Any questions from the audience based on those lectures today? Sure. Thank you for your presentation. I have two-part question. One, what's your experience in trying to measure ICP in acute liver failure patients? And number two, what's your experience in managing that ICP? So you guys can hear me, right? So, as far as measuring ICP in cirrhotic patients, one of the things we go into the chapter I didn't touch on in the talk, there is a significant move away from the use of any kind of invasive ICP monitoring in cirrhotics. Not surprisingly, they tend to bleed a lot, and so that kind of complicates any kind of invasive measurement of ICP. What we have actually found extremely useful is the use of optic nerve ultrasound as a great modality to identify ICP elevation. Now, obviously, it's there, but once it's there, it's not going to go away even if you fix the ICP. The optic nerve dilation stays dilated for a while. So we find that to be a very helpful modality. None of the invasive options are neurosurgery. You call a neurosurgeon about a cirrhotic patient, and they start laughing at you and run away. So and then for management, the other thing that we talk about in the chapter that I kind of left out of the talk for the purposes of time is there are a number of studies now looking at the difference between mannitol and hypertonic, or 23% sodium chloride, for the management of ICP in the acutely cirrhotic patient. And it does seem to be a reasonable signal that the 23% actually has a mortality benefit. It seems to do better than the mannitol. And we have used that. Again, you have to reverse the ideology. So this is that whole, the guideline says once you're at 150 in an acute liver failure patient, consider CVVH. The rate at which this rises, once you're at 150, your patient's already starting to get, starting to herniate. So if you don't have your CVVH catheter in by that point, and you don't have the machine up and running, you're going to be deploying something like 23%. But again, concurrently get your line in and get your CVVH up and running so that you can get the ammonia and the inflammatory cascade down. That should hopefully get your ICPs down. We've done it a couple of times. We've had reasonably good effect with it. The difficulty is these patients tend to do extremely poorly if you can't either stabilize them to a transplant, or their liver just gets better. So that's it. Mark Alterman from Fort Worth, Texas. I had a question on proning and working with other physicians in our group. A lot of times we say we make the decision to prone. But then after the night of proning, or during the day, oh, their PF ratios are much better. They're greater than 150. And so the decision is not to prone that next night, even though they're still intubated, they may still be paralyzed, et cetera, et cetera. Is there a minimum days, as long as the patient's not clearly going to be extubated, that you like to prone your patients once you start? I think we follow the inclusion criteria from the PACEVA trial. So if you prone your patient, and their PF ratios get better, and you supinate the patient, and you're no longer on a FIO2 of greater than 60%, then I would say that proning is no longer required. If the patient progressively gets worse after that, and still meets the inclusion criteria for the PACEVA trial, where you have a people of 5 centimeters water pressure, FIO2 of 60%, and PF ratio less than 150, then I would prone. You have anything to add? I mean, if they got worse, then you would re-prone them after not proning for a day? One of the questions is, if they start getting, I mean, I would say, trying to rule out any other causes that you can contribute to the worsening of the clinical experience. Can you see from the guidelines, as basically there's a time frame, you know, they didn't give you a time frame, don't use it, or how many days you're out there not to use it. I think it's the, you know, if the reason is they don't prone them, and their only challenge is basically they recruited again, and you need to recruit, I would try it again. Proning is basically is not an easy asset, especially the patient and ventilator. There's a lot of side effects, you know, with the ulcers, and this lodgement of the ET tube, and all the other stuff. But I would, to answer you, yes. If the only reason why they had a setback is that they recruited, and you don't have other etiologies for worsening of the, you know, PTF, PFE, PF ratio, I would prone them again. Okay. Thank you. For the plasma pharesis, so do you go over the 1.5 times the plasma volume? That's the first question. Then what is the proportion of FFP albumin that you use, and for how long do you do the plasma pharesis? So the available evidence looks like standard volume is equivalent to high volume, so 1.5 is more than enough. With respect to FFP and albumin, it's often an alternating approach, where depending on where your coagulopathy is, where things have stabilized out, FFP is a pretty limited resource. And so, you know, that's a lot of FFP ultimately to be using in one patient, so often it'll be an alternating approach depending on what the parameters are. And the duration, for how long do you do it? I mean, really, this is one of those that would be a bridge to transplant. If you're not seeing improvement in a handful of days, three, four days, the studies went for seven and showed benefit, really, in this setting, if it's three days and you're not getting where you need to get to, and transplant's not an option, I think it's very appropriate to be having goals-of-care discussions. Thank you. Hi. Steven Hsu from MD Anderson. I got two questions. So, going back to the proning, so we know when to stop when the patient gets better, but when the patient gets worse, do you continue to prone more than 16 hours? And second, how many days do you continue until you say, this is not working? That's the first question, because it is very labor-intensive, and I agree with Dr. Mina that these days, when we think about proning, it's like, oh, you have to get the whole team again, and not all the staff are trained in that. And the second question is going to the liver failure. So, do you treat a non-liver failure patient with hyperammonemia the same way you would treat a liver failure? So, this, I'm alluded to one of the cases I had, where during COVID, we were severely immunosuppressed these patients, and then with the ammonia level of 600, and we found they have disseminated cryptococcus. And so, in that case, we used L-arginine, we didn't have Lola, and I just found out Lola is 16 bucks on Amazon. L-carnitine, sorry, L-carnitine is the same thing. So, would you use that, these short-branch amino acids in both cases? And also, going for the CVEH, how fast would you run your dialysate rate? Because usually, they tend to double the rate, and then the nurses hate you because they have the change of fluid at double, so half of the time as well. Thank you. Okay. I'll do the short one. You know, actually, this is, well, your question is a very important question, because they're practical. We went through this during COVID, that you prone them and did not improve, and basically is that we didn't do it. I mean, it's a team effort, you take a risk, and if it did not recruit, and did not improve, we didn't, we stopped. So this is practically what we did, is it's a whole effort, the whole path of physiology is just getting the dependent area to open up by recruitment and distribution of, improve the VQ mismatch. But if it didn't work, then you know that they're not, there's no reason, I mean, to do it again. You did it by the book, 16 hours, and patient is synchronized with a ventilator, and everything is maximized to get a better, best benefit, but if they don't do it, we don't repeat it. So with respect to starting with the hyperammonemia, in somebody who's in that situation, you know, interesting, I thought you were going to say immunocompromised with mycoplasma, that's been the big thing recently, it's mycoplasma, ureoplasma in our lung transplants, it's a unique hyperammonemia syndrome. I like to cheat, I like to make my life as easy as conceivably possible, CVVH doesn't care what the ideology of your hyperammonemia is, and it'll fix it really quickly, while I get the other things up and running. So I would absolutely use lactulose to what they would tolerate. The one thing to be careful about is the kind of lactulose you need to give to get somebody to clear high-level hyperammonemia, I mean, you're inducing pretty profound osmotic diarrhea to achieve that. And if the patient has not had or been exposed to lactulose prior, it's a pretty big setup to develop a pretty significant ileus. And so you might try a little lactulose, absolutely would layer on the Lola, but at an ammonia of 600, that HD catheter would be going in like that, and then sort of go from there. Intriguing with the cryptococcus, I wonder if there was a bunch of crypto in the liver in that setting with it being that disseminated. With respect to the flow rates, yeah, it is a higher flow rate on the CVVH, and we have a lot of issues with filters going down. And again, that's in discussion with other centers that do way more of this than we do. So we're developing our protocols and working with them to kind of get that up, but it is a higher flow rate. Thank you. Hi, Adi from Cleveland. For the hepatorenal syndrome, you mentioned the importance of volume resuscitation. I was wondering if you can make a comment about the value of increasing the mean RTR pressure above 65. So it certainly seems like... So one, the volume resuscitation is less in the management of hepatorenal syndrome, more in the diagnosis of hepatorenal syndrome. So the volume resuscitation is to rule out your other pre-renal ideologies, as well as to assess if there's an underlying ATN physiology, which is the most common other thing that you see in that situation. We won't generally target a map above 65 in these patients. Certainly we try to get the mean RTR pressure up, but I wouldn't put somebody on presser specifically to get them to that level. The data is not inconsequential. There does seem to be some benefit at the higher pressures with respect to that, hence the MOA therapy, LOA therapy, not LOA, LOA. But it's a very super therapeutic map for many cirrhotics. And it doesn't seem like it's necessarily a sustainable one. So you might improve kidney function transiently, but then once you stop, you see it kind of trend back down again. So we don't... We at our own shop don't push really hard to get the map above 65. We usually aim for maps around 55 in most of our cirrhotics based on what we see as their prior blood pressures. Thank you. I'm Algeet Katan from Santa Rosa, California. My question is regarding ARDS, severe ARDS. When you do make the decision to place that patient on VVECMO, and if the lungs don't improve in the specific time period that you may have predicted, what is your exit strategy? How long do you keep somebody on VVECMO? And then when is the time, or what's your exit strategy if the lungs don't improve? So how long do you keep them in the VVECMO? One of the thing is, you know, that depends on the center you are, to be honest with you. Us, we have a central ECMO center, so they go to the mothership hospital where they have one center for 23 hospitals. But if you do the literature, it depends if this is improving or not. I mean, there's no time frame, but if this is a patient, is it transition to transplant or not? If the patient... So it depends on the underlying disease, underlying physiology, what caused the ARDS. But I think it's a resource, and then our strategy is, we communicate it with the VA. If they're improving, and you keep doing it until they improve, and start weaning them off and start, you know, decantilate them and detract them. But if they're waiting for a lung transplant, they're on it and then... But if they're not improving, then the goals of care, if that, we start talking goals of care. So this has happened recently, and one of the patient is, he was ILD, was sent to transfer to the ECMO center, offered transplant, was not a candidate. So basically, he was not improving, then they made a goals of care, and just took him off the ECMO. I have a proning logistics question. How do I prone a patient with trach? It's... We don't do it very often, but I have seen it. And this has to do with the equipment that your hospital has. There are certain pillows that go underneath the chest that creates a nice window between the head of the bed and the trach site, so that you're not putting any applied pressure into the trach. We tend not to prone these patients that have a trach, but I have seen it. I don't know if you have more experience in seeing this. Not with a fresh trach. So it has to have a really, when you prone them, that you really have already secured the trach site. I mean, the thing is, you can do the same precaution with the EJ tube, they can dislodge. But the problem with a fresh trach, if you lose it, you have no airway. So I'd be very careful with fresh trachs. Other than that, it was like, you can see if they trached, there's no time limit for the proning. It's not like when you do a neuromuscular blockade or other things, you have a set time, you can see within 48 hours or within a week. But an older trach, you secured the trach, it already has a trach, you can pop it in, use the normal precaution as you use the EJ tube. Fresh one is, we don't do it. We didn't do it. We don't, actually, we don't do it. Just to add one more thing, if your hospital happens to have the resources of having those water-prone beds, you can utilize those beds, but they're way more expensive. Just one, so I think we've all come up with our jerry-rigged approaches to these sorts of things. We found that arts and crafts with a Carter pillow can be extremely effective. So you use a lot of pillows to just get the head and the chest, but then the Carter pillows that people use to keep the arm elevated, go to Ortho, grab one of those. They're all foam. You can carve that up and create a, essentially, kind of a cavity where the trach comes out and everything comes out to the side. I'm from Springfield, Illinois. Couple of questions for ARDS and for the ammonia lecture. One thing is, we developed a protocol which is called a tempo of ARDS, the pace at which we attack. In that, we have, like, two-hour window, four-hour, six-hour, and 12. By 12th hour, we are referring to ECMO, just to see the progress and initial referral to ECMO. In that, we have epiprocinol and nitric oxide, too, depending upon pulmonary pressures. And by 8th hour, we paralyze, 12th hour, we are proned, and by 16th hour, pulmonary pressure is a bit high. Prior to that, we just start off EPO at one center, and the other one, we do nitric oxide. What are your thoughts on that, particularly in terms of preference? And the second question is, when we are recruited and the PEEP is coming down, what I personally do is, I increase the tidal volumes, too, from, like, let's say I started at 4, 6, 8. As the PEEP comes up, come down, simultaneously, I go up on the tidal volume. I feel like that's more comfortable for patients. When the sedation is coming down and I'm coming down on the PEEP, the tidal volume comes up. There is no protocol, per se, for people to come up on the tidal volume and to what extent. But that's what I personally follow. What are your thoughts on that? Let me understand the first question. First question is that, by 16 hours, you get them to ECMO? We refer, we identify patients, and we refer, in case, yeah, in case that's where. One thing we didn't present in our presentation here is the adjuvant therapy with the nitrous oxide and everything. And you can see from 2019, it was in there, but really, it was still the gray zone, not really recommended. When we reviewed the data for the chapter, there's really not much, a lot of literature of support. They use it. I know we use it, nitrous oxide, and, you know, adjust with the ventilator. Some people even used it with even non-invasive ventilation. You know, you can litter fancy stuff. It works, doesn't work, you know, the data is not really supportive. And then, in our personal experience, we use it some, some, did nothing, sometimes, you know, it helped. Maybe it's a transition until the underlying process helps it get a little improved, but the data is not supportive in it. But the time to get the ECMO, the only things that came out in the last 2024 publication is you have exhorted all your measures and nothing else is working and this, that. Whether you're 16 hours or beyond that, that I think is center to center. I think for us, if you have the ECMO team and they're available in your institution and discuss it with them and you can do it, for us, you know, some places, it's a fight to get them to the ECMO team to accept them. And sometimes it was the backup for the trunk transplant center, they have the discussion. So I mean, it seems to be there's really no time frame, 16 hours, 7 days, as long as everything exhausted and you want to transfer them early and have the resources. But I don't think this is a standard of care in a lot of institutions. But the guidelines doesn't give you time, how long you keep them or when you have to wait 48 hours or something like that. And for your second question, the way I would address it in terms of weaning down your PEEP and how do you go up on your tidal volume, in that case I would actually focus more on your driving pressure because you're scaling your tidal volume or your PEEP down based on the functional lung size that you have available at your disposal. So as Dr. Mina said on his presentation, your driving pressure is the ratio of your tidal volume to your respiratory system compliance. And it is calculated by your plateau pressure minus your total PEEP. So there's a lot of things that you have to consider, various parameters, whether the patient is still very hypoxemic, if the patient is very acidotic. So if you have the question of what do I do, do I go down on the PEEP first or do I go up or down on the tidal volume? And so I would say that if you've been able to decrease your FiO2 to at least 60% and you're still at a high level of PEEP, then you can start focusing on decreasing your PEEP as long as your driving pressure is not getting bigger. If you decrease your PEEP and your driving pressure shortens, then that's good. If your patient is very acidotic and you don't have room to go down on the tidal volume because you have to keep a certain amount of ventilation, then I would leave the tidal volume where it is and try to decrease your PEEP. And also keeping in mind that you want to keep those driving pressures below 15 centimeters of water pressure because it's associated with decreased in-hospital mortality rates. And it's still within the guidelines. It's 4 to 8 millimeters per kilogram. So even though if you go up to 8, I mean, it sounds like compliance is improving and this is a process until eliminating mechanical ventilation. So even up to 8, you're still within the framework of guidelines. Yeah. Once the driving pressures are improving, they have recruited to go up on it while we lower the PEEP strategy. I see that many people stay on the lower tidal volumes, even with improvement of driving pressures and lowering PEEP. I felt like when I'm weaning, when I take over these patients, I felt like atelectasis kicks in too when the lower tidal volumes are still there and the PEEP is lowered. Correct. From the ammonia point of view, we have patients with ischemic hepatitis, these hypotensive patients who get into these hyperammonia situations too. In those kind of patients, do you think NAC, because of the antioxidant burden or something, you think NAC can be used? What do you think about these modalities of PLEX? And second question is, among the PLEX, what was the etiology for those PLEX usage? It's not like every acute liver injury, I'm using PLEX, or what was the etiology used in the studies that PLEX was used with? So the first question in regards to ischemic etiologies of liver injury and the role of NAC. So the vast majority of transient ischemic injuries, so somebody who has the air quote shock liver injury, or now hypoxic hepatitis, because it's really the DO2 equation with respect to inadequate delivery, those are usually fairly self-responding. They're fairly recoverable injuries. It's a transient hit. And if it's not so severe that you've had an extensive degree of liver necrosis, the patient's going to get better. There's not a lot of literature on the use of NAC in that context. NAC is used extremely widely for a significant number of acute liver injuries, partly because it has very little overall downside. I can't say that we use NAC specifically in the context of shock liver slash hypoxic hepatitis, partly because the vast majority of those are just going to self-resolve if you've fixed the perfusion and hypoxia issue. And then if you have incurred a profound level of hepatic injury, so the other version of that ischemic injury that we deal with, we try not to deal with very often, but happens, is hepatic artery thrombosis, specifically after liver transplant, NAC's not going to help you there. You just got to get perfusion in those situations. So it may mitigate some injury, but it's certainly not something that's been studied and we don't usually use in that context. With respect to PLEX, the studies looked at kind of a range of the most common ideologies of acute liver injury. So the UK study was predominantly acetaminophen, paracetamol, and then the Southeast Asia study was predominantly viral injuries, hepatitis A, hepatitis E. There's a smattering of some other ideologies in there, a couple of, I think there was a PBC, autoimmune hepatitis, et cetera, but the large majority was hep A, hep E in Southeast Asia and paracetamol in the UK. Thank you for a very informative session. I'm an intensivist based in Macon, Georgia. One question for the ARDS about duration of paralysis. Cystic atricurium, I think the original study, it was used for 48 hours, but we do see cases that the patient is getting better and then you stop the paralysis and now they're worsening again so they have to go back on it. Is there, in your experience, a timeline where we should say that we have used paralysis for enough duration? And for the acute liver failure, between PLEX and CBVHD, what is the number on the PLEX? Like for CBVHD, if the goal is to keep it below 140, when do you start thinking about PLEX? And if you have both available, you can do PLEX and CBVHD, which one should be picked? Regarding the paralysis, I think it's a clinical judgment, is it working or not working? One of the things that I like about the 2024 guidelines, it really gives you a lot of precautions about what we're doing and the side effects. So it's a clinical judgment, it's going to help me, can I keep going or not going? So there is a, you know, even before when to use it, the precaution. We know all this neurological status, prolonged weakness, you know, and you have sedation and delirium and everything that goes after that as a side effect. I think it's a clinical judgment if the purpose of paralysis is just basically maintain, you know, you lose the, improve the compliance by knocking in the chest wall and synchronizing with the ventilator, but after all this underlying process is not responding, this is all by time until the process resolves and you see a recovery, but you're going into all this fibrotic, you know, ERDS stages and he's not going to turn the corner. I think it's a decision, you know, to stop, it's not working, that we're going to be more dealing with side effects rather than benefit. So it's a benefit, risk, if there's no benefit, you have the risk, you can make a judgment it's not working. The same thing as to see when you want to stop proning, and the same thing as benefit, risk. So this is our experience, if nothing is working, the patient is going into multiple oropharyngeal or the ERDS, he's a transplant candidate, nothing, then maybe I'll start getting ECMO, look at the next step, which you have it on the next step as highlighted, this is the last effort, did your effort now. So this is what we would do is kind of more case by case, if there's no benefit, have a risk, and we're not going to ECMO then or transplant, then I take it off. With respect to the CVVH versus PLEX in acute liver failure, the primary use of the CVVH in this setting is going to be if you have hyperammonemia, controlling the hyperammonemia and mitigating the risk of cerebral edema. The vast majority of acute liver failure patients, when they really classify as fulminant acute liver failure, so you can have acute liver failure, just secondary acute liver injury due to a toxin or whatever, but your fulminant liver failure, once you've kind of crossed that altermental status, which is often associated with ammonia risings, cerebral edema, there CVVH should get your ammonia down. And in the meantime, you're figuring out your ideology and hopefully getting that patient to a transplant center where if you're at a transplant center, you're being evaluated and can you get listed for transplant. Those patients aren't out of the gate, all hypotensive, in screaming coagulopathy, etc. Many of them are going in that direction, you'll see the parameters start to deteriorate, but you're not actively exsanguinating from everywhere. And in that setting, CVVH is fine to kind of keep the ammonia and the cerebral edema under control while you get set up and figured out if you can either, either your NAC's going to work and it's going to get better, or you're going to get listed for liver transplant. Where the PLEX really seems to have its primary role, again in the literature, and how we sort of think to use this, is in those patients that are clearly progressing, and now you're seeing the shock state, you're seeing the DIC, you're seeing the coagulopathy, the cytokine storm, and really the only, and that's, it's got to be a patient that's being listed for transplant because once you're at that stage, the likelihood of reversing that and getting better is extremely low, but getting them stabilized and seeing if you can get them to transplant. Now, it does seem that you can do it and get people through and there is some recovery. In our experience, our primary thing is bridge to transplant. I have a question and a comment, Ahmed Gohar from North Alabama Intensivist. The comment is about a question by a colleague earlier and the response to it. I guess it was the proning and when do you stop. And in the response, when we say lack of response, I think you meant lack of response to proning, meaning after you're proned, you should assess your response. Do you have a rise in your PO2? Do you have an improvement in your PF ratio or not? And if you don't, that's when the patient is not responding and hence there is no need to prone them because you're not getting the result. But if they are responding and you keep pushing, you know, if they drop again back to their – if their PF ratio drops after I need them, then, you know, that's because you lost the recruitment. You're still prone as long as you're getting response. I think the trial, they went up to 21 days if I can recall correctly, but the question that I have though is with regards to chronic liver disease and, you know, ACLF, the use of Mirelax or polyethylene glycol versus lactulose, alias is a real problem. So what do you think? And if there's any data just beside, you know, like antidotal or like experience? It's an excellent question. I left it out of the talk. It's in the chapter. There are studies looking at Mirelax, particularly looking at PEG to use as a mechanism to manage hyperaminemia. It is absolutely doable. The degree of electrolyte disturbance that you create in the cirrhotic is pretty significant. So I've never – we've never had to kind of go – we've never chosen to use that instead of lactulose in the acute on chronic liver failure patient. We often have more of an issue with just the significant electrolyte disturbances we create with the lactulose. Thank you, guys.

intensive care

intracranial pressure

ARDS

mannitol

optic nerve ultrasound

cirrhotic patients

clinical judgment