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[00:00:00] Hello everyone. Welcome to the start of our series of abdominal transplant episodes. We are the team from the University of Nebraska Medical Center. My name is Maddie Luan and I'm a general surgery resident and number one fan of the transplant department here at UNMC. I am joined by a star study crew.

First, our senior transmit fellow, Dr. DW and future Mosts Junior faculty member. Hi, and I'm happy to be here next, Dr. Rahi Murani, an associate professor here at UNMC, an abdominal transplant surgeon. He has spearheaded our growth in Norma Herink Machine Profusion and Norma Thic Regional Profusion here at Nebraska.

Thanks so much for having me, Dr. Kan. Lastly, we have Dr. Alan Ness, professor of surgery, chief of the Division of Transplant here, and former A STS President. Hey Matt. Our focus today is in normal themic machine profusion or NMP in liver transplant. We'll explore some cases that highlight the uncertainty and evolving criteria around when to use norm Themic machine profusion and what it can mean for our patients.

We'll also discuss two big papers in the [00:01:00] field. Ultimately, we wanna tackle the big question, how do we make clinical decisions when a new technology shows promise, but evidence is still emerging. Dr. Marani, could you briefly explain what Norm Themic machine perfusion involves and how it differs from traditional static cold storage?

To understand norm themic machine perfusion, we really have to go back and look at what organ preservation in the setting of transplantation means. And traditionally, organs were taken from either. Deceased or living donors and stored X situ two in what's called static cold storage. A situation where an organ such as a liver spends time in a cold preservation solution on ice at hypothermic temperatures, and the rationale for that, they've had a reduced metabolic rate results in a reduced energy requirement, as well as a reduced.

Oxygen requirement resulting in hypothetically reduced reactive oxygen species upon reperfusion of the organ when it is sewn into the recipient, and therefore last mitochondrial and cellular entry. [00:02:00] Norm Themic machine perfusion is a situation where organs are exposed to norm themic temperatures and perfused with blood, which is oxygenated and caries nutrients.

And the theory behind this is that those organs, even though they are Exci two, still have a metabolic environment that mimics physiologic conditions, thereby hopefully reducing ischemia reperfusion injury, resulting in the ability of these organs. To be able to tolerate a transportation period outside of the body until they're brought to the recipient, and hopefully reducing some of the complications that we see with ischemia, reperfusion injury, potentially even increasing utilization of marginal or extended criteria donors.

Wonderful. Thanks for breaking that down, Dr. Do, can you give us a high level overview of the two articles? Sure, I'd be happy to. So we're discussing two of the articles that represent randomized control trials that study the role of normal thermic machine perfusion or NNP in liver transplantation here in the United [00:03:00] States.

First, we have the per. Tech trial published in JAMA Surgery in 2022. This was a phase three multi-centered randomized control trial that took place between 2016 and 2019. With 20 United States Transplant Centers participating, the author sought to answer the clerical question, how does normal thermic machine profusion using the edix OCS liver device compared to cold static storage and deceased donor liver transplantation?

The investigators hypothesized that NMP would be at the very least, non-inferior to cold storage in terms of early graft dysfunction. The aim was to compare livers preserved on the OCS device to livers with static cold storage in regards to rates of early allograft. Dysfunction. The intervention was preservation of the liver with the OCS liver and MP device from organ recovery until transplantation.

The comparison group was preservation with conventional static cold storage. Primary outcome was the incidence of early allograft dysfunction in the recipient [00:04:00] population. Secondary outcomes included indicators of ischemic reperfusion injury, post reperfusion syndrome, biliary complications, graft in patient survival, and overall organ utilization.

N NM P preservation was significantly associated with improved early outcomes. The OCS Liver Group had a lower early allograft dysfunction rate than the cold storage group. They also observed less evidence of severe reperfusion injury in the NMP arm. Additionally, non anastomotic biliary complications or what we think of as ischemic cholangiopathy, we're reducing the NNP arm.

30 day graft in patient survival were high in both groups and not significantly different. Notably, the trial also found that more donor livers were utilized for transplant in the NNP arm than in the cold storage arm. Great. Can you tell us about the second article? The second article was by Chapman at al titled Normal Derig Machine.

Profusion of Donor Livers for Transplantations. In the United States and was published in Annals of Surgery in 2023, [00:05:00] Chapman et al set out to determine if NMP would reduce early allograft dysfunction in routine practice, especially given the promise seen in earlier trials like the Protect trial. NMP has shown encouraging results and improving early outcomes, but questions remained about its overall benefit in the brag donor pool.

They suspected that while NNP might not change outcomes of low risk livers, it could make a big difference for high risk donors. The hypothesis was that NMP would lower the incidence of early allograft dysfunction overall compared to static cold storage. A secondary hypothesis was that NNP would particularly benefit livers from DCD donors or other high risk donors improving their transplant outcomes.

The study was a large multicenter randomized control trial conducted at 15 US liver transplant centers. Population was recipients of deceased donor livers. The intervention was continuous XI two ROIC machine profusion of the donor liver, using an NMP device called organ from procurement until implantation.

The comparison group was standard static [00:06:00] cold storage. Dormers were randomized to one preservation method or the other. Prior to organ recovery, primary endpoint was the rate of early allograft dysfunction in the recipient. Key secondary endpoints included incidences of post reperfusion syndrome, graft survival, patient survival, and subgroup analysis of EAD in high risk or low risk organs.

They also tracked how many livers actually made it to transplant in each arm. Interestingly, the overall primary outcome did not show its statistically significant difference between NNP and cold storage in this trial. However, in the subgroup analysis as the author suspected, the high risk organs benefited the most.

Among livers from DCD donors, the early allograft dysfunction rate was lower with NNP. Similarly, for the highest risk quartile of donors based on donor risk index, NNP livers had early allograft dysfunction, 19.2% versus 33.3% of the time in the cold group. Another important finding post reperfusion syndrome was [00:07:00] significantly less frequent when NNP was used in terms of utilization, the numbers of transplanted organs were similar between arms, indicating NNP did not lead to a huge difference in overall organ use in this trial.

Her notes NNP, was safe with similar survival outcomes and no unexpected adverse events from using the device. A crucial insight is that NMP provides the greatest benefit for higher risk livers. While you might not need NMP for every single donor liver, it can be a great tool for expanding use of higher risk organs.

Awesome. I think it's really easy to see the similarities between these articles. But Dr. Marani, do you mind calling out some of the differences? So I think one of the key differences is. The statistical observations of the primary outcome, which in both of these studies was early allograft dysfunction.

I think it's important to talk about early allograft dysfunction because clinically it's probably not something that we think of or routinely monitor or discuss when we're taking care of patients. But early allograft dysfunction was involved as primary outcome measure [00:08:00] in both studies because these were.

Phase pivotal trials that were essentially being performed to obtain FDA approval for the device to be brought to market realistically on a daily basis. We don't talk about early allograft dysfunction. We don't really care about it so much. However, prior studies have shown an dissociation between early allograft dysfunction and primary non-function, which is a much more rare event.

Awesome. Dr. Lingus, can you highlight some current national trends in liver transplantation, particularly regarding the use of DCD organs? Thanks, Madie, and that, that was a great review, Jackie and Shaheed. That was really helpful. I learned a lot. So first of all, I think organ donation and transplantation throughout the United States has shown a huge.

Increase, which I think is just fantastic and it remains a little imperfect in some ways. Distribution allocation policies still have a lot of room for improvement. But overall, the number of transplants being performed in the United States is, is fantastic. It exceeds 40,000 in the past year. And along those same lines, liver [00:09:00] transplantation is also increased.

The reasons for that are always multifactorial, but there's no question that the two major drivers for the increase in transplantation. Been the use of these machines that we're talking about today. This machine profusion combined with the increased identification of donors deceased donors after cardiac death, a so-called DCD donor.

And, and the number of DCD donors I think has increased by over 20% in the last year. So that's had a huge impact on the number of available organs that we can use. And now we also have a mechanism not only for preserving them, but also as a. Tool for testing these organs to make sure they're just suitable for transplantation and allowing us to be more confident in our ability to safely help people.

Yeah, I think that's really great and it's such an exciting time to be in transplant. Before we start with our modern day cases, we're gonna do a little throwback to a time prior to NMP being routine in practice. So for our first case picture this. It's 2017. You're listening to Taylor Swift's new [00:10:00] comeback album Reputation on your iPhone seven on repeat.

So you broke the internet with her twin reveal Instagram post. Millions of people stared at the sun to watch the solar eclipse. Dr. Marani is your senior transplant fellow, and DCD makes approximately 5% of UN C's total liver trans high volume. You receive an offer for your 62-year-old patient with a history of alcohol use disorder.

And a meld of 21. This is a standard DCD donor who is 36 years old and has a BMI of 20 history includes reported head trauma after NBC with port prognosis. Can you walk us through what evaluating an offer from a DCD donor looked like at this time? Sure. So I think there's a few important considerations in this case, and the first I think, goes back to the DCD consideration that Dr.

Langness was talking about earlier. DCD donors have typically been associated with higher rates of. Post-transplant complications, specifically ischemic cholangiopathy, which can result in biliary sepsis, intra hepatic abscesses and graft dysfunction, sometimes [00:11:00] oftentimes requiring retrans plantation.

So, DCD liver allografts were approached with caution. However, on the other hand, you have a patient who has a relatively low MELD score and. The wait time for this individual to receive a liver transplant may be really long. They may suffer from complications related to their advanced liver disease, and so obtaining a liver allograft that is appropriate for transplantation is also important.

So weighing the risks, benefits and alternates of accepting this DCD ALLOGRAFT versus waiting for another. Liver allograft offered to become available. I would opt to accept this donor offer for the recipient. Great. So you accept this offer. Total warm ischemia. Time is 24 minutes. Functional warm ischemia time is 14 minutes.

There are no concerns on recovery or back table preparation. Your senior transplant fellow sos in the graph and you're ready to uncl clamp. What's Dr. Morani be thinking about implant for when refreezing this DCT liver in 2017? So that's a [00:12:00] really great question, Maddie. So, so, right. So everything's gone great.

So far, everything has kind of fit in sort of the box that we create, or a matrix that we create. You know, the donor's not too old, they've expired in a reasonable amount of time. The fellow has managed to get the liver out safely without any damage. The biopsy's, okay? Mm-hmm. And the recipient operation has been going just great so far.

The liver's sewn in and at this point. All, all the things that we can do are really have been done successfully. The trouble with UNC clamping and fusing these livers is that as a consequence of this, there's gonna be a huge cytokine release. These are gonna go directly to the right heart and left heart, and the anesthesiologists are then gonna have to battle.

With all the hemodynamic compromises that take place. And you know, the anesthesiologists typically do a great job, but it isn't always within their abilities to keep, literally keep the patient alive. So despite the fact that every step of the way, we have [00:13:00] kept well within the guardrails of using A DCD, both from a donor side and a recipient side, done a good operation that's been safe and relatively.

You know, low blood loss, you're still faced with this sort of crescendo of events that are gonna then take place that then, you know, the patient has to survive. And both the anesthesia and the surgical team have have to work very hard to get the patient through that phase. Dr. Morani removes the upper and lower cable clamps and he begins to release the portal vein.

You notice some peak two in hypotension. Your anesthesia colleagues are able to stabilize the patient, but he requires significant vasopressor support and resuscitation for the remainder of the case. The patient is taken to the ICU post-op ultrasound is normal. Liver enzymes are elevated in the two thousands, but slowly downtrend over his course and he is discharged.

However, four months later, the patient calls in and reports new itching and worse skin fatigue. He's brought in for labs and found to have an elevated bilirubin and alkaline phosphatase. The ultrasound chose no vascular abnormalities and liver [00:14:00] biopsy is normal. An MRCP demonstrates mild int hepatic ductal dilation and narrowing at the common hepatic duct confluence.

The patient is scheduled for ERCP. You suspect an non anastomotic stricture. Can you elaborate on what ischemic cholangiopathy is and what it looks like for our patients? So I think ischemic cholangiopathy is oftentimes seen as a radiographic finding of altered biliary anatomy, especially with, you know, what we think of as pruning of the bile ducts, basically potentially diffuse stricturing, both intrahepatic and extrahepatic, and really is not really, as you described.

An problem. It's problem with the bile ducts, both in and outside of the liver. And that can result in problems such as jaundice, as well as cholangitis, as well as intrahepatic abscesses. So these are severe clinical outcomes for our patients that can cause. Of their graph. Right. So, so these things typically then require biliary interventions.

Non anastomotic stricturing [00:15:00] mm-hmm. Can result in severe debilitation of the patients. And oftentimes these patients will be left with percutaneous trans hepatic tubes that require frequent changing and. Ultimately, many of these patients end up needing to be considered for Retrans Plantation.

It's a, it's a horrible consequence following what was a relatively successful transplant. Let's move on to the same case, but it's 2025. You accept this DCD offer for your patient with a meld of 21, and you decide to use NMP. If there are no concerns on recovery or back table preparation while cannulating to pump, how do you plan to assess the function of the graft while on NNP?

So on NNP, there's actually like a computer device that sits where you can actually look at the perfusion dynamics of, the hepatic artery and the portal vein and just kind of better understand if, if you need to do some manipulation. In addition to that, we actually follow labs specifically a lactate level where we get actually a [00:16:00] baseline lactate level of really the blood that we use for the pump itself, and then later, every 30 minutes thereafter.

Ideally, for us, we like to have a lactate level, less than two within two hours, but that is something that. Continues to be investigated in addition, understanding the graph function by actually seeing bile being produced. And that's something that we can see in real time. And yeah, I think it's important to consider that, you know, the following, the lactates was something that has been done historically, but there is no strong evidence to say that lactate clearance really means anything.

I think it makes us feel better. It makes us think that. The organ is participating in aerobic as opposed to anaerobic metabolism. And so theoretically it makes sense. Additionally, we have evidence from the protect trial that livers that were used for transplantation did have a rapid decrease in their lactate levels in this first several hours.

And livers that were not transplanted tended to have lactates levels that did not decrease or [00:17:00] plateaued early. However, that. Doesn't really tell us that it's a good biomarker for allograft viability. Great, great. So the graft is placed on pump, starting lactate is eight, and lactate at two is two hours.

Flow dynamics are appropriate. Bile starting to be produced. Do plan to transplant this graft? I would, if the lactate is coming down, the liver is producing bile. It has homogeneous liver perfusion and appropriate flow dynamics, meaning appropriate hepatic artery and portal venous flow without high pressures.

I, I think this the liver that sounds like it's on track to be suitable for transplant. The graft is transplanted. There's a media graft function with no issues, and the patient does well. What if I said starting lactate was 11 and two R, lactate was seven. Does this change how you look at this graft? So that's a, that's a really thoughtful sort of a, sort of a.

Almost as a trick question of sort, I would even say because I, I think, you know, I think as we've gotten more [00:18:00] experience, I think in the beginning we would be very nervous about that, but I think we were also cautious about taking that as just a standalone bit of information. Mm-hmm. I think when we look for low lactates, that's reassuring.

A high lactate makes us a little more anxious. And I think today, I think that just means we would leave it on the pump longer to see what it would do and look at other parameters as well. Taking into consider the consideration the whole constellation of the clinical events that led us to getting this liver on the pump.

So flow raise. Bioproduction or the circumstances of the donor. And then a biopsy also may be useful. So all those things come into play, but I think a lactate of seven makes, you know, makes us quote unquote anxious. Mm-hmm. And just tells us we have to wait a little longer and be patient, which may not be, in general, the strong suit of most transplant surgeons.

Four hour lactate is less than one you decide to transplant. Early [00:19:00] post-op enzymes are high, but the patient progresses well and is discharged home without issue. So next case you receive an offer for a graph from a 27-year-old brain dead donor with A BMI of 31. Your recipient is a 55-year-old patient with previous liver transplant and graft failure, who's currently listed with a meld of 34.

Is there an indication to pump this liver? So like a lot of things, it depends. Mm-hmm. So the, one of the great, maybe not unexpected, but gives us more time and it gives us a longer logistical band that we can work within. So in this case, we could accept the liver from farther away. We could leave it on the pump longer and allows us to do the recipient's hepatectomy, which is gonna be much more difficult than a routine case, and allow us to take our time and not be under sort of the typical static cold storage constraints that we typically have to deal with.

Fact that a redo liver [00:20:00] transplant recipient is gonna rehire an extended hepatectomy during due to the adhesions in the abdominal cavity. And I think it's important to go back to the primary literature and, you know, Chapman's article talks about the total duration of ex excite your time for the organs.

Citing that in thermic machine, perfusion arm, the livers spent over 500 minutes outside of the body in. Comparison to the statics cold storage arm where livers were typically transplanted in less than six hours. In both of these papers, they excluded status one A patients and the Protect trial also excluded, redo recipients.

How do we apply the data from the studies to recipient characteristics that may have fall fallen outside of their inclusion? I actually wondered. The same question when I was reading these article, there's gotta be a reason why they were excluded, but I wasn't a part of the the conversations. But I know Dr.

Morani is listed as one of the authors on one of these papers, so I was curious to [00:21:00] hear his opinion on this. Yeah, so I think when designing. You know, pivotal trials or phase three clinical trials, it's important to have a relatively homogeneous population. Knowing that there are enrollment restrictions in terms of how many patients can feasibly be enrolled in these studies, you really wanna focus on a particular patient population.

And I think these studies were designed to look at kind of an average. Recipient redo liver transplantation, I believe is in the order of about 10% or maybe less in the United States of all the liver transplant volume. So if you start to put in those higher risk recipients, it does create a lot of heterogeneity in the study, which make make it more challenging to interpret the results.

So, in answer to your question, Maddie, I think this is one of the challenging things with using clinical trials and papers, is that you might not be able to look a patient up in a [00:22:00] particular textbook or in a particular trial. And so oftentimes when. Medical devices or medications, pharmacologic agents or particular interventional strategies are approved for use.

Sometimes we do have to start using those tools off label, and I think that's appropriate in a. Careful calculated patient-driven rationale. Great. So we've covered how DCD looked in the past indications for pumping an organ, including donor recipient and graph characteristics. Let's take a little look into the future and for the areas that we don't necessarily have answers for, for the final case you receive.

An offer from a DCD donor who's a 66-year-old patient with A BMI of 35. Patient passes after extubation with a total warm ischemia time of 20 minutes and functional warm ischemia. Time of 12 minutes. There are no issues with recovery, but intraop biopsy comes back with 30% macro steatosis. How do you go about weighing these donor and graft [00:23:00] factors when deciding whether or not to transplant this graft?

So an another really hard question, Maddie. So I, I think, you know, we can use our sort of the issues in some ways. I think going back to some of the, the metrics that you mentioned, what was the functional, warm time? What was the, what does the liver look like? Is it, does it gigantic? Is it three kilos? Is it grossly appearing normal or abnormal?

I think those things take on greater weight. Because, you know, there is a certain inherent risk in that. So I think a brain dead donor, even with those characteristics, would make us all a little skittish. Mm-hmm. Pumping. It may give us some reassurance that it will be functionally effective when we put it in.

So I think that's really kind of where we're probably most people would say that's kind of where we're at in terms of limits. And a person in that age group with that amount of fat and having an elevated BMI, you'd almost [00:24:00] imagine that they're gonna have some fibrosis on that biopsy as well.

There's a lot of things there. I think. I think it would require some conversations about using it or not. So I think, I think that's a great case because I think those are the types of things we're gonna have to wrestle with in the future, because that's what we're being offered. Mm-hmm. And in the context of being offered what we consider non-ideal donors, I'm not even, I'm not even sure that expanded or extended criteria even makes, is a, is a language that we should use anymore, but I think these are just a little bit more hazardous in some ways.

Mm-hmm. We have to develop tools or confidence to know how to, to use them because just to remind your audience, still, we have 10 to 15% of our patients dying on the waiting list. Despite the improvements in organ donation in the United States and the fact that we're busier, most programs are busier. Everybody's doing great, helping more and more people, we're still seeing 10 to 15%.

Are people dying on the waiting list without transplantation. So we [00:25:00] still have to not dismiss these organs 'cause we're concerned, but we had to find ways to successfully try to use as many as we can. Mm-hmm. Can we talk about what donor graft characteristics that were previously thought to be exclusionary to transplant that were reconsidering.

Sure. I, I, I think that's sort of easy, just the DCD that you talked about. I can't imagine five years ago, even considering a 66-year-old morbidly obese DCD donor. I think it just would be just a bridge too far. The stakes would be too high, I think. I think that the, the needle we have to thread is, is that because if we put a.

A liver into our patient. I mean, the stakes are super high, right? And, and so if you do a liver transplant to somebody who's in their thirties and forties and a liver doesn't work well, maybe we, we can re-transplant them urgently or get 'em to lymph through with that liver. But so many of our patients are getting to be a little older, you know, sixties, late sixties, early seventies.

It's mm-hmm. It's pretty common. And so I think you just have to [00:26:00] be really cautious about that. So I think, you know, the d the expansion of DCDs in general. Particularly the age has been really exciting. And then I think now we're trying to decide, you know, what is the warm ischemia time that we can tolerate?

I think it used to be 30 minutes period. Now we're willing to go warm ischemia, time from extubation much longer over an hour. As long as the functional warm time seems to be within 30 minutes, and maybe that. Line is also gonna be extended as we gain more and more experience. So I think it's, it's very exciting.

Mm-hmm. I think, you know, we keep pushing the envelope and seeing what, you know, what we can use. Because I think that, you know, I think the, the need is really great and, but it, but it's a little scary. Mm-hmm. And it's, and it's a little hard to know sometimes. Mm-hmm. That wraps up our discussion on normal thic machine profusion and liver transplantation.

A big thank you to Doctors Langness, Ani, and Dalk for sharing your insights and experience. I hope our [00:27:00] listeners found this as a lightning as I did. The field is moving fast and it's always an exciting time to be in transplant surgery. Thank you for listening. Until next time, dominate the day.