Dr. David Frederick Mercer - Paradigm Shifts in Intestinal Failure- Pushing the Limits of What We Can Achieve

you you Thank you. We will go ahead and get started with our grand rounds today. We are honored to have Dr. David Mercer as our visiting professor and grand round speaker. Dr. Mercer joins us from Alberta, Canada, where he completed his MD-PhD as well as surgical residency. He then went on to complete fellowship in surgical transplantation at the University of Nebraska Medical Center. There he is currently professor of surgery and serves as director of the intestinal rehabilitation program, as well as the liver and small bowel transplant program. His scholarly track record is very extensive with over 80 invited presentations or 60 peer review publications, and some of his most recent grant funding investigating the use of Tudugletide among pediatric patients with short bowel syndrome. He's here to talk to us this morning about paradigm shifts and intestinal failure, pushing the limits of what we can achieve. Thank you, Dr. Mercer. Good morning, everyone. Thank you very much for having me. It is truly a great honor. When we approached me about doing the talk, he said, can you give us a talk on, can you talk about a transplant surgeon's perspective on intestinal failure, or can you talk to us about some of the stuff that you guys are thinking about with your totally gang-reinosis? I was struggling because I was thinking, how am I going to blend all that into one thing? Is there some way that I can do it all at once? I went through a ton of different iterations of this talk, and I'm hoping what I've done is tried to blend it together, talk a lot about sort of the philosophy of what I think about things, and then touch at the very end about the issues of the gang-reinosis. Let me just... Just my disclosure, I'm involved in a number of clinical trials, because I do work in pediatrics and adults. I'm involved in clinical investigations with most of the major companies that are doing all of the GLP2s in the field, which I will touch on at some point. Everyone now says it's truly an honor to come and give a talk, but it is truly an honor to come and give a talk. Of course, I'm going to sit here, and I'm going to talk about paradigm shifts in the field, and the reality is, the paradigm shifts have dominantly come from this institution, and I think that's cut it to all of the sort of the brilliant minds that have been here and are here presently. I thought I should show you a little bit about myself and where I'm from and what I think, because if I'm going to talk to you about my own philosophy, I think you have to understand me a little bit. Here's the Nebraska Medical Center, and you can see there's the department surgery, there's me, and we're pretty excited about... We're going to be doing some renovations in the upcoming year. There's going to be a new building that's built over by the dirt pile, which will be nice because I'm going to have a place to put the cow. And so, you know, really looking forward to big things in sort of 2024, 2025, but no, reality is, you know, we have the whole, the whole nine, you know, we get big modern medical center, and we were talking a little bit last night about that. One advantage you have being in the Midwest is there's ample space all around you, and so it's relatively easy for us to expand because we can just buy all of the blocks around the university and put up new buildings and stuff. And I know that's a lot more difficult when you're in, when you're in a place that's more space constrained. So the talk is going to be light on data, have you on philosophy. Because I think that the, for me, the most important thing in doing intestinal failure is having your philosophy aligned with your team. It's getting all of the right people together, getting a bunch of brilliant minds in one room, and then giving them a direction to go in and making sure that everyone's aligned philosophically. And if you're aligned philosophically, I think you can achieve some pretty good results. So I won't read to you most of my slides, but I will read to you one slide because for me, this is, this is a, you know, not necessarily a famous philosopher, but this is something that really drives the way we think about things. It's the idea of empty your mind and before and list of shapeless like water. So water, if you pour water in a cup, it becomes a cup. If you pour it into a bottle, it becomes a bottle. If you pour it in a tea pot, it becomes a tea pot. It can flow, it can crash. Be water. So what does this mean? What it means is don't be locked into thinking about one thing. Don't be constrained by the way things that I always been done. Don't think that just because this is what it was is the way it has to be. It's all about flexibility of thought about the idea of does everything need to be protocolized because people ask us all the time, give us your protocol for X, Y or Z. And I say, I'm not really sure I have a protocol for that because I think the more I do this, the more I realize it's so individualistic and there's so many factors going on in anyone case that I'm not so sure it's easy enough to, to reduce everything down to just one set pathway. So with this in mind, we'll touch back and forth on this idea of being water and having flexibility of thought as we go through some of the different issues. So I'm going to talk about paradigm shifts. It's probably fair to say what actually is a paradigm shift. So this was really a term that was that was came from Dr. Deming, when Everett's standing, who was the engineer who then went on to graduate work in physics and math. And with sort of a statistician who looked at process development quality development and the idea of that there's fundamental shifts in the way things happen in a field and those shifts lead to a big leap forward. And then we make progress along that leap until we get stalled again and then somebody makes another paradigm shift and we leap forward again. So I'll talk about that concept as we weave in and out through what's happened in the field over the past 20 years. What are they going to try to explain to you? I'm going to try to explain to you what I feel about intestinal transplant and why. And it may be a bit surprising. So by training, I'm a transplant surgeon. I my practice right now is nearly exclusively intestinal failure, children and adults. I really don't do transplant in the grand scheme. The things are relatively small part of my life. You know, I sew in some liver transplants because it keeps the lights on and pays the bills. But the reality is it's not that's really not where my heart lies. And it isn't what my practices. My practice is mostly about avoiding transplant. And hopefully that will come across. What do I think the paradigm shifts have been and maybe what do I think they will be. And then I'll at the end, I'm going to try to talk to you a little bit about what what we're doing in a kids when you're totally gangly annulce is in a relatively informal way. And in a way that I hope almost just precipitates a bunch of discussion at the end if it can. Okay, so many people in this room are experts and I won't dwell on this for too long, but intestinal failure. You know, we're familiar with me. No failure. You know, respiratory failure and cardiac failure. But intestinal failure may be in a broad room. People haven't necessarily thought about it. But it's really fundamentally the inability to maintain your nutrition or hydration with your own intestines. Now, in this room, when we're talking about kids, it's maintaining growth and development. Which actually becomes interesting when we can talk about what's the impact of growth and development on how intestinal failure plays out over years. But in any event. What's a goal, our goal. Arguably is to get rid of the central Venus catheter. You could say that that's what we're trying to do in a intestinal failure. We're trying to get rid of a central line because if you get rid of a central line, that means we're not on TPN, which means we're not going to get any toxicity from it. We're not going to get line infections and we're not going to lose access sites. And so we do transplant right down to what is it all about. It's fundamentally if it's working, it should be to get rid of the central Venus catheter. And so I'll tell you when you look at the way people analyze your transplant results, there's a lot of people who will tell you that their transplants are successful, but the patients still have lines. And so I'm not convinced that that's a successful transplant. I could actually probably in a group of transplants, they can tell argument to say that that's that still constitutes graph failure. In any event, we're probably trying to achieve entral autonomy, maybe oral autonomy would be the ideal goal if we can. When I started this super, super fixated on the idea of we have to get the line right away. We have to achieve entral autonomy as quickly as we can. It's possible that that's not entirely correct. At least it's possible that it doesn't mean that we have to drive and drive and drive and drive at that when we're two years older, four years old. It could be that we can take a bit of a long view of things. And I'll probably start to talk about that. I started at dinner last night and I'll probably talk about it as we get more towards the end of the talk about maybe making all kinds of major changes to achieve entral autonomy at all costs early on isn't necessarily the best approach, but that maybe it is. One of the things that's real pain, but is just returning the scope of the problem. It's really hard to tell how many patients actually have intestinal failure in the United States. This is a paper that that that product last year I co-authored with a guy from Mayo, Man, P.M. Where we were trying to figure out how do we even know how many people in the country might have this we looked at this big giant database that covered about 270 million lives and through a bunch of coding tricks and everything else trying to figure how many people might have intestinal failure. And we came up with this number. The number itself doesn't really matter whether it's 24 thousand or not doesn't matter, but at least it's a scale that's kind of in the order of 10 to the, you know, 10 to the fifth year, sort of in the 10,000, 20,000. So if somewhere in that range of adults and children that have intestinal failure, which is a number we don't even know, right, we don't even know how many people have this problem in the country, which is certainly not something we can say about many other disease states. We have a pretty good sense of how many people have colon cancer every year, breast cancer or something like that, but we literally have no way of knowing how many patients there are how we even find them. This drug companies insane, you know, they're trying to figure out how to find people so that they can sell drugs that are 500,000 dollars a year per patient and they can't figure out how to find the patients because it's really, really complex coding is brutal. There's all kinds of problems. So when you, that's the scale of the problem, so when people say, hey, can you give us a talk and intestinal failure and I think what in the US we're doing like 100 and test and transplants a year. So yeah, I can give you a one hour talk and intestinal transplant and how we help that point 1% of the population of intestinal failure patients or we can talk about what we do with the 99.9% of the patients. So I tend to focus on that a little bit more. Now, in fairness to transplant, I'll give you just a couple of slides on it because I think if I want to talk about why we don't want to do it almost all the time, then it's only fair to at least say what is it. So what can you do basically fundamentally there's two types of graphs you can do an isolated and test and graph. So you just you have an isolated and test and it's pedicled off of this period mesenteric artery and this period mesenteric name. You know, it's really not that difficult to do. It's kind of like doing a floppy kidney transplant with better exposure. So it's really, you know, as long as you wrap the intestine up, it's really not technically all that hard, but we kind of have to wrap it in mystery so that people think transplants surgeons are cooler than they are. And then it combined liver, you know, all the multi this will transplants multi this will transplants fundamentally you can see with them just like grapes on a stem. This stem being the thoracic aorta and you can plug that thoracic aorta and you can add or subtract organs from the graph. So you can have stomach if you want to you can have pancreas and testing you tend to keep just because you want that little complex of higher structures deliver you can have intestine you can have coal and you can stick a kidney on there. So you can just you can you can sort of have whatever you want pedicled off of that aorta. Any use have to do a little plumbing at the end once you have the blood vessels hooked up so. So that's what we're talking about in terms of major intestinal transplants. When would you do an intestinal transplant? Well, fundamentally it's like any other organ, which is you're going to do it when the risk of not doing it is greater than the risk of doing it. And there's a lot of I would say this is a bit of a at times controversial area when you sit and talk with other transplant surgeons about indications for intestinal failure this becomes a very heated topic the classical indications are right here which sends sage liver disease life threatening line infections loss essential means access to unreconstructible GI tract. The thing with intestine transplants is the actual indications to do them are really nebulous so it's the only transplant I would say where I think people can get transplanted just because somebody kind of wants to transplant them. You know it's not like you have defined you don't have a necessarily a meld score or you know that says I'm at this point and therefore statistically I should be transplanted or I'm on dialysis and transplant is advisable. In intestine transplants kind of people sit around and go oh maybe we should transplant this one or maybe we shouldn't transplant this one. And I can tell you if without being too incendiary if you look at the adult world of intestine transplant I would argue that that the pattern of transplants fall is the patterns of where certain surgeons move around in the country and where they work as opposed to whether people really need to have transplants or not. And I don't know this for sure but my guess would be if you looked at compensation models you would probably see peaks of transplant relating to the type of compensation model in individual institutions so people don't want to hear that but that's probably the reality and a lot of intestinal transplant. Okay, so let's talk about a paradigm shift so I'm going to use this kind of format of looking at O.P.T.N. data because I was trying to think how do you look at national outcomes for intestinal failure. You can't because we can't hardly you know we always fail at making registries although we're sort of starting to maybe get a little bit better out with the one that you guys are driving right now from the. The got X registry but in general we don't do very well tracking national data so I thought the one thing we can do is we can look at transplant data and we can use that as a surrogate for how good we're doing an intestinal failure. This isn't even a testing data. This is pancreas data why because I just want to show you an example of a paradigm shift so here's back when I'm a fellow 2,400, 600 pancreas transplants a year. My first couple years when I came back to the United States and came back to Nebraska and Canadian so came back in 2006 and I personally was doing you know here's my flex like I was doing 25 pancreas transplants a year. But within a few years you're doing 350 transplants then you're doing 245 then you're doing 192 then you're doing 108 well there's not less people with diabetes and we're not crappier at doing the operations but what happened is there's a there's a better mouse trap right there's something better that you can do than doing a pancreas transplant. You can have implantable glucose monitors implantable pumps so when something better comes along there's less reason to do transplant. So I'm going to use this as an argument to show you why I think looking at intestinal transplant data gives us a really good indication for how much better we're doing in the non transplant element of intestinal failure care. Okay, so let's look at intestinal transplants. I'm going to block out the adult just to simplify things and we'll go back to this this time here. So this is sort of right around just after my fellowship or during the time of my fellowship. So for me what was life like then well when you looked at certainly at the little kids so the under one year kids. Here we would be in Nebraska and little kids would show up from all over the country just you know five months of age. Great big tummy's looking like you know just little fragile little birds. Yellow is can be on death store and we would scramble to get them transplanted as fast as we could. And half the time we would get them transplant half the time we wouldn't. And when we transplanted them they would be definitely ill and we would have you know a pick you full of kids on oscillators and all kinds of stuff and I would spend my entire life in there just putting in our lines and putting in lines and dealing with new authorities and stuff like that. So we had to do all of this stuff and it was um you know it wasn't necessarily that good of feeling having to do it. You felt like you were doing something but but it just didn't feel like it was necessarily the right thing. Well then what happens I think that suddenly a paper comes out and it changes every and I it's just one little paper. It's one little one little case report and then there's another one that comes out that goes well actually you know. Maybe it's got some utility here I love this because it just did the you know the implications for future management which is really prescient of what happens over time. Right then you see this series of papers coming out and then Dr. Pooters paper that comes out afterwards and the annals showing all of the data and and the reality is this is a paradigm shift right and how do you know because boom look what happens. This comes out and people go oh yeah okay that's a good idea you know that's better than what we were doing. And so instantly in the little kids we stop harming them which is what we were doing. Now what you could argue about the papers is it wasn't even I would see the strength of this all of this this body of work wasn't so much oh there's this you know magical thing that if we do this it makes everything better. It was more that it changed the way people thought about things I think because it made you sit back and go away to second maybe we haven't been doing this right maybe we actually have to think more about lipids maybe you know maybe using this kind of lipid is really really important but then other people said well maybe if we just do lipid minimization or we do other things we can get the same sort of results and then there was some truth to that. So the reason this was so pivotal is because it was a paradigm shift in the way we thought about things and it had a big impact so then what was the impact going forward so you can see there's the impact carried out to the modern day right. This was an intervention that changed things for kids that were three months old six months old nine months old and so you got in this data going from the numbers that we always did down to zero or one one child so. So this intervention alone was enough to have a great big impact and remember this doesn't mean that you only helped 40 kids in the country because all you're seeing here is just a genius little fraction of the kids that were actually helped this is just the most extreme you know most extreme so it's more the pattern of what you're seeing with a factor what was happening nationally so with this paradigm shift we could change the outcomes for little kids very quickly. Okay so so then what happens well same sort of thing will clean up the data block of the adults so if you look further down though and you look at older kids you saw some impacts from that but not quite the same impacts if you look if you look over this you go well gee the numbers still they go down over time for a variety of reasons but in that early era where you saw sort of the post a mega van paper era where all of the little infants your drop of the data. In the infant's your drop right down to no transplants and they all start to get better it lags in the older kids so for example if you look here you see these little kind of bell curves right each one of these like a little peak you know in the in the upper one the one to five rules it will peak around 2015 in the 60 10 year olds or peaks and that 1617. Why it's not like we were more keen to do transplants then what we're probably seeing here the realities which are probably seeing here is that's about five years after these little bell curve blips so those are probably mostly reduce. That's what we were seeing you know it's not so much that we were doing more new transplants but the graphs were failing from the kids that we did when we did these high peaks in the in the 2000s and so the graphs failed and kids community have to do the reduce and so you get the little blips of transplant and the unfortunate thing in transplant is. The you know part of the reason why I'm so pro rehabilitation is the height of the blips get smaller and smaller because the reality is you do redo transplants but less and less kids make it to that next that next peak. So the one thing that you can kind of tease out is where the next paradigm shift comes was when you're looking between these these peaks you see little natives where the numbers are lower and I think what that reflects is maybe the impact of the next paradigm shift. Which I think is enter a classes so you know this is this is doing things will be changed to shape of the intestine. So just conceptually if you have a big giant pipe you have a ton of stuff flowing through the center of the pipe and what we can absorb is what touches the sides of the pipe and so if we have a large diameter pipe fundamentally most of the volume is going through the pipe and it's not touching the sides right so so we're not really able to absorb that very effectively and it's lost as a vehicle stream. So if we can take that and we can reduce it down in size what we're really doing fundamentally in these operations is we're changing the volume to surface area ratio of the intestine that's really the point. And that becomes relevant a few slides from now we start to talk about even how conceptualized the way we should be doing this one way or the other. But the idea is to get this large more pipe is ineffectual and get it down into a much more effectual size. Okay, so here's just a picture I put together for a book chapter a while ago showing the different sort of antroplastic and there's the you know up in the upper corner is the Bionki procedure which is you know is a fine operation. I mean really it's mostly best done by Dr. Bionki and not so well done by anybody else but but there are lots of other people who have tried over the years but really when you look at the big series they mostly come from. From those guys tapering antroplastic i'm going to touch on because I think that's a much more important part of the way i'm doing things right now. But the one that really had I would argue the biggest impact was the step procedure. And of course that comes through this you know now sort of almost legendary iconic series of you know papers the idea of this you know new inventions being a new operations coming up and and sort of the you know this. It's a cool story when you're a trainee and you hear yeah you know about how these operations are designed and and the development of all the different papers and it's frankly fascinating reading going through and looking at all of these things that we've all studied over the years. So let's talk just a little bit about procedures. I'll show you a little operation just a little operative video. So this is a nine year old had a nigga bob of the set six years into us somewhere just a little bit maybe a year before this operation. So this is that this is a child who's got bowel at eight centimeters you know eight centimeters plus and that ball is trying to move but it but it really isn't you know it really can't effectively move and so in the OR here. Just passing the fully through looking for intrinsic strictures and stuff like that sectioning out the liminal contents getting it all flat out. And then I tend to do these operations not so much transpursely the way it was described in the original operation but mesenteric anti mesenteric I find it so easier for me to stay aligned I think it helps me to stay on access and so I can keep that the actual performance of the antroplasty much more consistent. When you do have to go in and do revisional surgeries it's maybe just a more straightforward way to do it. You know I've done an awful lot of these over the years now maybe in the hundred and sixty hundred seventy case range which is another flex but it just I've done a lot of it so I think I picked up little tricks over the years. So just that was an anti mesenteric side step and then a mesenteric side step they're just teeny little holes you don't have to worry about them nothing's going to herniate through these tiny little holes. I like to use an energy IA with the tricepal tantalodes they tend to be pretty effective for me in general. So just you know finding back and forth and when you do this it unfortunately the video doesn't project very well but those but those little contractions that you saw in that eight centimeter dilated bowel it really weren't it factual become much more more effectual now it transit better on my laptop it really looks like too much for you guys but unfortunately when you stimulate now you can see you can see effective peristals as you can see closure of the lumen and you can see propagated waves. And so this actually really doesn't make a difference. Okay so let's talk about philosophy. So the step procedure and just anthropocies in general I think if what you're doing is you're looking at a child who's got massively dilated bowel and you're cycling through antibiotics and you're really not making a lot of progress in cutting out TPN. Then you can say okay we'll just you know we'll live with this and we'll just manage we'll manage the TPN as best as we can and keep the morbidities down and just cycle them on antibiotics but but I think you're unlikely to make progress in antro autonomy if you don't do something to deal with that dilated bowel. Now the brilliance of the step procedure is conceptually it's pretty easy to do the the biggest challenge of the operation is it's conceptually easy to do. And so the problem is everybody in their dog thinks they can do this procedure because you look at the picture and you go well who couldn't do that let's just staple back and forth and everything's going to be fine. But this is a procedure that really really does work but the devil is in the details you have to really pay attention to how you do it and he isn't it so so most of what I see actually is revisional surgery of poorly done operations and you spend your life trying to figure out how people even thought they were doing the right thing in the first place because you're doing steps that are ineffectual with tiny little bites or they get off access we were talking last night. This gets really technical but for the surgeons like you really want your steps to be on access and staying exactly just meticulously repeated over and over if you start to rotate that you become helical it really is a pain in the butt to fix over time because it's hard to conceptualize and three dimensions how to redo that when there's problems in the future. So I really do think that intervening to deal with dilation has a real positive impact but it doesn't necessarily always have to be a step anymore and here's a really interesting time and surgery where I would say the impact of drugs has changed your surgical decision making a little bit. So when I first started off doing this it was all about preserving you know every bit of absorptive surface that you know we have to step everything we have to say it every little bit but we'll as we get in a little bit further along and talking about the GLP 2 analogues you know we can do better and better with shorter and shorter lengths of native bowel it starts to change in my mind the calculation of how I might consider surgery on some of these kids because there is there is maybe some advantage to preserving that natural sort of linearity and longitude. The reality of the bowel rather than making it go through a step confirmation the step confirmation bowel works fine but if you if you can taper it maintains a little more than native confirmation and so maybe that's advantageous. I'm the way you do this generally you got your dilated bowel I just had a set up a series of that caught clamp on the anti-mesin check border and then just I don't even use the stapler just old pictures but you know you can just fire longitudinally and you can use this to take off very long legs about some of these. This is you know sort of a more dramatic example of doing this on somebody with an ACTG2 mutation which actually affectively for if you're doing sort of pseudo obstruction you type kids who have specific kinds of specific kinds of defects. So I think that as we get better and better at dealing with shorter and shorter lengths it's changed in my mind the way I'm thinking about this not so much to always have to preserve every bit of length and every bit of absorptive surface but rather that you try to preserve the most natural looking bowel. Getting rid of the most disease looking stuff and keeping a healthy stuff because we're really getting pretty good at dealing with short lengths of bowel and I'll touch on. A little later on towards the end where we're at with adults and how that has an impact on I think how the decision making is now. So then you look so now you fast forward to sort of a more modernary and you can see we're actually really have managed to reduce the pediatric transplant numbers down pretty well in some of these years I'm not sure like I was a bit surprised actually when I looked at 2021 to see there was 19 kids between the age of one and five that were transplanted because we didn't do we did like two. So somebody must be doing a ton of transplants but I just really haven't felt the need to have to do much of it so so I need to go and dig through all of the different centers to look at people centered data to find a few who was still doing a ton of transplants but but it definitely isn't us. Okay so this brings us up then to what I would say is the third big paradigm shift which is intestinal growth factors. So here what you're trying to do is you're trying to fundamentally take small little billis and make it into a large reveal is try to improve the disruptive function so the big drugs right now to do gluteide which is gattis so we have available and then the ones that were in trials right now so we're doing that we just finished up the. The pivotal trial for glutegletide and a pregnant tide is in trial right now so so I've had in our out of practice I've had patients on glepa now for about four and a half years. And so we're starting to get pretty familiar with some sort of have a long acting class. What are these drugs for people that aren't as familiar with them. There's a protein that we all make GLP to glutegletide peptide to we make it is sort of our terminal element or right colon and it has a variety of different control functions it kind of works in a the native peptide has a pretty short half life and it works in sort of a parachron fashion. So it's expressed in and works quite locally and it controls billis height and control cell turnover controls blood flow probably tight junctions a few other different things. And so the approved drug that we have right now is gattis to do glutegletide in general I would say it's pretty well tolerated. I think when you use it correctly it tends to lead to reduction I be supported most of the children adults who are treated with it. I think that where you see that these drugs not working especially in the larger clinical trials or places where patients are probably not as optimized as as programs thought they were. So if you have a patient who comes into you and we see this is not so much in the kid side but the adult side adults come in and they'll say you know somebody told me that I want to get put on to gattis but they're drinking six mountain dues a day. There's no point putting a amount of $500,000 a year drug or $400,000 a year drug if they get a drink six mountain dues a day like they're not going to get any clinical benefit. So you have to look after the details first and then you can generally get pretty good efficacy from the drugs. I think that if they get approved and they're probably are going to get improved the newer versions like glepa and apra are going to be done more infrequently and they're probably going to have about the same benefit. That's what we're seeing in the clinical trials. So this is just the original for people who've never seen it. This is the original to do the tide data. The adult trial we've been doing gattis down adults for about 10 years. You know we're not really seeing any safety signals that I think are concerning in terms of stuff like neoplasia. We haven't really seen generally an increase in polyps over the general population or we've seen an increase in malignancies. The pediatric data is on the other side there fundamentally just showing you if you go on to to do glatide you see a you see a progressive reduction in in parental support volume and calories over time. This is brand new data that I just presented down this is the data that we just presented in ddw a few weeks ago. So this is showing the glapid data. So this is a this is a little bit of a different version of modification of the gel peachy molecule so that it can be administered once or twice weekly. It's soluble and so what's really nice what this actually is is it's going to come out in like an happy pen. So it's really really simple. It just comes pre loaded. It's not really dose. So you just take it. It's about you know hold it for two seconds of walk away so the adults love it because it's super super easy to administer. Apra still has to be mixed up so it's not quite as it's not quite as slick but the glapid works really good. So that you know that and so you can imagine in the pediatric population I would forecast I think when we get to the point that we actually have it. You know I can't imagine it's going to be too many parents who are going to want to mix up a lot of life protein seven days a week versus just having something that comes pre loaded and easy to give once a week. So it looks like it's going to be pretty good. So now we get way out to here where we're at the sort of we're getting almost to where we've gotten rid of intestinal transplant completely not not entirely but but we're getting there I again I still wonder why there's 10 kids between the ages of one of five that after transplanted but in any event I will say we sometimes because of where you guys are and I think where we are we get a little bit of a skewed view of how the world works. Because people will come to us still and you probably see the same they'll come to you from places that you would say are actually not small little places and you'll look at what the management was and you'll go really like that you know that's you just stuff that's happening that you thought was so 15 years ago is still happening in lots of places in on the country. So for us the only kids really transplanting their ones to show up on desk store and there isn't that many of them but they do show up once in a while. So what do I think the next paradigm shift is I think this is probably what it is I know you guys already had a curve on this but I think I think that the the ETA locks are probably going to be a big paradigm shift. Because when you look at the data that they from the sort of paper up to Paul Wilson in Toronto you know it's a small study and I think I wrote a little editorial about this in in the journal is just to say it's a small study with a big impact and it really does because you've got you've got now data that shows maybe you can actually eliminate line infections and get pretty down close and you're never going to get rid of them completely but you can get pretty close and maybe you can keep line patents you really really good. So we'll have a big multi center trial and I know you guys got probably the most United the most American experience with it right now but I think this is the next big thing. Let me just jump back so the reason I think this is really critical to us is because this raises the issue of can you know can you almost have TPN has destination therapy can you just be like okay if we could if we could wave a magic one and we can keep line access forever and we would never have line infections. You could argue that well we can just stand to say on TPN and because I think we're pretty good at doing the actual TPN itself now so so I do think this has an impact on changing the way I talk to families a little bit and I'm going to touch on that a few slides as I get closer to the end. Okay so if you want to look at how do I really feel about in test and transplant which is my first charge and in giving the talk well here's what fundamentally what graph survival has been like an ingest in transplant over the last 20 years it's about the same right same drug same operation. Same this thing not the little bit of survival advantage that we have I would say is because you know there's probably some improvements in care overall so so you maybe your your pick you cares better. But fundamentally those curves I would say are pretty flag. Now you can argue from that data you can say okay well that's worldwide data it's all over the place unselected it's from a bad era so okay in fairness for transplant let's look at some more modern data right so here's a good center here's George town very thoughtful group. You know they are technically good surgeons so let's see how do they do well this is what I would say is the most sort of the most contemporaneous data that we have where they looked at can be five and 10 years surviving the transplant patients and they're about 60% right so that's better than zero for sure I mean it's the alternate was death it's okay. But this is what they're up against right they're up against you guys you're up against this data and this and and you can argue even this data this is still looking at an era that's not as good as we are right now this is looking at data that was when we still didn't have most of the paradigm shifts that we've talked about and this data kicks the ass of that other data right because you've got got transplants you should probably get 90% if you're sure audit 96% if you have an autonomy 98% even if you don't even if you look at this and you take this paper and you say okay this was an era where we still didn't know a whole bunch of stuff and we didn't have a bunch of shifts and you take the very hardest kids who can't achieve the entire autonomy you still have way better survival than you have the other way so you know I have to say it but it's the it's it's an apples and oranges comparison it's just it's just it is what it is this is just better you know somebody wins and somebody loses and this just wins it's better data so so I think that how do I feel about things well here's here's the numbers this is what I personally think about transplant right this is our center so here's our center data so here's back when I'm a fellow and then 2008 I take over in test and rehabilitation and you know I'm still the junior guy and so you can only fight so much in selection conference right everybody's more senior than me so I can only argue so much but eventually you get senior enough and eventually you get enough clout that you can start to argue that we shouldn't be doing this and so then you start to see the numbers going down and down and down and we're almost to where I want us to be which is zero so so what do I personally think about it you know I think that it's that there's probably a time in a place for it I think that it's probably rare in these days that there's a time in a place for it I think we're getting so good at doing some of the other stuff that you know I've often said it's it's weird to be a transplant surgeon to go around and talk about you know not doing transplant trying to eliminate it but but if I could finish up my career and have felt that I contributed to us no longer having to do in test no transplant I think that would make me feel pretty good about myself when I retired okay so getting I'm gonna spend the last sort of 15 minutes or so 10 or 15 minutes talking a little bit about the egg angling and all this stuff because I did want to touch base with it because it's something we've been working on a collaboration together and I just want to point out a little bit about things. So this is just to refresh in our minds the idea of unlocking what you always thought was the way to do things you know I always thought you have to do things one way and maybe we can do it differently so. So what are we doing now this was hard to figure out how I actually wanted to present this to you because it's difficult to look at this population of kids and try to find a compass is statistics there's no good way to say oh you know here's the meanness of the media now or something else so it's fun event they're going to come across you as a case series and I'm just going to I'm going to do it in what's kind of a clunky way but it's the only way I can think I can convey to you what this is actually like. I'll just show you one little case just to get us kicked off so a little girl that we saw is born at term presented has said about two months old so she had early obstructive symptoms all the right stuff is down they went to the yard of multiple backs you show that she had ganglia cells at 12 centimeters past the length of trites made an ostomy there and when she showed up to us she was on full pn of course taking a teeny bit of oral stimulation some little five little bottles by mouth and of course you know both of her parents are pediatricians. So so they shrugged and we and we started talking about what we wanted to do. And I'm going to show you a little interoperative video of her. Video to me a little bit so you can see it better I hope it doesn't unfortunately just project as well but but so what I'm what I'm looking at right there so that's all a ganglionic vowel and here when I hold up the. For some so that's a ganglionic but see those are waves of contraction right so so and those are not just contracting the response to be flicking it that's contracting spontaneous and those waves of contraction are propagated so are they propagated completely normally no it doesn't look phenotypically normal the way playing old ganglionated but it also in zero it's doing. It's doing it's moving forward and it's moving forward and it's going to integrate fashion the control is not optimal I think sometimes it seems to stall sometimes it all seems to go backwards but it isn't zero so so what I had a long talk with family and I said I think that we should use this. Because it absorbs okay we at least we have reasonably we should absorb okay and maybe what we can do is we can balance the high output state of the short ball centrum against the sort of. Structively low output state of the egg anglia no sense and we can find a sweet spot because you would think there should be some sweet spot where we can blend together ganglionic and egg anglia on a foul and just find equipoise. So and see again I don't know how about projects but you can see these contraction waves going through all of this this phenotypically a ganglionic vowel. Okay so so what do we end up doing well you know I by the time we have got into the OR that you know I could I could the length of the ball had grown a little bit you know it probably just dilated and stretched itself up a teensy bit because you're not going to get that much growth in sure three months but it was a little longer and so I could take that piece of intestine and put about another so maybe it was let's say was 30 centimeters and I think I put another. 45 centimeters I don't remember exactly but bottom line is we two years later now houses kid doing well we haven't had to do any Aboriginal surgery so they haven't really been any obstructed we didn't create an obstructive phenotype we created a kid who had lower outputs she is about kind of in the range of 40 to 45 mils per kilo or so per day. And we've been able to get her potential calories down to 70% of her needs 1200 mils of volume she's eating a normal toddler diet you know she'll eat a ton of mac and cheese one week and then hate it the next week and you know eat you know eat cheeses and you chicken you know McNuggets and all that kind of stuff. But but it's progress right and I would argue that if you had an ostomy at 13 centimeters you're probably not going to be eating a regular toddler diet you're probably not going to be doing boluses you're probably not going to be weaning down parental nutrition. So what I'm going to do is just literally show you some of the different cases and I'm going to show you an interesting so this is this is willow right here I guess she was 25 ganglionic and 35 a ganglionic so where she at now after a couple years while her parental nutrition is down to 70%. So the little girls I didn't think little boys and blue. Okay so here's Jonathan john's nine now his you know I started off when I when I first did his case I actually put a pile of a ganglionic bowel attached to the because I don't know the answer is I don't know you guys and that's going to come out over the next 10 minutes. Or if I don't know how much bowel it is I've tried to figure out is it a ratio is it is an absolute length it's more complicated than that I don't know what the answer is I really don't and I'd be quite happy if somebody you know if we discussed this because if anybody can come up the answer that helps me I'll take it. But so in john's case I put in a bunch I always figure it's worth putting more in because it's easy to shorten you know if you have a loop oss to me it's easy to move a loop oss to me proximally with no real additional morbidity because you're just you're not leaving any at risk staple our sutra lines so I've tended to go long and shorten. In this case what was funny here is I did that and that seems insane and it started off me looked awesome like I thought I'm a genius right this is the only god I'm just the smartest person in the world because he's now got this low output it looks really good and his teacher this clamped and he get on feeds and holy cow I'm going to change the world. And then after a couple weeks it's like that's not that awesome how he's kind of obstructed e you know he's not totally instructed but it's also not great he's a little more puffy than he was so I ended up shortening down. And and so now this is what the anatomy that we're left with now but you know for what it's worth nine years old it's got an ostomy is output is we've actually I when I was trying to summarize his outcome I would say well it's complicated why because I've actually gotten Johnny as close as just down to ivy fluids but but we're back on tpn right now we've had ups and downs. So so we've had good progress and better progress than we would have had if we just stayed with just the egg and we are about any pretty functional and now that kids coming up on you know almost 10 years. Now this is a little girl who's just has no gangly and sells pastor like in a tritz at all but she's got 80 centimeters in stream and you would think that she has completely normal bowel. You know I think if we went longer it might have been a bigger problem but that's what we have to work with so you know she was just up with us for a couple of months doing feeding therapy. We're making progress you know 70% parental calories that's not so bad it's it's a start it's definitely progress in the right direction. This is a little girl who had a fairly short segment that was gangly and needed to add it's an egg gangly on it gone over time to gangly and his stuff grew up and so actually I was in there for another reason I was removing some of her colon that was all impacted and it was just making her feel drag you miserable and overgroughty. And so what I did then is her gangly needed stuff that actually lengthened up and up that I didn't think we they was even worth keeping the egg gangly on it's definitely more because now she's up to 100 centimeters where I think most kids are probably going to do you know if you got 100 centimeters to anostomy you're probably going to do really well in the long run with that. So now we've got her down to you know four days support per week 15% calories probably she'll come off eventually you know I think sometime the next year or two so I think that's pretty good. Um this is a little boy who unfortunately came to us they had cut out most everything that he had so there really wasn't much but I put this one in because it's kind of instructive in that he had 14 centimeters gangly and I had I hooked up all the egg gangly on it's that he had and it just kind of I wouldn't say blew up on my face but just didn't work and this is why kids like this puzzle me because you would think with all these other kids that have longer lengths of egg gangly on a ballot works okay but in his case he did have the subtractive phenotype we just never could get going and so I think that's the only way to do it. Ultimately had to shorten him back to his gangly and he did a bowel but he's not a growth factor now for what it's worth he's actually making pretty good progress. Now in a weird way you can look at this kid and you can say well maybe that used backwards against you using the egg gangly on a bowel because he's actually fairly short and he's making decent progress. He's probably going to be somewhat limited for a while just because you know it's tough when you got 14 centimeters to an endostomy to be able to come off of all potential support but and these are a couple of ones that just been doing recently Calvin this little kid I did this is just a couple weeks ago so he had 31 gangling aided I put about 35 because they had cut out all his other small bowel so that there was some coal left and so what's really interesting about this is you have this kid who's got 30 centimeters gangling a 35 egg gangly on it but he shoots stuff out of his ostomy like it comes out of his ostomy you know and it'll it'll shoot out 20 centimeters so either that's a contraption that's propagated through 35 centimeters they ganglion a bowel is coming out with that kind of force or something else is going on on the inside I haven't done another contrast study X it's only a few weeks but I kind of am curious to see what's happening early but he's doing pretty good so far I know he's fully clamped he's handling it okay and we're getting on some feeds and everything else nobody here's another little boy who very similar circumstance but not working so well so I joined this one up and I thought it was going okay but he's really been a little bit more obstructive even not so I'm actually seeing him tomorrow in clinic and I'm probably going to take me to the water on Monday and shorten him a little bit just to see so what have I learned I think that removing the egg gangly on a bowel early is not the right path I think that's that I feel confident saying that's a true statement I do think that that probably we talked a little bit at dinner about this probably the early thing to do is actually to genuinely make that ostomy at the junction where the gangly needed a bowel is just because you guys are in a heated battle and you just need to get over that and make sure that things go smoothly I don't think you need me have to be playing around with it three day older a four day old trying to finesse gangly needed an egg gangly on a bowel but I do think that once you do that and you get them over it I think it behooves you to think about can we put some of that egg gangly on a bowel back in stream earlier rather than later I think there's more to determining the utility of bowel than just the presence of absence of gangly and cells it's more complicated than that but I don't know I don't know what the answer is you know I all what I can tell you some kids do really really well if you feed egg gangly on a bowel and other kids don't and it's probably a more complicated thing than than what I'm reducing it down to it's probably more complicated than just x centimeters of this and x centimeters of that so I'll wrap up in just the last few slides so this is slide of some of the short bowel kids who are now in they're all in college right so these are like the transition kids so that the the second girl over you know she plus 11 centimeters you know born at 27 weeks 11 centimeters of bowel she was actually in the gattif's trial but and then came off with TPN and now is a nursing school is going to be a pediatric nurse come back and work on the floor and and she's not even on gattics anymore she's the entralian dependent the next boy just finishing up his degree as an engineer the third girl next to her mom is this total hippie girl from Montana who I just love who I've looked at she's actually the little girl who was in that step video that I showed you so she's entralian dependent now at you know whatever she is 12 12 years later after that and then the gattian is a he's a kid from from the south who's like a must be a crop analyst and he's a real hunch and stuff but the the importance of this is we're getting really good at getting adults off of TPN with really really short thanks about so I would say in our program now if you give us a reasonable length of colon so and by reasonable length that's that you lost your right colon you've got early to mid transverse colon down which is fairly typical pd anatomy and if you give me an adult who's got 30 centimeters of bowel we're going to get most of those adults off of TPN if you give me 70 centimeters of bowel we're going to get virtually all of them off TPN over time and so why does that matter well I think it matters because it changes the way I think about this and kids now because now you can sit down and you can talk to a parent and you can say well look you're doing okay right now and maybe you've got a kid who is seven years old and they're on 40 let's say let's pick an up let's say 30 calc per kilo per day per natural support 35 or something like that and maybe you could say they you know at that age they should have 65 calc per kilo so they're demonstrating to you that they're capable of absorbing 30 35 calc per kilo to grow well when they're an adult they're only going to need about 28 calc per kilo ish maybe they need a little bit more in absolute terms because they malibus are some of it but but what they're demonstrating to you is they're demonstrating when I don't have to grow anymore when I don't have to develop bones and muscles and everything else and all I have to do is maintain myself I'm probably going to be okay with the anatomy that I have right now and I think that's what we're bearing out in our adult population now as these kids are you know are getting into their 20s is the sure pile gets easier they kind of grow out of the disease a little bit and so now it starts to make me think in some cases maybe what we're really trying to do is just keep them healthy and let nature take care of everything over time and if we can keep them eating and we can keep them having a good quality of life and if they can play the sports they want to play and they can succeed in school and they can you know be socially developed in everything else maybe that's not such a bad approach either so when I look back to you know Dave Mercer from 15 years ago I can be critical of young Dave and I can say well maybe you don't need to push as hard as you did because maybe it's more about giving them a really really good life and keeping them healthy knowing that if we can keep their bowel in a reasonable shape and we can keep giving them some stuff and we can make some natural progress their management is probably going to get easier and I think this is what's born out from what we're seeing so I'll leave you with a last one last slide which is just to say I think when you you know when I'm in this room with everyone who's contributed so much the way I think about things and to our entire field I think I look at it this this is something that I tell the team all the time which is you know take what's useful discard which you don't think is useful and try to add uniquely what's your own contribution and I'll finish with that this is all my contact information that's my cell number if anyone ever wants to call me or text me or whatever and if I don't recognize your number I won't answer so just text me first but but otherwise um thanks very much for the time the attention and I'd love to have a discussion about any of the stuff that we talked about so thank you well Dr Mercer we would really love to thank you for joining us as a visiting professor we really enjoyed dinner last night um your talk it's you kind of as you said you're bringing Colson Newcastle here there are a few people in this room and on the zoom screen who might have had something to do with many of the paradigm she thought he thought about and but your own massive experience really brings them into context and you added so much to it and I'm sure there's some pretty gratified souls in this room right now who can see the impact beyond Boston of what they've done yeah and I want to give them a chance to to speak as questions for those of you on zoom you notice that the chat is gone um we just decided to get rid of all the banner bars in front of the in front of the slides so email me or text me and I will check and if we have time we check doubt we'll get some more but there are some really important people in the room but I'm sure have comments hi David hi great see you thanks for the talk amazing overview um sorry i could make them last night but uh and and and uh i wish you were there last night for me because you made sound transparent so very very straightforward that's so easy right nothing to it nothing to it just pop it out pop it in yes yeah um what it has i should have called you anyway um uh i think you know i like your idea of the paradigm shifts and uh the comparison and looking at the you know status actually very insightful insightful i think the one of the biggest ones we've seen recently is actually lung transplant pediatric lung transplant is basically gone because of the cf drugs yeah and uh actually the the pediatric lung transplant centers are trying to figure out what to do literally because there are no pediatric lungs to do anymore and looking for new indications actually um there are still some intestines done as you point it out and uh we haven't done one here for a while for intestinal failure but there might be some other indications for it what are your indications in the intestinal failure world because it sounds like you still do a few and we still have occasional children who come here on parents and they really want to transplant for whatever reason uh the kid really wants to eat um you know all sorts of sort of more i guess quality of life reasons and uh wonder what your current indications are for the few that you still do so you know the question of who would we really want to transplant i think when when when kids show up on it's rare that we see them with bad end-stage liver disease but but we have you know we did a couple of kids in 2019 who literally showed up old school like they showed up at nine months of age just you know with encephalopathy and you know clearly where there was no time to sort of mess around and see if you can get this better because the kid is encephalopathic you know that kids you know can die anytime so i think when they have the truly overt you know bad end-stage liver disease and not just cirrhosis or low platelets and stuff like that because a lot of that stuff doesn't matter i think that stuff stabilizes if you can do well with the intestine the thing that probably stresses me the most now because i don't even get that rid of a line infections i think for the most part you know it the nobody has that many bad life-fending line infections in general there's the occasional kid but access i think it's maybe one of the issues you know so i do think if you have a kid if you're taking the long view of trying to get 70-year survival and one thing that drives me nuts in transplant is we talk five-year survivals right and because we steal that from oncology and and transplant it's not really fair to talk about five-year survival because your transplant doesn't go away in five years right you say five-year survival in cancer because the idea is supposed to be your care if you make it five years but in transplant you still have transplant so so so i think that if you when you're trying to get a kid from two years of age could be 70 years old and if they present to you and they've already lost a bunch of access sites and they're a mile away from coming off of tpn that that's probably the one where where i do think it's okay to still pull the trigger on even that i must say i agonize over because sometimes when their access is bad you almost say well it's already so crappy like how much worse is it gonna get you know once they've lost all their vessels you know you're gonna be doing a transplant decline anyway or something so it's almost worth giving it a try just to see how it goes but you know when you have the kids who are on a hundred percent you know they show up they're eight years old they're on a hundred percent tpn no one's ever really tried to rehabilitate them they've lost both ij's and ones of clavian i mean you can try and i must say you know sometimes we'll give it a month or two just to see but the reality is that that's kind of what it's coming down to for me is just those last few so and then and then there's the occasional we did one this year that was just a bad trauma then gunshot wound to a teenager that just sort of shot away as duetium and the highlight and everything so that was you know a kid who had no no quality of life so that was the unreconstructible GI track but i'm really not a big fan of you there's a lot of push amongst the out of side of quality of life and stuff like that and i'm just i can't accept that i just don't buy quality of life as an indication so my indications are so tight now they thanks again for thoughtful and thoughtful and talking talk one of the things that that i think you pointed out with the multiple paradigm shifts and with your unostata that is really important in my mind is that these children are living longer right so so we have the advantage of growing up in an intestinal rehabilitation world where now kids that were dying are living and the biggest difference when it when it comes to intestinal transplant for me is that you're really as you say you're not curing these kits this is a long term essentially chronic illness which is immunosuppression and all the things that come with transplant the benefit of all the things that you just pointed out is that now the kids can be a part of the decision-making process if they become 14 and they're still on pn and they decide they'd rather eat normally than than or that eating normally is more important to them than taking immunosuppression and being at risk but they can be a part of that conversation so in your in your career i wonder if you've seen that progression because there are still some older kids as you see getting transplant is that the reason i mean you say quality life isn't in your mind a big indication but i think for patients and for families it often is so i i would the argument i have against quality of life is is i think that in a proper program you can give people a really good quality of life so sometimes they come to you and they have a poor quality of life and it doesn't take that long to tweak what they're doing and give them you know you they come in there on 20 hours a day at tpn and you go well geez you know that could be done over 10 hours and suddenly their life is dramatically different but i i think you're point about getting them older and allowing to participate is is a very good one this whole this whole and we have the same discussion i mean that's literally one of the things i'll say when i'm talking to families and i'll say well look here's what i'm prognosticating for you 15 years down the road but i said even if you do go to transplant at the very least we'll be talking with a 20 year old or a 22 year old or a 30 year old or something like that who's had that many years and if you're going to take a path that has a fixed risk no matter how good a surgeon you are no matter how good the patient is no matter how good your center is the risks are fundamentally fixed for almost everybody plus or minus if you percent percent or so if i got to take that risk on and it's my kid i wanted to fur that risk as long as i can if you know if i guess feel softly you believe that longevity of life is the most important thing no you could make an argument to say that you know i mean you and i i think both interested in looking at how people perceive quality of life and and i do think that does impact so i'm not quite sure what the where that's going to factor in right now is to you know how would i cancel a 14 year old who says i'm just tired of being on tpn and i'd like to have a transplant so that i can just be equal to normal it's really really hard to get what i would say is truly informed consent because because people always think they're going to be this successful patient right and nobody prognosticates in their own mind that they're going to have new core you know they're going to get you know and and that their scientists are going to you know their half their face is going to get eaten away or they're going to get some horrible aspergillus in their brain or something nobody ever thinks that everybody thinks that i'm going to do it i'm going to be the you know and it's going to be great i'm just going to eat everything's going to be fine so it's it's it's a it's a it's a fascinating issue to decide what the right thing is um i you know i i would have a hard i would have a good long chat with that kid you know with that fortune you're all that we're talking about to say you know maybe you want to give this in time yet and just see because when you're done growing things might be very different so thanks very much David for for a great talk and one of the paradigm shifts that beer and wrote up several years ago that shouldn't have time to include a course was the introduction and implementation of multi-disciplinary care for the still growing one i should have had no worries but it did strike me when i was seeing how you were evaluating how much of the egg anglionic bowel to leave in are you using gastrointestinal monometry to help with those surgical decisions no the short answer is no i i am not um and not that that not that that wouldn't be a a bad idea because it's just i just haven't so far because i've literally ingested and sort of sitting and looking at it phenotypically in the OR and saying what do you think like what does it mean because i i don't know if i could start to see some patterns emerging a little bit then i might know how to use more input data but i but i'm still not even sure so if i saw that you know maybe that contraction data i don't know i don't know what it would mean because i'm still not even sure how much to add in so it's probably part of it and and maybe something that you know just in in the interest of formalizing and trying to attach numbers to it other than just Dave saying well that looks like a good place to try it you know like that's not very scientific right it's it's terribly unscientific but it just seems to be the best i can come up with right now but but it means a good thought Chris something would probably think more about it. Hi um thanks for a nice talk nice walk down memory lane and um i you know all the things you mentioned i mean if oh if Kathy if 15 years ago talk to Dave of 15 years ago we were quite different people and i think the nice thing we have now is time and we agree that that what does not want approach multiple approaches and it's nice to see the kids grow up it was nice to see the pictures and i think it's great when the kids talk to each other because now our kids are going to college and they didn't know they could go to college and some of them never even saw their baby pictures until they came into my office and saw their yellow pictures because their parents never showed them how sick they were yeah so it's kind of nice that we have time. It really is thank you thank you. Well intentionally let's go a little bit over because um it is pretty rare to have um the number of people in the room with such history with which we're talking about the and to see your perspective on it in Iraq so we took a few minutes out of your professor answers we're going to go directly to in the library. I want again thank you for joining us and for all your collegiality and collaboration and enjoyable dinner last night we look forward to the rest of the morning activities and we did change things around today so so um people can reward professor rounds as quickly as possible we'll join their next thanks to all. Thanks Aeroign studies.