by urea clearance because chronic uremia down-regulates urine transporters on the blood-brain barrier, while liver failure increases the expression of aquaporin for water channels. The consequences of overlooking inactive versus active osmolality in the ACLF population can be severe. A few years ago, I was urgently paged about this patient who presented with ACLF after a GI bleed and a missed outpatient dialysis session. She was treated with conventional hemodialysis because the primary team felt that as a chronic dialysis patient, she would tolerate a session of conventional dialysis. The patient unfortunately developed an acute brain herniation characterized by bilateral blown pupils after two hours of hemodialysis. Her osmolality had declined 34 milliosms per kilogram due to clearance of urea and unmeasured osmolites in the setting of her renal failure. Volumetric assessments of her serial CT scans demonstrated a 58 milliliter increase in brain volume. While aggressive rescue hyperosmolar therapy reversed the patient's blown pupils, her neurologic exam never returned to her pre-hemodialysis baseline. Subsequent MRI and CT scans demonstrated bilateral, thalamic, and posterior hemisphere infarcts in a pattern described after transcentorial or central herniation, compressing the posterior cerebral arteries and leading to infarction. I think it's important to note that dialysis disequilibrium syndrome can effectively be treated, however. This is an ALF patient who developed herniation after dialysis was used to address fluid overload following liver transplantation. The patient experienced a 54 milliosm per kilogram acute decline in osmolality with a 35 milliliter increase in brain swelling. A very aggressive infusion of hypertonic saline, increased serum osmolality back to his prior baseline and reversed the clinical brain herniation. This patient actually was able to return to part-time work six months later. He had a very good outcome despite having a clinical brain herniation event. Though I've shown you two examples of neurologic deterioration related to acute osmolality decline in the setting of renal replacement therapy, our group published data suggesting that renal replacement therapy performed with attention to osmolality may be able to blunt cerebral edema evolution and contribute to neurologic exam improvement in ALF and ACLF patients. It has become our group's practice to advocate for controlled and gradual reduction in serum osmolality in ALF and ACLF patients in whom we believe there is adequate intracranial compliance. For patients in whom any exacerbation of cerebral edema can be detrimental, we avoid osmolality reduction by providing hypertonic saline if therapies that may affect serum osmolality, like renal replacement therapy or plasmapheresis, are going to be used. Dr. Karvelas has covered renal replacement therapy and liver support devices in detail in another part of this session. From the neuro-intensivist perspective, I believe there is evidence to support these interventions in select patients to reduce the brain's exposure to toxic and inflammatory insults. While mortality advantage is debatable, these technologies may be means to reduce brain injury while trying to bridge patients to liver recovery or transplant. Provided these interventions are implemented with careful attention to complications such as acute osmolar shifts. In my last couple of minutes, I'd like to highlight some high-yield considerations for the encephalopathic liver patient. Nutritional deficiencies such as thiamine deficiency can present as encephalopathy in the critically ill. It appears that ACLF patients are at particular risk for thiamine deficiency. This may be because the liver is the body's main site of thiamine storage, and this thiamine reserve can be depleted in a few days. Incidentally, thiamine deficiency may also have a role in mitochondrial metabolism at rate-limiting steps that are also affected by hyperammonemia. I have a low threshold in my clinical practice for daily thiamine supplementation as a result of this data. ACLF patients are exposed to a wide variety of medications. Medications such as antibiotics, which are usually considered to be benign, may actually be underappreciated contributors to encephalopathy. The most notorious example is probably cefepime-associated encephalopathy, particularly those in renal insufficiency. Lastly, critically ill patients in general appear to be at increased risk for non-convulsive seizures. The frequency of seizures is poorly defined in the critically ill because of methodological limitations of available studies. But some theories suggest the rate may be as high as 30 percent. Furthermore, EEG findings that have classically been interpreted as benign metabolic findings, such as triphasic waves, appear to actually be associated with a 30 percent risk of seizures. I'd like to thank you for the opportunity to provide this brief overview of the neurocritical care perspective on ACLF. Hello from Toronto and good afternoon to you all. I'd like to thank the two SIGs and the ASLD planning committee for the kind invitation and privilege to speak to you today on the topic of ACLF in children. When is it too late for liver transplantation? I have no financial disposals to report. In the next 15 minutes, my learning objectives are here as listed below. We've heard several excellent talks detailing the several definitions and diagnostic criteria of ACLF, which exists by the Asian Pacific Association for the Study of Liver, by EASL, by the North American Consortium for the Study of End-stage Liver Disease and by the Chinese Group on the Study of Severe Hepatitis. The common themes of very applicable children, including chronic liver disease with previously diagnosed cirrhosis, who develop acute hepatic decompensation resulting in liver failure and one or more extra hepatic organ failures that is associated with increased mortality within a period of 28 days and often up to three months from onset. Given the high mortality associated with ACLF, liver transplantation remains an important and critical treatment option. The published literature on ACLF in children is limited. The lack of both pediatric-specific ACLF definitions and validated clinical criteria for use in children certainly contribute to the challenges of data accrual and lack of generalizability. This table shows the first studies on ACLF in children from colleagues in India affirming important findings that ACLF absolutely occurs in children, and mortality rates without liver transplantation is high. However, generalizability was certainly limited due to geographic differences in the childhood conditions studied. The very few patients with atresia or cholestatic liver conditions, which most commonly are the indications for pediatric liver transplant, with instead diagnoses of patient cohorts primarily composed or comprised of Wilson's disease, autoimmune hepatitis, and hepatitis B, as well as a high prevalence of viral hepatitis B precipitating effects for the liver failure. Studies characterizing ACLF in children from the Western world include the study by who retrospectively reviewed ACLF in their single center cohort of 99 children with biliary atresia awaiting liver transplantation at King's College, where they reported the development of ACLF in 20 percent of 20 children. They found VA children who developed ACLF, whilst on the waiting list for liver transplant, have a five times greater pre-transplant mortality compared to those listed VA children who did not develop ACLF. Liver transplantation occurred in over half of the patients with one death, but no additional details on longer-term outcomes. A multi-centered retrospective analysis of 130 children with cirrhosis admitted for GI bleeding and septus in over half in four European ICUs did review that liver transplant occurred in just under a quarter, while still in ICU with no deaths reported. We have heard some American studies, including Dr. Bancusu's careful characterization of 20 listed children at her center in Chicago who developed ACLF. I'll just briefly mention some of two of the large multi-center studies from the UNOS database, one of which reviewed over 11,000 children listed for liver transplantation. Utilizing a modified research definition for PDH and ACLF, we're able to characterize 246 children with the ACLF at the time of listing. Some key findings that they reported was that there was a significant high weightless mortality of 47 percent within 90 days of listing. The one-year patient survival was 87 percent with most of the post-transplant deaths concentrated in the first 30 days. Increasing ACLF severity at transplant corresponded with poor transplant particularly in the first 90 days. Just as children with more organ failure doing worse while listed, the number of organ failures at time of transplant also impacted post-transplant survival. I've reflected the lack of elevated late post-liver transplant mortality with one-year survival being 87 percent. This suggests a relative benefit to early liver transplantation for children with ACLF. Very recently, while attending the split annual meeting in Pittsburgh, Dr. Leslie Matea, one of our presenters in the panel, presented a UNOS study where she characterized over 470 children with ACLF as defined by patients listed as a status 1B. Dr. Matea very kindly shared her slides with me. Basically, her study evaluate the characteristics and outcomes of a high-risk cohort of children identified as status 1B, honing in on those as listed here with a PEL score greater than 25, and evidence of organ failure as manifested here by mechanical ventilation, by dialysis dependency, or by glaucoma scale greater to less than 10 within 24 or 48 hours. What was really interesting is this is a very comparable cohort to what we see in North America, and she chose to contrast the subgroup with other non-ACLF status 1B kids, kids with metabolic conditions, emergencies, as well as children with former liver failure who are listed as a status 1A. The key findings that she found was that these children had the highest post-transplant mortality, including up until three years. It really does allow different hypotheses for this finding about potentially poor pre-liver transplant functional status or severity of illness at the time of liver transplantation, a potential future direction. But what's really, really interesting as well is that these children also have the lowest transplant rate amongst the three groups. These children have the highest pre-transplant mortality and post-transplant mortality, and they also have cumulative organ failure prevalence similar to the dominant liver failure group, which then really brings us to the idea of these children having significant pre-transplant mortality about the challenge that clinicians encounter when trying to ascertain could and would and is liver transplant too late? When I think about this question, I really like to sort of stratify these children into two groups. The first group of being those children that we first meet in trying to assess suitability of liver transplant at the time of transplant candidacy assessment leading to listing. And in this first instance, these children are certainly, we as clinicians certainly have the benefit of listing criteria, clinical practice guidelines, such as this one on the indications for pediatric liver transplant as published in Hepatology back in 2014. And what's really important is that this time there are elements, components of the workup which really strive to try to identify potential contraindications to liver transplant or clinical circumstances where the outcomes for the patient or for the graft would be less than desirable in a setting of limited resources. However, it's in the second instance of actually trying to ascertain a child who was suitable for liver transplantation at listing who can become over the course of waiting, such as an ACLF, too sick and no longer suitable for transplant that this threshold of too late warrants further discussion. And I think it really, this threshold does vary. Indeed, little consensus exists on how a transplant clinician should approach this question, namely on when not to proceed with transplantation in the already listed child who was deemed at the time of being put on the wait list as suitable on meeting indication and certainly lacking contraindications. The threshold of too sick or too late certainly varies by patient, by provider, by program. And as a result of the condition of a transplant patient while the waiting list being so dynamic, this can certainly be a monumental decision often made on a case-by-case approach following some significant precipitating event or decompensating event. And it certainly requires a physician's keen clinical judgment. Now, clinical judgment is a powerful tool in the practice of medicine. However, without a guiding framework, it may leave the clinician vulnerable to factors that are understandably difficult to separate from decision-making, but perhaps should not influence them. And by way of an example, we as transplant clinicians in pediatrics often develop strong bonds with our patients and our caregivers, sometimes the best part of our jobs. However, this does often put us in a challenging position through often frequent follow-up visits necessitated by recurrent admissions, visits to clinic to monitor the child with end-stage liver disease who has recurrent decompensating events may lead to the clinician having empathy that may cloud judgment on what is best for the patient. I wanna really underscore that each condition that raises concerns about suitability for liver transplant surgery in isolation is often not sufficient to overcome the enormous pressure to proceed with liver transplant from the patient, care provider, caregiver, family, or transplant team that accumulates with time on the wait list. And indeed, the reason a child so desperately needs a transplant may be the very reason he or she is too sick to receive it. So how can we develop a strategy for a decision so dynamic and personal as when to say no to a liver transplant for our own patient on the wait list? How does one sum some of the above considerations to determine when a patient has reached that threshold of being too sick for transplant or transplant being too late? Indeed, we have to reflect on some of the concerns of suitability requiring a summation. And we realize the complications of end-stage liver disease physically impacts children in very different ways that may not be reflected by PAL scores. There may be additional chronic comorbidities that contribute to vulnerabilities that may impact post-transplant outcomes. And ultimately, I believe we do need more additional objective tools, particularly in pediatrics, where we're not just simply taking care of little adults, which could better help us have validated assessments of physiologic reserve of our children to weather the storm after transplant surgery, particularly if we may feel as clinicians a subjective feel or an eyeball that a child may have or have evolved to particularly excessive vulnerabilities. I believe that we also need tools that will be able to better help us measure the extent to which extra-pedical morbidities may persist and will impact outcomes. And I'm reminded in ACLF about how the increasing number of organ failures can actually negatively affect post-transplant outcomes. Saying no is hard. And I think the question is that if organs were not such a limited commodity, the question of liver transplant being too late or futile certainly would not be as much of a discussion point warranting a talk like such today. And so I'd like to sort of bring up that rather than creating very specific criteria, Dr. Jennifer Lai, an adult hepatologist at UCSF has proposed a framework for individualized patient-level decision-making as illustrated in this figure. And I think the premise is the decision to proceed with liver transplant should depend less on a patient's risk for weightless mortality, but rather the likelihood that the new liver will reverse the patient's pre-transplant vulnerabilities the longer a patient has been waiting on the wait list on writing a demise. And vulnerability certainly refers to any condition that decreases the zoologic reserve and increases the risk for adverse health outcomes to any acute stressors. And ultimately the goal is that liver transplant will be able to quickly reverse transient responsive conditions. And for our kids, it could be persistent cholestasis, persistent ascites, recurrent GI bleeds, encephalopathy, and really minimize the opportunity that liver transplant will be not able to reverse transplant non-responsiveness. And in children, I think this is far less common given the fact that we have far less extra-hepatic comorbidities, such as heart disease or diabetes, peripheral neuropathy, just by way of example. Ultimately, I believe that we encounter many more patients that are like candidate B, and it's really on our sort of meticulousness in care that we try to minimize the movement of children towards candidate C to make them actually ultimately less desirable and less able to have a good outcome post-liver transplantation. And so towards that end, two tools that have been sort of increasingly mentioned in the adult literature are now opportunities for us in pediatrics. Frenelty, it's a multidimensional construct that represents the end manifestation of derangements of multiple physiologic systems leading to decreased physiologic reserve and increased vulnerability to health stressors. And a lot of work has focused on looking at these five core elements of weakness, wellness, exhaustion, shrinkage, and decreased physical activity, all of which can be objectively measured with adult tools. I'd like to do a quick shadow of that, actually, thanks to a pediatric collaboration, measurements of pediatric frenelty is now feasible with adaptations to pediatric frenelty tools, which I would love to discuss with anyone afterwards. Myself and my colleague, Dr. Benita Kamath, have been part of this sort of effort. The second concept that I'd like to sort of also introduce is the idea of sarcopenia. And certainly sarcopenia or reduced skeletal muscle mass and reduced muscle function is a component of malnutrition. And the presence of sarcopenia has been associated with adverse outcomes widely in adults of serotics, and certainly has been associated more recently after this expert working group opinion of CT assessment is being recommended as a ideal technique in assessing sarcopenia in the serotic adult patient, that there have been pediatric studies that have similarly shown the presence of sarcopenia in children awaiting liver transplantation. One of our panelists for today, Dr. Julia Bosser from Colorado, has recently published that there's higher mortality in children on the wait list identified as sarcopenia. And our own group in Toronto has similarly shown increased comorbidities post-liver transplant of children identified to have sarcopenia while on the transplant waiting list. Ultimately, assessment of sarcopenia is now definitely more easy with the availability of pediatric age and sex-specific growth curves from measuring the total psoas muscle at L3, L4, and L4, L5 that generates a Z score as well as a percentile ranking. So in conclusion, I'd like to say that pediatric acute pancreatic liver failure is certainly not uncommon. With increased pre and post-transplant mortality, we certainly do have significant work to try to address gaps in our knowledge of definitions and validation criteria and through multicentric data from prospective studies. And because of high mortality on the wait list for these children, I believe it really underscores attention to try to guide our liver allocation strategies and try to adopt more novel strategies such as sarcopenia frailty to try to assess for sort of enhanced outcomes other than just peer patient survival, which as pediatricians, we do strive for. I think the final rule of the National Organ Transplant Act has long provided the transplant community with a regulatory framework for organ allocation policies. And I believe that we still have work yet to do to try to systematize an objective, transparent, and reproducible framework approach to facilitate addressing that really challenging question of two-sighted transplant, because certainly we do know that is one of the most difficult decisions that any transplant clinician would have to make, but we undoubtedly owe it to our patients and their families to make this decision more objective, more transparent, and more uniform. I wanna thank everyone for their attention. I really want to sort of particularly highlight how these potential challenging situations in Toronto have certainly been a group and team effort with best clinical judgment actually exceeding and involving a great number of expertise, both locally and beyond. Thank you very much. Good afternoon. I would like to thank the organizers of this meeting for giving me a privilege to present a topic of liver transplantation for acute and chronic liver failure in adults. When is it too late? I have nothing to disclose. I would like to start with this landmark article, the new liver allocation system moving toward evidence-based transplantation policy, the new era in liver allocation in US based on MELD score, and soon we'll be celebrating 20th anniversary of MELD-based allocation. However, and I'm citing, a consensus was reached to cap the MELD score at a maximum of 40 points and give candidates with MELD scores of more than 40 no additional priority. This allows centers to attempt transplantation in candidates who were thought to have a reasonable chance of success despite the extremely high risk, but does not give extra priority above a MELD score of 40 to achieve this. It was thought that MELD more than 40 is likely to represent futility of liver transplantation in such patients, or in other words, it is too late. One of the definition of futility or poor stewardship of limited resources is five years survival below 50%. This slide is actually our recent match run in our DSA in Southern California. As you can see outlined by red box, and this is a constant scenario in our region, there are several MELD 40 patients. On this match run, they all declined, whether it's for being too sick at the moment, of this particular donor, or contemplating other offers. As a matter of fact, it's rather unusual not to see several MELD 40 patients top in the wait list. Obviously, we have no ability to say whether that true MELD score, what is that true MELD score due to MELD capping at 40. This was a retrospective review from our center on short and long-term outcomes in post-transplant survival of patients with MELD 40 or higher. As you see, the meaningful survival of such patients can be accomplished with close to 65% of patients surviving at 10 years. However, the resource utilization was substantial, with nearly 40% of patients remained hospitalized for more than four weeks post-transplant, and 20% of patients were discharged to acute care facility. As expected, the most precipitous drop in survival was during the first year post-transplant. This was a SRTR database analysis where authors look at predictors of survival after liver transplantation in patients with the highest acuity of MELD 40 and above. You can see here the gradual improvement in patient survival throughout the years, and now approaching 87%. This progress is most likely due to increased experience and expertise in managing such patients, timeliness of liver transplant, and overall medical progress. The strongest predictors of death within the first year included patients on mechanical ventilation, prior liver transplant, higher donor age, longer cold ischemia time, higher recipient age, and the nation after cardiac death or DCD donors. This study is the SRTR database analysis comparing weightless mortality and post-transplant outcomes of patients with MELD equal 40 to patients with MELD more than 40. This study demonstrated inequity in organ allocation for patients awaiting liver transplantation with MELD 40 or above. It was shown in this analysis the number of the patients transplanted with MELD more than 40 has increased over the past 15 years. Patients with a MELD more than 40 incrementally had significantly greater weightless mortality than patients with MELD equal 40. There was no difference in survival for patients transplanted with MELD 40 compared to MELD more than 40. And liver transplant conferred a survival benefit as MELD increased above 40. This was the first study that demonstrated the rationale why MELD score should be uncapped to allow equitable distribution of livers to patients most in need. Now going beyond MELD, the new concept of acute and chronic liver failure has been developed in recent years. This concept lists the six important organ or organ system failures, namely liver, coagulation, circulation, respiratory, kidney, and cerebral failures, and provide three grades of ACLF based on the number of organ failures. Although more descriptive and comprehensive, it still lacks the precision of MELD score. And going even farther, we should not ignore cardiac risks, comorbidities, and infectious complications. This was a retrospective study from Single Center underscoring major importance of cardiac risk and age-adjusted Charleston Comorbidity Index that turned out to be even more important than MELD or pre-transplant sepsis. The futility score was created based on mentioned factors that demonstrated its ability to predict less than 50% five-year survival rate. Recipient age, grade four complications, hepatitis C, which is obviously less pertinent nowadays, and then metabolic syndrome were risk factors for failure-free survival. The study concluded that cardiac risk, pre-transplant septic shock, and comorbidities are the most important predictors and can be used for risk stratification in this highest acuity recipients. Frailty has been shown to significantly impact pre- and post-transplant survival of patients with liver cirrhosis. This study is a longitudinal cohort study conducted in two centers. It demonstrated larger prevalence of frailty in patients 65 and older. It also demonstrated the impact of frailty in age on weightless mortality, where older and frail patients were the most at risk of dying on liver weightless. Also, frailty was more important than age in impacting patient mortality. In this SRTR database analysis, the authors studied the factors associated with the survival of patients with a severe acute and chronic liver failure before and after liver transplant. Among patients who died within 30 days of listing for liver transplant, the number of organ failures was an important predictor of short-term survival, with 92 to 98% of patients removed from the waiting list because of death or transplant in the presence of three or more organ failures. In these patients with three or more organ failures, if this patient with three or more organ failures received liver transplant in a timely fashion, 80 to 85% would have survived one year and beyond. Based on this data, patients with cirrhosis and multiple organ failures should be given priority for expedited liver transplant. Observations also suggest that the effect of recent decompensation could be ameliorated by liver transplant, and transplant fertility may not apply to these patients. This analysis supports previously mentioned study of the patients with mild more than 40 and the importance of early liver transplantation in such patients. In graph A, the more organ failures patient have, the less one-year survival was observed. Nevertheless, even in patients with five to six organ failures, higher than 80% one-year post-transplant survival was noticed. In graph B, respiratory and circulatory failures played the most important role in diminishing patient survival. In graph C, patients with combined renal failure and dialysis, life support, and mechanical ventilation had the worst outcome. In this analysis of data from units registry, authors found that high mortality among patients with the ACLF3 on the liver transplant waitlist, even among those with the lower malt sodium scores. Certain patients with the ACLF3 had poor outcomes regardless of malt sodium score. Liver transplantation increases odds of survival for these patients, particularly if performed within 30 days of placement on the waitlist. Mechanical ventilation at the liver transplantation and use of marginal organs were associated with the increased risk of death. Indeed, graph A shows significantly lower post-transplant one-year survival of patients with the ACLF3 on mechanical ventilation compared to non-mechanical ventilation. Graph B shows decreased one-year post-transplant survival with the progression of ACLS grades. Nevertheless, 87% one-year survival of those with the ACLS3 is still observed. Graph C shows impact of donor risk on survival of CLF3 patients on mechanical ventilation with decreased survival of patients with donor risk index higher than 1.7. And graph D shows the importance of early liver transplantation with a decreased survival of ACLF3 patients on mechanical ventilation who receive liver transplant after 30 days. The importance of early transplantation was again emphasized in this study that compared waitlist mortality of patients listed as status 1A and patients with the ACLF grade 3. 14 days waitlist mortality was significantly high in patients with the ACLF3. However, post-transplant survival was comparable in both groups. Lastly, the effect of the clinical course of acute and chronic liver failure prior to liver transplantation on post-transplant survival was analyzed using this SRTR database. Improvement of ACLS3 prior to transplantation improved the probability of one-year post-liver transplant survival from 82 to 88%. Patients aged more than 60 years have a post-liver transplant survival probability of 75% if transplanted with the ACLF3. This post-liver transplant survival probability rises to 83% if patients were transplanted with the ACLF0 to 2. This study underscores the importance of aggressive management of patients with the ACLF3 with all the efforts directed at downgrading the severity of ACLF. This slide is the summary of consensus conference by multidisciplinary panel of 35 international experts that included surgeons, intensivists, and hepatologists whose task was to determine when critically ill a cirrhotic patient is too sick to transplant. In their opinion, the number of organ failures was most important in determining the acuity of the patients, while mouse score was the least important. Additional failures, called metabolic failure, as determined by lactate level, was added to other six failures previously delineated by ACLF concept. Three organ failures deemed most important by majority of the panel were respiratory, circulatory, and metabolic. Consensus was reached to consider PAO2 to FiO2 ratio less than 150, or norepinephrine support more than one micrograms per kilogram per hour, or arterial lactate more than nine millimole per liter as the possible threshold to decline or postpone liver transplant in ACLF3 ICU hospitalized patients with a clinical frailty scale less than seven. The decision algorithm depicted were summarized, depicted here summarized expert opinion. Although not commonly performed in the Western world, leaving donor liver transplantation in patients with ACLS, including ACLF3, can be done with a reasonable outcome, especially when cadaveric liver transplantation is not available. This slide summarizes the organ shortage in the US. In 2020, 84 cadaveric liver transplants were performed, 500 leaving donor liver transplants were done. The same year, 2,300 patients died waiting for liver transplant. In the US, annually, we are short of 2,300 liver grafts. Further modification of cadaveric liver allocation is unlikely to mitigate the organ shortage. SRTR focus on graft survival is likely to diminish center aggressiveness towards the marginal organs, and leaving donor liver transplantation is the only reasonable solution to organ shortage. So what is a transplant center perspective? There are three metrics on the front of each center, survival on the wait list, getting deceased donor liver transplant faster than one year liver survival. So which center is the best? About four centers shown. In my opinion, it has to be a better way to determine the quality of the program by looking at overall patient survival based on intention to treat that would reflect both the quality of the pre-transplant care, aggressiveness towards the transplant, and quality of post-transplant care. Futility is poorly defined and remain mainly subjective. Futility is a moving target dependent on center SRTR standing. Outcomes with MELD-40, ACL-3, and the organ failure 5-6 are acceptable. There is a significant evidence to uncap MELD score. Patient optimization is critical. Timing of transplantation is critical. Center experience is important. Financial burden may be a factor in defining futility, and leaving donor liver transplantation may be solution in offload organ demand. Thank you for your attention. Hi, everyone. It's a pleasure to welcome you to the final portion of the part two of the combined ACLF-Pediatric SIG program today. This is, once again, an interactive session where we have hepatology fellows and critical care fellows presenting challenging cases on the PEDS and the adult side to stimulate some discussion with our panelists. So our first case will be presented by Dr. Hirsh Traviti, who's a transplant hepatology fellow at Beth Israel Medical Center in Boston, Massachusetts. So this is a 36-year-old female who has a past medical history of type 2 diabetes, hypertension, and alcohol use disorder. She presents with jaundice, ascites, and volume overload, and she was diagnosed with her first episode of acute alcohol-associated hepatitis. Her initial vital signs were overall unremarkable other than a mild tachycardia with her heart rate in the 90s. Her pertinent physical examination findings were significant for jaundice, moderate ascites, and mild asterixis, but she was alert and oriented times 3, however slow to respond. She did have a 2-plus pitting fetal edema as well. Her initial workup showed a leukocytosis with a white count of 14 with neutrophilic predominance. She had a mild anemia with a hemoglobin of 10 that was macrocytic in nature with an MCV of 113. She was thrombocytopenic with platelets of 38. She was hyponatremic with a low sodium of 128 and a mild AKI, the creatinine of 1.6. Her liver chemistries were significant for elevated AST and ALT at 139 and 55 respectively. She also had an elevated bilirubin at 22 and a severe coagulopathy with an INR of 5.2. Her mild sodium score at presentation was severe at 41. Her Madry's discriminant function was also elevated at 99.4, indicating a severe episode of acute alcohol-associated hepatitis. She underwent an ultrasound with Doppler that showed cirrhosis, patent portal vein, splenomegaly with ascites, and a recanalized umbilical vein suggesting portal hypertension. She had an infectious workup that was negative in terms of her diagnostic paracentesis as well as her blood and urine cultures, which were also unremarkable. As her course continued, she was initiated for a liver transplant evaluation based on our hospital's acute alcohol-associated hepatitis pathway. However, she then developed her first bout of clinical deterioration where she developed severe uterine bleeding requiring aggressive resuscitation. She then went on to develop progressive encephalopathy and respiratory compromise, requiring ICU level of care with intubation and mechanical ventilation. She developed hypovolemic shock requiring the initiation of vasopressor support and progressive renal failure from acute tubular necrosis, prompting the initiation of continuous veno-venous hemofiltration. However, her bleeding had ceased after she underwent a uterine artery embolization, and this allowed her vasopressor support to be weaned, and eventually she was extubated. Additionally, her CBVH was transitioned to intermittent hemodialysis. At this point, her transplant evaluation was complete, and the patient was then listed for liver transplantation. As the course continues, over the next several days, she, however, developed a second bout of clinical deterioration where she developed recurrent bleeding. She developed an enterococcus bacteremia, and again, a shock ensued. She had pulmonary edema, requiring the reinitiation of vasopressors and reintubation with mechanical ventilation. She developed progressive renal decline, requiring restarting of her CBVH as well. At this point in time, her CLIF-C ACLF score was elevated at 71 points, indicating a 93% probability of death at 1 month. Her APOSL score was also high at 13, suggestive of ACLF grade 3. In summary, this is a 36-year-old female with a history of alcohol use disorder who comes in with her first bout of alcohol-associated hepatitis in the background of cirrhosis and portal hypertension. She goes on to develop hemorrhagic and septic shock, complicated by multi-organ failure. The questions that I pose to the panelists or discussion include one, would this patient benefit from liver transplantation? Two, which vasopressor-dependent patients are acceptable candidates for transplantation? Three, does the degree of support required influence this decision? And four, does this change for patients listed for simultaneous liver and kidney transplantation? Thank you. Thank you so much, Dr. Trivedi, for that presentation. I would next like to introduce Dr. Leslie Mattia, who is currently a Pediatric Critical Care Fellow at the Children's Hospital of Philadelphia, and she will be presenting our pediatric case for discussion. Thank you, Anna. This is a case of a five-month-old girl with syndromic biliary atresia consisting of an interrupted IVC with azygous continuation, midline liver, polysplenia, and malrotation. She underwent a PASI, as well as a LADS procedure at three weeks of life, and received a standard course of steroids postoperatively, and was discharged home on prophylactic antibiotics. At four months of life, she was admitted with concerns for PASI failure, including coagulopathy and hyperbilirubinemia. Her presenting symptoms at admission were loose stools, vomiting, and irritability for four days, with fever for one day. Vital signs at presentation were remarkable for low-grade fever, tachycardia, preserved blood pressure, tachypnea, and mild hypoxemia in room air. Significant lab findings upon admission included leukocytosis, anemia, and thrombocytopenia on her CBC. Inflammatory markers were also elevated, raising concern for active infection. She also had coagulopathy with an INR of 3.2. Basic chemistry yielded normal sodium and renal function. Her liver function panel was remarkable for hypoalbuminemia at 2.4, hyperbilirubinemia to 24.4, and significantly elevated transaminases, GGT, and pneumonia. I'll now review her hospital course by system prior to being listed for liver transplant. Cardiovascularly, she was initially resuscitated with crystalloid and then required a norepinephrine infusion to maintain blood pressures and adequate perfusion. An echo done on hospital day three showed hyperdynamic function with dilated atria, left being worse than the right, with left-to-right shunting at her PFO. This was initially thought to be due to volume overload. However, echo repeated on day nine with agitated spleen, showed rapid return of contrast to the left atrium concerning for hepatopulmonary syndrome, which was not definitively confirmed on CT angio. From a respiratory perspective, she was admitted initially on low flow, but rapidly progressed to requiring non-invasive positive pressure ventilation with generous FiO2s. From a liver and GI standpoint, she exhibited mild malnutrition upon admission and was started on nasoduodenal feeds. Abdominal ultrasound obtained on hospital day one showed heterogeneous echo texture of the liver concerning for developing cirrhosis with blunted venous waveforms. Transplant evaluation was done on hospital day two. From a hematologic perspective, she required intermittent blood product administration, including PRDCs and FFPs. Renally, she had adequate urine output and was given intermittent diuretics in the setting of her total body volume overload, particularly after blood product transfusion. Neurologically, she was started on rifampin and lactulose for hyperammonemia and grade two encephalopathy. And given concern for infection, she was started on broad spectrum antimicrobials upon admission, but these were discontinued when nothing grew from cultures. I'll now review her hospital course post-listing for liver transplant, as well as critical points in decision-making. She was listed for transplant on hospital day 10 after workup with a PELD score of 43. The next day, she developed an acute respiratory decompensation with refractory hypoxemia leading to intubation. She was then upgraded to status 1B given these events. Two days later, a deceased donor liver became available. However, the offer was rejected due to size mismatch of the left lateral segment. The next day, she developed a tense and distended abdomen concerning for abdominal compartment syndrome. Outside abdominal ultrasound revealed intussusception and pneumatosis. Given her coagulopathy and high surgical risk, the decision was made to maximize medical management and forego surgical intervention at this time. She continued to worsen the following day with refractory hypoxemia, hypotension, and oliguria, requiring significant escalation in her vasoactives and ventilator settings. The decision was made to pursue a bedside laparotomy where 60 centimeters of ischemic bowel were resected and stool and ascites were washed out of the peritoneum. Her bowel was left in a silo for decompression after this procedure. After these events, she experienced a couple of days of stability and was able to lean down on her vasoactives and ventilator. She underwent abdominal washout, ileostomy creation, and partial abdominal closure on day 17. Her oliguria worsened despite a Lasix infusion, so a dialysis catheter was placed and continuous renal replacement therapy was initiated. Over the ensuing days, her coagulopathy markedly worsened, requiring blood product administration, PRDCs, platelets, FFP, and cryoprecipitate. She underwent full abdominal closure and developed frank bleeding from her JP drain, was reoperated on to try to localize a source, which was unsuccessful. She was then started on an FFP infusion to achieve an INR goal of less than two. She continued to have refractory bleeding, requiring upwards of one and a half to two liters of blood products transfused per day. Hematology recommended Factor VII and Amicar to treat her coagulopathy. She also developed refractory hypoxemia and was started on inhaled nitric oxide. Her abdominal distension and liver function tests continued to worsen. She underwent a right upper quadrant ultrasound, which demonstrated no flow through the portal vein on day 22 of admission. Her abdomen was washed out and a wound vac was placed to try to decrease her intra-abdominal pressure and promote portal flow. Despite these interventions, repeat ultrasound the following day continued to demonstrate no portal flow, thus the patient was delisted and transitioned to comfort care. A DNR order was placed and she expired the following day. After reviewing the critical portions of this case, there are a few questions I would like the panel to address. As multi-organ failure progresses, what factors would make a patient no longer an appropriate candidate for liver transplant? When is a patient just too sick? Should the pediatric liver transplant community consider specific criteria for futility of transplant in children with ACLF? How and when should delisting or transition status VII occur in ACLF? And finally, how do you approach acute surgical interventions and weigh risks and benefits in a patient with ACLF? And how should coagulopathy be managed in ACLF? Thank you so much. I'd like to take a moment and thank all of the speakers and the fellows who participated in today's session on the management of ACLF in children and adults. We had a wonderful discussion over the course of the last several hours and learned about ACLF in children, as well as in adults, and new areas in terms of management and defining this condition in this population. I'd like to thank all of the fellows as well, and the panelists who participated in the case discussions. And I hope that everybody enjoyed these sessions as much as we did. Thank you so much. last two cases, which are both very interesting and challenging. I'll just start briefly with the adult case, which was the unfortunate young lady with the new diagnosis of alcoholic hepatitis that also developed uterine bleeding precipitating ACLF. So this is kind of a general question, would this patient benefit from liver transplantation? Maybe Uri, I'll start with you. Well, thank you for the opportunity to participate in the session. Yeah, absolutely, yes, she would benefit from a liver transplant, just based on the numbers that presented and her risk of dying in the short term, it's all approaching 100%. So the alternative would be mortality. Yeah, I think, and I think the tough one here and some of the data you presented is very interesting, is that while the, you know, the mortality on the wait list is very high, obviously, there's this particular that you know, data, there's kind of a select population of people with, for example, ACLF3 or five or six organ failures that may do okay with liver transplant. And this is really kind of the hard part. And it's probably not every, for example, it's not going to be a 65 year old with five or six organ failures, but somebody like this with five or six organ failures, but somebody like this who's 37, assuming that you've got the runway to get it through a transplant may actually benefit. Would you agree? Yeah, absolutely. She's young, although it's acute alcoholic hepatitis, provided that she passes the guidelines and the special institutional guidelines, she would absolutely benefit from transplant. The challenge is it's a timeliness of transplant has been shown that if you can transplant those patients within 30 days, you can reap maximum benefit. Unfortunately, it's not always possible and especially, and again, it's region dependent. It's not uncommon, let's say in our region to have 10 patients with mouth 40 waiting on the organ and I'm pretty sure this lady will be mouth 40 and will be among those 10 patients awaiting transplantation. So that's the biggest challenge is the timing of organ transplant. And number two, well, if you have a program that transplant only these patients, it's unsustainable. So if you have 100 patients that have a transplant coming from home, they have excellent outcome. And you have one patient that comes like this, of course, you would probably give this patient a possibility to receive the transplant given her age, and given your excellent outcomes and excellent statistics, and this won't harm the programmatic appearance, I mean, the appearance on the SRTR. But if that's the type of the patient you do all the time, you have to be careful so you don't sink the program based on your good intentions. So I guess I'll kind of tie it into the second question, because I think questions two and three, we can kind of discuss together. And the data you showed also that's very interesting is that probably of all the organ failures, we know that if you truly have respiratory failure, and I don't mean that you're just on a ventilator, because there are patients that are intubated for hepatic encephalopathy, and they can be on 30% oxygen. It's really the patient with lung injury. And as you kind of mentioned, we had that Delphi panel of 35 people with the paper and transplantation trying to come up with we know that futility criteria are futile, as it were, it's because there's so many moving parts and so many biases in studies, because they're obviously we can't do a randomized transplant versus no transplant paper. But I think a couple of things that come up, and maybe you can comment on this too, is, you know, for our group, for example, you know, part of this is, do you have enough runway to get through the OR for the transplant? So if somebody is on an FiO2 of 30%, you can probably get them through a transplant, where obviously, if they're on 70%, or they've got significant lung injury, now you've got to lie them down for an operation for seven or eight hours, it might be very complicated, that's probably difficult. If you're on, you know, low doses of pressors, like 0.15 mikes per kilo per minute of norepinephrine, the anesthesiologist has runway, but obviously, if you're on 0.5, that's a no-go. What do you think about things like that? I 100% agree. It's difficult to look at the respiratory failure and what exactly it means. It can be airway protection of patient with a major encephalopathy or cerebral failure. It can be fluid overload that can be managed successfully with a CRT, or it can be aspiration or multifocal pneumonia. Those three things will probably have different prognostic factors. So, if you transplant somebody with a multifocal pneumonia or ARDS from aspiration and acute phase, the mortality will be probably very high. If you're in a van for airway protection, it's probably okay. So, it's really hard to just use the respiratory failure as a no to the patients. Now, the latest expert or consensus conference, if you notice, they set the bar very high. It's a very high bar. In other words, I don't think they want to make a verdict for anybody. I agree with you. And they give a lot of flexibility and a lot of judgment left to the centers to decide who they want to transplant. I don't think they would want to be too arbitrary in their recommendations. Yeah, I totally agree. Given that we have seven minutes left, and I don't want to cut into Anna's seven minutes, I'll let her move on to the pediatric case. Perfect. Thank you, Dean. So, just a reminder, the pediatric case is another five-month-old with biliary atresia who presented and had acute decompensation and had a pretty complicated course in the ICU, including abdominal compartment syndrome requiring surgical intervention. So, I think specifically to this question and to this case is something that a lot of us in clinical practice face every single day. And the main question, which I'd first like to address to Dr. Eng, is as multi-organ failure in these patients progresses, what factors would, in your mind, consider this patient no longer an appropriate candidate for transplant? And when is a patient like this just too sick to transplant? I should unmute myself. Thanks, Anna. I think what's really, really key is that you mentioned this is a five-month-old biliary atresia, and these kids are the most, biliary atresia and aphelicocytes, the most common indication for liver transplantation. So, it's really devastating when you hear about this progression to multi-organ failure and essentially potentially make them non-transplantable. This patient was definitely very, very complicated. And, you know, one can really be heartbroken to really think that there were definitely windows where he would have been quite opportune to be transplantable. And then, as things progress with the compartment syndrome and the bowel ischemia, it just gets more dynamic and more complicated. But I think if you really want to look, as you know, as pediatric programs, we really hate to say the idea that someone isn't transplantable, but I think there's definitely some variables that would impact. And your data showed very clearly that the more organ failure impacts mortality significantly more than the PELD score severity of liver disease score alone. I think we have to look at sort of refractory infections, particularly those who actually, and we're not talking about this case, but just in general, the patient, particularly if they start having things like fungal invasive tissue disease, I think those are pretty, pretty well clear. I think patients who actually were talking about respiratory failure earlier, not talking about significant respiratory failure, whether it's to ARDS, whereas we have, we've had patients on the oscillator, so that's a no-go. And I think those would be sort of the three main ones that sort of jump out to mind. And I think finally, the one that actually I think most would dispute is a significant neurological injury with obvious cerebral edema and herniation. I think those that would be sort of not disputable. And I think those would be when a patient's too sick. I can certainly talk more, but I want to really answer the question for Dr. Mattano. Yeah. And I think the next, you know, I'd like to address and pose that question also to Dr. Desai to sort of hear his perspective as a pediatric intensivist. You know, oftentimes we're having and including our intensivists in a lot of our transplant decisions, especially in our patients who are critically ill. Yeah. So that was a great case presented. So as Dr. Uri said that, you know, institution develops over time and what they're comfortable with and what they're not. When I started my fellowship back in 2004, a child with multiple inotropes or abdominal intervention or a high frequency oscillator was definitely, you know, they got status seven and then kind of, they did not, they got delisted in the, because of a certain irreversible, they were called irreversible. Now, even on the oscillator, we will not transplant, we'll still be status seven, but we will wait for the child to come off the oscillator. Whatever his acute and chronic reason for respiratory failure is ARDS, most of the times infection that is resolved. And for us now, the anesthesia will be comfortable if you are on a FIO2 under 60, PEEP under 10. Even those who have previously been tricked, we have five kids who were previously tricked for inability to wean off mechanical ventilation, not just encephalopathy, but we have successfully transplanted them with one of them having died post-transplant. So we have done that. Inotropes, 0.15 unit per kg per, I don't know, the adults may have a different, for us, 0.05 of epi and 0.05 of vaso, 0.04 of vaso and 0.05 of non-epi. Two inotropes, we are okay, we're calling it vasoplegia and we're okay with it. The anesthesiologist just wants some room to play in an anaphylactic phase and when there is sudden metabolic acidosis, when the liver is taken out or wants to have a good, you know, some room to play with. We have not yet needed intraoperative or post-operative ECMO to support these kids. But as in this day and age, two inotropes, we will be ready to take the child. And if the respiratory status is good enough, of course, cerebral edema, bleed, pulmonary, you know, if you have bad ARDS and on an oscillator and cannot come off oscillator or some, any irreversible condition, yes, that we will status seven and withdraw most likely. But this one, we would have probably not gone ahead with transplants. There's no intestine for them and I don't know, we don't do liver, intestine, small bowel. We don't do at least TCH, so we probably might, but CRRT is no contraindication. In fact, this child, if we would do intraoperative CRRT also, if this child were to be stable for, CRRT would definitely, we put them on all of that. Dr. Liotta, you had a comment. Yeah, I think, you know, both of these cases raised the question of not just survival, but meaningful survival. And they're both kind of the typical cases that I get consulted on where a patient's been through weeks of a gauntlet. Any of those events could have caused a catastrophic brain injury. And then I get consulted to give neurologic clearance. You know, you're lucky if you have a neurologist who's very interested in these patients, like we do at Northwestern, not every place is like that. It's much easier to follow these patients from the beginning to get a sense of, does this particular event really represent an irreversible brain injury or not? But I noticed just a couple of red flags in both of these cases. So like a patient who's not very encephalopathic to begin with, and then they become septic and suddenly they're comatose. Well, they could be in status epilepticus. They could have had a subdural that expanded because they were coagulopathic. Both of them became bacteremic and depending on the organism, so particularly bacteremia with staph, they can get mycotic aneurysms and then have a mycotic aneurysm bleed. And those things could be missed. And then you end up transplanting a patient and you're wondering why the patient's not waking up from transplant. So I think it's very helpful at each point of these major hurdles that people come over with is not just thinking about survival, but has something happened to where I think that, you know, it's not realistic to expect meaningful survival. So in both of these patients, you know, I would, before I would clear them, I'd want a CT scan. I'd want to make sure that they're not seizing, that I wouldn't have some sort of a reason to think that they've had an irreversible brain injury or that they've been in status epilepticus for the last three weeks, which is a completely, you know, separate bag of worms or, you know, even beyond the liver failure. Yeah. I mean, Dr. Liu, I think that that, you know, I really appreciate your comments because that just is another point where we as clinicians need to work together with all of our subspecialists taking care of these patients to make these decisions, because many of these patients who are critically ill have a prolonged course in the hospital where a lot of, you know, acute events such as the ones you described can occur. So, you know, I think time is up. So I will like to go ahead and close the session on behalf of my program co-chair, Dr. Coravellas. We would like to thank all the speakers, all the fellows for their participation, both in part one and part two of today's session and for their outstanding presentations, as well as the stimulating discussions we've had both during part one as well as during part two. We hope that you all enjoyed these sessions as much as we did and hope you enjoy the rest of the liver meeting. Thank you so much.

Acute-on-Chronic Liver Failure

ACLF

liver transplantation

cardiovascular complications

treatment options

perioperative outcomes

physiological reserve

frailty

sarcopenia

acute alcoholic hepatitis

multi-organ failure

biliary atresia

ICU course