[Music] hello and welcome to every possible angle a new conversation Series where we're going to be delving into the world of transplantation we're going to be discussing with community members from every part of the field to get a better understanding of what's going on in the space my name is Michael Tajima and I'm joined here today by my colleague pratique Patel thanks Michael this is really exciting time in organ transplantation we're able to do things that we couldn't do just a year ago and Dr kulan's Our Guest today is going to be talking about the concept of time shifting uh and he's going to talk about how his Center is able to use this concept to do some really amazing things with that welcome professor laurren kulan of the University of louen Hospital in Belgium we're we're really excited to to have this conversation today hello Michael good evening hello PTI good evening very nice talking to you and thank you for the opportunity of the of the podcast which is which is a terrific idea I think um thank you for making time um we're we're really excited partly because the louen lung transplant program you're doing some really exciting things right now uh an impressive work these days in terms of uh advancing the research in lung preservation and lung transplantation but I was wondering if we could start just by you telling us a little bit about your journey in lung transplantation how you got started why why lung transplantation as a career so thank you for the int uction I indeed work as an academic lung transplant surgeon at University Hospitals of of Loven where I also had the lab of thoracic surgery and and lung transplant which PTI could visit a few months ago and so I'm really fortunate to work there because we can really take the clinical questions that we encounter in the field of lung transplantation to the lab to our small animal models try to study them and then try to find a solution that can be incorporated in Daily clinical practice because there are so many many challenges still in the field of in the general field of transplantation that need to be answered in such an exciting field of research it's really a privilege to work in to work in that in that field and one of the questions we had simultaneously with the um introduction of the of the lard technology was about temperature one of the most interesting findings we made over the last year was mostly about the rewarming esia during the implantation of a lung during transplantation and how this esia and this this this temperature change affected the lung while it was still not profused and how also time was critical in the deterioration of the of the organ AB absolutely I think I think for a long time preservation has been uh sort of uh assumed in transplantation for the last 50 years it's been a sort of Colder is better mentality with with transplantation but your your lab's been now paying a lot more attention to temperatures and the metabolic processes as well as injury going on during uh the preservation period I was wondering uh maybe you could tell us a little bit about uh your career how did you get into lung transplantation what's been your journey to to uh really uh get into this space thanks for that question Michael so as as a young resident I had the opportunity to practice uh work on a on a PhD in the lab of abdominal transplant surgery in Len where I focused mostly on in the field of intestinal transplantation on Immunology um it was a very exciting um field because the intestine is quite similar to the lung they're both what I call barrier or so they are in contact with with our environment and for that demonology is is is really an exciting field to study because of the strong innate immune response of these of these organs and what I encountered in the field of transplantation was that it was a relatively young field with very exciting questions what you're actually doing in a transplant is transferring one organ from a person who's not genetically predisposed to be connected to the recipient and you do something which is biolog from a biological point of view doesn't make sense at all and that's why you're encountered with and challenges that are really on the edge not only of transplantation but on the edge of medicine what you can see is that trying to push that that that edge further trying to push the field does not only improve the field of transplantation but improves the whole field of medicine there are many discoveries in transplantation that find their way later on in the general field of of medicine so already that aspect made me very passionate and interested and then the other aspect that it is a young field and that there's not a real competition between different disciplines and and researchers in transplantation there are so many ongoing questions and challenges that that the competition is not as as harsh as for example in in other medical Fields like like oncology or vascular surgery um this is more an open field of open interaction and communication and also that that I like I like to lot I must say I I fully agree I think the the international and and uh collaboration across this community has been fantastic uh it's been a great experience at least for me yeah I mean I think it's interesting you talked about your background as a resident right when you're a resident it's in your formative years you get exposed to so much in medicine um and it's really interesting that you were drawn specifically to the field of transplantation because it's essentially less chartered than other parts of medicine uh did you have any other interest like besides transplant that you know that you were deciding between and then you ultimately decide to go with transplant so we were trained in in in general surgery that's how our training program in in Belgium looks like and then I was I was interested in transplantation mostly from a from a research perspective and then in DC surgery in in in general so I was trained as durc surgeon simultaneously because it was especially the the organ the lung that attracted me a lot because of its unique physiological capacities for example if you compare to to a kidney which is more like like a filter mechanism or or liver which is more metabolic mechanism the lung has the unique capacity of of of this uh being a privileged organ with the storage capacity of the oxygen which is then diffused and then you have that perfusion and so don't only think as a surgeon but you think as the as a physician and as a physiologist and an imist at the same time so I was really attracted not specifically to to to a certain profession but but more let's say to an organ and then everything came together in the field of transplantation so the real passion is in in lung transplantation I feel like um that sort of mentality to be willing to go into a pioneering space a space that's not fully defined yet and there's still so many um untapped questions that that's got to take a certain mentality but but also I'd imagine it's helpful to be in a place that's very supportive of uh research and and answering those questions that that really can can take that and at least prti when you visited Len it sounded like that was that was really the environment you've cultivated there yeah I I I have to agree with Michael when I visited I remember the experience or the few days you know every single day we were you know going between the lab to you know the clinic I was observing you go literally between seeing patients to being in the research lab within you know within a matter of of a few minutes um but I also saw frankly the culture of the of the young younger generation that you were training they really shared in on that you know interest and that passion so uh I I'm really interested to know if if the training model that you you know you have at Len how that came about because I noticed a lot of the trainees were pursuing both an MD and a PhD is that is that something that kind of has organically evolved as a focus for Len or is that you know is there certain reason why that that exists today no so I came back from a Fellowship in Zur in 2019 and I got responsibility of of the lab of THC surgery and lung transplant at that time but there were no um no PhD students at that time in the lab so so we had to start somehow of of scratch with the experience I had and the experience I had was in fact the template of how I foresee our laap in the future which means that you do a simultaneous training both in surgery as as well as in research but you have dedicated time for for research and the best um way to to organize this to is to to offer to a young motivated colleague an actual PhD a PhD you have to see it like a a form of of Education it's not about a title it's a form of Education where you really develop into a mature independent researcher who can not only ask questions but also formulate hypothesis translated to a certain research model try to find results and also present them to to the audience and and write them down in in in a paper and then Mentor them again to another generation and so in this model I was raised by by my mentor Professor Jac pen who was raised himself in the in the in the '90s in the US yeah and this is the model that he that he was raised in the US he brought it to Len and this is the model I took over to raise the new generation of of of surgeons and and Transplant surgeons and I must say that that I'm very very fortunate to have found motivated passionate young colleagues because these young colleagues no matter how old the university gets these people always stay at the same age we have a university of 600 years old but the students are still have the same age as 600 years ago and these are the ones that that that put the questions forward these are the ones that that challenge you and and drive the real research and this is a really stimulating environment and now our lab has grown up to 28 uh 28 researchers focusing on intestinal transplantation uh multiv visual transplantation lung transplantation L volume reduction surgery um FAL transplantation so it's really a stimulating environment we have a lot of interaction between different disciplines also it's not only surgery it's basic science it's pulmonology it's anesthesiology all the disciplines together work very closely I feel I feel like that mixing of different disciplines is that's often where Innovation happens you know for us I think that's been very stimulating things crossing different organs working in different spaces uh having that mixing of different discipline is where you you find those those Innovative and interesting ideas they can really move the field forward yeah no I agree I don't know if you know but Michael has actually a background in mechanical engineering and he worked in aerospace engineering before wow uh be uh you know joining a medical technology so couldn't agree with you more you used to design satellites but that was a long time ago um can I ask you you know in terms of some of the the Innovations in in the field um how do you see what's going on in the field uh one of the areas that I think has been uh of a lot of interest lately is around preservation around uh uh controlled hypothermia uh can you tell me a little bit I know pratique was over doing some research projects with with your team how has temperature become more part of the consciousness of of the transplantation process at louen so I think that from the beginning of transplantation and even before the question and the interest in the field have have always been quite similar already Alexis gel before the first clinical transplant was performed was developing some kind of machine profusion together with Charles Lindberg in order um to preserve but we see over the over the last decade is that the technology is there if you're background as mechanical engineer you will you will indeed see that that we were able as a as a as a human race to [Music] develop techniques that were transportable that could be incorporated in daily life and and that makes these ideas and thoughts that were already there for 50 60 years that made them transportable translated to the actual actual daily practice it's not only in medicine that this is happening this is happening throughout different fields in our in our daily life and so also the whole idea about temperature it's not it's not a new idea already in the beginning of the '90s in Toronto in the lab of Joel Cooper they were doing good strong research on preservation and it was thought and hypothesized that the colder you preserve an organ the better the function of the L would be after reperfusion however to they to their surprise when they analyzed several temperatures they found that by accident preserving a lung at 10° outperformed lungs preserved at 4° and so a whole line of research early in the 90s not only in Toronto but also in Japan came out to find the ideal temperature of of lung preservation especially for the L in contrast to kidney and liver because the lung is such a privileged organ it's a privileged organ because it has this unique oxygen storage capacity and because of this oxygen storage capacity it has the potential to maintain the aerobic metabolism and preserve better the cell function during preservation in contrast to an organ without that oxygen storage and so already in beginning of the '90s they they were convinced that the best temperature to preserve an organ was not on ice at 4 3 2 0 degrees but slightly higher which is the concept of what we know now as controlled hypothermic preservation which is somewhere in range between four and 10 degrees we do not exactly know yet what the best temperature might be and there are some indications in an old paper from Nakamoto I think in 1993 which showed with a mathematical model that the best temperature is probably between 7.6 and 8.4 degrees so we still have to do some research there to find exactly out what the best temperature is and and and so the IDS were there there was no technology to incorporate to incorporate them in in the clinical practice and this technology has now evolved over over the over the last years can can I ask you across organs we're seeing a big impact on temperature on clinical outcomes and and uh Transportation total es schic times one of the things that I'm I'm really curious particularly with L that when you're talking about lungs and intestines being barrier organs with that strong innate immune response I think in the early days that colder better his philosophy was was heavily driven around uh sort of a metabolic thought I mean we call it es schic time this thought of reducing metabolic activity reduce metabolic injury um but I feel like what what the current trends are are about reducing any form of injury potentially freezing injury and and and kicking off particularly in lung and intestine that that that that strong uh innate immune response that to lead to edema and inflammatory Cascades where do you how do you see that balance point and these different mechanisms playing in regards to temperature so I think that indeed what you touch there is very important aspect and that's is keemia hyperfusion injury and of all organs the lung and the intestine are the most vulnerable to this esia hyperfusion injury which is nothing more than a cytotoxic storm that is released upon hyper Fusion of an ischemic organ and what you have to consider is that what is long thought to be the golden standard of preservation and the golden standard of this esia time was ice cold preservation but ice cold preservation means freezing cell injury with a direct impact on mitochondrial Health mitochondrial swelling and mitochondria you have to understand that's the energy safekeeper of the cell which is completely destroyed yeah and so this immediate effect of of freezing a cell and really entering the cell and in the end it ends up in a lot of reactive oxygen an oxidative stress which is released at the moment of hyper Fusion will lead to a lot of esia hyperfusion injury yeah and especially the lung and the intestine are so vulnerable because of their strong innate immune response and release of of of cytotoxins at this moment of of hyperfusion that that that's that's one important aspect and we also have to consider in a side note that preserving a lung on on I is not preserving a lung on four degrees we have shown during the last year in our clinical grateful study every time a lung came back from a procurement and it was preserved on Ice we took it out of the ice cooler which is nothing more than a camping box filled with ice not really ano 2023 but still this is the current practice it came out and we immediately took a surface temperature and because it was a lung we were able to introduce a very small probe into the Lumen bronal Lumen of the lower Lopes and what we found out was that ice and immediately measuring temperature afterwards resulted in temperature of around 0 to 1° and we know that 0 to 1 degrees has a severe impact on on Cellar injury so Dr kulan's that's really fascinating kind of what your team is seeing when lungs are preserved on Ice you mentioned when they come out of ice storage that they're not 4 degrees at the closer to zero essentially can you just share about how exactly the lungs are packaged uh when we talk about ice storage because there is some variation across the community where some teams put ice within the bags and some people don't put that ice in the bags so I think we have to consider that that the standard mode of preservation has been I over the last 30 40 years any any form of eyes mostly in a in a classic camping box filled with liters and liters of ice which is really not slushy ice but which is really really eyes that you find on on the North Pole yeah and so what I think is that we should abandon ice completely and I say this with a bit of an Adagio leaving the Ice Age behind we really leaving the ice behind now it's time to leave it behind and to to go for a more controlled way of preserving and maintaining the temperature that is surrounding the lung you what we have done over the past 30 years in Len is a camping box filled with ice and then you have these lungs we pack them individually inflated and we pack them classically in three Bs so we have an inner back which is filled with preservation solution at an ice cold temperature uh um and then you have have a second back where you have some ice cold water sometimes they pour in some ice and then you have a third back just to keep the sterility to hand over the organ after the after preservation and so what we are doing now is Shifting towards the device of the of the lard paragonix where you have this this this cooler where with a with a certain temperature maintained at around 6° and we fill it again with two individually packed lungs so which means six bags in total and we pour around 2 L of preservation solution in total um well not two lit of preservation solution we have one liter of preservation solution per lung and then one liter of um cold water around that preservation solution so in total we have around four lers of um of of water or preservation solution together with the lungs in the in the in the cooling box absolutely and I'm curious how has this been uh used and implemented in your CL clinical practice I know we've worked together on the The Grateful study and the measurements of of cold temperature opposed the ice but you've also started to implement controlled hypothermia as part of uh your practice how how has that indication been used how where where do you have you uh implemented that so it was a bit of serendipity again all good things in research happened with serendipity so what we found out I think now already two years ago when we did retrospective analysis of our Len series we found out that actual implantation time of lung which means the moment when the lung is deflated and exposed to warmer temperatures up to the the body temperature that we could see that the longer you need to implant an organ and in fact it was it was the lung the more pgd the organ developed afterwards so we knew and we understood that there was a link between timing temperature and eske hyperfusion injury and so we set up a study which is called The Grateful study and we wanted in a first phase to assess to which temperatures and which timings the lungs is or exposed during the the implantation and to do that we didn't only focus on the implantation but we wanted to to visualize the whole process of xfo preservation starting from the donor until the reperfusion we've even taken biopsies of 1 hour after reperfusion so instead of a whole clinical protocol for that and exactly at that moment we were approached by by the company we introduction of of the lard you had the studies from from Toronto and Vienna coming out with their preservation Bridging the night and so everything came together and we decided after first initial phase of feasibility to switch the entire system in in Len and to really stop transplanting at night in the first phase we uh set together with all involved Partners anesthesiology o management nursing staff and we decided that if we would have a clamping of a lung after 10:00 in the evening we would start the transplate at 7:00 in the morning yeah um and then already quite soon after the first few cases you have these cases coming up between 7 or 8 in the evening and 10: and 10 and what were you going to do because last time was so nice to sleep and the patient did very well and he had no pgd at at time 72 so could we not shift a little and what you see now and this happens I must say retrospectively seen quite natural and in a period of of only a few months we started 1 of January 2023 we are now beginning of November and now we have shifted towards when there's a clamping after 6 or 7 in the evening like they do in in Toronto then we keep the L stor in the office of the nurse locked in the OR and we start in the morning between 7 and 8 uh with a fresh team wow and and it it went quite natural in the beginning of course everyone had to be convinced and and it was important to have everyone's input because we could not compromise the outcome for our patients so we were lucky that we had um that we had this This research already performed by by by by other International Teams and we we could stand on these first initial feasibilities and safety trials and then we had also the luck that we were doing this this this clinical research and that we were keeping a record of all our cases to a very detailed level and it's always good when you start changing your your um your program or the way you handle things that you record what you're doing and so so these two came together at the beginning of the year and from then on it flew it flew quite natural I mean I I think those synergies just happen sometimes in type times of of evolution of of new technologies and I think it it should be underscored one of the things you said that the the intentional extension of esic time um you know would have been quite provocative quite uh counterintuitive historically but it's it sounds like you're experience has been been strong it's you're doing that now as routine clinical practice it sounds like um and and purpose-- wise when we talk to different institutions around this concept of of sort of time shifting of of Shifting The Times They uh institutions use it for different ends and different purposes um Prett you you've spoken to institutions around around the world about this yeah you know we we speak to lung transplant programs on a weekly basis and the interest to shift the timing of the procedure for transplantation is is widespread every program is thinking about it I think what's really interesting about Len is that you know what I understand is that that indication you know can sometimes be from a Time perspective but sometimes it can be for another indication clinical consideration can you share with us a little bit about what what are some of those examples where you might shift the St uh transplant timing uh Beyond just the cross clamp that's a very important topic and I'm happy that you that you raised that because for me it's far beyond night briding what I call it it is introducing flexibility without compromising the outcome so we have to safeguard the outcome we're doing it now for a year we didn't see any adverse effects so far so we are quite confident and also with the with the data coming up from the registry and and other centers we're quite confident that we don't compromise the outcome but this introducing flexibility has several several aspects first of all you to have the avoidance of the nocturnal transplant and trying to shift it during the day which have several advantages maybe we can come back to them later um and then you have the the concept of logistical limitations which also impacts the your your in a direct way your lung transplant for example today right now we have a case um going on of controlled hypothermic preservation because of the fact that we had a difficult oncological multidisciplinary case plan this morning and we had limited or capacity so we had to choose between the transplant on the one hand which is always an emergency for patients waiting for one two years and then you have these patients with a complex oncological um problem that need to be electively planned and so it's always a very difficult um choice between them and with what I mean with introducing flexibility is that we don't have to make the choice these days this morning we we performed my colleagues performed the case of of the the difficult oncological surgical procedure and we could easily shift towards this afternoon 3:00 4:00 in the afternoon with the transplantation which was procured this morning between 8 and 10 in in another hospital and so in all only one year ago probably we would have declined this lung offer just because we had no capacity of Performing the transplant or we had to postpone this difficult to plan multidisiplinary oncological case yeah and so this just gives a lot of flexibility and with this flexibility you also see that there are less arguments between different caretakers you can imagine that if someone has to has to cancel their program and everything that is related to that and you have someone who really wants to push the lung transplant program that this might lead to some um some some difficulties within the hospital but sometimes also within a department and I'm happy that that with this controlled hypothermic storage we increase our flexibility to take care of all patients in the best possible way that's the second um part of flexibility and then the third part of flexibility and I think that's also very important one is that we see that the quality of available organs is really declining rapidly mhm we don't see the same quality lungs anymore as we did 20 years ago luckily we have less trauma with young people um but what we what we face now or or or people who who have been smoking or people who have been admitted to the hospital for two three weeks with a lung exposed to to ventilator Associated pneumonia or injury um patients who have been um exposed to other detrimental factors during their life lot of comorbidities age is also an important factor and so you have this what we call Extended criteria uh organs more and more together with with a higher rate of of DCd organs and so what I think is really important for this organs that you limit your ischemic injury as much as possible and you can do that in two ways either you further limit the time of hiskia which is already now try to to be around 6 to 8 hours if you have to to squeeze it further that will become a logistical Nightmare and you also decrease especially in North America and other regions of the world you decrease the the transport time a lot and and and these logistical issues or you find the preservation mode which just decreases the seller injury that is performed to this already very sensitive organs and I think that's that's a third one and therefore um I would like to refer to to to recent case I think we did now a month ago where I had it was a Sunday afternoon if I recall well prti where I had an offer from from a from a suitable 94 year old donor it's probably the oldest lung donor ever recorded the world and I called prati and I said listen this organ has been exposed for almost a century to our environment we just have to preserve it in the best possible way to make it the success and and we agreed to put it in the in the lard although it was not for an extended preservation it was just to create the most optimal environment for that lung I mean that's that's absolutely incredible I mean and this these lungs started their Journey on this planet long before lung transplantation even existed as a discipline and now they're starting a new life in a new patient how's the recipient doing recipient is excellent he went home after I think two to three weeks wow he had not been seen any complication and he's doing very well I'm looking forward to His ponary function at at three months and we will present this case at at this ishlt symposion I mean it's literally a different generation that the lungs have now gone into right um where they were originally um I think it was really fascinating how you just covered the three kind of areas how you think about um you know what controlled hypothermic preservation allows you to do and as you were talking I couldn't help but think what this allows you to do is really make sure you get the right donor organ at the right time with the right team to the right recipient um and that's quite quite fascinating and I think uh like you said in 20 30 years ago this was not even possible so so I have to ask when you go out and do these procurements you have other team members there too right from other for other organs um what's what's been their experience what is some of their feedback or reaction to now the lung team being able to kind of schedule their procedures L team was always a bit lagging behind because they were coming in sooner than for example the the heart they were leaving later they had to rush to the hospital transplant immediately the the kidney team is already um reclining from doing Nal transplant for many years and so all of a sudden this L transplant team takes a big leap and they see that we're going to sleep there's another team in the morning taking care of these organs and so of course they're interested to see if the same technology could extend their preservation times as well I think for kidney it's not it's not a major issue because we have learned um with these machine profusion technologies that we can keep also marginal organs for extended preservation times but I think especially for the liver they're very interested to see if if the same same would would happen as well because the whole logistical challenge of putting an organ on a machine where you try to maintain it high termic normal termic perfused um for for a longer time it's also a logistical Nightmare and what they see now is that we come back to Len it's also in the device but we put the device um unguarded in in a locked room and we we track the temperature on on on our phones and um we we the whole team goes to sleep and that that's that's a big difference with with the logistical challenge of keeping an organ perused there's always someone who needs to be there to to safeguard the organ and see that that nothing happens that's a major difference so also other organs are interested and I must say that the the experience with the heart team uh and and the and the the heart registry that we have with this higher temperature really um is is is a lightening example for the other organs how this preservation technology not only not only better safeguards and give you more flexibility but that it also actually improves the condition well not improve but in comparison to the standard storage of I how the how the short and longterm outcome are improved yeah absolutely I can can I ask I mean coming back to the on the one hand uh I think your points two and three in terms of of the use of the technology to create that flexibility um you know that potentially makes or more organs available to more patients which is just just remarkable you know because you have the right teams available um you can coordinate these challenges where you in H past may have had to turn things down but I also you you touched on a couple times the the idea of avoiding nighttime procedures I I have to imagine one of the one of the things about transplant is that it's it's such an intensive uh field that in the middle of the night all of a sudden you have to leave uh you have to cancel your cases the burden and burnout that is faced by teams is is a real thing um Can can you tell me a little bit uh I think I think the idea of avoiding night time's procedures is is not to be underestimated its impact on a program yeah so I think that that this that it is indeed indeed true that for a long time a transplant surgeon or transplant physician has been seen as someone who doesn't like to sleep who like to work during the night during case then during the day stay waking up staying up for 36 hours I can tell you it's it's not true okay we also like to sleep and I must say just from my own perspective how my life has changed after um the introduction of this controlled hypothermic preservation when you do a night transplanted complex case at Sunday night going to the Monday morning where you have your elective case PL your whole week is ruined yeah and and it's just better from my own perspective to have regular sleep that that's just my own perspective no disagreement there but I think it's important that to consider in avoiding nocturnal transplants it that there are different benefits yeah but they're mostly related to what I call human factors you take care of of the patient that that's one factor and and maybe the patient will in the end benefit from the fact that the organ is better preserved that that that's one aspect that we touched already the other aspect is the aspect on the quality for the the human factors of the transplant team first of all I think that reducing time pressure on the young colleagues who are going out for procurement and who have to decide in a remote hospital without not always a lot of experience if they should accept the organ or not knowing that if they accept it they have to assist the transplant the whole night and then do a whole day shift yeah so they are always in some subjective bias that if they accept the organ they inflict their own night rest and so you take away that that pressure and you shift it just to a very objective decision for them should I avoid this organ is the quality of or this organ good enough for the patient who needs who needs the this transplants and that's one important aspect you improve the objectivity that that that's one thing that should not be overlooked the other thing is of course the fitness of the team I think when you have a fit team you reduce the likelihood of Errors no matter how you see it and I I agree that there are conflicting literature on that especially in the field of transplantation where another systematic our own group showed analyzing more than 300,000 patients who had either yes or either no a n transplant that there was not a real impact on short or long-term outcome however ever most of these analysis have been done for kidney and there can be several biases in this research but if you compare it to to general surgery or trauma surgery or whatever you just see that the fitter the team is the less you have a reduction of errors and the more expertise especially in the field of transplantation you gain during the daytime especially for Len for example um I can tell you that our philosophy is to do a transplant without extra Corporal life support MH but if we need it it needs to be there and then the cardiac surgeons have to come over if they have to come over at 2:00 at night from home to put a patient urgently on ECMO or if they have to come over from a nearby or during the day that makes a big difference yeah so just the whole and also regarding the anesthesiologist during the day we have a we have a specialized um thoracic anesthesiology team there which which is not always the case during the night so there're just more more um more expertise and all these factors will result in in also less burnout there has been a very interesting um cross-sectional Anonymous survey of the American College of surgeon who captured I think around 8,000 surgeons yeah and they important an association of burnouts and decreased career satisfaction with nighttime surgery mhm and there was a significantly higher proportion of Surgeons who said that they would not consider surgery as a profession again so I think avoiding this nighttime surgery will also increase the attractivity of the of the profession and the retention uh of the of the transplant person that that's a very powerful data point I think you know uh before covid the the idea of of a CEO of a hospital paying attention to burnout was not was not a major topic but I think I think we're hearing that across the board in terms of Staffing challenges burnout challenges not only it sounds like you're getting the best most specialized people that you can arrange during the day but for the program sustainability to retain young talent to keep them in the profession there's a a huge investment of time and effort to to get uh a professional to the point that they're they're a transplant attending or or any of the the specialized support staff um and to lose that because of burnout is is got to be a huge program cost to suddenly have that Gap and have to retrain someone new to fill those rules I would assume that's absolutely true Michael and um also I must say from my own perspective I rais a young family I have three small children I have a newborn this year just being able to sleep and be there for them in the weekend and not be tired the whole weekend and and do things together with them that's that increases your your quality of of life as well and there's a positive feedback loop in in both directions I think yeah it's really not to be underestimate these young professionals they they also have have young families and and then they are forced to to work to three times a week at night and then it also leads at home to difficult situations I can imagine so it it's better to have that in a good balance as as someone with three kids um the the fact that you you could in addition to losing sleep from the newborn and then also have to lose sleep for staying up all night for cases I can imagine that's got to be brutal I mean it's it's it's striking to me when you think about uh professions outside of medicine right especially professions which require a lot of um High cognitive ability and and focus I can't really think of any other profession which is expected to not sleep for 36 hours and then perform at that high level right you think about Pilots you think about other really high intense Sports um people get good sleep but when it comes to surgery like you mentioned it's almost kind of you know historically something that people have to deal with yeah yeah I agree I agree on that and I think we have to evolve more towards these um these controlled systems like like Aviation yeah where we just Safeguard not only the patients but also the one who executes the procedure yeah can I can I just briefly go back to the 94 year old donor that you mentioned I think what was interesting is was you know you've done research and published from the the louen team about how donor age is potentially something that we should reconsider as as a risk factor what was particularly interesting about this case was not only is it potentially the oldest donor but it was also a donation after circulatory death lung if I remember correctly can you talk to us a little bit about both of those risk factors and you know at least historically been risk factors how the team came to the point where they felt comfortable with this type of donor long yeah so that's a very important topic prti and that's what I call with our experience in in extended criteria donation which has grown over two decades in in Belgium and in Europe we don't face the same kind of donor as as you face in in North America know what we face is the 50 to 60 year old who might have been smoking with comorbidities um and in most of the C in in many cases which in the end becomes a donation of the circulatory debt or DCd our program alone accounts um in 40% of cases it it accounts for DCd um and what has been shown not only by us but by the whole International uh community and there's a very strong paper from from islt on that is that there's no difference in in outcome regarding DCd lung versus donation after brain de L yeah um and that is different than for example in comparison to kidney or liver where you see a more detrimental outcome with BCD and the pro the reason probably is that that lungs are quite unique and privileged because they have this oxygen starch and they are less prone to this first warm iskia as long as they are ventilated a lung is somehow protected yeah so regarding the CD we have built a very strong experience and we are not afraid and we do not consider anymore DCd Lear as as an additional risk factor as it is used to be in the North America or is it used to be in in in more than a decade ago at our own Center so we're very confident we've accept accepting good DCd a good DCd um might even be sometimes better than than than than than the dbd who has been ventilated for for for two weeks then last year indeed we were able to show for the first time that in our retrospective uh Series in Len We performed a propensity matched analysis of all donors that were transplanted beyond the age of 70 years and we compared them to donors under 70 years and I think we had a comparison of a median age of 74 year versus 54 so a difference significant difference of of 20 years between these two groups all other parameters were the same and we have seen this this propensity match analysis that there was no difference in short neither in the longterm outome what we did observe was that we were more selective if we chose or accepted an an older an older donor so I think calendar age should be interpreted as um relative risk factor but the most important is to look at actual biological age of that donor what are the comorbidities um how has he or she lived has he been smoking what's the BMI and to have a good understanding of how marginal that organist in this extended criteria donor is more important than focusing on calendar reach I can tell you this 94 year old donor was still living on his own doing activities riding a bike and just this tells you that this whole body has a has a younger biological age than some of the organs that we see at 49 or 50 years old so and based on this experience with this 94 year old donor we're setting up a whole research line on the impact of um age on on donation and transplantation and one of the new PhD students will start on this on this next year so there's some truth to when people say age is just a number at least when it comes to to to donor lungs that's that's really fascinating and and the fact that you guys have now kicked off a entire research focus on that Absolut absolutely I'm curious actually has your team's gotten aggressive towards evaluating uh more and more extended criteria or marginal uh organs how uh how is have you viewed different Technologies you said you've used controlled hypothermia do you also use evlp towards that is that part of your strategy towards extended criteria so we have been involved in Len um in the in the the clinical practice of of xfo lung perfusion um at the moment of the of the start of the clinical trials we were involved in the inspired trial in the expand trial which was assessing donor organs with the OCS technology which was normothermic um perfusion and ventilation with with whole blood and what we have learned not only from from these trials but also from the Vienna trial Etc was that despite the the logistical challenges that were performed there was no impact to be seen on on pgd on its own primary gra D function and so um the the real indication I think that remains for xivo long profusion currently is assessing um questionable donor lungs and this is how evlp technology is is used throughout the world especially for um DCd lungs however in Len as I explained we have a very we have built a very strong experience with DCd and so we don't feel the need to um assess these lungs on the on on xfo with XF lung profusion um we assess them um based on the criteria we have from from the donor and our own experience and we also look at at how the recipient is um and so we don't use it in in in that field any anymore I think what we have also experience over the past is that some of these lungs which might be transplantable gets get aitis on the on the machine which is normal because they go through a first phase of esia hyperfusion but then it just more challenging to transplant an aditus lung with less exposure um leading to more surgical complications and so it might be more um understandable to let that esia hyperfusion injury to have that cytotoxic storm after actual hyperfusion in the in the patient and because then you can you can handle this with better ventilation strategies or the use of ECMO postoperatively but you don't lose that that organ and you don't make the transplant as as complex as this so I think I think evlp is still there and we're using evlp um again in the in the near future one of my colleagues is is leading that that project and we will um we will use it probably in in in research setting as well um for questionable um donor Lars we will not use it anymore to extend preservation like we have done in the past I recall a case that we published in the American Journal of transplantation where we did a combined liver lung transplantation and we were forced due to the nature of the disease of the patient to transplant the liver first so we kept the lung on the machine for almost 12 hours um to transplant it then afterwards in in the recipient um looking at it back now it seemed quite quite strange to do it because with such lung preservation um times on on the machine you might actually damage the lung we have learned and nowadays for these cases we would always use the the strategy of controlled hypothermal search so I think there's no indication for EVP anymore in in controlled preservation but where I see the real indication is where I see real indication is in the allograph treatment and modulation I call it ATM the money is in the ATM yeah that's where you have to use it and also Toronto has been leading that path showing that with genetic modification that's actually what we're doing right now in the lab we are genetically modifying red lungs when they are on the evlp and this out of body xfo modification just has so many potential advantages that I see a transition to the clinics in in the future yeah yeah I you know it's really interesting um the XV lung profusion uh approaches are are are quite interesting and and I and if I remember correctly a lot of those trials happened before controlled hypothermic storage was even a preservation option right so that all those control groups that XV profusion Technologies were studying was against ice storage um so so to me that's really interesting um you know that basically teams have now made a leap uh from Ice storage beyond evlp for the most part to controlled hypothermic storage I think one of the things you touched on I think that that is interesting and I think again this is sort of that crossing over of disciplines one of the things we're we're hearing from physicians in the the NRP space particularly on heart is uh that when you have the the full complement of the physiology of the body the the the recovery of the organ that the the impact on the organ is really different than just uh sort of replacing blood and circulating in isolation so I think that's that's a fascinating sort of aspect to it yeah and and just to build off of that Dr kumas I also know that your team um at at one point if I'm not mistaken you know did NRP um at least the heart team did right and and your team feels pretty comfortable um taking donor lungs from NRP cases can you share a little bit more about that because I know that's also really a Hot Topic in the US whether donor lungs from an NRP case are viable for transplantation so I think indeed NRP has been performed in in Len and we have transplanted some lungs with NRP with with good results I was involved in these cases as well the benefit for the lung itself was that you could do the actual assessment of the donor lungs um after that the body was was recirculated and so what I remember what I recall from this case that actually drew some blood gases from the pulmonary veins in C2 after the heart beat was beating again so you could assess which was therefore never possible in a DCd setting and therefore you had to use the machine to to do a proper assessment what I think is really critical um in NRP besides the the ethical um challenges that we are still facing but they working on that there are studies currently being performed to to assess the the fact if the Raper Fusion leads to to brain reperfusion or not but ex except for that besides that I think it's important to consider that the lung transplant programs were not um hared or limited by the driving force of the cardiac Physicians and and surgeons to uh accept accept Hearts instead of instead of lungs and I think as a lung transplant Community we have to safeguard the fact that DCd lungs are equally allocated um in regards to the use of NRP what I understood from North American colleagues was that in the first analysis of the Unos data it seemed that with the um implementation of of NRP um there was a relative decrease of the use of of suitable lungs yeah um I think overall NRP is really important because it is um a whole strategy that will dramatically increase the um possibility of of hard transplantation but um yeah we really have to have to develop International protocols that that Safeguard links one of these is that you have to take into account that we need to monitor that is Reser culation does not not harm the L one of the most important aspects is that I think is the is the to to avoid an overflow of the lung and that you need to to vent the lungs properly during NRP um and we're working on that also with the European Society of Thoracic surgery this year coming up in Barcelona we will have a special session dedicated to that that that's fantastic the special session on NRP to to really look into that issue I think that's definitely called for at this time I want to come back to something you had mentioned a little bit earlier so it sounds like the historic time frames that you'd use for cold es scheming times might have been on the order of six to8 hours with controlled hypothermia how how long are you going uh how what is acceptable to your team for uh lung to maintain uh a cold a scheming time that's a very good question Michael um I can tell you that the longest preservation we did now was 222 hours um 2 minutes 22 hours 22 hours it was not preservation um the whole it's what I call esia time esia time cross to cross clamp with a preservation over 18 or 20 hours I think in the in the lard and so I must say at the end of the procedure the reason to do it was first it was Bridging the night second it was a very complex uh complex case um so we needed a lot of of specialty um during the day and then it was also very complex case in regard to the explant of the lungs and so just the whole surgery took a lot of time to do it steadily um and then after this 22 hours the lung was reperfused and I must say it was really very compliant yeah what you sometimes have when you have a an or reserved on ice for such a long time that it just it's really cold it's like taking a steak out of the fridge it's it's cold and hard yeah and it just isn't compliant this L was really elastic and and compliant and so that's that made us very confident to indeed routinely use this this extended preservation and I think um we have now gathered um we have sent an abstract for the islt next year Gathering I think almost 15 cases of extended preservation which means is schia times Beyond 15 hours and in not a single one of them we have seen pgd grade three at 72 hours so I think for us this this is this is this is not um not a problem to to extend preservation for that long I think probably the limits with this technology if I look back to the old literature is probably around 24 hours and I say this because what you see with this controlled hypothermic preservation controlled hypothermic preservation is avoiding freezing injury but at the same time keeping an equilibrium between the the aerobic metabolism that is performed and the oxygen consumption and probably after 24 hours a lot of this oxygen has been consumed um we don't know this for sure this is based on on literature for more than almost 30 years ago and where they did experiments and measure oxygen saturations over time that I think probably around 24 hours is is is the current limit if we find a way to replace the oxygen um we might even further extend it and I refer also to a paper of Toronto where they did the pick experiments and kept the lungs viable for for three days so what I think you have to imagine it's more like um in a very naive way may maybe but this this mitochondria you have to keep them viable MH and these are the batteries of your cells and you have to refuel them after a while so what they did was they had these piig lungs they were preserved then they were refueled with four hours of evlp then preserved again refueled again and so by doing this you can you can extend the the preservation for a longer time in the liver now they can pres preserve livers for up to up to seven days and if you get into that um time limit and I think it's possible I think it should be possible over time then you get a situation where you might think about focusing more on um trying to create tolerance in your recipient because that gives you the opportunity to take donor cells I think about donor regulatory t- cells expens them out of the body that that requires time and give them to the recipient before you actually transplant the or and so over time since the beginning of transplantation there have been developed so many protocols to trying to make to to reduce the need for immun suppression of transplantation by by making the the whole transplant procedure more more more um more prot protogenic but it always requires time and if you can buy time with extended Pres obervation you can focus on the on the really Grail of transplantation which is creating tolerance that's fascinating that's fascinating um I was speaking with a laboratory researcher who's been in in perusing organs for a long time and he's this analogy of uh it's like if you introduced two dogs in a fight they will never get along ever again if if you can introduce them as friends they'll be best friends forever and this is sort of to what he was saying about getting in organs uh in a state that that will uh lead to the best outcomes um but doing so in a way that you can create time that you can extend the the flexibility and the coordination of everything you need to do to pull off this this incredible procedure it's truly amazing Dr kman one of the things you mentioned which is really interesting was about the use of uh oxygen over the preservation period uh that's actually another interest for us from research perspective we we recently got a new technology cleared uh by the FDA not yet C marked that the goal is to maintain inflation pressure of donor lungs between the site of donation to the site of transplantation um you know these pressures can vary based on how the lungs are packaged but also during the transport period they actually we've seen that the pre the pressure goes down and with that the oxygen level also goes down so one of the benefits that I'd love to talk to you um you know more is how this type of preservation could potentially retain the oxygen concentration that you talked about and how we could extend preservation so I'm I'm curious since we're on that topic from a from a inflation uh standpoint you know we've talked a lot about temperature uh inflation as a parameter of preservation what are your thoughts on that the Imports in focusing on that so where I see this going is that we're going to towards a technology where you try to control as many parameters as possible and the first logical parameter was the temperature because you can you can do that quite quite easily with current technology there are two other parameters which are crucial in lung preservation and that is pressure and pressure is rel
2024-02-15