Thank you very much, and thanks everyone for coming today. So the first talk is going to be on the critical care management of acute liver failure. So just as a way of reference, I know that we have a very erudite audience here today. Liver failure tends to come in two flavors. The vast majority of what we see is actually cirrhosis, and when those patients develop multi-organ failure, we call this acute on chronic liver failure. And these are patients that have fibrosis of the liver and develop complications of portal hypertension. In contrast to that, patients that develop an acute insult of the liver, where it is a necro-inflammatory process, this is what we call acute liver failure, and that's what I'll be discussing for the next 15 minutes. And while there are similarities, there are subtle nuances and differences between the two. And probably the most important thing is that patients with ALF do not have portal hypertension, but they can develop specific neurological complications that we don't tend to see in acute on chronic liver failure, and really specifically that is intracranial hypertension. So within acute liver failure, and by this definition, we mean an acute insult to the liver with the development of hepatic encephalopathy that defines this syndrome. This also comes in a couple of different flavors. So the most kind of rapid onset we call hyperacute liver failure, and classically this is acetaminophen toxicity, which in North America, this makes up about 50% of cases with ALF. And these are patients that primarily end up presenting to critical care initially and have a high burden of multi-organ failure, and furthermore, have the highest risk of developing intracranial hypertension because of the rapidity of onset. But paradoxically, these are also the patients that have the highest potential for recovering with ICU support. So it's really this population of patients that probably is intensivist that we may have the greatest impact in terms of getting somebody to walk out of the hospital. At the other end of the spectrum, you get people with subacute liver failure, and classically these are idiosyncratic drug reactions, or indeterminate liver failure, where this can be grumbling along for several weeks. And while these patients don't typically present with the same burden of multi-organ failure, by the time they meet poor prognostic criteria and develop hepatic encephalopathy, where it's been going on for several weeks, often there's very little chance of recovery without liver transplant. And this kind of highlights the first point that the cause of ALF, or the etiology, has a significant impact on outcome, and particularly transplant-free survival. So if you look at this data from the US Acute Liver Failure Study Group, which is a large NIH-funded registry that's been prospecting and rolling from 1998 till 2018, about half of the patients were acetaminophen. And as you can see, that even though they have a high burden of illness, including highest prevalence of high-grade hepatic encephalopathy, it was only a minority of these patients that actually go on to need liver transplant, where there's a high number of these patients that recover, probably even over 70% now, without liver transplant. And at the other end of the spectrum, you have unfavorable etiologies, which are typically these subacute liver failure patients, such as drug-induced liver injury and fulminant hepatitis B, where the transplant-free survival rate is only about 20%. So building on that, we know that there are favorable etiologies, as mentioned, like acetaminophen, hepatitis A, shock liver in isolation, and fatty liver of pregnancy. And then there are unfavorable etiologies. But what we know is that, independent of the etiology, the severity of hepatic encephalopathy, and primarily we're talking about a hepatic encephalopathy grade of 3 or higher. And another way to think about this is this is generally a Glasgow coma score of less than 9. These are patients that often need airway protection. Having high-grade coma is a second factor that, in many different studies, has been demonstrated to be associated with a worse outcome, independently of whether you have a favorable or an unfavorable etiology. One of the questions that comes up is we all know that, when we look at these different etiologies, is there a role for N-acetylcysteine, which we know there is a large amount of data in either acetaminophen-induced liver injury or hepatotoxicity, and in APAP-induced acute liver failure. But I also want to highlight that there is evidence that this is actually of benefit in other causes of acute liver failure besides acetaminophen. And in particular, it's those patients with lower coma grades that potentially may have a more favorable prognosis that tend to benefit from the use of NAC, as we learned from this randomized study from back in 2009. So probably the most worrisome complication, particularly of hyperacute liver failure or acetaminophen toxicity, is the development of intracranial hypertension and cerebral edema. And one of the comforting things to know is that we're actually getting better at this. That if you look, and this is data that our group published a couple of years ago, that the prevalence of clinically significant intracranial hypertension has dropped dramatically over the last two decades. And mortality from intracranial hypertension or cerebral herniation has also dropped in half. And this is where we can probably pat ourselves on the back that this is probably due to good critical care management. Just to remind us that the two main pathophysiological mechanisms of this are cytotoxic edema from astrocyte swelling. And this is due to interruptions in the urea cycle and the Krebs cycle, which leads to the rapid accumulation of ammonia, and by extension, glutamine, which is an active osmol in the astrocytes. We know that ammonia is a neurotoxin. And one of the reasons why this is so important in hyperacute liver failure is the rapidity of onset and the inability to compensate by expelling other osmols out of the astrocytes. And then the second factor to it, why we don't tend to see this in other causes of chronic liver disease, is the fact that ALF is a very pro-inflammatory condition, and you get alterations in the blood-brain barrier, and you get loss of autoregulation, leading to extravasation of other macromolecules from the plasma. So one of the challenging things to discuss, specifically in stratifying acute versus acute on chronic liver failure, is the role of ammonia. And while we know that ammonia levels don't tend to correlate well in cirrhosis patients with the grade of hepatic encephalopathy, or by extension, its improvement, we know that ammonia is very important in acute liver failure and has been shown in multiple studies to be independently associated with the development of intracranial hypertension. And this study from Will Bernal and colleagues at King's College Hospital demonstrated that factors independently associated with the development of ICH besides ammonia really reflect this whole kind of pro-inflammatory cascade from all these necrosed hepatocytes, including circulatory failure, high-grade hepatic encephalopathy, and the need for renal replacement therapy. And it also shows us that a good cutoff for consideration for treatment for hyperammonemia and ALF is a cutoff of 150. So in terms of neuroprotective strategies, we're all very familiar with this. There are nuances that may be different from other neurocritical care patients, but generally a lot of it is kind of similar. We try to avoid suctioning these patients. We try to maintain a low normal CO2. Our preference is for rapid-acting sedating agents like propofol. There is kind of more information required on dexmedetomidine. We try to avoid benzodiazepines because they can exacerbate hepatic encephalopathy, and this might be important with the decision to list for transplant. Like in other areas, such as the cardiac arrest literature, there isn't good evidence for prophylactic moderate hypothermia, but targeted temperature management is potentially beneficial, particularly actively treating fever. And we'll try to counteract the osmotic effects of glutamine by maintaining a higher serum sodium. And in contrast to cirrhosis, where we're using medications to scavenge ammonia, in acute liver failure, it's mainly the use of blood purification techniques and specifically CRRT. So one of the things that's changed over the last 10 years is the shift from using direct intracranial pressure monitoring, particularly in high-risk patients like acetaminophen ALF patients with high-grade coma, to more non-invasive techniques, and obviously more data is needed. This study from the ALFSG registry, which was a retrospective cohort study that looked at high-grade coma patients that potentially may benefit from an ICP monitor, showed that about a quarter of patients were getting monitors, and about half of those patients had evidence on the ICP monitor of intracranial hypertension. And while having an ICP monitor tended to be associated with those patients listed for transplant, and the rationale for this was probably it was being used as a stop sign to say that if the ICP is 30, maybe we go ahead with medical management and bridge to a transplant. But if it's 60, then this is probably a hard stop. It wasn't actually associated with a mortality benefit. So probably what's changed is the use of more non-invasive techniques, and some of you may be familiar with transcranial Doppler, where we can get information from the middle cerebral artery of not only blood flow velocities, but also look at the pulsatility index as an indirect marker of the elastic reservoir, which may be giving us information on the capacitance in the brain. Just to mention, though, that these techniques do need more data. So this is a study that came from the University of Michigan that demonstrated that transcranial Doppler, using just the pulsatility index, only had an area under the curve of 0.55. But once you add that to the blood flow velocities, your area under the curve goes up to almost 0.9. So it certainly shows that this is something, potentially, that gives us information. And in our center, generally, we will start with non-invasive techniques before making a decision about whether or not to go ahead with direct ICP monitoring. The other thing to mention is that the data for hypothermia has been somewhat underwhelming. This was a randomized study that Will Burnell and colleagues did at King's with collaborators in Denmark back in 2016. And while they were able to stratify patients to either a temperature of 36 versus 34 fairly well, there was no difference in any clinically significant heart endpoints. But I think, like we've learned from other areas of the literature, while it shows that in the preventative or prophylactic setting, going down to 34 doesn't have an added benefit, it may be telling us, potentially, that at least being aggressively managing fever at least to a temperature of 36 and monitoring it actually has some benefit. So it doesn't give us a blank check to just avoid monitoring temperature. I know that Dr. Subramanian will be talking about artificial liver support in more detail. But just to give you a rationale that blood purification techniques are really the first line therapy to treat hyperammonemia and acute liver failure. And the reason that we start most of these patients on CRRT is not because of AKI or uremia, for example, but it really has more to do with treating volume overload, lactic acidosis, and the treatment of hyperammonemia. And we like continuous techniques because they minimize solute shifts, hemodynamic changes, and they mitigate ICP spikes. And usually about once every two months, I get a question from a nephrology colleague saying why not using intermittent hemo with a higher blood flow rate? But really, the problem is that a lot of these patients are hemodynamically unstable. And we know that with rapid blood flow rates, this can lead to dialysis, disequilibrium, and hypotension, which can affect the brain. And really, while this has probably been in practice for the last 15 years, this study finally came out in 2018 of almost 1,200 patients from the ALFSG registry that demonstrated that after adjusting for severity of illness, the use of CRRT was associated with a significant almost 50% reduction in mortality, and intermittent modes were actually associated with a higher mortality rate. Probably what's also important is that if you are going to do it, and this is data from Australia, that it should be done early and consider higher volumes. And if you look at this study from Stephen Worrello and colleagues, they were using dialysis dosing rates of almost 43 mils per kilo per hour. Sorry, if I could just go back two slides. Perfect. So one of the other challenges that we deal with, particularly in the ALF patient that you're considering a transplant is lung injury, because you end up with the competing organ systems, where we often, like a lung protective strategy, in an ARDS patient, we're willing to let the CO2 climb. And in an ALF patient, we simply can't do that. And I just highlight here that, you know, for example, if a patient aspirates when they get intubated, this can lead to a lot of complications, and having significant lung injury is associated with a lower probability of getting transplanted. And I just want to mention as well, and once again, Dr. Subramanian will talk about this in more detail, that there is actually data to demonstrate that probably of all, as opposed to acute on chronic liver failure, in acute liver failure, there is a potential for reversibility, which lends us to using some of these techniques, or blood purification techniques, as a bridge to spontaneous survival. And the example here is the use of albumin dialysis. And I want to mention as well that also Dr. Subramanian is going to be talking about this, is there's more data now on the use of plasma exchange, which has been independently associated with an improvement in mortality in patients with acute liver failure that did not get transplanted. And what that's telling us is that these are primarily acetaminophen patients with the highest potential for spontaneous recovery. One of the other questions that comes up is often these patients are hemodynamically unstable on high pressors, and the question is whether we should put them on prophylactic antibiotics. And in many ways, ALF patients have distributive shock, and they are very difficult to discern from a patient with septic shock. So one of the categories or data points that was collected within the ALFSG registry was whether or not patients receive prophylactic antibiotics. And to this point, there isn't data that suggests that prophylactic antibiotics improves outcome. But we do know that if you do get a bloodstream infection, this is associated with a higher mortality, particularly in non-APAP or the subacute liver failure patients, where the cause of death is more often from multi-organ failure and not from intracranial hypertension. In terms of prognostic scores, you're probably familiar with the King's College criteria, but I should mention that most of us don't use a single prognostic score to make the decision about transplant. And this primarily focuses on how this is a dynamic process. And building on the etiology and the coma grade, other factors that tend to be important include bilirubin, INR, vasopressors, and lactate. And generally, one thing to mention is that transplant outcomes have actually been improving in acute liver failure. And this is data that shows that in our most recent publication from the ALFSG registry, the transplant outcomes at one year in ALF patients, and this is combining data with the SRTR transplant database, are actually greater than 90% of the year, which is similar to patients with cirrhosis. One caveat, though, is that the vast majority of these patients had subacute liver failure and were not acetaminophen toxicity. And these APAP patients tend to be the bane of our existence because they have the highest rate of spontaneous recovery, but also, as you can see here, they have the highest rate of mortality on the wait list, partly because of the severity of multi-organ failure. And this is something that we deal with, and I'm sure you do as well. And I would just like to conclude by saying that, you know, certainly with acetaminophen toxicity, outcomes have clearly improved over time, and as mentioned before, partly this relates to decreasing rates of intracranial hypertension. And partially, if you look at this data that Andrew McDonald evaluated from the ALFSG registry, there's certainly been more uptake in the use of CRRT as a blood purification technique. So we are getting better at this. So in summary, transplant-free survival in ALF has improved over the last 20 years. Rates of intracranial hypertension and death from cerebral edema have decreased, particularly in APAP ALF, likely due to improved early neuroprotective strategies and ICU care. Noninvasive strategies for assessment of intracranial pressure hold promise for more widespread use, but need validation. Use of lung protective strategy in ventilated patients in ALF with lung injury, but use of high PEEP with caution because this can exacerbate hypotension and ICH. Consider continuous renal replacement therapy in ALF patients with an ammonia level of greater than 150 or vasoplegia. Plasma exchange or MARS may be considered following a trial or in concert with CRRT, particularly in those patients that have vasoplegia. Sepsis or bloodstream infection has a significant impact on outcomes in non-APAP ALF. So, you know, certainly the use of antimicrobial prophylaxis can be considered when you have a high index of suspicion. And finally, liver transplant outcomes in appropriately selected patients are similar to other transplant populations. Thank you.

acute liver failure

intracranial hypertension

acetaminophen toxicity

neuroprotective strategies

CRRT