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so Hello. Good evening, everybody. Welcome to our Scottish intensive care society. Even education update these events hopefully going to run monthly with, uh, the aim of connecting us as a Scottish ICM community. It'll let us take advantage of the fantastic and varied subject matter experts that we've got working throughout Scotland. It's built in to see that there's over 100 and 50 people registered for this event. And we've got representation from all of our N d t members, consultants, option training students, senior nurses, a ccps physios, dieticians, pharmacists, research nurses and educators all registered to come along for this evening. So that's fantastic to see and I think really represents the strength of our critical care MDT in Scotland, we have a brilliant timetable of sessions coming up for you for the next few months. Certainly got confirmed speakers until June of next year, and you'll be glad to know that these sessions are accredited for CPD with Royal College as well the chat functions on the right. So if you have any questions, please feel free to put your questions in there. I know that many of you are s I. C s members but just very quickly, I I thought I would just recap Scott, the Scottish Intensive Care Society, as an organization which seeks to really coordinate and represent the specialty of ICM throughout Scotland. I'm really the main focuses are on education, research and audit activities. If you aren't a member, there are various categories membership. And there's a number of benefits, including richest rates for the SM and other meetings in comprehensive transfer insurance. If you undertake patient transfers and you can apply for travel and study bursaries, which are often worth several 1000 lbs, another shameless plug here is for our six a s N meeting, which will take place on the 2nd and 3rd of March next year at the Fairmont in ST Andrews. A. Really fantastic, uh, program speakers coming together there and some notable names. So Mervyn singer Katherine Mannix Danny Bridon, who's the new chair of thick um, is going to speak, and there's an abstract competition, and there's an early bird rate available until the start January. So if you're interested, I can find out more the Scottish intensive care websites, but without further a do, I'd like to introduce our speaker for this evening. Um, so we are delighted to welcome Dr Scott McNeil, um, along to talk to us about acute liver failure. Uh, Scott is a consultant in transplant anesthesia and critical care at the Royal Infirmary, Edinburgh, where the Scottish liver transplant unit is based. Having been appointed as a consultant there in 2018. His interests are in acute liver failure and in perioperative medicine for major cancer surgery. And we're also really fortunate he acts as the South East Scotland rep for the Scottish intensive peer city. So, Scott, we're really delighted to have you here, Uh, this evening and I will hand over to you. Uh, thank you very much. Julie. Thanks for inviting me to talk and and to be the first person to because this thing is it's a great idea and looking forward to seeing how it progresses in going forward. It. Like I said, I'm a consultant in the Royal Infirmary in Edinburgh, and I've I've set in two camps. I sit between transplant anesthesia and critical care, and today we're gonna talk about cute liver failure and liver transplantation. So just to kind of tell you what we're going to talk about. Over the course of the evening, we're going to talk a bit back over the definitions and classifications of acute liver failure and some of the common causes. And when you should be worried about these patient's and when you should think about referring them to the Scottish liver transplant unit and a little bit about transfer itself. And then I'll talk you through our sort of acute liver failure protocol and how we manage these patient's and how they might proceed to transplant. So we'll talk about the listing criteria and then actually the practicalities of transplanting somebody who has acute liver failure. We'll talk briefly at the end about additional therapies for acute liver failure and, although not strictly related to liver failure, but it is something that's relatively new and worth mentioning is the new acute on chronic listing criteria and how you will probably see quite a few patients with this coming through your units. So So, first of all, what is acute liver failure? Um, cute Liver failure is a very rare illness, and there's less than 10 cases per million person years and in severe cases associated with multiple organ failure, quite high mortality. It's less common in the developed world and in general, the overall instances actually declining due to significantly better vaccination programs in Scotland. There about 8.4 cases per annum per million of the population, which equates to roughly about 45 to 55 cases per year in Scotland. And that's similar to sort of what you would see in other major countries. So it's about 10 million cases per annum per million of the population in the United States and worldwide of all patient's. In presenting with of all patients who have a liver transplant, about 8% of them are performed with acute liver failure as their as their primary indication. And in terms of numbers that we see at the Royal Infirmary, there's roughly of 35 to 40 patient's transferred to us each year. I'm with the kit liver failure. About 20 to 25 of those come to ICU and sort of 5 to 10 of those patient's will then proceed onto having a natural liver transplant itself. If you If you do have acute liver failure and you require a transplant, then you will get listed under the super urgent listing criteria as set up by NHS BT and this graph shows the number of patient's in the UK who are transplanted secondary to acute liver failure, and it works out as roughly between sort of 50 to 70 patient's per year. And this is a graph over the last 10 years, and over this 10 year period in Edinburgh, we've done about 55 transplants for acute liver failure. We've done 750 patient's due to chronic liver disease, so that equates to about 7% of our transplants in total being secondary to acute liver failure. Uh, the most common reason that's leading to a transplant both in Edinburgh and throughout the UK is normally paracetamol overdose. Throughout the talk I'm going to be referring to as acute liver failure. It's also commonly called fulminant hepatic failure and in terms of being interchangeable. But more and more nowadays, it's being referred to as acute liver failure, and sometimes you might hear people talk about an acute liver injury. This is very different, and this refers to deranged liver function and coagulopathy, but no in careful opathy, and it will become clear that encephalopathy is really a key component of acute liver failure and acute liver injury, like I just described as a much better prognosis than proper acute liver failure, the key components of acute liver failure. Like I said, our jaundice in careful opathy and coagulopathy and the initial definition was made by Tray and Davidson in the 19 seventies, and it's about 50 years old now. But a lot of it still holds quite true, actually, so that they and I'll read it out here. Described a severe liver injury injury potentially reversible in nature with onset of hepatic encephalopathy within eight weeks of the first symptoms in the absence of any preexisting liver disease. In reality, though, they're currently are about 40 odd different definitions being used in 87 countries. So there's no definitive consensus as to what constitutes acute liver failure and what constitutes coagulopathy. Generally an eye on our above 1.5 would classify as coagulopathy, and there are a few newer sub classifications of acute liver failure that break it down into the time between jaundice to the development of encephalopathy. So hyper acute presentation would be between zero and seven days acute between eight and 28 a subacute between 28 days and about 26 weeks. The etiology of acute liver failure varies quite significantly across the world, with viral infections being most common in in the developing world and drug induced liver injury in more developed settings. In terms of looking at drug induced liver injury itself, paracetamol toxicity accounts for about 50 to 70% Of all these cases, it's paracetamol. Toxicity is more common in the United States. And that's because in 1998 the law was passed that restricted the quantity of paracetamol that could be brought over the counter, and that coincided with a 4 to 3% reduction in death. Secondary to paracetamol overdoes. I take that with a pinch of salt, though it's probably fairly multifactorial as there's been quite significant changes in the ICU management of acute liver failure during that time Globally, hepatitis A and E are responsible for the majority of cases, Um, and the rate of death is about 50% in the developing world from from that hepatitis B is a common cause in Asian and Mediterranean countries, and there's a predominance of hepatitis E in the Indian subcontinent. There's lots of lots of causes on that list from some fairly rare ones two ones that are becoming slightly more common. For example, HSV has actually become more common in the last few years in the United Kingdom. We've certainly in our unit had a couple of patient's transferred in from throughout Scotland with HSV associated acute liver failure, as I mentioned earlier that the syndrome of acute liver failure can be sub classified and based on the timeframe for the onset of John. Just in case. Phillip with E. And anything where that time frame is long within 26 weeks would be classified as as chronic liver failure. And this sub classification can help to give us clues as to what might be the potential underlying etiology because it's not always completely clear as to what the presenting problem is. An actual fact. In 20% of cases, a full causes never fully identified. These subcategories can also be associated with prognosis, and that's mainly because they actually reflect the underlying cause, which is the main determinant of prognosis. Hyperacute causes on the left hand side. They are associated with severe coagulopathy it much higher grades being careful, opathy at presentation, and alongside that was an increased risk of intracranial hypertension and multiple organ dysfunction. Although the onset of symptoms here is very rapid, it also means that the offset is very rapid. And these patient's actually have quite good rates of transplant for your recovery. And if they don't need liver transplant criteria, in contrast, on the right hand side. And there's patients who have a sub acute presentation and they'll present with much more mild changes in their transaminases a much more mild coagulopathy. And they might also have splenomegaly ascites or shrinking liver volumes, which may mimic cirrhosis and can make the diagnosis of or sub acute liver failure much more challenging. Their survival without transplant is much worse, and actually, once they develop hepatic encephalopathy, they're prognosis without transplant is very poor just to briefly go over the path of physiology. Acute liver failure is characterized by direct hepatocyte damage and then the development of a massive inflammatory and it mean response both within the liver and systemically as well. And this huge systemic information leads to multiple organ dysfunction syndrome and has a clinical picture that presents in a very similar way to severe sepsis. And that often complicates matters because they have a significant immune dysfunction, which predisposes to new infections and are therefore at much higher risk of developing infections as well. As I said, hepatic encephalopathy is really the kind of cornerstone of diagnosis, and it is characterized by this altered cerebral blood flow and a dysregulated cerebral auto regulation. The hepatic encephalopathy that you get in acute liver failure is very different to the encephalopathy you might see in cirrhosis. So in chronic liver failure to get this low grade chronic brain swelling. And it's a kind of insidious process that happens over over weeks to months, whereas in acute liver failure this actually happens or can happen in a matter of hours. And there's a growing recognition that ammonia is an increasingly important marker of severity and possibly as well, prognosis. And there's new scoring systems that are being developed that include ammonia as part of their criteria for for predicting prognosis. So just to talk about ammonia in a little bit more detail and talk about what normally happens to ammonia in the body. In healthy individuals, the liver will remove ammonia by detoxifying it into your area and whereas in acute liver failure, this metabolic capacity is overwhelmed and that results in a hyperammonemia muscle, then becomes quite an important organ of detoxification, and it converts it into into glutamine and this glutamine, then that's a temporary buffer. But an ultra fact can cause direct astrocyte swelling, astrocyte injury and edema and ultimately, cerebral edema and, uh, intracranial hypertension. So a good way of thinking about this is, is a bit like it's a metabolic brain injury, and it is different to the changes that you might see in somebody who's had a traumatic brain injury or swelling as a result of that. And and there's more evidence growing about ammonia. And actually, there are. Some of it is suggesting that, as in as your ammonia actually increases and that will confer to a significantly, put your prognosis and again the higher your presenting level of the money out again. The worship potential prognosis. So we'll just talk briefly about piracy tomorrow, overdose and and the classical picture that you might see, because this is what you often think about or what you see when somebody with with hyper acute liver failure and they often have a an impulsive overdose, and often it's not the only drug they've taken. It's mixed in with different sedatives, and paracetamol comes in a multiple different compounds, often mixed with opiates like cocoa to mall or critical. Jamal and these patient's actually have a more concerning clinical picture because the association's the opiates have with reduced gastric emptying they don't often present at the time of overdose. Which is unfortunate because, as we know in national, assisting is most effective when it's given immediately. But they frequently presents of 24 to 40 hours later, being vaguely unwell with mild abdominal pain present at A and E. And they get the Bloods done, which show the classical picture. That's suggesting a very significant overdose, so they might have a very high L T. And transaminases very high PT a raised lactate, and another feature is associated with with poor. It comes like metabolic acidosis, acute kidney injury, a presentation and hypoglycemia presentation. These features are more likely if the patient's taken over 10 g and again they're more likely if they have other concerning cofactors, such as alcohol abuse in the background. If they're taking any enzyme inducing drugs or if they're malnourished and underweight. And this is the kind of classic picture that you might see with their with their bloods over the next few days. And the severe increase in I mean, the transfer is is about 38 hours after ingestion, and the hepatocellular damage itself will peak of 2 to 5 days after overdose, Coagulopathy might peek its day. Three encephalopathy will peak about day five, and then you might start to see a rise in Billy Ruben following this peak injury. And that's sometimes associated with attempts at hepatic regeneration. The other major cause that we see is is a drug induced liver injury, and I actually all those patients who have a non paracetamol, drug induced liver injury. Less than 10% of them will progress to acute liver failure, but if they do, then they're outcomes are much worse. And that's up to 80% die or ultimately need a liver transplant, partly related to the fact that it's a completely different cohort of patient's, then they're often much older. They have additional comorbidities, and they're much more likely to present with a subacute course, which, as we said earlier, is associated with with worse outcomes, and they may only become symptomatic several weeks after ingestion or administration of the drug itself. The drugs are most commonly associated with that are anti TB drugs such as Eisen ized and antibiotics in particular nitrofuran tone and antifungals like ketoconazole. And we know that anti epileptics like phenytoin evaporate can induce a drug induced liver injury, as can non steroidals. The in terms of who to refer, I think, or who to refer to the liver transplant unit. Firstly, anybody you're concerned about who presents with an acute liver injury. But if you're looking for sort of specific numbers, patient's who have a performance time above 20 or an iron ore of greater than two patient who has a persisting acidosis. Hypoglycemia at presentation is a particularly concerning feature, as is any degree of about taking careful opathy progressive acute kidney injury, hyponatremia and, uh, Hi Billy Ruben. The presentation may also be linked with that with the sub acute presentation. So really to summarize that any patient who has been careful opathy coagulopathy, or renal impairment complicating an acute injury liver injury should be discussed with the transplant unit, and that's taken directly from there referral guidelines. Okay, so when you have this patient, what happens next? So the referral will usually go through the NHS Lothian switchboard and you'll be put through to the on call transplant hepatologist. It will take patient's details and they'll take their blood results and you'll be able to follow any future blood results that are taken usually through national sky stores. There's twice daily transplant meetings and one in the morning transplant to itself and then one in the afternoon where these patient's will be discussed daily and the results will be reviewed. And they'll be flagged up to the cautious liver transplant unit coordinators who will be in contact with their referring unit. And I see you. I usually involved very early in the in. The discussion's protected with regards to patient placement and potential transfer and early psychiatry review at the referral site might be recommended. It won't change whether or not the patient gets transferred over, because even patient's who are who with an acute liver injury who are acute liver failure who are not a potential transplant candidate should probably still be managed over in the royal infirmary, but it will allow for an early site review before Darren, careful apathy might worsen. He may be given specific hepatology advice related to different drugs that can give timing and dozing of pastel system or any imaging or specific bloods that can be done on site before they get transferred. And then again, in conjunction with With IC, you think about planning for a transfer over night. Ultimately, the decision on how to transfer a patient is really with the referring team because because you are the people who are standing at the end of the bed looking at the patient and have a much better idea about how things are progressing, and I'm not going to tell you how to do it. But there are some key things that are definitely important to recognize, and the main thing is that the evolution of acute liver failure is very, very unpredictable. So all these patient's and what we normally see is should be reviewed early by critical care or by anesthesia, or by whoever would be transferring the patient. Ideally an early stage, because early senior transfer is very important. Another key point is that even mild hepatic encephalopathy can deteriorate very, very quickly and A good rule of thumb is that if you're transferring a patient uninsulated, it's likely that they're great. Event careful opathy will probably worsened by at least one during transfer and UK wide. There seems to be some fairly, um, robust guidelines regarding those who should be intubated beforehand. And that's patient's who have Grade three hepatic encephalopathy and you have hip, ongoing profound hypoglycemia or ongoing acidosis. Despite and volume resuscitation. They should. They would probably benefit from a controlled intubation and management of their physiology before transfer. Sometimes, as we said, they can present really acutely unwell and actually need a lot of the phone or the acute liver failure protocol instituted in the referring hospital. That might involve a certain lines. And if you are putting lines in, then ideally trying to leave one side of the neck free, and I'll come onto why that's important one side, the neck line free, and I'll come onto why that is important when we're talking about the actual transplant itself. Coagulopathy is a crucial part of listing criteria, so unless the patient is really bleeding, quipped, friendly with you recommend not creating coagulopathy. If you feel like you want to give products before line insertion. The platelets can be given safely and would alter transplant listing criteria. And if you're making up in a style assisting for the patient reacted, it gets made up in 0.9% sailing. I'll come onto Why, uh, and why Hyponatremia is particularly important, Okay, And all the things I'm gonna talk about in the acute liver failure protocol can be done in pretty much every other intensive care unit throughout Scotland. So why should they come to the to the royal Infirmary? I think that is a very valid question. And the real reason is because of the multidisciplinary team that exists there. So, as I said, they got a twice daily review from From a transplant team that consists of a consultant, hepatologist, consultant, surgeon and, uh, consultant. Transplant any cyst? So there's the relevant hepatology expertise. On site is the surgical expertise on site, as well as transplant radiology specialist liver pharmacy, and I see you. Um, the nursing care, I think, is really important to mention because the nurses there are very familiar with looking after these patient's. They're familiar, particularly looking after patient's post liver transplant and actually when these patient's arrive, you don't really have to specify the goals that you you want because they're so well established and everyone knows them already. And the other group of people to mention are the advanced critical care practitioners who work in in ICU here. I think we've had them embedded within the unit for about 10 years, and they are real experts in managing patients', particularly after after a liver transplant, because they're so familiar with the with them familiar with the complications. And they've got such a wide body of knowledge between them as a group that and you know, if they if they think something is wrong, then generally there always is. So, as I said at the start, acute liver failure really is a fascinating condition to look after. It's a It's a proper multi system disorder, and this leg just of highlights some of the issues that can develop in in these patient's. Uh, I'm going to talk you through how we manage each organ system, and I see you and I'll talk you through the rationale behind this. I've highlighted some of our key treatment goals in a sort of yellow box and these are the criteria are these are the parameters that we're that we're aiming for throughout the management of acutely version year. Firstly, I think it's worth mentioning in some of the specific treatments for some conditions. And we know that for paracetamol, overdose in acetylcysteine is crucial, and the earlier the patient can get it the better. Yeah, but it's also felt to be helpful in non paracetamol overdose. Acute liver failure and especially in cases if the cause of acute liver failure is is unknown, is thought to help improve liver oxygenation and actually has anti inflammatory and immunological effects as well. Making it up and 0.9% saline is probably quite important because it helps to prevent worsening hyponatremia. And that may, actually, or people looking back at the studies have wondered if that has a big impact on why it's proved to be so effective for other cases of acute liver failure and other specific conditions. So antiviral therapy might be helpful in patients with hepatitis B, but the evidence for that it's patchy early acyclovir for HSV is crucial and in pregnancy related conditions such as help or fatty liver pregnancy, then prompt delivery is very important in terms of again the national system that we make up there. There's different protocols for starting therapy. When they come to the world, we make up 100 mg per kilogram in a liter of normal saline, and then we give that over 16 hours and then continue it at the early rate until the patient either procedures the transplant over advice to stop it by the transplant team. And as I said, the clinical presentation, um, for the cardiovascular presentation is very similar and behaves in the same way as sepsis. So these patient's are profoundly basil dilated and have a reduced, effective circulating volume. Heather Lactaid is often significantly raised. The presentation that this probably initially reflects volume depletion that if this persists, then it is a good sign of severe underlying liver failure. As the liver is unable to metabolize, this increased in lactate production. In terms of fluid resuscitation, we use balanced crystalloids, so plasmalyte is what we use. But looking through the literature, there is no specific guidelines as to what fluid to use for resuscitation Again, some people might want to use albumin, but there is no again no evidence suggesting that that's better than anything else. The goals of our treatment are aiming for a mean arterial pressure greater than 70 and we use no adrenaline. Is our first choice visit pressure for this? If we're adding an inotrope, we would commonly adding adrenaline, first line and, uh, in some cases with institutes of early cardiac people monitoring. Other goal that we might look to achieve is if we are concerned that there's a raised intracranial pressure, then we might in first late, higher monetary pressure of of 80. And this last statement here that volume overload is just as detrimental as volume depletion was find it really frustrating when someone giving a talk just throws a great statement like that, but doesn't actually give you any ideas on how to manage it. And that's exactly what what I'm going to do. And we do know that volume overload is probably actually worse for these patient's and does confer a higher mortality. It leads to venous congestion, increased backpressure into deliver or intern already struggling liver and increased right heart pressures. I think the way to manage it is based on your clinical judgment and giving fluids appropriately. There's no. One test or one thing that's going to tell you how much fluid to give these patient's in terms of adding in shock dose steroids that again, There's no clear evidence for short dose steroids in this group. And but I think a lot of us, once they're reaching escalating doses in or adrenaline feel there's probably little harm in adding it. In, UH, intubation ventilation is normally required for airway support and due to the progression of hepatic encephalopathy and then a small number of patient that might be required for for hypoxia and respiratory failure. I think the key point here, though, is to try and avoid an emergency intubation, if at all possible. So if it's clear that somebody is progressing really quickly and early and control the inflammation is in their best interests and we aim in terms of respiratory targets, we aim to provide sort of neuroprotective ventilation strategies. So avoiding hypoxia, avoiding hypercapnia. Um, and we're aiming for a P 02 of 10 to 12 and a CO2 of 4.5 to 5 prioritizing ventilator synchrony and long protective ventilation. We do try and avoid high levels of people because of again back pressure and reducing hepatic blood and blood full once these patient's. Or if these patients develop ARDS, then that confers to quite a poor prognosis, usually because it means they're unlikely to be a suitable transplant candidate. And transplant is ultimately the treatment that that they need. Yeah, acute liver failure is frequently associated with significant electrolyte and metabolic disturbances, and, I heard described quite nicely as as a homeostatic disarray. And all these things are much more common in patients who present with a hyper acute presentation. So hypoglycemia is more likely in hyperacute cases is frequently associated with acute kidney injury in in over 50% of patient's, and again it confers to increase mortality. We should try and avoid, if possible, rapidly correcting these patient's glucose. Unless there is an emergency and we advocate, I really blood sugars for them. And if the blood sugar falls below 3.5, then we would start 50% dextrose infusion, aiming for blood sugars have sort of 6 to 10 million miles per liter. About a third of patient's and hyperacute cases present with hyponatremia. And by that I mean a sodium of less than 100 and 30 and this again is also associated with increased mortality because of it's linked to increased intracranial pressure and interest. Terrible hypertension. So to help try and mitigate against that, we make up our own acetylcysteine and 300.9% saline and would fairly routinely now start a 5% ceiling infusion, targeting a scolding of 100 and 45 250. And there's evidence supporting improved outcomes and reduced rates of cerebral edema in these patient's. Uh, the other important thing to recognize is that, just like any patient with hyponatremia, you should avoid a rapid overcorrection. And so no more than 10 million moles probably turn in a trench for our period. And actually, these patient's are actually at higher risk of the consequences of a rapid sodium rise. Yeah, kidney injury is is common, and it's about 75% of patients presenting with paracetamol overdose and an acute liver in acute liver failure will have an associated acute kidney injury. So about 40 to 80% of this presentation, and it's also associated with increased mortality and increased length of stay in terms of why these patient's get an acute kidney injury. It's generally uncertain, but it's thought to be a probable direct tubular toxicity from paracetamol toxicity itself. A lot of these patient's will progress to, you know, replacement therapy, mostly for the newer protective aspects which I'll come onto but also that standard. Classic indications for instituting renal replacement therapy and I see you and and the reason why we started failing routinely is because there's a clear correlation between creatinine clearance and ammonia clearance, and we're trying to remove the ammonia and minimize the risk of cerebral edema. And in general, continuous modes are preferred, and we use CVH d in our unit him. The brain in acute liver failure is, is what we all worry about. And intracranial hypertension as a result of cerebral edema is a major concern, and mortality is about over 50%. In patient's who develop this, it's no, it used to be that the primary cause of mortality, but actually it's been superseded by sepsis and in these patient's in careful, obviously, is the Hallmark presentation can be quite. They're not always presenting us in such a straightforward manner and often having to realize other potential causes for how duration neurology. Whether that's drug or alcohol withdrawal, I touched on the fact that, if possible, an urgent sick of you when they're all awake will help with decisions regarding listing and a general appreciation that these patient's can deteriorate very rapidly. If these patient's are in a non critical care environment that are developing agitation, which is associated with worsening in Cape Allopathy, then it's really important that they're not sedated. They're not managed with benzodiazepines or haloperidol, that they referred to critical care and that they're intubated and transferred because generally, aggression and agitation is associated with with grade three by the king. Careful opathy because they present in a different way in chronic and acute liver failure. And once they are asleep and we tend to avoid any sedation holds until we're happy that the risk of cerebral edema has passed, and again that would depend on whether or not they have proceeded to having other transplant. Regarding cerebral oedema, it's really important to identify those who are at high risk. And so those are the young patient's the hyperacute presentations, the parties about overdoses, really. Anybody who has integrated for encephalopathy is regarded as being at high risk anybody who has an acute kidney injury or who's him. Oh, dynamics are continuing to worsen in terms of numbers related to the ammonia. If your ammonia is persistently greater than 100 and 50 then we're worried. And if it's greater than 200 then we're really worried and in terms of monitoring for development of cerebral edema, let's just suggest that regular CT is not recommended for monitoring. And actually trying to transfer a patient down regularly for CT when they're on multiple levels of organ support would probably be overall detrimental to them. Yeah, I C P Monitoring is generally gold. Standard, however, is not performed routinely, certainly throughout Europe nowadays, because of the complications associated with IC people insertion in these patient's, it will give you nice numbers. It will show you if they have raised intracranial pressure. But the evidence has shown that it doesn't improve your outcomes, and ultimately, nowadays doesn't really change the treatment that that you're giving them. Yeah, our our targets for the brain in in the killer failure are similar to to good neuro protective measures that you would in in anybody who has a lot of interest herbal injury, so we keep them deeply sedated. They're ventilated. We optimize their being a strain ege who maintain the tight targets that I mentioned before. So I see you to your 4.5 to 5 and appear to of 10 to 12, and we closely monitor their sodium. And if we're worried about an acute rise in intracranial pressure, as suggested, maybe by papillary changes, though, as we're saying that these things are often much more challenging to elicit in these patient's, we would give them bullets of mannitol, uh, $200 or 20% over 20 minutes, or if their sodium allowed it, then a further bolus of hypertonic ceiling, and so $125 or 5% over 50 minutes, and would make sure that we were meeting our our sodium targets. But the main treatment nowadays for for neuro protection is renal replacement therapy and in ventilated patient's who have more than two of the following risk factors that I have listed regardless of the renal function or the urine output that we would institute immediate renal replacement therapy. So patient's who are over 40 again hyperacute presentations or ammonia's of over 100 and 50 patient's who are on high levels of these oppressors or who also have, you know, dysfunction or metabolic acidosis. Then we would start high volume renal replacement therapy, and and by that I mean high volume exchanges, or 60 miles per kilo. Which ties is the max of 4.8 liter exchanges. Blood flows of 250 to 350 mils per minute if they'll tolerate it, and you can consider fluid removal if they're tolerating it. And this helps to remove the ammonia filter at the ammonia and reduce the risk of cerebral edema. We tend to not and calculate them at first and see how the filter runs, and we we don't use em citrate immediately because of the diminished ability of delivered to metabolize the citrate load. It is used in some centers but does require much more frequent monitoring again, coming back to our sodium target. This can be a bit harder to achieve renal replacement therapy, which again is another reason why we run a 5% hypertonic saline infusion, and that's becoming more and more routine. And certainly like I said, any patient who's intubated with acute liver failure, and I see you will now be getting high volume, you know, replacement therapy and in terms of their G I management. Most of the guidance regarding the nutritional needs is fairly empirical, and it goes along with generally how you read manager Critical patient in In ICU, we do advocate for early introduction of enteral feeding in daily monitoring of their ammonia. In terms of other treatments that you think about liver disease. There is. There's no evidence for rifaximin or laterals in patients with acute liver failure. There is a higher instance of pancreatitis. And actually, I think that's probably something that we do miss reasonably frequently, and I'll S is much more calling these patient's. And it's a worrying sign because of its association with increased rates of success. Uh, and as a routine, these patient's would get 20 mg of pantoprazole, also slightly less than our standard 40 mg pantoprazole. Doing coagulopathy is another essential diagnostic criteria. On paper. The wrong numbers for these patient's often look horrendous. So I on ours of, you know, 89 pts of 70 and 80. Actually, that doesn't always correlate to an increased bleeding risk because of the rebalanced, rebalanced coagulation state that these patient's have. So they have a reduced synthesis of procoagulant clotting factors and by the disease liver. But that's compensated by a simultaneous reduction in natural anticoagulate like protein C prettiness and anti thrombin. Which again, that's why we don't advocate correcting the numbers unless the patient is actually bleeding and when you go and do point of care testing on these patient's. So So we used to use Rose, um, when I use Clot Pro Works in the same way. The studies have shown that when you do do point of care testing, actually, 35% of those patients are hypercoagulable, only 20% are hypercoagulable, and about 45% have this normal rebalanced coagulation state. So again, just to reiterate that although the numbers look awful, it doesn't always correlate to the patient's actual bleeding risk. In acute liver failure. You get this dynamic immune dysfunction, which is associated with significantly increased rates of sepsis and 50% of patient's developing pneumonia, and nearly 1/5 or over 1/5 develop. UTI and Catherine just bacteremia are much more common, and that's because the liver injury or any liver injury of the nature leads to activation of their innate immune system. It alters their Mac fridge function, and they get this functional immuno process, coupled with the fact that liver cell death results in huge release for inflammatory cytokine, increase vascular permeability and a difficulty to formally diagnose sepsis because they already have a lot of presenting features associated with their acute liver failure. So they're at much higher risk of developing infections, sepsis and septic shock. And nowadays, infectious complications are the leading cause of death in these patient's. It's a reason why patients might actually not proceed to transplant because they have severe, untreated infection. And there's significantly increased mortality in coexisting infection in these patient's in terms of what they grow. Gram negative, enteric basilica and gram positive cocci are usually the most common, and in any patient who is intubated because of acute liver failure, will normally start prophylactic antibiotics, so that's cool amoxiclav three times a day with the penicillin allergic, they get Super and Bank, and they all get fluconazole a standard because one third of these patient's can also develop fungal infections largely from candida species, and it's commonly co existent with their victory, allow infection. And worryingly, there are rising rates at MRC and VRE, which again are putting more and more challenging to treat just to touch on some other treatments that are available. Um, there's a move now to starting high volume plasma exchange in patients with acute liver failure, predominately based on this paper from from 2016, in which was a randomized multi center study of 100 and 82 liver failure patient's. And they instituted plasma exchange. And they showed improved biochemistry, improved immunological data and actually and specific benefit in patient's who didn't undergo liver transplant due to Contra indications and those who deteriorated whilst waiting for our graft. A lot of centers have subsequently adopted plasma exchange is standard based on this, and I'm not sure if there's any studies coming out. But there is definitely a database been collected of patients who have received plasma exchange for acute liver failure, and we're still sort of finding our feet with it. We we can provide it if necessary. Um uh, Well, we have used it. We've definitely seen a correlation and reduction of these oppressors, but the patient groups that are maximal benefit. I think we're sort of yet to to identify, so it is a treatment that we can offer him. But it's not being offered routinely in the Royal infirmary, so so moving on to actually getting listed for a transplant from acute liver failure. What actually happens so firstly, the patient will have to be inpatient in the i ICU, and they'll be regular MD tea discussions regarding whether or not the patient is suitable for that. And they will need to meet some of the super urgent listing criteria. And then you'll be added as a super urgent patient on the delivered transplant list. The surgical team will receive a number of offers for the patient and that will depend on the patient's and the speed at which they get offers will depend on the patient's blood group and the number of other super urgent patient's in the UK, and I'll talk you through the proper full NHS Bt super urgent listing criteria and once uh, suitable organ has been identified for the patient and and then there'll be a further MDT discussion regarding whether the patient is fit for transplant because, as I'm sure you've gathered from the last 30 odd slides that these patients are very sick and putting them through a major operation and might not always be possible. Um, once you're listed, the coagulation parameters are are less important, so the coagulation can be corrected, and but again it's It's not often required and can be corrected acutely during the transplant itself. If, if need be, they'll then be a decision regarding the timing of theater itself. And liver transplants frequently happen in the middle of the night, and that's a combination of factors. And if you think about when you withdraw on patients' and I see you when everything proceeds to donation, it tends to happen during the day by the time that organ then makes it to the appropriate site is often the middle of the night. And then there's a time pressure and for the organ to be transplanted. So that's one reason why it ends up that way. And then we will then proceed to the theater with the patient in terms of the offers itself. And like I said, your blood group will determine how quickly you get an offer, and if your blood group a B. Then you've got on the elective list. You'll have a mean waiting time for that about 27 days. If your blood group A it's about 60 odd days and if you're blood group O, it's 100 and 20 days, so your blood group type will depend on how quickly you get an offer just to give you an idea of numbers. And last year there were about 1400 deceased owners of those patients', about 1000 livers were offered into the system, and 800 of those 801 of those livers were used. So you frequently we'll get offers within 24 hours. I think the median waiting times between 24 48 hours for actual transplant of the organ itself. Once an organ does become available, it'll be picked up by the by the hub, and they will work it through the different tiers. And, as you can see, at the top of the list is a super urgent criteria. Working through the actual listing criteria itself. The first we classically think of the king's college criteria and you know two different tables, one for paracetamol overdose one for for non paracetamol, but it's actually much more complex than that and King's college criteria. It's not the only listing criteria there are. Other criteria is like the cliche criteria, which is used throughout Europe. In the UK, we use the king's college criteria. The first four categories are based on paracetamol poisoning. Most commonly, you'll see category, too, where they have a PT of greater than 100 cracked that have greater than 300 or a new area and grade 3 to 4 in careful opathy for the anybody who's intubated and ventilated, Category four, you'll see allows a little bit, a little bit of flexibility within the system and a patient who meets two of those three criteria. But there's clinical evidence that they are deteriorating so that maybe we're concerned about raised intracranial pressure, worsening oxygenation, increasing inotrope a visor pressure requirements in the absence of sepsis. They could maybe then get listed based on that categories five and six, or for the and seven, or for the non paracetamol patient's, so can criteria. I'll just leave it there for you to have a quick look up, very different to the to the party tomorrow. Listing criteria. Um, Seronegative Hepatitis was classically referred to as non H e hepatitis, but now Seronegative is the is the wording of choice to define that. You also see that patient's you present with acute Wilson's disease or blood. Chiari. You have coagulopathy in any great event. Careful open. They have their own criteria to be listed within a super agent criteria. Because we often think of Wilson's as a cause of chronic liver disease. You can actually listed super urgently if you have that. And then, finally, that the other remaining categories taking up to 11 are slightly more nuanced. So patient's who've had a transplant but develop hepatic artery thrombosis patient's who have primary non function of their graft or patient's you. For whatever reason, they've had a total hepatectomy and have complete absence of liver function. Category 11, I think, is quite quite interesting, and that's any patient who's been a live donor and part of the liver. You then developed cereal. Liver failure within four weeks can also be listed under this criteria in terms of the actual contra indications to transplant, uh, talk to you shortly about patients who are too sick to transplant. But in general, patients who have evidence of irreversible brain damage, additional malignancy or uncontrolled Septus would be contra indications to transplant. The other remaining factors are mostly picked out by the psychiatry team, so multiple episodes of self harm or recurrent wish to die in chronic refractory mental illness. Dementia, noncompliance These are This is why an early psychiatry review, if possible, is very helpful because it helps to tease out some more of these potential issues again. As you picked up these patient's and I see you're often very sick. But when are they too sick to undergo a liver transplant, which is ultimately the treatment that they need? And unfortunately, there are no guidelines or validated clinical tools that are there to help you with this decision making. It's very much a multidisciplinary clinical judgment. There are factors that are associated with a poor outcome, so older patient's patient's who have ongoing cardiac dysfunction or very high busy pressure requirements. But to remain like I said, it's it's common, but it's not an absolute contra indication to transplant, although they will have worse outcomes following that, um, profound hypoxia so ARDS with, uh, patient's are on 1 80% auction is generally a contra indication to transplant and those who have significant neurological injury, which is difficult to predict because they don't have the same clinical signs that you might see. And so again it makes that is a judgment call, and sometimes it might go the other way, and you have a patient who's been offered deliver, but they're continuing to improve. And actually you think that they no longer need a liver transplant, and I further feel multidiscipline discussion would take place as to whether that was appropriate. It's worth noting that the surgeons will get lots of offers, and they're more likely to accept a more marginal liver for these patient's and just because of the organs that are available. And actually having a transplant with a more marginal organ is better than not getting a transplant. And again, that's a start on the spot clinical decision, and in some cases, the actual liver that is within the patient is causing more harm than good. And if they have a liver that's on route and you can proceed to hepatectomy and start the transplant before the new liver arrives, it is obviously high risk and not done without significant thought. The transplant itself, um, the patient will move from from I see you around into theater. It's really common that they'll get a bullet in mannitol before transferred for lying the patient flat and the disruption that will cause movement through the theater just to kind of prevent any potential rises in the intracranial pressure. And we'll then prepare them for the transplant itself. So put some new lines in. That was why I was discussing keeping one side of the line one side of the neck free because they'll come to get a a Mac line, which will then flow to peak after down and probably a second central line. And if they're on, you know, replacement therapy, we will keep that running. And actually putting a line into the groin is probably helpful for the transplant itself because it allows the if you think about the things we of theater having, uh, the dialysis machine down the bottom of the patient connected to the growing saves a lot of space at the top end of the patient. And there there are three distinct phases through, uh, a liver transplant, that I'll talk about in a second because they each associated with their own complications and particularly in acute liver failure and transplanting these patient's. They have their own problems. The surgeons themselves really like doing these transplants, because patient demographic is is very different. For for chronic liver failure. They often have a shrunken scerotic liver with distorted anatomy, uh, abdominal wall, feel of viruses that they have to pick through before getting to deliver itself and then complicated dissection. Whereas in acute liver failure, these probably are not frequent problems that that that the encounter it's also worth seeing that following transplant for acute liver failure, re transplantation is more frequent than in elective cases, so the transplant itself has three real distinct phases. The first phase is dissection down to prepare the deliver commonly associated with bleeding. Like I said, that you may have trying to present these patient's have quite significant coagulopathy, and it's likely that they're already on high doses of phase oppressors before we even start the operation itself. Once they've taken the liver out, they have an antibiotic phase which is associated with worsening hypoglycemia, hypocalcaemia and again, severe metabolic derangement. And just as you've got the patient through that phase. We then re perfuse a cold ischemic organ and the ischemic reperfusion injury that's associated with that. They often develop significant hyperkalemia. And again, you might get escalating doses of your your basal pressures post transplant for acute liver failure. And these patient's remain intubated, and we, as a rule, leave them for a bit similar to ours before performing a sedation hold. As tempting as sometimes it is, we can now move to aggressively correct the coagulopathy if need be. And actually, once the new liver is in, you often see an immediate improvement in hemodynamics and even even in theater. Once the once a new liver is has been transplanted, you quite often see a fairly rapid drop in in their lactate and drop in their visa pressure requirements, and we tend to continue, you know, replacement therapy, and we'll continue our sodium and map targets for at least 72 hours. They routinely would get prescribed hydrocortisone, azathioprine and tacrolimus is in expression, but they don't often need as high doses in the immediate post transplant patient as the chronic liver failure group, And we would continue prophylactic antibiotics and and antifungals in these patient's. As I said, they're at higher risk of post transplant complications, so higher risk of bleeding. It's a bit harder to gauge their fluid balance. And because typically, anyone post liver transplant has quite a large fluid requirement. And trying to keep up with that can sometimes be challenging. They're at higher risk of thematic artery thrombosis and primary non function of the graft. The risk of acute renal failure continues. It can become significantly fluid, overloaded if they needed lots of blood products within theater itself and their risk of sepsis continues. And as I said, that is the main cause of mobility mobility, sorry there at higher risk of developing other cardiac complications. And, as I said, rejection and re transplant is generally more common than in the elective population. Having said all that, outcomes following transplant are actually very, very good and really comparative to patients who receive an elective transplant. So at 55 year survival, post acute liver transplant is 82%. Give you 2 83% in the elective population. Other things are worth noting as they're real. Function might not always recover, and if a patient can get away without having a transplant, and their acute liver failure gets better, then these patient's do have better outcomes than those who needed a transplant, and those are not transplanted. Depends on a variety of features. It depends on the initial insult in the pre existing liver function and whether or not you can avoid any other complications that we're all familiar with. The inevitable long stay. And actually that these patient's would have, uh, in terms of the future or other things that can be done. Uh, when I started, my first job when I see you was as an F y, too, when all the patient's with acute liver failure got started on the Mars machine through molecular absorbent and recirculating system. And there's still this this dream that there is a liver dialysis out there or something that can provide a bridge to transplant or recovery. And there are the technology that was used as a date. But people have not given up, and there's lots of new, um researching into possible extracorporeal liver assist devices or biological systems that involved porcine hepatocytes and different absorbents. So that may well be coming to a transplant unit near you. Other options are an auxiliary transplant. We don't do this, but it's not an uncommon procedure when the rest of the world, where a patient will have part of a liver transplanted alongside the native liver and it will remain there until the native liver function returns. And once it returns, administration has stopped, and actually this is associated with reasonable survival rates. Patient's can also have HBO incompatible graphs, but the risks that are significantly higher and actually in Japan for 98% of acute liver failure transplants. They're done with a living donor, and I'm not certainly not done. We've not done that in in Edinburgh before. Asked me to come to the end of talking about acute liver failure just for two minutes, I will talk about a new listing criteria that you might have seen when I put that list of nine different criteria, and that is acute on chronic liver failure, and this is different. Particular failure is very different, actually. These are patients who are known to have established cirrhosis but who developed acute liver failure. On top of that, I think classically the whole visit. This will pick up patient's who have got chronic liver disease and haven't known about it and then developed an acute injury, and it allows them to not be disadvantaged when receiving a transplant. It needs a significant MDT listing decision. It needs to be discussed between multiple centers as to whether they're going to proceed to to listening, and they're relatively strict entry criteria. So you have to be over 17. You have to have known cirrhosis with liver failure. You have to be an inpatient and critical care with organ support. And there are different scoring systems for acute on chronic liver failure. But you should have an expected 28 day survival of less than 50%. So it may well be that you have patient's with chronic liver failure who acutely decompensate to actually maybe meet these criteria. So it is worth if you think this is appropriate having a conversation with the transplant team and at least having a discussion with them because now there is a separate listing criteria for these patient's. It is below the super urgent priority. But it is above the the standard standard list have to be pragmatic. So there are a group of patients that will not meet this criteria. So if you're over 60 if you've had a previous liver transplant, if you have any active infection or CMV e again irreversible brain injury or multiple organ failure without worsening trajectory, if you go on ECMO very frail or have other malignancy or pancreatitis, then you would not be suitable for transplant on this criteria. And I think that probably would rule out a significant number of patient's in there. I see you, so thank you very much for for listening. I was useful to you just to say, That's my email address If you do have any questions that you want to ask out with this and a big thank you to a number of other consultants that I work with who developed the acute liver failure protocol and I talked you through your soul in particular David Cameron Relays, Oliver Robinson and Cream Beauty. And so, no. Yeah, thank you very much. Thank you very much, Scott, There for talking us through a really comprehensive overview of acute liver failure. Um, if anybody has any questions for for Scott, if we if you take them in the chat box, I'm and we'll be able to to pop them to him. Um, I've got a question, Scott, if that's okay, we talked a little bit about plasma exchange, which is something I've kind of heard you all delivering sense of us talking about in our meetings Occasionally, obviously, Plex causes quite a lot of, uh, coagulopathy with them itself. Um, and do you with so much of the listing criteria being based on, you know, meeting, You know, PT and I are how GT's apart coagulable caused by the play X versus worsening liver dysfunction. Yeah, so I mean, our our experience of it is relatively limited. But speaking to people in kings who use it for all patients with acute liver failure, um, they one of their concerns is they don't want to give plasma exchange and then possibly take the patient out of criteria or because ultimately the treatment that they do need is a liver transplant. The reality is that the half life of FFP is about eight hours. So even after stopping it, you will still be able to reassess their coagulopathy. And you would still see that deteriorating change in terms of how you provide it. I think it's it's about because it's done in three consecutive days. If there are periods of time where you are able to assess their quiggle out with them getting the plasma exchange Perfect. That's interesting. Uh, does anyone have any other questions for Scott? Better. Yeah. I don't know if people are just typing. Sorry. Right. Uh, okay. Yeah. Okay. Uh huh. You get some energy? No problem. Uh huh. Yeah. Mhm. Yeah. Champions just say thank you. And I guess, um uh, there's a There's a very large number of people have joined this webinar. So we had a one point over 100 people on, which is fantastic. And I think that probably reflects, uh, the want to hear a bit more from, uh, like, say, subject matter experts. So thank you so much, Scott, for joining us and for giving us that overview. Um, if I could go back to the shameless plug for the Scottish Intensive Care Society sm meeting that is coming up next year again lots and lots of really fantastic speakers that will be coming to that. As I said to you at the start, there's a really great program for these education evenings. Um, that we've got lined up for the next several months. So on the 15th December, which is a four weeks from now. Thursday, 15th at seven. O'clock. Um, we're going. We're going west. Um, And Robert, docking from the QE will be, uh, smoking to us to give us an ICU trials update. I've heard him give this similar talk before. I has a real art for turning complex, uh, studies study design into something that's interpretable, um, and tangible for the mere simple, simple intensive. It's like me. Um, so, uh, the registration link will be coming for that soon. There's some questions appearing in the chat box now, Scott for you. So I Andrew Redferns asking you mentioned there's little evidence for rifaximin and latch lows. Do you ever use these or could you clarify when when they would be used? We wouldn't use them in acute liver failure, I think because I was trying to touch on the the way the hepatic encephalopathy develops in acute liver failure and current liver failure is very different and were recently a talk that we're talking about these sorts of treatments and actually alias is very, very common in patients with liver failure and actually giving them the facts of intellectuals doesn't make any difference anyway. And so I think partly if you're giving, like, close to somebody with an alias that can make it worse, so we would certainly not routinely prescribed them in acute liver failure. How do I think it will develop over the next 10 years? Um, it's a very interesting question. Truth. I'm not sure I'd be interesting to see some of the future developments that I mentioned at the end. It would be interesting to see if any of those do come to fruition. Um, it was a lot of a lot of them work going into different studies, looking at this kind of concept of liver dialysis, and in theory, it feels like it's something that should work. It's just trying to find the right method method of doing it. I'm not sure whether a living donor liver transplants for acute liver failure will be something that comes in in the United Kingdom, and I guess there's a lot of work into other types of extracorporeal life support and their utilization in liver transplant, and people who work in kings do a bit of e C l s. And in patients with acute liver failure, either to stabilize them before transplant or to manage them post transplant. And they refer to as two different things. They refer to you CLS, extracorporeal life support or extracorporeal liver support. So, really, you're just supporting the patient's in circulation to allow their their new liver to work. So there's probably will be more work getting done in that field, not in Edinburgh, but certainly other sites. Can I ask Scott if, in terms of e. C. L s in mechanical support for patient's who have acute liver failure? Is that all only done in those specific centers when a patient's suitable for listing? Or do they do that out with that context as well? There's no real guidance on it, and I think it's very specific on the center that that you present to and the expertise that is available to you at that center. I have no experience in using it in context of these patient's, so I don't think I can properly answer that, Uh, Stephanie Kelly is asking about in patients who have had a transplant or in have had acute liver failure. Who's renal function doesn't improve? Is there a mechanism for listing them for renal transplantation? Or is that something that happens? Yeah, I don't know if there's a a special criteria for that. Certainly those that go on to and require dialysis post acute liver failure. A lot of them do actually have some kind of renal recovery, and they so they need intimate human dialysis for a relatively short period of time. But go on. But their native renal function does return in terms of whether there's a separate mechanism for listing them. I'm not sure if they in the chronic population, if you present with both chronic renal failure and chronic liver disease, there is mechanisms for performing both those transplants at the same time, and you can be listed and have both of them done at the same time. That doesn't will not be required for acute liver failure. The question is already they're finding through, Um, there is a question here about the acute chronic failure suggest that patient's are already receiving critical care. But in many cases, we might be reluctant to offer ICU for patient's who aren't going to be a candidate for, um for, uh, for listening under that new criteria. Uh, asking is it Is it an appropriate thing to do to just speak to the to the hepatologist before you're thinking about admitting them locally to your center? Um, I think the discussion would need to go through the hepatologist. First of all to make sure that they meet definitely meet criteria. I think it's going to be a complex patient group to manage in the future. And I think I would probably get fired by suggesting that all patient's with cirrhosis and I see you get transferred to the royal infirmary. That might cause problems, but there's a I get. I get the group that they're trying to target as these young patient's. You've got chronic liver disease. You've been managing fine, who have never reached the point of needing to be assessed for a transplant and then have a sudden acute decompensation that would prevent them from ever being listed in the normal way. I think that's the group that's really trying to target so that they can. They can get a transplant when they need it. I think what's more likely is you have somebody who's got cirrhosis who has a virus. It'll bleed. Who then ends up needing intimated for control of that, who then ends up on some laser pressure is because the urine propofol for sedation, then something. You've got a patient with cirrhosis who's requiring multiple organ support. And the UK certainly are very much finding the way with who are the appropriate patient's to then follow up on and proceed to to listing under acute on chronic criteria. And we have in Edinburgh, and I personally have fairly limited experience in it. So that's that's my taken it, having listened to different people talk about it, I think we're there's a bit to go before we really refine which patient's need it. There's an interesting question here about the use of tea we for Patient's. I'm assuming that's doing transplantation for patient's about yes, so we are mode of cardiac output. Monitoring in a transplant is a P A catheter, and other sites would use routinely use tea. We I think the reason that we probably don't use it more routinely is, um, just expertise within our group. I mean, I think it's I don't think it's an absolute contra indication I think it's definitely And there are cases where it might be useful. And there are cases. There are patient's on our list that we've flagged up to the cardiothoracic team as we may actually want some help with the t o e intraoperatively. If if that's the case, so it can be done, we don't do it routinely. But certainly other sites do right. And the last question is about, I think a site specific thing they use I h d rather than CVH d is the ability to inability to provide a kind of therapy. A reason in itself for transplant referred to a transplant center. Um, I wonder if it's slightly academic cause. I think anybody who has acute liver failure that's needing that's gonna progress to any form of renal placement. Everybody should be referred and should be transferred to the Royal whether they are a transplant candidate or not. That that is quite clear within the guidelines is that you know, even if they're not suitable for transplant, they should be managed in a center that's familiar with looking after them. Um, so, as in whether you whether you should give whether you should start to be on hemodialysis or not. I'm I am not sure of the right answer to that. I think a prompt transfer is probably the best thing for them. Great. Thank you so much in for your time giving up your Thursday evening for this. As I said, the next session will be on the 15th December. Bob talking will be talking about ICU trials, updates and keep an eye out for that coming. If you guys would like to, uh, give some feedback and generate a certificate for COPD purposes, I've popped the link in the chat there for you to give some feedback, and that'd be really useful, as it helps us kind of develop the session's over the coming months. So thanks again to Doctor McNeil. Thank you all for joining and hoping to see you all in a few weeks. Time on the 15th. Thank you. Yeah, right. Okay. Mhm. Yeah. Mhm. Yeah.