Thank you, Professor Bulluth, for the kind introduction. I'd like to thank the organizers of SCCM 2023 for asking me to talk on something which I'm very passionate about, that is survival of acute liver failure without liver transplant. Seems a bit silly, but that's the talk, and I'm gonna talk about is it a fact or is it fiction? I've got nothing to disclose. So in the next 20 minutes, my job is to convince you guys that liver transplantation is not the only treatment for acute liver failure. There are loads you can do medically, there are loads you can do from intensive care perspective before you embark on enlisting a patient on this very high-risk procedure of liver transplantation. So in doing so, we'll talk about the natural course of a child with acute liver failure and what all medical measures can be put in place to avoid liver transplant. For example, coming to a definitive diagnosis so that you can start etiology-specific treatment. We'll talk about the role of extracorporeal therapies, whether it's CRRTs, total plasma exchange, albumin dialysis, when to, how to, and why to neuromonitor and neuroprotect, and finally we'll end by talking about some novel extracorporeal devices and the role of hepatocyte and mesenchymal stem transplantation. Now this is what we have been traditionally taught. Liver transplantation is considered the gold standard of care for children with acute liver failure with a good long-term patient and graft survival. If this was true, then why not continue with liver transplantation and why are we here today? This is, if you look at critically, the process of liver transplantation is actually a disease, it's not a cure. You are on lifelong immunosuppression, you get frequent infections, there's growth failure, there's shortage of organ donors, and very important, there is some amount of donor mortality in areas where there's a live-related transplantation. So we need to be innovative and talk about transplant-free survival. And the concept of regeneration is not new. It's 1600s, if you look at the story of Prometheus, this was a Greek god who gave fire to the mortals and his fellow gods then chained him and left his liver exposed to a vulture. The vulture would come, eat on the liver every few days, and the liver would regenerate. And if you look at this explant from a patient with acute liver failure, you see these green nodules, these are the regenerating nodules, this one is your collapsed architecture, and it's this battle between your collapsed architecture and the regenerating nodules which is gonna decide where this particular patient is gonna end up with a liver transplantation or will survive without liver transplant. So it is very important when to and who to list for liver transplant. Because you might list a patient for liver transplantation who may have survived spontaneously, or you may list a patient who is too sick and with minimal hope of post-transplantation survival or have contraindications for liver transplant, thereby wasting a vital organ. On the other hand, yet there is a risk if you don't list a patient who will actually die without liver transplant, if you don't list them, there's a huge risk involved there as well. So we need a prognostic model. We need a model which can help us allocate these scarce organs to patients who will die without liver transplant, at the same time avoid unnecessary liver transplantation and its complications. Now, is there a proof of concept? How can we say that liver transplant can be avoided in patients? And that comes from a surgical procedure called the auxiliary liver transplantation. If you look at auxiliary liver, where you leave a part of the patient's own necrotic failing liver behind, this is the native liver, and you give a part of a donor liver to the patient. So at any given point in time, there are two pieces of liver, patient's own liver and a donor liver. And what happens over time, you will see here, this is immediately after the auxiliary liver transplantation radionuclear scans showing most of the activity in the donor liver. There's hardly any activity in the necrotic liver. At seven months, you see that this part has regenerated now and there's almost equal activity. We then withdraw the immunosuppression and you see at about 18 months, the piece of the liver which you had given has completely atrophied and you have got maximal activity left now in the donor liver which was failing. And this is shown in this histopathology slide as well, complete chaos in this slide because the whole architecture is destroyed. Look at six months, regeneration has started. At 18 months, there's complete regeneration as if nothing had happened. And what we have found is more than 70% of native liver regeneration takes place within one year. And that brings us back to the same question I started. Are we over-transplanting children? And if you look at the pre-transplantation era here, 72% of children used to die because there was no liver transplant. As liver transplantation, as depicted by this green bar, started to happen, more and more children used to get transplantation. But you can see here, as the years are going ahead, almost 70 to 75% of children are actually surviving without the need for liver transplantation. And very importantly, 10% of patients who are listed for emergency liver transplantation are delisted because their livers have started to spontaneously regenerate. And seeing all that, this is what the natural course of a patient with acute liver failure would look like, a rapid decline of liver function, patients slipping into multi-organ failure. We give medical therapy, the patient is too sick, patient dies without a liver transplant. On the other hand, look at this bar where your black and your maroons are on each other. This is when a patient gets a liver transplantation, patient survives 85 to 90% of the time, but then can still die 10 to 15% of the times after liver transplant. What we are interested is in this maroon bar going straight up, this means the patient's liver has regenerated, so you've got four outcomes here. Survival with transplant, survival with your spontaneous native liver, death following transplant, and death awaiting liver transplantation. And it is here where the patient is slipping into multi-organ failure where you give multimodal organ support, and we have summarized this in a paper in Intensive Care Medicine where we talked about non-transplant options in pediatric acute liver failure, what is new. We talk about general measures. Very importantly, starting etiology-specific treatment. We talk about neuromonitoring, we talk about neuroprotection, the use of extracorporeal support therapies, immunomodulation, very important in this patient, and we talk about the innovative measures which have got a pathophysiologic basis in acute liver failure, and hopefully they will be successful. I'm sure you have seen this slide from the previous speaker, and we'll see it again as well. This is the adult data. If you look at it, 68% of the etiology is drug-induced, whether it's paracetamol or other drugs, and there are four or five etiologies in total. Only 17% of their patients have got indeterminate or non-A to non-E pathology. On the other hand, this is what happens in children. Loads of etiologies, and despite all the funky tests we do, still 40 to 50% of our kids are left with no etiology, no diagnosis, again, indeterminate etiology. And it is not only the etiology which is different, it is different ages have got different etiologies, making life even more difficult for us as intensivists. And as my colleague has explained before, finding etiology is important because your rate of spontaneous regeneration is dependent on it. If you look at this figure, patients who had paracetamol, about 66% of patients survived without a need for transplantation. But if you look at patients who had indeterminate, only 22% had this. So finding etiology is important. These patients have increased incidence of hepatic encephalopathy, they have decreased spontaneous native liver regeneration, and unfortunately, you can't start any specific therapy. So what are we doing as a community to narrow this gap of 40 to 50%? I think we need to have a very systematic approach to work up. We have started doing next generation sequencing for these children, and when we look back at our data, of the 41 children who had indeterminate etiology, about 20% of them were able to find an etiology. So very, very important to find the etiology for treatment, but also in prognostication because you might decide, if you have a patient who had a mitochondrial disease, you might decide not to list the patient for transplant. So both for diagnostics and for prognostics is very important. Now if we are talking about the different medical measures, we really need to know what kills these children. And the main cause of mortality in these children is cerebral edema, raised intracranial pressure, and sepsis with multi-organ failure. Now this is a human data looking at the correlation of ammonia. Now there are loads of molecules which are implicated in the pathogenesis of hepatic encephalopathy, which my colleague is gonna address. But the one molecule which was the first molecule to be identified as a causal link and the treatment point was ammonia. So it is hyperammonemia at presentation. You see the different levels of ammonia, 100, 100 to 200, and more than 200. If you have a level more than 100, you can easily say this patient will have hepatic encephalopathy with 80% accuracy. If you have ammonia levels more than 200, this patient will have raised intracranial pressure with about, again, 90 to 95% accuracy. It's not only hyperammonemia at presentation, it is persistent hyperammonemia. You look at hyperammonemia, ammonia more than 200, less than 200. Patients whose ammonia fell in 48 hours, those patients survived better. And on top of it, if you get hyponatremia, that potentiates the effect of hyperammonemia on the brain. So hyperammonemia, hyponatremia, not a good combination. And what has completely revolutionized our thinking, our understanding of the pathogenesis in acute liver failure is the concept of systemic inflammation. So acute liver failure is an innate immune-driven disorder. You've got monocytes and macrophages which become pro-inflammatory. You can see here, there's hepatocyte death, loads of damps, and your monocytes, your neutrophils all become pro-inflammatory. Your pro-inflammatory macrophages and you get a cytokine storm. So in summary, what you see here is damps making it tissue inflammation and systemic inflammatory response. And what you get is a perfect model of multi-organ failure. It's a spillover of your cytokines from your liver into your systemic circulation, therefore leading to all the organs failing either simultaneously or one by one. So we talked about extracorporeal bridging devices. What do they actually do? They remove your ammonias, they make your encephalopathy better, they decrease your cerebellar edema, they take care of septic AKI, create space for nutrition, and very importantly, they can work as an immunomodulatory agent. And what they're trying to basically do is to create a conducive environment for either spontaneous liver regeneration or if that liver is not getting available, to bridge you to a time till the graft becomes available. So when we talk about extracorporeal devices, we talk about artificial support and bio-artificial support. And most commonly, we talk about artificial support in our day-to-day practice. We talk about albumin dialysis, we talk about CRRT, we talk about total plasma exchange. And when you talk about bio-artificial, it's talking about human hepatocyte bioreactors. And CRRT is strictly not an extracorporeal liver assist device, but that is what we actually use in our day-to-day practice. Now this is a slide from the PPCRRT registry showing the survival of children with different etiologies when they were put on CRRT. You see that the overall survival is 58%. But when children are put on CRRT for liver disease, their survival drops to 30%. So the question is, are these patients genuinely too sick or are we entering in late? And what are the indications? This is a European survey of adult patients with acute liver failure. And you can see people are putting these patients on CRRT for varied reasons, where it's acidosis, it's oliguria. So not one indication you can pinpoint and say this is the indication we are using. And this is what is our guideline at King's College Hospital for children who go on to CRRT. So we, as you can see here, start CRRT for non-renal indications, hyperammonemia, hepatic encephalopathy grade three and four, and what we say is early. Early for hyperammonemia, early for fluid control, early for nutrition. The next question is, what dose do we use? Claudia Ronco's paper had told us 30 to 40 mLs per kilo per hour. But then Jules Vendon and Andy Slack from King's looked at this comparison of 35 versus 90 mLs per kilo per hour, and you can see here linear correlation between the dose of ultrafiltration and ammonia clearance. So higher the dose, more is the ammonia clearance. And very interesting is this graph here, which shows an inverse correlation, which means if you have AKI, your clearance of ammonia decreases, which means AKI in the setting of acute liver failure is bad. And this is a high-volume hematofiltration paper from my colleague Pierre Tessere's group in France, where they had 22 children. All were sick, all were listed for transplantation, and all were on high-volume hematofiltration, where he defined high volume as 80 mLs per kilo per hour. The median dose was as high as 120 mLs per kilo per hour. So really high dose, but what's very striking is they were able to delist 25% of the patients, and they saw an improvement in hemodynamics, and they saw an improvement in the hepatic encephalopathy grade as well. Then we at King's looked at the effect of continuous renal replacement therapy on outcomes. We had 45 patients who went on CRRT. You can see our survival rate was 58%, but what is very interesting was 16% of them we were able to delist again. And what was very important was the difference between survivors and non-survivors. In survivors, you can see that at 48 hours, we were able to decrease our ammonia, whereas in non-survivors, either the ammonia is not coming down or it's actually going up. So failure to reduce ammonia within 48 hours of CRRT initiation was a poor prognostic sign, and that's what we concluded. Early implementation of high-volume CRRT, which reduces ammonia within 48 hours, it provides us with an increased window for spontaneous regeneration or emergency liver transplantation to become available. But of course, we need to be mindful when we talk of high-volume because we're gonna remove your drugs and it's gonna remove your nutrients as well. And talking about the cytokine storm I talked about and the inflammation we talked about, therapeutic plasma exchange seems to be an ideal modality. It's gonna do both your synthetic and the detoxification function of the liver, and I'm not gonna go into details because our next speaker, Dr. Manning, is gonna address this. And all I want to show is this paper, which again is gonna be discussed later, is the Finn Larson study where he looked at controls with standard medical treatment versus a high-volume plasma exchange. And based on this paper, the European Association for Study in Liver Disease incorporated plasma exchange as a vital therapeutic modality in the treatment of acute liver failure. This is a paper from Tokyo where our colleagues looked at children less than one year of age and they combined CRRT and total plasma exchange. Remember, they were less than one. This is a high-risk group, but still their survival was 88%. Does that give us a signal that combining CRRT and total plasma exchange will do the trick? So again, there is no one way people are giving CRRT and total plasma exchange. So we in Europe, the European Reference Group on Hepatological Disease and ASPENIC are collaborating to produce a position paper on the role of therapeutic plasma exchange across Europe, which will be out soon. Now you are removing the water-soluble molecules, but what about the protein-bound toxins? We talk about albumin dialysis, whether it's MARS or you talk about single-pass albumin dialysis, very much institution-dependent, very much depends upon what your patient population is, what your waiting time to liver transplantation is, and what is the level of bilirubins and hepatic encephalopathy. We at King's, as an institutional policy, have not used MARS for the last two decades and we get equally good results by using CRRT. Now there are new toys in the market, cytosolvent. This is an adsorber, which instead of using convection or diffusion, it actually adsorbs your toxins and your trigger substances and lowering your cytokine storm and it can be used with the same CRRT machine, either pre-filter or post-filter, but the problem is the priming volume. It's about 200 mils is the priming volume of the circuit. And this is the selective cytophoretic device. Again, it can be used in series with your CRRT circuit and what it does very cleverly is it does not attack your cytokines, but it actually attacks your activated monocytes and neutrophils, which are producing the cytokines. So in an ideal world, if this works, this probably would be the future. So the question, does extracorporeal therapy bridge patients with acute liver failure? The answer probably is yes. There's no randomized control study, but it does decrease your cerebral hematomornia levels. It controls your inflammation and immune modulates and by combining CRRT and total plasma exchange, it does make sense, but people do talk about the timing and patient selection. I would say early, enter in early, hit them hard and keep the downtime slow. Very important your filter keeps working. The next area to discuss in neurocritical care, very, again, highly contentious as everything else in acute liver failure is, you need to understand the concept of hyperemia and ischemia. Both these things can happen in hepatic encephalopathy as opposed to traumatic brain injury. We are mostly dealing with ischemia. The next question about bolting these patients, very few in number. Who's gonna go ahead, for example, at King's, my neurosurgeons have been very polite and came to me and said, of course, Akash, I'm gonna bolt your patient. Give me an INR of less than one. The answer is clear, right? So what we decided was we need to make a protocol which keeps us away from bolting. So we talk about non-invasive monitoring of these patients. And these are the various modalities. At King's, any patient who goes on to CRRT, onto a ventilator will get a transcranial Doppler every single day, either once or more than once, depending on what we are doing. We put all the patients on near-infrared spectroscopy and all of them get a reverse jugular venous catheter to measure the reverse jugular venous saturation. So this is standard for our patients and some of them might get an optic nerve sheet diameter, depending who is on, and tympanic membrane displacement is also heard of. So this is the protocol which we published in the Lancet about a couple of months back. We talk about neuromonitoring. We talk about neuroimaging here. CT scans, MRIs, we don't go for them unless you've got unilateral dilated people and you're really worried about the patient. And how do you neuroprotect? The principles of neuroprotection remain the same, except that if you've got hyperemia as well, for example, you've got raised ICP and your reverse jugular venous saturation is very low, you might want to give the patient a dose of indomethacin, one to two milligrams per kilo. It's a selective cerebral vasoconstrictor which can decrease the blood flow to the brain, but you need to be very careful that you're sure that there is hyperemia in this patient. We target normothermia and we use CRRT as a neuroprotective device. So this is the paper I was talking about, Advances in Medical Management. This was published in Lancet in August and my colleague Jan Kabalut was one of the authors of this paper. Now coming to the last part of my talk, innovation. So we always say necessity is the mother of invention. If that's true, then I think vision is the father of innovation and it's true to say it because if you look at the lack of donor organs, if you look at the complications post-transplant and the success of auxiliary liver transplantation, there is no reason to believe that if you transplant liver cells in these patients, that would not be successful and that's what we do at King's. So this is the donor liver and we digest and isolate the cells here. We cryopreserve them and store them and test the viability and very important, when you look at the donor liver, they're the unused or unsuitable livers for liver transplantation. There could be a whole lobe, there could be a split liver, there could be actually just the whole liver and once you check the viability, then they're infused here through the portal vein and they get seeded into the liver here and start working as a synthetic and detoxification function of the liver. Each ML of this solution will have 10 million cells and the dose is 10 mils per kilo and this is what happens. So in the portal vein, you can see the cells going and getting seeded into the right side of the liver but what you have to remember is you're trying to access the portal vein in a coagulopathic patient that might bleed. You will have to give immunosuppression to this patient and you'll have to re-infuse more cells into this patient because the engrafting is only about 10% and there will be a risk of liver congestion as well. So what cleverly people did was they actually coated these hepatocytes in an inert algae called alginate. They're alginate-coated beads. Each bead contains about 300 cells. Each of this ML will contain 2.5 million cells. You can see this is the alginate-coated beads. These are all the hepatocytes and through the pores in the bead, you will start seeing the detoxification function of the liver and the synthetic function of the liver but very importantly, the pores in the bead are very small. The immune cells cannot enter and attack these cells so there is no need for immunosuppression. So coated, alginate-coated microbeads do not require immunosuppression but before you start giving these cells, you need to make sure that the cells within the bead are actually viable. So this is under a fluorescent microscope. You can see reds and the greens. The fluorescent green are the ones which are actually viable. The red ones are the dead cells. We expect the viability of 65 to 80% for these cells to be infused to a patient and when you actually use another software, these cells actually enlarge quite a bit and you should be able to come to a conclusion whether you are going to give these viable cells to the patient or not. So this is the needle going through the peritoneum and you are injecting these cells intraperitoneally. The previous cells, the hepatocytes were given into the portal vein. These are injected with the acidic fluid there. You're putting the needle through the peritoneum and give it into the cells. You can see here the starry sky appearance. These are the beads before transplantation. You can see intact bead with loads of hepatocytes here and after the transplant was done because this was a child who needed a bridge to transplantation, when we removed these beads and looked under the microscope, these cells were still functional. And this was a patient, 2.5 kilo, 14 days of high volume support, liver necrosis but had a normal EEG. So the options for us was either we bridge this child to liver transplant which could have been a problem looking at the size of the child, the waiting list would have been longer or we actually pull the plugs and speak to the family about end of life or you give cell transplantation and this was a patient who actually survived. He had a good survival and human liver cells within alginated beads injected intraperitoneally with no immunosuppression worked for this child. So this is our experience at King's. We have eight patients to date, herpes simplex two, neonatal hemochromatosis four and indeterminate two. Four of them were actually alive without the need for liver transplantation which means we had 50% native liver recovery. And then people started thinking how can we increase the viability, how can we increase the function of these cells and they said can we combine the mesenchymal stromal cells along with the hepatocytes and co-culture them, co-culture them within the bead. So what they do is they co-culture them and you find that the mesenchymal stromal cells which you can get from either the umbilical cord or the peripheral blood or the bone marrow, it serves as immunomodulatory anti-inflammatory agent and it decreases your oxidative stress in leading to increased viability, functionality and increased attachment. So this is what I was talking about. If you look at the purple bars, they are threes to one ratio. Three ratio of hepatocytes, one of mesenchymal cells, they're being co-cultured and you can see that the viability is much better than the green bars or the red bars which are in a different ratio of hepatocytes to mesenchymal cells. So this is what we are starting at King's. It's called the HELP trial, hepatocytes co-encapsulated with mesenchymal stromal cells in alginated microbeads for the treatment of pediatric acute liver failure and the recruitment is starting this month or we're all looking forward to this. And in conclusion, what we have found is there's been a huge paradigm shift, a paradigm shift from most requiring transplantation to now most recovering with spontaneous native liver with medical therapy alone. And this is made possible because you've got early access to liver transplant center. There is improved multimodal multidisciplinary intensive care which I talked about. We control the sepsis aggressively by using antibiotics and antifungals and of course there is an increasing role of this therapies like hepatocytes and mesenchymal cells and the outcomes of acute liver failure without liver transplant are getting better. But we still need to work on the prognostic model. That is a million dollar question. We still do not know the answer. Who are we gonna wait for and who are we actually gonna jump and say, right guys, here's a time to list this patient for transplantation. So yes, I do agree. I do agree that when a patient with acute liver failure comes to us, the patient is in multi-organ failure. You'll be all wanting to save this child and you want to go and list this patient for transplant. But my advice would be go back, think holistically. Look at what is causing the acute liver failure and look at what all things you can throw at the patient medically before jumping in to list this patient. So let's talk about regeneration and not replacement. And in the end, Stuart Goldstein and the European Society of Pediatric and Anatomical Intensive Care and we from King's College are organizing this first Congress of Critical Care Nephrology in London and we'd love to see you there. With this, I thank you for your attention.

acute liver failure

survival

liver transplant

extracorporeal therapies

neuromonitoring

hepatocyte transplantation