Thank you, Akash. Hello, everyone. Dr. Akashdeep gave a kind of nice preview into what the answer would be to this question. So let's talk about therapeutic plasma exchange. Here are my disclosures. None of them are pertinent to today's discussion. So the question, like I said, is, is it time to incorporate therapeutic plasma exchange into the ALF armamentarium? And it's a leading question. You heard from Dr. Deep before. The answer is yes. And I would say the answer is yes with an asterisk. We kind of have to think about the right patient, what is the right duration, how long to continue, what kind of, what's that dose going to be. So keeping all those things in mind, let's look into this further. So I'm going to be talking about what is plasma exchange? Can it help in acute liver failure? If yes, how does it work? And what are the details, like I said? What is the right situation, when to use it? What's the appropriate prescription? And what's a reasonable duration? And I should say up front there, we don't really have any guidelines or evidence to answer any of those questions. So as a nephrologist does in the ICU, I'll probably be stirring the pot a little bit here and raising some controversies at the end of the discussion. And then finally, I'll summarize a little bit about hybrid extracorporeal therapies. So you saw this image earlier, and I won't go into more details, but this is where extracorporeal liver assist devices come into play to try and see if this patient would get better. Does this patient need a liver transplant? Or is this patient not going to survive after liver transplant? And when we talk about the alphabet soup that is extracorporeal liver assist devices, lots of therapies come into it. CRRT, not technically a true extracorporeal liver assist device, but it's very commonly used. And then the other therapies are mentioned there, which you saw previously. And I'm talking more about the TPE either alone or with CRRT today. So what is plasma exchange? Plasma exchange or plasmapheresis, both terms are used interchangeably. Plasmapheresis basically means removal of plasma, and then therapeutic plasma exchange is when a replacement fluid is given for the plasma that is removed. It very rapidly, very efficiently reduces some of these pathogenic substances that are in the blood, autoantibodies, complement components, cytokines. And importantly, it can remove large particles, it can remove protein-bound particles as opposed to dialysis or CRRT. So that's where the advantage is in certain situations. However, it is important to understand that it does not treat the underlying disease. It is not going to fix whatever it was that caused the liver failure. It's only going to fix some of the problems created by the liver failure. So again, you saw a similar figure earlier. Acute liver failure is an overall and immune kind of process, where whether it's an infection or some other factor that triggers damps or damage-associated molecular patterns, and pathogen-associated molecular patterns. All of that leads to inflammation, leads to all the cytokine release, further which cause cerebral edema, acute kidney injury, and cardiac dysfunction, among other things. In this situation, adding plasma exchange can reduce these damps and pamps and cytokines, and it may improve your patient outcomes. It is going to remove immunoglobulins as well. You get some clearance of albumin-bound toxins here. So like I said, plasma exchange can remove these albumin-bound toxins, as well as some unbound toxins, which include your aromatic amino acids, endotoxins, indoles, mercaptans, et cetera. It will remove some of the inflammatory mediators, and with the ability to provide FFP in exchange, it can replace coagulation factors, fibrinogen. So it tends to mimic the synthetic function of liver, at least in this narrow way. Now, what does data show us? These are some studies that I've summarized here. So various studies looking at either acute liver failure or acute on chronic liver failure. Singer et al. from the US, they looked at 49 patients who all got plasma exchange, two-volume exchange, and 6% had native liver survival, 35% survived post-liver transplant. Similarly, the other studies, you can see somewhere between 50 to 65% survival, either with native liver function or post-transplant. So overall, it does seem to suggest that maybe this works. Now, what about how do we do this details of the therapy? So traditional indications for therapeutic plasma exchange are often listed as medically refractory coagulopathy, but again, we heard from Dr. Bouloute earlier today that we don't really have to fix the number here, and these patients are more likely to have thrombosis than bleeding, so perhaps that's not necessarily the ideal indication. Multi-organ failure as an immunomodulatory therapy is definitely an indication for plasma exchange, and I would say probably acute liver failure by itself is an indication for plasma exchange, irrespective of these factors here. When we look at the ASFA, which is the American Society for Plasma Pheresis, their guidelines suggest therapeutic plasma exchange as a recommended therapy for acute liver failure. Now, it's interesting here, they mention high-volume plasma exchange as a category one indication, which means it's strongly recommended, and overall, acute liver failure is considered a category three indication. Category three basically means we don't have a lot of data to suggest that it works, but you should individualize your decision and think about every patient, and then make the decision looking at the risk versus benefits. So what is this high-volume therapeutic plasma exchange? This was traditionally used in mushroom poisoning in adults, that's where it started, and they used twice total plasma volume, and then later on, there was a study, limited studies from Denmark, Finland, by Finn Larson and colleagues mostly, and this was one of the studies in adults, which was a prospective multi-center randomized control trial. So they had 182 patients with acute liver failure who were randomized to standard medical therapy or standard medical therapy plus high-volume plasma exchange for three days, and their exchange volume was 15% of total body weight, so much higher than what we are used to thinking about when it comes to plasma exchange, and they noted a hospital survival of about 58% for the high-volume plasma exchange group and 48% for the control group, and they said high-volume plasma exchange prior to transplantation didn't necessarily improve survival. The incidence of severe adverse events was similar. Importantly, more than 50% of these patients were acetaminophen poisoning, so perhaps they might have recovered with just supportive therapy. What about data in pediatrics? So again, the same group they looked at, this was a much smaller study, 16 patients, and not a randomized control trial, this was a retrospective observational study where they offered high-volume plasma exchange if the patient had a bilirubin greater than 11.7 or they had toxic hepatitis, and they did 10% body weight replacement with FFP for three days, so eight out of 16 patients, that's 50% survived without a liver transplant, two survived after successful liver transplant, and six out of 16 expired, and the causes for these patients' underlying liver failure is listed there, but the group of patients who survived and who did not survive, there were key differences between these patients. So if you look at those who survived with native liver function, they were older patients, they were less likely to be ventilated, less likely to have hepatic encephalopathy, and they were less likely to be on an inotrope, so overall, a less sick group of patients. The patients who expired, or two of them who eventually went on to get a liver transplant, that was a much sicker group, so it's hard to say if the therapy really made a difference here, or if it was just these patients might have survived without any additional, or without the high-volume plasma exchange. Again, this was a slide you saw earlier, so putting the same study back in context here, if you see 50% native liver survival and 13% survival post-transplant, that looks somewhat similar to the other studies which have done lower-volume exchange, and again, this study here by Qian et al. from Taiwan, they did a two to four times plasma volume exchange. They also had similar outcomes as those who did either a 1.5 or two-volume exchange. So when we think about high-volume plasma exchange, it's kind of important to know that as you prolong the therapy, or as you exchange more volumes, you kind of get, it's the law of diminishing returns here. Your curve starts to flatten out here, so this curve on the x-axis, you see the volume of plasma that's removed, and on the y-axis is the fraction of original plasma remaining. So at some point, this curve starts getting flatter, and again, you can see the same corresponding values in the table here. So one to 1.5, you get between 65 to 78% removal, but then further on, as you keep increasing, the additive effect is not a whole lot. So when it comes to high-volume plasma exchange, I would say we don't really know what high volume is. Adults have used anywhere from 10 to 15% body weight, or eight to 10 liters. In pediatrics, it can be two times plasma weight, or 10% body weight, and again, to give you some context, if you have a 25-kilo patient, and if you do the numbers, their total plasma volume is probably, one plasma volume is going to be something like 1,200 mLs. So 1.5 plasma volume is 1,800 mLs, and if you do a 10% body weight, that might be something like 3,000 mLs or so. So it's a much different volume that we are talking about here. There is limited data when it comes to high-volume plasma exchange. It has the potential to remove more drugs, do a prolonged procedure, and potentially more citrate, more blood product exposure, and ideally, to say that high volume is better than standard-volume plasma exchange, you would need a study that looks at standard medical therapy versus high-volume exchange versus standard-volume exchange. I don't think comparing high-volume exchange to standard medical therapy is the right way to go about this. Now the next question comes, when to start plasma exchange, and for how long? And this is a figure from Dr. Akash, a review with Emma Alexander, where they talk about these phases of liver injury. In the early phase of acute liver failure, there are pro-inflammatory cytokines being released, but later on, there is kind of an inflection point where it moves on to the recovery phase of liver injury, where you have repair-associated cytokines being released. So depending on what phase you might be seeing this patient, perhaps you might end up removing some of those repair-associated cytokines, and you might end up causing more damage to them. We don't really have a lot of good data on how to identify when that patient moves into the later phase or into the recovery phase, but again, the hyperacute phase is when you have macrophages in the pro-inflammatory state. They're causing tissue damage, they're causing SERS, multi-organ failure, so coming in with plasma exchange early would be beneficial, but later on, those macrophages might be working to regenerate the liver, and removing those might cause harm to the patient. There are studies ongoing which are trying to look at what biomarkers can help identify these phases of liver injury, and perhaps something like serum neopterin or soluble CD163 might be used in the future to identify those. So once again, this graph here shows you the different phases here, so you have the initiation phase, yellow propagation phase, and the resolution phase in green, and the different markers that have been seen with each of these phases of liver injury. We don't have very good ways, we don't have a lot of data on how these correlate, but some of these are simpler markers, alpha-fetoprotein, phosphate, perhaps soluble CD163, so I'm hopeful in the future we will have better data to guide us when to start and when to stop plasma exchange in patients. So when it comes to prescription of therapeutic plasma exchange, I would say overall, refractory coagulopathy, multi-organ failure, acute liver failure, that is your indication for doing plasma exchange. Somewhere between one to 1.5 plasma volumes, replaced with albumin, and I put within quotes some, replaced with FFP and some albumin. There is some data, there's a lot of body of evidence that circulating albumin in liver failure is often dysfunctional, so providing albumin here could be beneficial. Do daily sessions initially, however reassess every day if you need the sessions or not. Are you kind of moving on to that phase when you might be causing more harm? And definitely review drug dosing with the pharmacist because you might be removing some of these things, and one of our next speakers, Alison Chung, will be discussing this in more detail. Finally, on to hybrid extracorporeal therapies. So we heard briefly about CRRT and plasma exchange from Dr. Akashdeep. Advantages of combining the two therapies are that there's high detoxification capacity. You can remove the water-soluble toxins as well as the lipid-bound large molecules. In a way, you're able to provide some FFP and replace some of the synthetic function of the liver. You can maintain a good volume balance, provide nutrition to these patients so they can recover faster. And both of these are more widely available than, say, MARS or single-pass albumin dialysis are. So they are relatively easier to implement in your ICU. So the study is looking at these hybrid extracorporeal therapies. Dr. Erikan's group from Texas Children's, they looked at 15 patients with ALF or acute on chronic liver failure, and they provide a combination of CVVHDF, that is continuous veno-venous hemodiafiltration, plasma exchange, and add-on MARS if needed. And they reported 13% patients had native liver survival, 27% died without a transplant, and 60% survived post-transplant. Similar study from Japan, where they had CVVHDF and plasma exchange. And this was a study Akash had shown earlier with 88% survival post-transplant. And then this larger study, a slightly larger study by Rodriguez and colleagues, which had 51 patients, of whom 20 received plasma exchange. And in this group, 57% patients died in the hospital. 51% overall received a liver transplant. The protocols that have been used in places, CRRT is usually done for oliguric acute kidney injury, fluid overload, hyperammonemia. The level is reported as different centers use different levels. But key thing is hyperammonemia rising on maximal medical therapy, using a high-dose CVVHDF. If you're dosing in body surface area, doing 3,000 or 90 mLs per kilo per hour, if you're using the per kilo weight dosing, adding plasma exchange. And then Texas Children's adds MARS for patients who have hepatic encephalopathy. More than grade three or grade two in the setting of multi-organ failure. Like I said, MARS is not commonly available at most centers. And a combination of CRRT and plasma exchange is what we do at our center in Seattle. And this is unpublished data from our center. Our fellow Caroline Jackson is working on this. So we have 23 patients, ranging from four months to 20 years. 10 had acute liver failure. 13 had acute and chronic liver failure. They all received a combination of CRRT and plasma exchange. 100% of the acute liver failure survived, with two having recovery of native liver function, and eight receiving a liver transplant. Of the acute and chronic liver failure, four died before they received a liver transplant, but nine of them got a liver transplant and survived. So overall, I would say the combination should be used for patients, especially if you have the ability to do that. So, you know, when it comes to liver failure, comes to extracorporeal liver assist devices as a bridge to transplant, I think CRRT and plasma exchange are both important pillars in that algorithm, or on that bridge, for that matter. So my take-home points are that extracorporeal liver assist devices are a very important bridge towards either spontaneous recovery or successful liver transplant, and therapeutic plasma exchange is a key component. Start early, reassess need every day, and patients needing prolonged TPE, ask yourself, is it no longer beneficial in this situation, and reassess again every day. High-volume CRRT has added benefit, so do not hesitate in using the combination of the two. That, I just want to thank you all, and we can take questions in the end. Thank you.

therapeutic plasma exchange

acute liver failure

replacement fluid

pathogenic substances

patient outcomes