Episode 306: Strategies to Mitigate Early Allograft Dysfunction After Liver Transplantation with Dr. Beth Wilson
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Hello, and welcome back to ACRAC. I'm Jed Wolpaw, and I am really excited. We have a fabulous show for you today, and I have with me a wonderful, wonderful anesthesiologist, liver transplant anesthesiologist, one of my prior residents, Dr. Beth Wilson. Dr. Wilson did a pediatric residency, a PICU fellowship, then came to us for her anesthesia residency, where she excelled and was just stellar. And then she went to UCSF for a liver transplant fellowship.

She was then at Emory where she was the director of the liver transplant fellowship there and she got some pilot grants looking at reperfusion after liver transplant. She's going to tell us a little more about that. She's now at Duke doing a lot of really exciting work with liver transplantation and I'm thrilled to have her on the show to talk about early allograft dysfunction after liver transplantation and what we can do to help mitigate that. Beth, welcome to the show. You got it. Thank you. I appreciate it.

All right. Thrilled to see you again and have you here. So let's start by talking about you. Tell the audience a little bit about kind of how you got interested in liver transplant in general and then this topic specifically.

Yeah, as you can see, I've had a bit of a circuitous route to get to this point. I used to be a pediatric intensivist. I always remind residents that opportunities will arise and you should take them if interested, because I never would have thought I would be an adult liver transplant anesthesiologist, but it's one of the best decisions I've ever made.

So I got into liver transplant actually as a resident at Hopkins. Hopkins has a pretty big liver transplant center. And I, you know, it's the ICU physician in me. I really love that it was dynamic and affected all organs in the body, the kidneys, the brain, the heart, the lungs. I also think the liver is one of the coolest organs because it's the only one that could be cut and regrow into the full size shape.

And, you know, we talk about this in the context of living donor donation. I mean, we actually remove a portion of a living person's liver and give that small mass to a recipient. Both the donor and the recipient will have a full-sized liver within a period of months. It's just fascinating and incredible. Yeah, very cool stuff. And so when we talk about early allograft dysfunction, what does that mean?

So early allograft dysfunction is the post, it's effectively like a post-operative functional hepatic insufficiency and it classically occurs within a week of liver transplant. It occurs in about 20 to 25% of deceased donor liver transplant recipients.

It's pretty significant because it's associated with increased morbidity, mortality, and increased hospital costs. In fact, you actually have a tenfold higher chance of death within six months if you meet criteria for early allograft dysfunction. And then let me just clarify. So we don't, or do we mean when we say this, like the graft is dead? Or do we just mean it's not working as well as it was hoping, we were hoping it was going to work and, you know, it could go either way?

Good question. This kind of gets into its clinical presentation. It's a bit of a spectrum. So in its most severe form, which is quite rare, it's called primary non-function or PNF. It's...

effectively a completely non-functioning liver and it's associated with death or retransplantation within seven days. It's extremely rare. It's like less than two to 6% of cases, but if it were to happen, patients often go right back on the transplant list and need a new transplant. Otherwise it's associated with morbidity and mortality. So generally speaking, early allograft dysfunction is the spectrum of delayed graft function. You know how some livers post-reperfusion really kick in quickly?

While others take their time, and this is obviously complicated, and that's for multifactorial reasons. This is that spectrum that I'm talking about. And it's kind of clinically associated with persistent coagulopathy of varying degrees, so bleeding, metabolic acidosis.

hypothermia, which contributes to bleeding because if your liver is not working, you can't regulate temperature very well. Um, multi-organ system dysfunctions or renal failure. Some of those patients need, um, dialysis and CRRT or continuous renal replacement therapy, post-op cerebral edema, um,

And then just poor graft function and patient survival in general. Sometimes it's even can be associated with sepsis. So it's a pretty important ICU phenomenon. And there's one reason why it's so important for anesthesiologists to be aware of it. And we'll get into this, but yeah,

We're really going to kind of break it down by the donor case, so donor procurement, the storage of the allograft, and then recipient liver transplantation. And at some centers, general anesthesiologists, actually in most centers, general anesthesiologists perform the donor procurement case if we're involved.

And then at some of the big liver transplant centers where we have a say are involved and really can be advocates for how we store livers, like, for example, with machine perfusion, which we'll get into. And then at a lot of the big liver transplant centers in the country, there are specialized liver transplant anesthesiologists. Like, for example, I did a liver transplant fellowship recently.

And so a lot of those teams are all specially trained anesthesiologists. But then you might have centers that are smaller or private practice where it could be a critical care anesthesiologist, a cardiac anesthesiologist, or a general anesthesiologist that's had a lot of exposure to liver transplant.

Right. So is there anything, you know, when we see a patient come out and like their lactate is already coming down on arrival in the ICU, like that's pretty reassuring that this liver is working. Is there any single marker or constellation of markers that makes you right away think, oh, this could be early allograft dysfunction, like a rising lactate, you know, rising LFTs? I mean, you're always going to see that right away. But is there any kind of single thing or is this just a big constellation? You have to look at everything.

It's kind of a constellation of things, but there are some things that can be more striking. Like, for example, if somebody's post-op from liver transplantation and they are not clearing their lactate, that's pretty ominous. And that means that liver is at least, at the very least, not working well. If not, you have to perform an evaluation to see...

Why it's not working, you know, but it's usually an associated with other things. Right. So that patient is going to be bleeding more. They're going to be more coagulopathic. They're probably going to be acidotic. They're going to have a high vasoactive requirement. They're going to have renal dysfunction, all those other things. And this also kind of gets into how we.

and define early allograft dysfunction. So I've kind of described that clinically, it's a spectrum, again, in its most severe form as primary non-function to a point where it could just be a sluggish liver that just takes some time to kick in, but then ultimately is able to generate coagulation factors

abate bleeding and clear the lactate. It just takes hours to maybe even a few days. So there's this spectrum, right? The historic or the most traditional or gold standard definition of early allograft dysfunction comes from Oltoff et al.,

And it basically defines EAD as greater than or equal to one of the following. So if you have a bilirubin level greater than or equal to 10 on day seven, an INR greater than or equal to 1.6 on day seven, and or a peak AST or ALT greater than 2,000 IU per liter within the first seven days post-op. So as you can already imagine,

There's some good things and some problematic things about this definition, right? So it's binary. It's dichotomous, right? With this definition, you either meet criteria for EAD or you don't, where you're going to have some livers that are sluggish or may have delayed graft function, but they don't technically meet criteria. Like maybe their peak AST is 1,800, where you're so close, but you don't technically

technically meet it. I do want to acknowledge that OLTOF, that criteria is a good predictor of three and six month allograft and patient survival. So it has been well studied and it's commonly used. And like in my studies for some of my research, I use it as my primary outcome.

It's not as good at predicting long-term survival. There are newer scoring systems that kind of take some of this into account and really see early allograft dysfunction as that spectrum. So a lot of people, like some of my colleagues at UCSF, use their primary outcome as the MEF score. And that actually looks at the max ALT, max INR, and the total bilirubin over the first three days post-op. And that's a continuous score. So it's not like you either have it or you don't. You're

you get some value based on a scale and that actually facilitates potentially early intervention. Though that, the MIE score does require access to a nomogram. So it's, you know, it takes an extra second other than doing like the ALTOF at the bedside. There's also the L-GRAFT and the E-SCORE, which are really fancy newer kinetic models, but those require statistical software or at least a quick link or access to it. And there's a lot of data entry points. So they're just,

Although they're physiologically fascinating and can really kind of talk about that spectrum of clinical presentation, they're harder to input. It takes more time, more labor to input the data to determine it. So let's talk about the etiology. You know, some graphs have early outland graph dysfunction, some don't. You know, what do we know about what leads to this?

Okay. So as you can imagine, it's multifactorial. So it basically includes donor, recipient, and surgery-related factors, and then their interaction with each other. But I do want to acknowledge that the underlying large pathophysiology is ischemia reperfusion injury.

So some of the risk factors for early allograft dysfunction, or if you hear me say EAD, that's the acronym for early allograft dysfunction, are donor and recipient age, donation after circulatory death, so DCD, prolonged ischemia time, allograft steatosis, which is

Basically, to what extent there's or the percentage of fat droplets or fat in the liver. Recipient body mass index or BMI and recipient severity score, most commonly the MELD score, the model for end-stage liver disease. And basically, careful donor allograft and recipient optimization and matching can help reduce BMI.

the risk and impact of EAD. And obviously, hepatologists, surgeons spend a lot of time when they're picking who should get what liver on the list, how to best match these things. And I'm also going to put in the plug, this is a way in which anesthesia could be really helpful at a lot of the biggest liver transplant centers. Liver transplant anesthesiologists are involved in selection conference. And I think it's important that we have a stake in those conversations too.

Great. Now, you mentioned ischemia reperfusion injury as a major risk factor. Let's talk about that. What is it and what do we know about it?

So we have to decide how nerdy we're going to get as we talk about it. I can talk about this all day. So IRI, I can kind of talk about it from a clinical perspective. And then I'm going to spend just a little bit of time talking about it from an immunologic perspective, because that'll become important later when we talk about mitigative strategies in the operating room, because some of those studies will look at various immunologic factors. So

Ischemia reperfusion injury is this complicated immunologic phenomenon. It involves the dysregulation of cellular oxygen homeostasis, innate immune defenses, and microcirculation within the allograft.

So it occurs after temporary cessation or ischemia and later restoration or reperfusion of oxygen rich blood flow. So it's, and it's simplest way, lack of oxygen and then the reintroduction of oxygen and the damage that is caused in the setting of that, because this in the context of the liver results in substantial hepatocellular damage. Now in the clinical description of,

I can kind of break it down by procurement, storage, and implantation. And I talk to residents a lot about this intraoperatively because this is a surgery when you're in the liver transplant recipient case where you really need to know what the surgeons are doing and the risk factors that

that go involved to anticipate what reperfusion is going to be like so that we can better management manage it. So ischemia can be described clinically from the perspective of the donor or the recipient, and it can differ by temperature, either cold or hypothermic or warm, which, you know, I'll refer to as like normal thermic or physiologic. Now donors can pass away from brain death or circulatory death and

So for donation after brain death, donor warm ischemia occurs after aortic cross clamping through allograft procurement. But for DCD or circulatory death, donor warm ischemia begins during pericardiac arrest.

which is obviously characterized by decreased perfusion and desaturation, malperfusion, through aortic cross clamping and procurement. So you can see why DCD already is classically considered to be higher risk because there's a period of time in which that allograft is exposed to decreased perfusion. Now,

This I'm going to put in my plug here. We're going to talk about this a little bit. I'm going to just bring up normothermic regional perfusion at this point really quickly for DCD procurement. Donor warm ischemia can really be attenuated by in situ normothermic regional perfusion. And this is a cool new innovative technology that basically restores oxygenated blood flow to the liver postmortem after the cardiac arrest.

So it's similar to VA ECMO. It's a form of temporary mechanical circulatory support, and it maintains organ perfusion, but with the exception of the cerebral circulation. So as you imagine, ethically, you wouldn't want to reperfuse the brain with oxygenated blood after declaring death. But it is awesome because it can really mitigate donor warm ischemia time. Now, for brain death or circulatory death,

When we're talking about ischemia reperfusion clinically, that allograft after procurement can be preserved either through static cold storage, which is the most conventional mode and the most commonly used around the world, or ex situ machine perfusion, which we're going to get into a little bit later. So static cold storage involves flushing that allograft with cold preservation fluid and maintaining it on ice in an attempt to decrease allograft metabolism and oxygen demand, and

And this is kind of what we call cold ischemia. And then I'll talk about this later, but there's two types of machine perfusion. It can get a little confusing here, right? Because the cool thing about machine perfusion is that it facilitates early reoxygenation. So whether you're using normothermic or hypothermic machine perfusion, you're actually re-exposing that graft to oxygen for the first time on the pump.

So if you really want to get technical, that's actually reperfusion. It occurs on the pump, not the way we colloquially or conventionally think about it in the recipient transplant case. But again, we'll get into that a little bit.

Now, recipient warm ischemia occurs after the allograft is removed from static cold storage or machine perfusion, and it's implanted into the recipient before autologous blood flushing or venting or unclamping of the hepatic vascular inflow. So as you can see, this has gotten more complicated over time. In the liver transplant recipient case,

So there's one of two ways in which reperfusion conventionally occurs. Now, autologous blood flushing or venting is basically, it's basically a form of therapeutic phlebotomy, honestly. It involves venting previously static recipient blood flow that's distal to the portal vein and the IVC either side clamp or cross clamp. It basically...

Vents, that static blood flow distal to the clamps from the abdomen or the lower half of the body through the allograft, through the inferior portion of the cadaveric IVC. And it does that via the reanastomose portal vein while the recipient IVC clamp is still on. So you're basically phlebotomizing or bloodletting the patient. And this is typically performed just before you're actually unclamping hepatic vascular inflow. It's not performed at all centers. It's not even performed by all surgeons. It really depends on the context, you

you know, clinically. But my point is, is even in that scenario with venting or flushing, even though it's decreased blood, you know, decreased oxygen content, because it's largely venous blood, you know, the portal vein is, you know, we learn in anesthesia still carries a decent amount of oxygen to the liver. So it is actually the, you know, arguably a time in which the graft gets re-exposed to oxygen for the first time if machine perfusion is not used.

Um, but honestly, reperfusion is classically or conventionally what we do in the OR during the recipient case where they release the IVC clamp, then they release the portal vein clamp. And then, um, you know, blood flow is, you know, in continuously going from the recipient through the graft back to the IVC to the heart and then throughout the body. Now I can get really nerdy on you and tell you, uh, even like the order in which we, um,

Anastomose and unclamped things that reperfusion can vary around the world. Some people reperfuse with the hepatic artery. Some people reperfuse with the portal vein. That's the way it's classically done in the United States and Europe. Sometimes it's simultaneous and it's with both.

So another reason why anesthesiologists really do have to know exactly what the surgeons are doing and why this is becoming a really specialized field within anesthesiology. Now, that's kind of how I think about ischemia reperfusion injury clinically, like what happens in the OR. Immunologically, long twister, immunologically,

I'll go over this a little bit, but don't worry. Nobody fall asleep. I won't spend too much time on it. It's a little nerdy, but ischemia is basically characterized by oxygen scarcity, decreased energy availability, intracellular acidosis,

in hepatocytes, sinusoidal endothelial cells, and cup for cells, which are like liver macrophages. So basically you have ATP depletion, ion pump dysfunction. This can get really nerdy. Go back to, you know, Krebs cycle med school stuff. You basically have this ion pump dysfunction in cell membranes, calcium overload, cellular swelling, your mitochondria gets swollen. They become more permeable.

You have narrowing of your sinusoidal lumen, disruption of the microcirculation, which ultimately leads to hepatocellular damage. So this is all just from ischemia. Then you reintroduce oxygen at reperfusion, and this leads to a paradoxical oxidative stress, actually, which is associated with severe inflammation and further hepatocellular damage. And so this is caused by alterations in your homeostatic regulation of radical oxygen species.

So radical oxygen species are physiologic. They play normal roles in our body. They're involved in cell signaling, immunity, differentiation, apoptosis. But in this context at reperfusion, after there's been a scarcity of oxygen and then a reintroduction of it, there's a disproportionate increase in these radical oxygen species. And that exceeds the body's antioxidant capacity for their compensatory metabolism. And you get this oxidative stress effect.

That leads to market myocardial dysfunction and permeability. Now, there's like two phases of reperfusion injury. There's the initial phase and the late phase. The initial phase occurs within the first two hours post-reperfusion, and the late phase can occur six to 48 hours post-reperfusion. So...

When we think of that initial, you know, you're in the OR, you're doing this, they reperfuse, and you went over the reasons why reperfusion can mean different things, but basically they reestablish flow through the liver in the inside too, in the body of the recipient. And you can get, right, classically, you think about you can have cardiac arrest, you can have, you know, severe hypotension, you can have severe hyperkalemia. That reperfusion is...

what we think about, and that's the initial one. And then you're saying there can be a later, you know, six to 48 hours later, you can have other kind of ischemic injury. Yeah, ischemic injury can last up to 48 hours. And you actually made me think of another important thing to bring up that I talked to residents about, because people don't necessarily think about this, although it makes sense when we actually say it out loud. Ischemia reperfusion injury occurs within the graft, like microscopically.

We often, as anesthesiologists, see it macroscopically as ischemia reperfusion syndrome. And that's kind of particularly the things that you talked about. The hyperkalemia can lead to EKG changes, cardiac arrest, arrhythmia,

vasoplegia, profound hypotension. And this is all from, I didn't get into the nit and gritty, but with the re-exposure to oxygen, you get these radical oxygen species, a marked escalation of cytokine release,

And that macroscopically is that horrible vasoplegia hypotension near cardiac arrest or possible cardiac arrest that we see clinically and that we treat in the OR. Okay, so that's a great, great distinction to make. The things that I was talking about are kind of the results of reperfusion or the syndrome, but the actual ischemia reperfusion injury is happening to the graft.

Okay. So obviously, you know, whenever we talk about organ transplantation, we think there's not enough organs for the number of people who need them. And so there's this concept of marginal allografts and extended criteria donors. Talk to us a little bit about that. What does that mean and how is that playing a role?

Yeah, and I'll back up a little bit because this is really important just for context. So obviously, liver transplant is the most widely performed treatment for end-stage liver disease. And over the last two decades, we've had marked improvement in innervation, right? So surgical techniques have changed. Like a lot of centers do the piggyback or the side IVC clamp.

Preservation methods have changed, as I've already alluded to. Normothermic regional perfusion, machine perfusion, immunopharmacology has changed. However, challenges remain, right? So we have increased demand for liver transplant in sicker patients. So even our recipients are older than they used to be. We have allograft shortages. And then we have these huge long wait lists.

And sadly, people are dying on waitlists. So to address these challenges, as you kind of were alluding to, we've increased living donation and we've actually expanded the deceased donor pool. So in regards to living donation, it's becoming more common in the United States. It's very specialized. So it's specific centers because it requires extra donations.

training. As you can imagine, when you have a cadaveric case, a cadaveric allograft comes with donor IVC, but you don't take IVC from a living person. So as you can imagine, it's more technologically challenging for the surgeons. And it's most commonly performed, at least in regards to the world and Southeast Asia, so particularly South Korea. I mean, South Korea does some of the most

living donor in the world. I mean, it's amazing. They predominantly do living donor more so than deceased donor. In fact, a lot of surgeons go spend time in South Korea with the liver transplant surgeons to learn those techniques. And it is becoming more common in the United States. Another country that actually does a lot of living donors, India as well.

And obviously Europe, like us, is starting to really increase its numbers. Now, we have really expanded that deceased donor pool because we do do more deceased donation in the United States than living donor. And so you'll hear these phrases, extended criteria donor and marginal allograft. You're going to love this, but it's a little subjective. There is no strict definition on what either of those means.

So each center or even each surgeon within a center can decide based on risk. And you will have surgeons even in one center that might be willing to take a riskier organ than others. But I do want to mention that in theory, these expanded donors, so these extended criteria donors or these marginal allografts are more susceptible to ischemia, reperfusion, injury, and possibly early allograft dysfunction. And this could worsen post-op risk.

So, ECD donors might have advanced age. So, now we're taking livers from people who are older than 20 years old.

People in their 70s or sometimes even older, they can have electrolyte derangements like hypernatremia. So previously, we really tried to avoid if the sodium is greater than 155, which you can imagine might be challenging in brain donation because a lot of them are on, you know, hyperosmolic management. Hemodynamic instability, so ones that have been on vasoactives in an ICU. Even hepatitis C, you can donate if you have hepatitis C.

prolonged ICU stay, donation after circulatory death like we've talked about. These marginal allografts can also have macrovesicular steatosis. So this gets into the ways in which we kind of define how fatty a liver is. And if you have greater than 30% macrosteatosis, it is associated with an increased risk of ischemia reperfusion injury.

And also prolonged ischemia time. So these are the ways in which we've really tried to expand who can be a donor so we can try to help all the people on the wait list. Yeah. And right. It seems like if your choice is die waiting for a graft or have a marginal graft, a lot of people would opt for the marginal graft.

Yes, and machine perfusion has dramatically changed this. Now, I want to acknowledge machine perfusion is expensive, so it's not as accessible in all areas of the world, or even in the United States, there's a lot of variability in its use. But you can even look at into this with machine perfusion, help assess the viability of a graph. It's helped us use, for example, more DCD graphs around the country. And you can put a graph on a pump, check its viability, and it can be on a pump for hours.

And, you know, arguably an early study said 19 hours, but arguably even 24 hours before you, you know, re-implanted in the recipient. So everything's changed. The machine perfusion is pretty amazing. And I want to get to that. Let's just talk though briefly about why do you think anesthesiologists need to know about early allograft dysfunction? You've mentioned a couple of things along the way, but just summarize for us. Why is it important for anesthesiologists to know about this?

It's really important that everybody has an idea of this, because even if you're not a liver transplant anesthesiologist, you might at some point in your career work at a center in which you perform the donor procurement case. Or again, you might even perform a recipient case if it's a smaller center or private practice. There are private practice institutions that do a lot of liver transplant procedures.

Now, people who are critical care or cardiac trained are also good candidates for doing liver transplantation. But honestly, a general anesthesiologist should be just as knowledgeable. Yeah, fabulous. All right. Now, so let's say we know about it. Now, what can we do to either lower the risk of early allograft dysfunction or maybe mitigate its effects if it does happen?

So I'm going to kind of break it down by stage. So we'll talk a little bit about intraoperative strategies during donor allograft procurement, during allograft storage, and during recipient reperfusion. So in regards to donor allograft procurement, I'm going to kind of focus on kind of four things that we can do. Historically,

The first one I'm going to bring up is actually pharmacologic preconditioning with volatile anesthetics. So historically, volatiles were not used during organ procurement as the donor is deceased and in theory no longer requires general anesthesia. So historically, they're not used. However, there is some evidence, though I acknowledge it's limited, that actually pharmacologic preconditioning with volatile anesthetics during procurement can decrease the impact of

of EAD or early allograft dysfunction. So Manu et al. demonstrated that actually donor ischemic preconditioning with seboflurane can decrease the incidence of early allograft dysfunction in liver transplant recipients of steatotic grafts, those like more fatty grafts.

And so they actually examined 60 brain death donors and they randomized them either into a SIBO group or a control group and found that the incidence of EAD was decreased in the SIBO group compared to the control group, about 16.7% versus 50% respectively.

Interestingly enough, the beneficial effect was dependent on the degree of donor allograft macrovesicular steatosis, and this was determined by biopsy. You're also going to love this. Whether or not a graft gets biopsy really varies by institution and surgeon.

And there's no strict guideline on this kind of thing. But they basically found decreased early allograft dysfunction for those who received allografts with mild or moderate macrosteatosis. It was actually only statistically significant for mild steatosis. They didn't find an influence...

and the incidence of EAD in those without steatosis. Now you might say, okay, well, Beth, I don't know if a graft is going to get biopsied. And first of all, this is procurement, so we can't even biopsy the graft yet. So how do I know if this graft is going to have steatosis? There are some risk factors for it, but you are making a judgment or making a presumption. Steatosis is more often seen in donors of higher body mass indexed

or ones that have stigmata of metabolic syndrome, so things like diabetes. Stay with us. We'll be right back.

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So it's something to consider, like borrowing any hypotension secondary to peripheral vasodilation from our volatiles. It's actually an easy thing you can just turn on in the background during the case. Now, the underlying mechanism is theorized to be due to increased activation of HIF-1-alpha, which is hypoxia-inducible factor 1-alpha.

And it's a transcription factor that's involved in cytoprotection, cellular metabolism, angiogenesis. Now, so number one, I'll say consider using volatile anesthetics if somebody has risk factors for maybe having a steatotic raft. Also, and honestly, this is again, largely historical, consider pre-harvest. So during procurement, donor hyperoxemia. I can't even believe I'm saying this because I'm someone who's always like, lower the FiO2, lower the oxygen.

But actually in the 1990s, pretreatment with hyperbaric oxygen therapy before ischemia actually attenuated ischemic reperfusion injury in rat models. So this was animals, not people.

Corradini and all have demonstrated longer recipient allograft survival when donor PaO2, they looked at mean and median PaO2 within four hours of reperfusion. They found that there was longer recipient allograft survival when the donor PaO2 was greater than 150 millimeters of mercury, which is kind of interesting. And that was prospective and involved like 89 deceased donor OLT recipients. Oh, and forgive me when I say OLT, if I do that, I mean orthotopic liver transplantation.

I do want to acknowledge, I'm not suggesting everyone should use 100% FIO2 during donor procurement cases. This is really more intellectual. Be cautious, right? Because other organs are also being harvested. And particularly if the lungs are being harvested, that could actually be deleterious for someone who's going to receive a lung transplant. So I largely mean this just in regard to, you know,

intellectual academic discussion. Now, it actually has a similar, it's theorized to have a similar underlying mechanism of basically inducing a sublethal burst of oxygen-free radicals that can actually protect from ischemic injury. Now, the third thing I'll mention under donor allograft procurement is normothermic regional perfusion. Now, this is cool. Not every center in the United States is doing this.

But it's basically temporary mechanical circulatory support. It's really similar to VA ECMO. It maintains organ perfusion with the exception of your cerebral vasculature, like we said previously. And it really mitigates warm ischemic injury during a DCD procurement. And there's been numerous, there's actually a plethora of studies that demonstrate its benefits here.

So it's been shown to decrease the risk of early allograft dysfunction, decrease biliary complications, decrease allograft loss. And this is actually compared to what we call super rapid recovery or just standard DCD without the normothermic regional perfusion. And it actually even has a comparable incidence of early allograft dysfunction when compared to just classic donation after brain death, which is a pretty big deal because, again, historically, DCD was seen as really high risk.

Watson et al. in particular found a decrease in EAD, a decrease in 30-day allograft loss, a decrease in ischemic cholangiopathy, and a decrease in anastomotic strictures. So bottom line, data suggests that normothermic regional perfusion may lead to better or at least similar outcomes when compared to conventional DCD procurement and donation after brain death, respectively. Okay.

Now, my last one I'll say under donor allograft procurement, I'm going to, again, exhibit some caution because I'm a norepinephrine lover. But there's some data here in the animal world. But consider the attenuation of norepinephrine use in the donor as able, I'll say.

So previous studies regarding vasoactive medication use and allograft function and recipient survival are quite conflicting. No one knows the best vasoactive, like norepinephrine vaso, vasodilator.

But there is some evidence, Cora Dine-Ayal, who actually did this study with pre-harvest donor hyperoxemia, found that donor norepinephrine use was associated with initial poor graft function independent of surrogate markers of perfusion like creatinine and acidosis pH and AST and ALT. Basically, there's a concern, and this is debated,

that norepinephrine could decrease hepatosplenic microcirculation or decrease perfusion to the liver, but this was in animal studies and not people. And it may even exacerbate IRI in animal models. Now, I think at the end of the day, the most important thing is to keep a goal map greater than 65.

and maintain adequate perfusion to the end organs, whether it's norepinephrine or vaso is still under market debate. But I just think that's kind of an interesting thing. Yeah, it's interesting. I mean, I would say it's got to depend so much on the dose, right? Low doses of norepinephrine are not going to vasoconstrict very much. And then also you have to wonder the...

The animals in this case who needed more norepi probably had a reason for that that may also have gone along with causing more allograft dysfunction. So it's hard to tease that out, I would guess. Yeah, I would never tell somebody don't use norepinephrine in a donor procurement case. Yeah. All right. Let's talk about so that's the donor allograft procurement stage. How about the allograft storage stage?

Okay, this is the fun stuff. This is the exciting. Yeah, this is the exciting. Yeah. This is machine perfusion. Okay. So machine perfusion, it's ex vivo. It mitigates the impact of IRI by extending organ preservation time. Big deal. It really improves lifestyle if you're in transplant. Increased organ utility. So we're, again, extending the people who can be donors. Decreasing early allograft dysfunction.

And we're basically using more of those marginal quality allografts that may have been otherwise declined, which is awesome. Both types, hypothermic and nomothermic, maintain continuous allograft circulation and moderate shear stress to sustain like endothelial functionality of the allograft.

I'll talk about hypothermic first and then we'll talk about normothermic. I do want to mention in the United States, we use normothermic. Where in the world and in Europe, they use a lot of hypothermic machine perfusion. So hypothermic utilizes temperatures between 8 to 12 degrees Celsius to decrease allograft metabolic activity.

Though similar to that used in static cold storage, the perfusate in hypothermic machine perfusion maintains a continuous flow of oxygen. So this is early re-exposure to oxygen. And you can see how this really mitigates total ischemic time, right?

prior to replantation of the recipient. Now, this is termed the flow of oxygen in this context is called HOPE or hypothermic oxygenated perfusion, but it can reach PaO2s of like 450 to 600 millimeters of mercury. Now, I would argue, does it need to be that high? Are we actually causing more free

radical release. Maybe a question for the future. But HOPE has definitely decreased the release of reactive oxygen species, at least in the recipient, and really abated that inflammatory response and ischemic reperfusion injury. And it can even restore mitochondrial ATP within two hours in some studies. So it's really encouraged the widespread

spread use of DCD marginal allografts. There's actually been multi-center randomized control trials. So Ganey and all found that hope significantly decreased EAD and improved outcomes and extended criteria donors. 90-day outcomes, decreased ICU and hospital length of stay. And this was all compared to like...

Set a cold storage. So, and again, when I say set a cold storage, if I didn't kind of bring this up earlier, when we're talking about storage, basically after the liver is removed from the donor, a perfusate goes through it. It's not oxygenated. So it's ischemic and it's put on ice to lower the metabolic rate. That's like still the conventional way. It's still the way a lot of the world does it.

But machine perfusion instead, right, you're pumping blood through the liver, right? Oh, good point. So in hypothermic, it's not actually blood-based. Okay, normal thermic it is.

Yeah. In normal thermic, that's a good point and a good distinction. In normal thermic, which is what we see in the United States, it's blood-based. Okay. The way we do it here, normal thermic, it's essentially ECMO, right, for the liver. You're pumping blood through the liver and blood's coming out and you're perfusing the liver just like it would be perfused inside a body. Yeah. It's incredible and it's really extended preservation time up to like 24 hours and

Normothermic basically replenishes glycogen stores and ATP. It can alter expression of genes involved in liver regeneration and control inflammation. Unlike hypothermic, normothermic can even assess allograft viability. So you can assess the macroscopic appearance of the liver. You can look at vascular flows. You can draw labs, look at a lactate clearance, bile production. I mean, if you go talk to the United States, we use a lot of organizations.

If you go talk to the transmedics technician, they can give you gases and you can know exactly what the lactate and the PaO2, which again is usually high. Not only is it blood based in normothermic, they also Y in additional oxygen. So the PaO2s are really high. Again, I wonder, do they need to be that high?

But that's a question for another study. Now, in regards to normothermic machine perfusion, there is a very well-known international multicenter randomized control trial. So it was called the OCS Liver Protect Trial. OCS stands for organ care system. They basically randomized 293 patients to either the normothermic machine perfusion group or conventional static cold storage.

And they found that the neuromothermic machine perfusion group demonstrated a significant decrease in early allograft dysfunction, 18 versus 31 percent, a decrease in histopathologic evidence of ischemia reperfusion injury, an increased use of DCD allografts.

and a decrease in ischemic biliary complications at six months and 12 months. So a lot of these studies I've brought up so far are basically comparing machine perfusion to static cold storage, the conventional mode of storage. There are studies currently going that are comparing hypothermic to normal thermic. Because if you go to conferences, that's the big debate, which one's better. And as you can imagine, people debate it. And it's

And it's probably bigger than this podcast, but stay tuned for those studies. Yeah, that'll be great to see. But the, you know, as you said, this being able to do this machine perfusion decreases early allograft dysfunction. It allows livers instead of being done in the middle of the night to be done in the morning, which, you know, makes it just a better kind of lifestyle lifestyle for the physicians and nurses and everyone involved. Yeah.

Not to mention patients not getting called in the middle of the night. So you really can kind of optimize the setting. And the most important thing, of course, is the outcomes. And it sounds like that's pretty clear that with this kind of perfusion, they're better. Now, you did mention earlier that there's a cost associated. Someone quoted to me that it's something like $80,000 to $100,000 additional per transplant to have that machine perfusion. So not a small amount of money, but big effect.

Yeah. And to your point, even within the United States, its use can really vary. So some centers, so I was an assistant professor at Emory, shout out to Emory, love you guys, prior to my time at Duke. And we only use machine perfusion for DCD and very extended criteria donors. But otherwise, we were still using a lot of static cold storage. At Duke, we are doing machine perfusion on almost every case and almost all

All of our cases are extended criteria donor or DCD. And it's a way where we've really increased our numbers of liver transplant because we are pulling grafts from all over, putting them on a pump. The many hours later, like you said, able to do the case in the morning. Yeah, very cool.

Let's talk about the recipient reperfusion stage. What can anesthesiologists do during that period to try to mitigate EAD? Okay, so this is definitely what's important to us in particular. So I'm going to talk about optimal oxygen exposure, optimal anesthetic, which everyone will be curious about, magnesium supplementation,

I'll mention exogenous nitric oxide and octreotide, and then we'll talk about free radical scavengers, which everyone always loves to debate. And there's market variability in their administration. So going back to optimal oxygen exposure, forgive me, this is my line of research, so I could get really nerdy and excited in this, but there's no evidence-based standard of care regarding optimal peri-reperfusion oxygen exposure. Now, since I've talked about how

complicated reperfusion could be. I'm talking about it colloquially in the recipient after, you know, hepatic inflow unclamping, what you classically think of. I'm not talking about reperfusion on the pump if machine perfusion is used, if that makes sense. Yeah.

Yeah. So in 2022, an expert panel of anesthesiologists through the International Liver Transplant Society recommended a restrictive oxygen strategy with a PAO2 of 70 to 120 millimeters of mercury throughout the liver transplant case. So they weren't specifically talking about the peri-reperfusion period, but there's actually not any evidence in transplant. It was actually all from abdominal surgery.

So actually many, so it hasn't really been widely accepted. And one reason why I'm so interested in it, many liver transplant anesthesiologists actually administer a high peri-reperfusion FIO2 to buffer cellular hypoxia during malperfusion.

While others say, well, I'm not going to give a high FiO2, I'm going to lower the FiO2 to really mitigate ischemic reperfusion injury. I should also distinguish at this point, so I don't confuse any listeners, hyperoxia versus hyperoxemia. So again, hyperoxia is like the fractional amount of oxygen that we give to the patient.

where when I talk about hyperoxemia, I'm talking about oxygen dissolved in the blood. And this actually becomes important in the conversation if you're doing research with liver transplant, because a lot of liver transplant recipients have hepatopulmonary syndrome or intrapulmonary shunts. So you could give a patient a high FiO2, but that allograft may not see all of that oxygen because of these shunts. So actually in studies, arguably looking at a PaO2 ratio,

better kind of reflects what the allograft truly sees in regards to oxygen exposure. But basically there's been studies in anesthetized mice that have shown that when subjected to hepatic, um, ischemic reperfusion injury, um,

They basically had mice that were exposed to FiO2 60% and then 21% postoperatively. And the group of mice that got exposed to the 60%, which equated to about an average PaO2 of 230, led to a significant increase in alloimmune-mediated hepatocellular damage as compared to the FiO2 21% group.

There's been some studies in living donor, which again has a different risk profile than deceased donor, but I'll still kind of quickly mention it. Miyachi et al. demonstrated that intra-op FIO2 or increased FIO2

or like increased average, what they called calculated average FiO2 greater than or equal to 50% was associated with worst allograft survival in about 199 living donors. Liayol also found lower intraoperative arterial oxygen content during the antihepatic phase was independently associated with early allograft dysfunction. It didn't really examine the best means to optimize the oxygen content, whether it be, you know, fixing the anemia, giving PRBCs or increasing PaO2.

But I do want to note that we know from that equation that the hemoglobin and giving blood may have a more profound effect. And actually, hemoglobin was lower in the EAD group, 8.7 versus 10.1 in the non-EAD group.

Now, okay, cool stuff. Now, again, we're still talking about recipient reperfusion. Well, let me ask you real quick. So it sounds like, you know, there's kind of a mixed bag of evidence. So what do you recommend? What do you do in terms of the oxygen that you provide?

So I'm hesitant to say this because my manuscript has been submitted but not published yet. So take this with a grain of salt. But I did perform a single center retrospective study on almost 1,000 deceased donor liver transplant recipients. And we actually found if your median PaO2 is greater than 190 millimeters of mercury within two and a half hours of reperfusion,

Um, that was associated with a higher odds of developing early allograft dysfunction. So in my personal practice, um,

I institute a lower FiO2 and I really just use that to try to target a PaO2 and I try to get it under 190 or 200 for reperfusion. Now, a lot of people will argue, you know, a PaO2 of 160 is still hyperoxemia because a normal PaO2 is 100 or less. And I know you're an ICU person, so you're probably thinking of that.

But as you know, all of our patients are intubated and ventilated and given some degree of supplemental oxygen. So, um,

I don't mean to suggest that hyperoxemia, I guess I could say it's relative, but ideally you want it on the lower. You want your PaO2 to be lower, although in theory, too low can be bad as well. Yeah, you don't want hypoxia. Yeah. Normoxia. We want normoxia. All right. Well, I'll be excited to see your study when it comes out. All right. So oxygen is one thing. What else can we do to optimize the outcomes during reperfusion? Okay.

Okay, so let's talk about anesthetics. So there's a bunch of commonly used anesthetics which possess desirable antioxidant or anti-inflammatory properties, propofol being one of them. So propofol has a phenolic structure that's similar to vitamin E. And so there's a bunch of cool nerdy things it does, but it activates...

hemoxygenase 1 which really mitigates inflammation during ischemic reperfusion injury and there's been a couple of studies so in one um living donor liver transplant study they examined uh propofol tiva and saw that it had decreased post-reperfusion um inflammation basically through an upregulation of hemoxygenase 1 and then improvement in um graft recovery post-op compared to desflurane now we don't use desflurane quite as much it has a it's a

Huge greenhouse gas. We don't see it, but interesting nonetheless. And another study in which basically they gave a propofol infusion. They called it post conditioning where they gave it peri reperfusion as a drip. And then after reperfusion in conjunction with a SIBO anesthetic. So it was an, it was used as an adjunct, not the primary anesthetic. And they found that it decreased oxidative stress significantly.

um, via the upregulation of hemoxygenase one and allografts. Now, I don't mean to suggest we should all be doing Tevas on livers. I mean, you could, right? Um,

It would have its own challenges, but volatiles also possess antioxidant and anti-apoptotic and anti-inflammatory effects. Another cool thing, there's a study out there about dexmedetomidine. So there's some evidence that dexmedetomidine as an infusion can decrease ICAM1, which is an adhesion molecule. So basically...

In the later stages of ischemia reperfusion injury, all those reactive oxygen species, all those cytokines increase these adhesion molecules on neutrophils and then on hepatocytes and sinusoidal endothelial cells. And ICAM-1 is one of those. And basically, it makes it so that neutrophils can attach and then infiltrate EMT cells, actually.

say neutrophils and T cells that infiltrate the liver parenchyma. And that's what causes so much injury to the parenchyma. So dexamethylamine, that's interesting. I still want to exhibit some caution with dexamethylamine in a liver transplant because I would be concerned about bradycardia because that's what we often see at reperfusion.

But still interesting nonetheless. And maybe if you had a low dose infusion and if a patient had a higher heart rate prior to reperfusion, you could consider it. But just be mindful. I don't know what your thoughts are.

I love dexmedetomidine, but I hear you about the concern about the bradycardia. In general, it tends to be dose-dependent, right? So you could use a low dose without having to worry too much, probably. And yeah, a low-dose infusion, not a bolus. Not a fastly administered bolus. Now, conversely, ketamine in animal studies has been shown to exacerbate oxidative stress.

via mitochondrial dysfunction. So in my personal practice, even though this is just animal studies, I don't give patients in transplant ketamine. Also, it can affect their mental status and mental status is another thing I really pay attention to when I'm deciding if I'm going to extubate somebody.

So be mindful of ketamine. Um, now magnesium suppletation is another really easy thing that we can give, right? It's anti-oxidative, anti-inflammatory, anti-apoptotic, um, in an animal model of the paddock IRI pretreatment with mag and mice subjected to about an hour of ischemia and then six hours of reperfusion. Um,

Show decreased IRI-induced hepatocellular damage. So it really mitigates the effects of ischemia reperfusion injury. And then in a living donor study, pre-reperfusion administration of magnesium, they use doses of 25 mg per kg, which for like a 70-kilo person is around like 2 grams. In my personal practice, I'll sometimes even give 4 grams per

They basically found that the administration of magnesium pre-reperfusion decreased lactate levels, which again is a marker of graft function, at 30, 60, and 120 minutes post-reperfusion. And this was compared to just like a placebo of normal staining lean, like 100 mLs.

The thought being that magnesium can mitigate the impact of calcium overload during ischemic reperfusion injury. I'll just say dilute it and give it slowly during the antepatic phase. Because remember, these patients are hypotensive and usually on vasodilators and vasoplegic. Good advice. All right. Other things that can play a role here?

Yes. So I'll say exogenous nitric oxide quite briefly. It is not routinely administered. There's some evidence to suggest, Langanol did a study, it was a prospective blind placebo-controlled trial that exogenous inhaled nitric oxide improved hepatic function after liver transplant by mitigating ischemic reperfusion injury.

My concern, though, and why it probably has limited use is the concern for peripheral vasodilation, again, in these patients. It can also potentially inhibit platelet function. And again, these patients bleed and it's expensive. You know, it's interesting. In theory, you know, these patients have decreased endogenous nitric oxide on the microscopic level in the graft, but macroscopically in the blood, they actually have an upregulation of it. And that's one reason why they're so vasodilated and have such low SDR.

So to be honest, this is not routinely used, but just interesting. Another thing, octreotide, a drug I love for liver transplant. There's been some animal studies that suggest it can mitigate ischemic reperfusion injury by decreasing TNF-alpha and IL-1-beta, which are involved in that cytokine self-perpetuating cascade effect.

I'll bring up free radical scavengers because that's another one everyone's going to want to talk about. I'll specifically talk about N-acetylcysteine and mannitol. So sadly, there's mixed, limited, or negative results regarding their effectiveness in liver transplantation.

So past studies in animals were promising for N-acetylcysteine, but there's been limited reproducibility in humans. You can find some studies in which there have been some beneficial effects. So there was a clinical pilot study in which N-acetylcysteine decreased ischemic reperfusion injury and really contributed to increasing liver function, synthetic function, I should say, and decreasing the risk of primary non-function. But then you can find a plethora of studies which

demonstrated absolutely no benefit. So it's really center-specific and most centers don't use it. Manitol also has quite limited data. I think one of the hard things about Manitol is that most of its studies are performed in kidney transplant, where it's also used for its diuretic effect, and it's hard to extrapolate that to the liver transplant population. Now,

So Medini et al found that a mannitol infusion of one gram per kilo during the antepatic phase and liver transplant better maintain hemodynamic stability versus controls, but they did not look at ischemic reperfusion injury or allograft dysfunction. So I think...

In all honesty, with how mixed the data is, most centers don't use either of those agents. But again, it's up to the center. Sure. All right. So what does the future hold? What should we be keeping our eye out for? Anything exciting? I mean, the big innovation is the machine perfusion, obviously. What else? What else should we be keeping our eye out for?

So again, my little plug, I think we do need to better examine the optimal oxygen exposure for these grafts, whether it's on the pump or during colloquial reperfusion during the recipient case.

There are current studies. You know, a lot of the studies I talked about were looking at machine provision versus static cold storage. There's studies out there now comparing them to each other and potentially hypothermic might have slightly better biliary complication rates. But again, both are absolutely excellent. There's cool serum IRI, like ischemia reperfusion injury and early allograft dysfunction studies.

studies out there really trying to look into the mechanism. There's clinical trials, for example, on IL-8 inhibitors. So IL-8 has been shown to escalate at reperfusion. And if we can abate that, that might lower our risk of ischemic injury. Omega-3 lipid emulsions,

There's all kinds of stuff. There's cool RNA interference therapeutics that are above my head. But it is quite clear that machine perfusion is changing the landscape of liver transplantation. Yeah, very cool. Awesome. All right, Beth, this has been fabulous. Let's turn to the portion of our show where we make random recommendations. What do you have to recommend that the audience check out for fun?

Okay, so I'm going to put a plug in there for season five of Stranger Things for a couple of reasons. This is selfish of me. Matt and Ross Duffer, the creators, are my really good friends from high school. Uh-oh.

Yeah, they are wonderful. So it's actually season five just completed filming. I think I'm allowed to say that TMZ is not listening. Everybody knows it. It just completed filming in Atlanta. So I was in Atlanta when they were filming it. And that was wonderful. So I got to see Ross a lot.

Is this the final season? Yeah, this is the final season. We're going to really find out about what happens in the upside down. Very good. So a plug for everybody to stay tuned. Filming is done. Obviously, they're going through editing and production and whatnot. I think there's a hope it can get released for viewing on Netflix in 2025.

But I am so proud of Matt and Ross Duffer. I mean, I have a vivid memory of us, like you'll laugh, when we were in high school. And I don't know why. We rarely did this. All we did was watch movies. But we were shooting hoops. We were, like, playing basketball in their driveway. And their dog, Flossie, was, like, running around. And Matt...

was shooting and he kept like bricking and he kept missing over and over again. I don't think he would mind if he knew I was sharing this story because it's not like he really cared about basketball. But I remember and I think I even have this on videotape. I was like, Matt, if you hit this next basket, you're going to be famous and you're going to make all these movies. And, you know, we were all like, no way, no way. And he actually made it. Matt like never made shots. So we were all like, whoa!

And I remember their dog Flossie was running around.

But I'm so incredibly proud of them. They are extremely hard workers and excellent writers. So everybody, please stay tuned for season five of Stranger Things and see other projects that the Duffers are going to be involved in. They're very secret. They don't tell me stuff. So I don't know too much insider info. That is awesome. Very, very cool. And yeah, Stranger Things is a great show. I'm going to recommend a book I read recently. Someone recommended it to me called Scythe, S-C-Y-T-H-E.

It's part of a series, The Scythe Books, by Neil Shusterman. The first book is Scythe or The Scythe. It's great, really interesting, dystopian fiction, really well done. I'm in the middle of the second book now, but I would recommend checking them out. All right, Beth. Great seeing you again. Thanks for coming on the show and taking us through this really important topic. All right, thank you. I greatly appreciate the opportunity as well.

All right. Hopefully you got as much out of that as I did. That was really fantastic. Let us know what you thought. Go to the website, akrak.com, where you can leave a comment. Others can learn from what you have to say. If you are a fan of the show, you can follow us. We're on Twitter. We are on Facebook. We are on Reddit. And we are on Instagram. I'm at jwolpa on Twitter. And we're at Akrak Podcast. And you can find us on all those other platforms as well.

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