Hello and welcome to today's Journal Club Critical Care Medicine webcast. This webcast, hosted and supported by the Society of Critical Care Medicine, is part of the Journal Club Critical Care Medicine series. This webcast features two articles that appear in the November 2022 issue of Critical Care Medicine. This webcast will be recorded. The recording will be available to registrants on demand within five business days. Log into mysccm.org and navigate to the My Learning tab. My name is Tamas Zagmani and I'm a Professor of Intensive Care at Cardiff University in the United Kingdom. I will be moderating today's webcast. Thanks for joining us. Just a few housekeeping items before we get started. There will be a Q&A session at the conclusion of both presentations. To submit questions throughout the presentations, type into the question box located on your control panel. If you have a comment to share during the presentations, you may use the question box for that as well. And finally, everyone joining us for today's webcast will receive a follow-up email that will include an evaluation. Please take the five minutes to complete it. Your feedback is greatly appreciated. Please note the disclaimer that the content to follow is for educational purposes only. And now I would like to introduce today's presenters. Harry Pallad is the Medical Director of Cardiology and Critical Care at St. Jude Medical Center in Fullerton, California. He is ABIM certified in cardiology, critical care, neurocritical care, palliative care, as well as internal medicine and geriatrics. He graduated from the Albert Einstein College of Medicine with special distinction for research in cardiology. His insights have been published in the New England Journal of Medicine, JAMA, CHEST, Annals of Internal Medicine, and others. He holds a master's degree in bioethics from Loyola University. Beatriz Dominguez-Gil is a medical doctor, specialist in nephrology, and holds a PhD in internal medicine. She joined the National Transplant Organization in November 2006 and became its Director General in May 2017. She is the immediate past chair of the Committee of Transplantation of the Council of Europe, President of the Ibero-American Network on Donation and Transplantation, and member of the WHO Task Force to Promote Ethical Practices in the Donation and Transplantation of Organs, Tissues, and Cells. She has more than 200 publications in scientific journals and book chapters. She has presented more than 450 communications and papers at national and international conferences. Thank you both for joining us today. I will now turn the presentation over to Dr. Pallad. Thank you very much. So the question for today is really for intensivists especially, should you permit normal thoracic regional perfusion to be performed on your patient? So what I would like to do today is clarify some of the factual differences, explain why these factual differences are clinically important, which really speaks to why we wrote this paper. I especially want to advocate for getting informed consent if this procedure is going to be performed because of the differences between NRP, but I do want to make the case why the hospitals, medical staffs, and the ethics committees really should be the primary deciders if this is going to be performed. So first thing in this chart, I want to do clarify the differences. The first thing is that the declaration is not the same as DCD, and these are really the clear differences, is you have to look at a context. With DCD, death is declared after five minutes of no circulation, and there's no plan to restore circulation, which is the case in NRP. The blood flow is restored after the death declaration with NRP, which is different. The arch vessels are ligated, which again is the difference from DCD. Again, people can argue as to whether the moral or practical relevance, but it is important to know these, especially what's very important is that there's a risk of brain blood flow despite ligating the arch vessels. What's also important is international guidelines recommend brain monitoring if you're going to do NRP, and you also have a plan to abort the procurement process if such flow is detected, which again is unique to NRP. In terms of how other people view this, it's important to know that the ATS, UNOS, Institute of Medicine have all specifically endorsed DCD, but they have not endorsed NRP. They've not come out against it, but they have not endorsed it. American College of Physicians has recommended a pause on this, and from an international perspective, what's important to note is that in Australia, Canada, they have done their due diligence and have decided not to perform NRP. I think what's important that people know that circulation will be restored with NRP, which is different than standard DCD, and there's also the risk of perfusing the brain unintended, which again is unique to NRP. What's important to understand is even if NRP is a better procurement method than standard DCD, even if that is true, the fact that people want to do things, autonomy and consent do not justify procurement of vital organs if there's a question if the patient is in fact really dead or violates the dead donor rule. The main thing I have to remember with DCD is that there is the permanent cessation of circulation, and whether it's irreversible or permanent, it really comes out the same thing. So, to say that the death declaration is the same is simply not, is just not really quite accurate because you're removing the whole context. You can't look at one thing just in isolation. You do have to look at the whole process. As I do mention, NRP is not permitted at this time in Australia or Canada, and essentially in some ways it's really extracorporeal CPR after the death declaration with the addition of the ligation of the arch vessel. So, of course the intent is very good and people want to do the right things, they want to feel that they're respecting the DDR, but it doesn't change the biological reality that after a death declaration you are restoring flow and there's a risk of brain circulation. The ligation of the arch vessels, again, is done only with NRP, and the reason you're doing it is because you're restoring circulation. And if you do not ligate the arch vessels, the brain flow will resume. So, arguably there's a causality here between ligation of the arch vessels and for this extracorporeal resuscitation, you know, despite, you know, it's not done to resuscitate the human being, but that is what is going on. So, the ligation of the arch vessels, especially with TA NRP, is really nothing to do with procurement. You know, arguably when you're doing abdominal NRP, the aorta, the descending aorta is going to be clamped in either case. And there's a nice article in CHEST which presents both sides of the point which says why NRP is felt not to be ethical and a really very nice piece from the NYU people saying why they think it is ethical and another piece that I recommend to people. Separate from the ethics, you have the practical issue of the risk of brain flow via collaterals because even though you can ligate off the arch vessels, you have risk of collaterals through various circulations, especially to the posterior circulation. And what's important to know is this is the opinion of the Papworth group in the UK who actually pioneered NRP. So, it's important to understand, you know, these are not arguments coming out of left field. And to the extent that we're worried about posterior circulation, remember that if you're using a BIS monitor, which is, you know, standard of care in Spain or a cerebral oximetry, you're not really monitoring the posterior circulation. And because of this risk, which is unique to NRP, is that you need to monitor for this flow and you also need a plan to abort in case there is signs of brain perfusion. And what to me is concerned is the NRP advocates do specifically feel that they do not need specific informed consent. And you know, I think in Dr. Dominguez-Gil, she does mention in her piece, you know, that you do need to monitor the brain activity and the technical issue of draining the arch vessels. The U.S. transplant teams, as far as I know, have not publicly committed to doing this technical modification to ensure drainage of the aortic arch vessels and reduce the risk of brain flow. And as far as I know, at the present time, the U.S. protocols are not publicly describing when or how to halt NRP. So, I want to do a little background as how we came to write this paper. You know, I'm not from a transplant center, I'm not from an academic medical center, but we're a high-level community center, we are a comprehensive stroke center, we've been, you know, getting some accolades, and our OPO approached us to permit DCDNRP, certainly like, you know, other places in the U.S. have been approached. And because of the complexity of this, we really decided we needed to bring this to the ethics committee and the medical staff, because this is not merely a detail of procurement, let's say, on a patient who's been declared dead by neurological criteria. You know, we felt that this was a lot more complicated and involved in that. You know, just to mention the dead donor rule, you know, there's a concept patients cannot be killed for donation or have the donation result in their death. Some well-respected bioethicists advocate for its elimination, but it certainly is the law of the land. And what's important is lack of circulation is necessary to declare death, but it's not sufficient if you actually plan on restoring flow. A common question is, well, then why is DCD okay? And we have to remember with DCD, there is no brain blood circulation, and it will not occur, because you're not doing any intervention which could even risk the brain flow. If you're doing the five minutes, you know, of standard time, the longest auto resuscitation time documented is four minutes, 20 seconds from Dr. Chemi's data. A couple of sort of experiments I want to give to people in terms of the ethics as well as the practicality. So imagine you're doing a regular DCD, you know, five minutes, asystole, and you're about to do everything, right? If the family burst into the room and gives epi and started CPR, the patient's obviously not dead, right? There's an unexpected intervention where we reverse the death declaration. The same thing would occur if at six minutes, the family burst into the room and put the patient on ECMO, right, and there's brain flow. Again, I don't think that's somebody that we would consider dead. Imagine if a patient comes in with an overdose to the ER, right, refractory B-fib, and you start, you know, extracorporeal CPR. There's no spontaneous circulation, but again, they're not dead, right? If you're perfusing them and the brain's alive, lack of spontaneous circulation does not define death. Now, let's talk about an NRP case, right, because there is widespread agreement that you need to monitor. Let's say for the sake of argument, you know, it's five minutes, asystole, you know, patient's been declared dead properly. You ligate the arch vessels, and then you start the ECMO or the bypass circuit, and then you see the cerebral SAT increases and the BIS goes up, right? I don't think we would say the patient was resurrected from the dead. We would say the patient was resuscitated, you know, albeit inadvertently, and therefore wasn't really dead, and with DCD, you're not really allowed any brain flow, and I think the other part of the thought experiment is imagine if you have an NRP case and the surgeon says, hey, I just want to skip the ligation of arch vessels, right? I want to reduce my warm ischemic time. Let's just go do the D. Obviously, you have to ligate the arch vessels, but if the patient was really dead and, you know, sincerely dead, you wouldn't have to do the procedure. So again, the claim that they are dead after five minutes when you are going to restore circulation and there's a risk of the brain flow is just simply problematic, and again, as I mentioned, the concern is the advocates for NRP have specifically said that a different authorization process is not needed, but again, I think what's clear is there's risk of the brain flow. You know, we think that if you want to respect, you know, the patients or the surrogates, you have to let them know that there is a difference and give them enough information to object, and just because there's not a standard of care yet as to how much information should be given NRP doesn't really change our basic rules of when and how we get informed consent. Here are quotes from three different groups involved in transplant, and everybody agrees you have to be assessing for function and you need a plan to abort if brain perfusion is seen. So we agree with the NYU group that you have to give the morally relevant information, and given the fact that multiple organizations feel there's a risk of brain flow, I just don't see how this can be done without that, which seems to be standard of care in the United States, and that's from, you know, the patient and the donor point of view. I think from an organizational point of view, right, and as a prudent intensivist, right, because I'm the medical director of ICU, I have obligations, you know, to other people too, you have to know when people permitted NRP, whether it's the IRB or ethics committee, did they have the relevant information to make that decision. I won't get into details. Dr. Bernheim, who's one of our co-authors, is a well-known world authority on this. The reason I mentioned him is he's one of the big believers in DCD, and a lot of his concepts are important to the ethical and practical acceptability of DCD, as well as the acceptability of death by neurological criteria. So I think it is important that for all of us, when we're having this discussion, we make sure that as we're having this discussion, that since we all agree on death by neurological criteria is valid, we all agree that standard DCD is valid, that nothing we say is misconstrued to go against that. These are just some of the possible misconceptions, and, you know, I think what people need to think about, that the death declaration really is different, cessation of circulation does not define death. If you're going to restore the circulation, ligation of the arch vessels is not part of the procurement process. And some people make the claim that the NRP technology is new, so it's not really understood. But if we go back almost a decade ago, okay, one of the important consensus DCD papers, which was signed off on by the Society of Critical Care Medicine, UNOS, ATS, the authors could not agree whether the use of ECMO was appropriate in the DCD setting. They were talking about abdominal NRCP, and certainly any lack of consensus would apply to the thoracic abdominal also. So I think, you know, when an individual intensivist is deciding, hey, do I want to be part of declaring death, when we're not sure if this is ethical, whatever one wants to do or not, I think it's important for people to know that there is a lot of difference of opinion out there as to whether it is, you know, ethically acceptable, whether it's legal, and this practical issue of the brain flow. What do we do next? You know, U.S. does not have a centralized decision-making authority like, you know, the UK and some other countries. So we think it is important that a body which is not directly part of transplant will also be part of the discussions. And this is not in any way to assume that conflicts of interest or anything negative on those involved in transplant or organ donation, but I think it is important for credibility that, you know, that umbrella organizations be involved. And that's why the Institute of Medicine was really very respected, very important in getting DCD accepted. So we think that there have been so many other new developments in DCD, you know, besides NRP, ex vivo, and the other issues involved. I think everybody agrees that it's important to have representation by those not directly involved in transplant or procurement. Obviously, they have to be at the table as those experts. But remember, death declaration and whether this is ethical or not, we as the treating intensivist who may or may not, who obviously we're working cooperatively with the donation of transplant community, but we're the ones who are ultimately responsible. I think if it is going to be done, there should be some consideration to making sure there's informed consent. I think this is a decision for the local people, right? DCD is more complicated than brain death, right? Because the treatment team is involved as much as we try to keep the separation. But I think at the end of the day, every hospital's medical staff and the ethics groups really has to make their own decision as to how those patients are going to be treated. Because whatever one thinks about the issue, there is certainly lack of consensus about that. I think IRBs that have been involved for their own protection and everybody's should explain the why and what of their decisions. And if they have made a decision going against guidelines, which is okay, right? We don't always agree with guidelines. I think they should publicize the why of that. What's been exciting is everybody's been very respectful. The proponents of NRP feel they're saving more lives, that the concerns about collateral flow are overstated, they're manageable, that they're not violating the DDR. As I mentioned, it's important that we do not lose track of what we all agree on, right? That DCD is inherently ethical as is the concept of death by neurological criteria. And fully informed, impartial, rational people can reasonably disagree. And it's just a matter of society how we deal with that. I've had a chance to speak to some of these people and I've really been honored to be a part of these discussions because everybody's trying to do the right thing for everybody. Here are some questions that if you do want to do it, I think are reasonable to ask for your OPO and transplant group. I won't get into that in much detail. But I think an important question is if there is evidence of brain perfusion, right? Who's going to take care of that or medicate the patient? Is it the transplant team or the care team? So just to summarize, I think what you need to know is that there's a risk of cerebral brain flow. You know, some of the NRP proponents do not feel special informed consent is necessary. I think the treatment team has to, you know, is ultimately responsible for the proper death declaration. I think everybody has to do their due diligence. I think from an international point of view, Australia and Canada have said no. At the same time, the United Kingdom and Spain have said yes, right? So at the end of the day, a lot of informed people have not come to a consensus and, you know, that's okay. We just have to figure out how to do that. I encourage everybody to read our paper in the ACP. I think, you know, the NYU group, the Vanderbilt group, you know, Dr. Dominguez-Gill have written very, you know, coherently and well on this subject and let people decide. And if there is a polling question is, you know, I don't know what people thought coming in, but would you be willing to personally declare death for NRP as practice today? And what's interesting is we have a split here, which sort of seems to reflect society. If we go to the next question, do you think special informed consent needs to be given for NRP? Okay. And I think, and it's very interesting to see the results here of our small sample size, you know, people are very split. I do think the case for getting the informed consent is, you know, is there. And I think the most important thing, and really my message to people I speak to, if you're the intensivist on the case, it is your responsibility to make the decision, listen to both sides, but ultimately that decision of how and when to declare death and what's going to be informed to the patient, this has to be something that we are taking ownership of, obviously working collaboratively with the transplant and procurement groups. And that is it for me. Thank you very much. Oh, there's just, I just want to mention in terms of for hearts, there is some data showing that even though it's hoped that NRP is better than direct, than standard DCB for hearts, a recent propensity analysis showed no difference in survival. Some of the early data on direct procurement showed a higher rate of needing ECMO early on for RV failure, but that has decreased significantly over the past couple of years. For those who are concerned that, you know, if you turn down NRP, you are risking the heart, you know, some of the more current data shows that they're very similar. And now for Dr. Dominguez-Gil. Thank you for your presentation. Thank you for giving me the floor. And thank you for the opportunity to dedicate some minutes to offer a different perspective about NRP, about normal thermic regional precision. Within the next few minutes, I'm going to try to answer the question of why NRP has emerged, what has been the need to make it happen, and then I'm going to try to defend why we do believe that NRP is ethically appropriate. So starting with the why, we need to take into account first the need of organs for transplantation. According to data that had been reported to the Global Observatory on Donation and Transplantation in 2021, there were close to 145,000 solid organ transplants carried out in the world. And despite the activity is impressive, the WSD made estimates that it barely covers 10% of the transplantation needs of our patients. This has made DSTD emerge as an important practice, not only to satisfy the needs of our patients, but also to give more individuals the opportunity to donate their organs after death. So according to the GODT data, we know how all the deceased organ donors that were reported in 2021, you can see how 22% were DSTD donors. They were reported by 22 countries, and we can see in yellow how the city substantially contributes to deceased donation activities in these countries. For example, in the US and in Spain, it contributes to more than 30% of deceased organ donation activities. Also, we take a look to data for the 22 countries that did report DSTD activities in 2021. We can see in light blue how the majority of these countries are relying on type 3 DSTD donors. This means donors who have died following the decision to withdraw life-sustaining therapies. So 91% of DSTD donors in the world are individuals who have died in these circumstances. And very importantly, DSTD has become progressively a multi-organ recovery procedure. Sorry, let me go back. So if you take a look to data for 2021, you can see how we're not only performing transplantation of kidneys, but also, as you will see very successfully, we're performing transplantation of livers, lungs, hearts, and pancreas from deceased donors. So we're now talking about a multi-organ recovery procedure. Now, what are the results of organ transplantation when using organs obtained from controlled DSTD donors in particular? Well, you have here some information in pills about these results and results that are prior to important advancements that have occurred in organ preservation. So, for example, in kidney transplantation, we know that the functioning and the survival of these kidneys is very similar to those of GVD, but they are at increased risk of developing a delayed graft function. Definitely, the liver is the Achilles heel in DSTD. According to different meta-analyses, we know that livers from controlled DSTD donors are at increased risk of biliary complications, ischemical angiopathy, graft loss, and mortality. Pancreas seem to do relatively well as long as there is a high selection of organ donors, and lungs do perform extremely well, though in this meta-analysis, the authors reveal apparently a higher risk of airway and asthmatic complications. And until very recently, until those advancements in organ preservation took place, heart transplantation was basically not feasible. So we did have acceptable outcomes with organs from deceased donors, however, not exactly the same that we were getting from the standard, which is that of GVD. So, as I said, this has made some advancements in organ preservation be necessary in the controlled DSTD setting, in the DSTD setting in general terms. So, here we have basically two options, that of using excited machine perfusion devices that are organ-specific, this means one per organ, and the other possibility that has emerged based on the experience that was acquired in Spain during the 90s in uncontrolled DSTD, is that of normothermic regional perfusion. Based on the use of ECMO devices in NRP, we perfuse organs that are going to be subject to transplantation with oxygenated blood after the determination of death and prior to organ recovery. Where NRP is quite used in the European setting, in fact, you can see how in this study that was performed in the Council of Europe, to the 12 European countries that control the DSTD programme, how eight countries, in eight countries, NRP is allowed and is actively practiced. It is still emerging in Belgium, in the Netherlands, and in Switzerland. However, it is a well-established practice in France, Italy, Spain, and the United Kingdom. In these four countries, NRP is very well established. Moreover, in France and Italy, and you will see the reason why, NRP is mandatory in case liver donation is considered. So, it is a well-established practice in several European countries, and also emerging in some European countries, as well as in some US centres, as we have heard from the previous speaker. So, why has NRP emerged, and why are we considering this possibility? Well, an image is worth a thousand words. Here you have a big model where you can see the macroscopic appearance of the liver and the small bowel after 30 minutes of cardiac arrest, and after 30 minutes of cardiac arrest and 30 minutes of NRP. So, what we know about this strategy is that it can help us to regenerate ischemically damaged tissue. It facilitates organ recovery. So, organ recovery is closer to the recovery in the DVD setting. It allows us to evaluate the viability of organs prior to transplantation, and very importantly as well, it allows the simultaneous perfusion of different organs without the need of using organ-specific excital devices, which makes the good outcomes of organs from GCD donors be feasible at a much lower cost as well. I'm not going to enter into cost effectiveness issues, but I do want to expand on whether these potential benefits of NRP are reflected into post-transplant outcomes and organ utilisation. So, I want to make a question to the audience. In principle, what effect do they think NRP has on transplant outcomes? So, you have different options there. So, I would like to learn what you know or what you think you know about the outcomes that we have observed with the use of NRP in controlled GCD. So, you have different options there. Well, okay. So, most of you agree that it has some value, particularly in the field of liver transplantation. Let's go back to my presentation, and I'm going to try to show you very briefly the evidence that we have so far on the outcomes of abdominal organs, where you will see how these outcomes are improved by the use of NRP. You will see how NRP makes heart transplantation feasible, and very importantly, apparently, does not have a negative impact on lung transplant outcomes. I'm going to review this evidence with you all. So, first of all, in the field of liver transplantation, the best evidence that we have has been built in Spain. This is the largest score of the study that has been published so far. We acknowledge this is not a randomised controlled trial, where we have compared the outcomes of more than 500 controlled CDLs obtained with NRP versus 258 obtained with the standard rapid recovery technique. And you can see here in the patient and graft survival, in the scapular nerve curves, how NRP is superior to the standard recovery technique. But most importantly, in this propensity score matching model that you have in the bottom, you can see how NRP significantly decreases the risk of early allograft dysfunction, of biliary complications, ITBL, re-transplantation, graft loss, and patient death. This is another very interesting study that has been very recently published. To my knowledge, this is the first study that has not only compared NRP with a standard rapid recovery technique, followed by cold storage, but also another group with a normothermic machine perfusion. So, relievers have been obtained with a standard rapid recovery technique, and they have been placed under an excitomachine perfusion device in normothermia. And the authors, again, this is a single-centre retrospective study, can observe how both NRP and normothermic machine perfusion are associated with better early liver function compared with standard cold storage, static cold storage. But NRP seems to be superior in the preservation of the biliary system. I'm not going to expand on all the data in this table, but in terms of non-anastomotic restrictors, they can see how compared to static cold storage, NRP significantly decreases the risk of this biliary tree complication. And this improvement is not seen, however, in the excitomachine perfusion device group. So, NRP seems to be superior, according still not to randomised control trials, to the standard rapid recovery technique, followed by static cold storage, but also compared to normothermic machine perfusion. This is what we know so far, and of course, the evidence is still being built. What happens with the kidney? Here you have the most important court study that has been published so far, also from Spain, in which we, again, compare kidneys recovered with NRP versus kidneys compared with the standard rapid recovery technique. So, here we don't see differences in the univariate analysis in terms of patient survival or graft survival, but when we take a look to a propensity score matching model, the standard rapid recovery technique significantly increases the risk of delayed graft function defined by the need of dialysis during the first week after transplantation, and it significantly increases the risk of graft loss during the first year after the transplant. So, we could see in terms of delayed graft function, which was one of the complications that we saw before in control decedent, we can see how NRP helps us to improve significantly the outcomes of kidneys from control decedent donors. Now, I'm trying to show you some data that have been published by other authors, particularly from the UK. This is a paper that has been very recently published in the journal Transplantation, where the British took a look to the experience with more than 4,700 control decedent donors, of whom several had been subject to NRP, and they could see that NRP increased the rates of organ recovery from 2.6 to 3.3 organs per donor. NRP increased the odds of organs being transplanted by threefold, for example, in the case of liver transplantation, and aligned with what we have seen from Spanish data, they could see improvement in post-transplant outcomes, both in liver and in kidney transplantation. Now, NRP also allows heart transplantation to happen, particularly thoracodominal NRP, and without the need of resulting to excite the machine perfusion devices. This is the strategy that we have adopted in Spain from January 2020, with several centres having been able to reproduce this approach. So, thoracodominal NRP is used, and then there is, this is followed by starting cold storage. This means no use of excited machine perfusion devices. And of course, this is still a growing experience, a preliminary experience that we are building, but you can see how almost 50 heart transplants have been performed in the country with appropriate post-transplant outcomes in the short term for the time being. And I also wanted to bring this data that are still not published. This has been submitted for publication, in which we have put together the outcomes of 157 heart transplants obtained with thoracodominal NRP from controlled disease honours, and compared with DVD heart transplants performed over the same period of time from 15 centres in Belgium, Spain, the UK, and the US. And you can see in the slide how we haven't seen differences in survival between these two groups, acknowledging once again that this is not a randomised controlled trial, and there are likely some biases in the selection of hearts to be used for transplantation in the thoracodominal NRP, this city group. And though I have not displayed this data in this slide, we have made an analysis of the use of excitomachine perfusion after thoracodominal NRP with no significant differences in the outcomes of both groups either, which reinforces the likelihood that thoracodominal NRP allows heart transplantation from disease honours without the need of using excitomachine perfusion devices, which could make a heart transplantation from disease honours possible in settings where excitomachine perfusion devices are not available. Finally, of course, we feared that abdominal NRP could have a negative impact upon lung transplant outcomes because the lungs benefit from cold, besides technically it is tricky, the performing lung recovery when abdominal NRP is used. These are data that have been submitted for publication from Spain, where we have compared the outcomes of lung transplants obtained from controlled disease honours when NRP was being used compared with DBD lung transplants, where you can see no significant differences in survival, no significant differences in primary graft dysfunction, grade three at 72 hours, or mortality at 30 days. So apparently, based on our experience, the lungs are not damaged by this approach. Particularly, we have focused upon abdominal NRP. So in principle, and of course, acknowledging that we don't have evidence 1A, but the growing body of experience that we are acquiring, particularly in the European setting and also in the U.S., makes us think that we really can get appropriate results, very similar to the sensitivity with the use of NRP. Now, we of course acknowledge that there are ethical and legal barriers that preclude the expansion of NRP in many jurisdictions, as we have seen before, and particularly with regards to the determination of death by circulatory criteria. So my question to you here is, which of the following is accurate with respect to the determination of death when NRP is used? We're going to discuss about the concept of death by circulatory criteria, and what would be the costing measures that we should be taking when NRP is applied, that have been previously introduced in the previous. Okay, so you have mostly selected that drainage of earth vessels diverts collateral flow from rain. Okay, let's see what I have to share with you. We go back to the presentation, and well, first of all, we need to think about what death is, about the concept of death, and we should remember that there is a unified concept of death, and this is defined as the permanent cessation of consciousness and all brain stem reflexes, including the capacity to breathe. So in the city setting, we will talk about the permanent cessation of brain functions as well. So it's not the permanent cessation of circulation, what defines death, but the permanent cessation of brain function, or circulation to the brain, where permanent means that the brain functions could be restored, they could be potentially restored, they are not going to be restored. Now to declare death on the basis of the permanent cessation of brain functions in the city setting, following the circulatory arrest, we first need to confirm, or to respect an observation period, to make sure that return of a spontaneous circulation does not occur, as previously mentioned, and based on some chemist's data, we know that five minutes of observation seems to be appropriate, but secondly, we should not perform any interventions that restore circulation to the brain, and of course, if we apply NRP, brain circulation is going to be restored, and brain functions are going to be restored, which means we need to apply certain techniques to avoid this from happening. So just to remember, the unified concept of death, what it is relevant here, is the permanent cessation of circulation to the brain, not permanent cessation of circulation, but permanent cessation of circulation to the brain, and as I said, we need to apply certain technical means to avoid reperfusion when the pump is started. What are those techniques? Well, the techniques that are being used are basically a balloon occlusion, or the surgical clamping of the aorta when abdominal NRP is used, and this can be monitored by the absence of constant pressure at the radial artery. Now, with thoraco-abdominal NRP, we should be particularly cautious, we should be acting with particular caution, and here, the clamping of the aortic vessels is not enough, but also the drainage to atmospheric or negative pressure that will help us to divert collateral flow from the brain, and indeed, we do agree with the previous speaker that brain activity and or brain circulation should be monitored, this is actually monitored at least in Spain, to identify a failed exclusion of circulation to the brain, and should that happen, the procedure must be halted, and also importantly for you to know, in the case of thoraco-abdominal NRP in Spain, surrogates are informed about this possibility. So finally, I think it's important to also state that intentionally excluding circulation to the brain does not cause the death of the patient, it is the disease or condition that led to the decision to withdraw life-sustaining therapy. Moreover, we believe that it respects the decisions made by the donor or their surrogates of not resuscitating, and it helps us to maximize the benefit of organs to be used for transplantation. I brought you this interesting study that has also been very recently published, this is a pig model, in which, 16 pigs, in which cardiac arrest was induced, and they were subject to NRP for up to three hours, the pigs were allocated either to a group in which the arc vessels were clamped, or a group in which the arc vessels were not non-clamped. In the non-clamped group, of course the EEG activity was observed in all eight cases, somatosensorial evoked potentials were observed in six cases, agonal respiratory movements were observed in six pigs, and some data associated with brain perfusion and brain perfusion were identified in the monitoring, however, none of this was observed in the clamped group. So the authors could conclude that reperfusion of the brain during NRP led to return of brain activity, but conversely, clamping of the arc vessels, and please note that there was no actions to divert collateral circulation, but just the clamping of the arc vessels or the cerebral circulation, ensuring the permanent cessation of brain function and maintaining the determination of the endicity. I agree with my colleague that we need to speak, we need to build evidence, we need to discuss, and we need to confront our views on these approaches. We acknowledge the relevance of ongoing debates about those ethical issues that surround the practice of NRP and control the CD. We also agree with the need for frameworks that regulate its use and set appropriate safeguards, but we are also convinced that efforts should be made to facilitate the implementation of a preservation strategy that can increase the number of organs to deliver for transplantation, improve post-transplant outcomes, and help us make the most of the altruistic gesture of organ donation. I thank you very much for your time and for your attention. And I hand the floor to our moderator for the question and answer period. Thank you again. Thank you, Dr. Mingus-Gil for that. I think what we clearly agree on, right, there's two separate questions, if NRP should be done and how NRP should be done. I think there's a lot of overlap. We agree on how NRP should be done, you know, in terms of consent, the degree of monitoring. So that's really a how question. I think in America, really my, the essence of my sort of pitch is that even if we disagree, if and how it should be done, we need to refine the how it's gonna be done. In terms of the if, you know, whether the ligation of the arch vessels is listed or not is I think something that people will never disagree on. And I think as a society, that's something we're just gonna have to sort of deal with. You know, if one goes by Dr. Bernat's theory that death, the unifying concept of death is the cessation of cerebral blood flow, it does work the way DCD is done, even if we disagree whether that should be done. Well, of course, well, I do agree. I think we all are in agreement with the way to perform it. Regarding the if to perform it, of course, we need to take into account how the different legislations have been phrased, which is an important issue to take into account. So for example, the way the legislation has been phrased in Australia or in Canada, preclude them apparently from developing NRP, and this might not be an issue in other jurisdictions. But I think that, of course, one important aspect to take into account is logistical and related to cost, to the cost of the technique. So here, we have the opportunity of developing the simultaneous perfusion of different organs at the same time. And this simplifies procedures in a great manner, particularly when the management is performed by professionals who are very knowledgeable in critical care and the management of ECMO devices. So it really simplifies the process and besides the advantages in post-transplant outcomes that have been seen with NRP, have not seen so far with the use of excitomachine perfusion. So the advantages that have been seen in our experience and in those in Italy, in France or the UK, in terms of survival, decreasing biliary complications, in delayed graft fusion, this has not been seen with excitomachine perfusion devices. So of course, we need to address that question from the perspective of transplantation, but of course, from the perspective of ethics and respect from the donor. So I do think that there is, well, we really need to study because it is really something that can help us, as I said before, to make the most of the gestural organ donation as long as we moderate or we establish appropriate standards to guide the practice. But so this has come in a very natural manner in many European countries, as you have seen, with no host debates as the ones that you are having in the US for the time being. So, well, maybe it's an issue of the Atlantic Ocean, I don't know, but in Europe, these hot conversations are not being held seriously. And I think you really hit the nail on the head, right? It's very much an international thing, because again, reasonable people are gonna disagree. And even if you look at the legality, right? In the US, to be honest, if you look at the letter of the law, it says permanent cessation of circulation, it would seem to violate the law. The NYU people make the case that you have to look in context. If you look in the literature, you have a CEO of a US OPO who says it doesn't really seem to be legal. And you have another CEO who believes it is legal. So, I think when there's no consensus, the best people can do is put it out there. And if people disagree, right? From a practical point of view, simply figuring out who's in and who's out. And I think the other thing is, is that obviously not everything is gonna get a randomized controlled trial. And certainly the liver data seems to be a big difference. And assuming that data is just not because of the difference in later time and you get results better later in time, we do have to go with the best data we have. And I think certainly the liver data, you see the difference between that and the other organs, which does suggest that it is a real phenomenon, not a artifact of a time shifting. And Dr. Perlitz, however, if I may jump in there, please correct me if I'm wrong. But from what I know of the determination of death in the US, the way that the legislation is phrased, it actually talked about the irreversible cessation of circulation. However, at one time, the definition of irreversible or the concept of irreversible was understood as the permanent cessation of circulation. So I'm wondering whether we could go a step forward and talk about, well, we meant permanent cessation of circulation to the brain. I mean, sometimes we do identify obstacles for some practices just because the legislation was phrased in a manner, in a given manner, because at that moment, we were not foreseeing advancements that came afterwards. So correct me if I'm wrong, please, because I may be wrong, but I remember that you had the debate of whether irreversible meant irreversible or permanent. So now maybe the discussion should be whether it should be the cessation of circulation or circulation to the brain. I'm sorry, I'm not sure I explained myself properly. No, you did it perfectly. If you look at the UDDA as a phrase, it says the irreversible cessation of circulation. That's all it says. Everybody has agreed for 25, 30 years in the US without much debate that the phrase irreversible is equivocal. Does that mean biologically impossible or it will not? Really, everybody agrees it's the permanent cessation of circulation. So if you read the UDDA as it is, the permanent cessation of circulation, that doesn't say to the brain, it says permanent cessation of circulation, then doing NRP would seem to violate the letter of the law. The NYU group from Parent and Kaplan, they make the case, hey, you gotta look intent and you gotta look what it says and that's not fair. So you gotta look at that. So people sort of disagree on that. I think if you wanna be fair, remember the American definition of death says that it's also the irreversible cessation of all brain functions, right? And everybody agrees there's pituitary function, right? So the World Death Project all agrees that we declare death the way we really do and we sort of ignore the hypothalamic and pituitary function, right? So you can make the case, you can't really pick and choose and do that. So I think to me, it's more important to figure out what the ethical is and make the law align, right? Because arguably we don't really follow the words of the law exactly when it comes to death by neurological criteria. And I think it will come down to that, even if we agree that death is the permanent cessation of brain blood flow, right? Which is doctor, you know, my senior authors, you know, even though it's not the letter of the law, I think most of the people sort of accept that conceptually. Then it really comes down to is, is it okay there to get there by ligation of the arch vessels? And then we sort of clarified the discussion. And I do think it is, it's better to look at getting the law to align with practice. And in fact, what's fun about this thing is there's a paper by, which is co-authored by Dr. Burnot, right? Who's, you know, co-author sort of against NRP and co-author Dr. Kaplan from NYU, who is, you know, for the NRP, advocating that the UDDA should be slightly modified to align with practice. So I agree, law should align with practice and what we as the clinicians and the ethicists and the whole, you know, stakeholder community agree what is correct. Well, thank you. I think we both agree that legislation usually goes behind advancements. And of course these advancements make us reflect about once again, the limits between life and death. And of course, the sorts of debates are important and makes us, helps us improve in our practice. So I think, I'm not very sure we're gonna get agreement on our view on the topic, but at least I think we do agree that there is a need to discuss about this, to clarify, to gain evidence, because I think evidence and data help us to solve many issues as well. And whether this is worth it or not, and if it is worth it, how to make it happen in the best possible manner. And of course, respecting the dignity of the dead patient and respecting the donor role. So happy to have this discussion today. Yes, thank you both very much for your very insightful presentations and thank you to the audience for participating as well. Again, everyone who joined today, joined us today for the webcast will receive a follow-up email that will include an evaluation. Please take five minutes to complete the evaluation. Your feedback is greatly appreciated. So thank you once again to everybody, especially our presenters, and this concludes our presentation for today. Thank you.

Journal Club webcast

normal thoracic regional perfusion

organ transplantation

NRP

ethical implications

clinical implications

determination of death

brain circulation

informed consent