This is Ian Glenn, editor for State Current and Pediatric Surgery. This episode features Doctor Brad Warner from Washington University in Saint Louis and Saint Louis Children's Hospital. Doctor Warner will be discussing intestinal failure, including diagnosis, medical management, surgical therapy, and intestinal transplant. We hope you enjoyed the episode. Thanks. Stay Current is a multimedia publication designed to keep healthcare professionals up to date with standards of care and new emerging ideas. Stay Current is created and edited by Todd Ponsky, Ian Glenn, and Sophia Abdulhai and is recorded and produced at Akron Children's Hospital in Akron, Ohio. This is Todd Ponsky from African Children's Hospital. And today, our audio chapter is going to be focusing on intestinal failure. And with us, we have definitely an expert in the area, Doctor Brad Warner, who is the Jesse L. Turnberg MD PhD, Distinguished Professor of Pediatric Surgery, Department of Surgery at Washington University School of Medicine, and surgeon in Chief at Saint Louis Children's Hospital. Brad, thanks for joining us today. My pleasure. This is certainly a tough area, and I'm really actually anxious to talk to you about it. We just recorded a chapter on necrotizing enterocolitis with Dr. Bessner, and we kept alluding to intestinal failure but stopped short of really digging deep into it. So I'm glad we're going to have a chance to go into it today because I know a lot of people have questions about it. Let me just ask you, what is intestinal failure? Well, it's an umbrella term for When the small intestine is unable to absorb or digest enough nutrition to support the patient entirely by oral or enteral feeding, so, you know, a part of intestinal failure is short gut syndrome whereby The intestine has been removed significant length or the baby's born with inadequate intestinal length to permit absorption, digestion to maintain their body weight or to grow without the need for supplemental nutrition. Other components of intestinal failure are really non-surgical and may be Primary motility disorders like really long segment Hirschprung's disease or mucosal diseases, some enteropathies and things like that that don't allow for normal nutrient absorption, digestion, those would be under the same heading as intestinal failure but really are not shortcut syndrome. OK, so you know people are always throwing around numbers of specific length of the bowel and whether or not you have the ileocecal valve. What are your thoughts on those? That's a great question. We do know that the intestine of a newborn or of a fetus essentially doubles in length in the last trimester of gestation. And so that's relevant when you take a 24 week or 25 week baby to the operating room and do a bowel resection for necrotizing enterocolitis. If you leave them with 20 or 25 centimeters, they're going to actually probably increase to at least 50 centimeters just on the basis of growth alone. And so that's very different than taking a an older kid, maybe a teenager, to the operating room who's had a midgut volvulus, and you leave them with 20 centimeters, it's unlikely they're going to grow significantly from that, so. Um, it really sort of comes down to what, what are sort of cutoffs for when you declare someone salvageable potentially or potentially able to wean from nutrition by vein. So I sort of for a neonate, I think probably if they have an ileocecal valve and therefore their entire colon. That probably in the range of 10 to 15 centimeters of small intestine would be, uh, you know, a ballpark figure. And of course there are a lot of other things that go into that decision making, you know, what's the social situation of the child? Is there coexisting head bleeds and things like that, but that's kind of the ballpark figure that I think of. Without the colon, without the ileocecal valve, I think at least probably. 15 to 20 range would be sort of a ballpark figure and again it depends on how much small intestine. We know in adult studies, and so these take away the element of of children and the element of growth of their bowel, that adults with less than 50 centimeters of intestine. About 40 of those patients, 40% of those patients will not be alive after about 5 to 10 years with that small amount of intestine length. So, um, you know, that's sort of an adult ballpark range, and I think you can move the length downward, the smaller the kid, and depend on other features of intestinal adaptation to occur. OK. That's a, it's a great ballpark and a lot, it definitely helps when you're coming out to talk to the parents about giving them some sort of idea of prognosis, right? Let's take a baby with malrotation, so they have mid gut volvulus, and you, you do have, let's say, 15 centimeters of bowel and you do have an ileocecal valve. What do you expect is going to be the natural history with this disease in this child now? Yeah, that's a, that's a tremendous question and You know, I assume then that one would do everything potential to save as much intestinal length as possible, but, you know, someone with 15 centimeters of intestinal length in the entire colon, I would say probably, I would expect long term 50% of those kids should be able to wean from TPN. Other 50%, it's going to be split between those that would require an intestinal and or liver transplant. And the other 25% of that entire group then would probably die as a result of their shortcut syndrome. So and what I'm sort of quoting to you is the Data from the Pediatric Intestinal failure Research Consortium that was published a few years ago now, but looking at the long term consequence of children that are on TPN for, you know, more than several months as a result of shortcut syndrome, about 25% die, 25% need a transplant, and 50% of those can wean off of TPN. And is the most common cause of death sepsis? You know, it's a combination of factors. Liver failure is one very important thing. Another is septic episodes from the central line and or from their bacterial overgrowth that occurs in the bowel. Sometimes it could be variceal bleeding, you know, from their liver disease. Sometimes it's loss of IV access due to. Requiring multiple central lines in different sites and no longer have the ability to provide reliable, consistent access. What do you tell the parents is usually how long they'd have to wait to get the baby size-wise or age-wise to be a candidate for a small bowel transplant? I think it's reasonable to understand that intestinal adaptation occurs after small bowel resection. And that in humans it probably takes place over about a year or two. So if they're achieving enteral autonomy prior to that, that's great. And you know, I think the goals of management of children that have short gut syndrome from an acute massive enterectomy. would be to wean as much TPN as you can and push the enteral feeding to the point that you can ultimately get them off of TPN. That's, that's the real goal. And in doing that, I would accept stool outputs of up to 40 ccs per kilo per day. That's when I would say you're hitting the limits by which you should, you know, back off on your enteral feeding. But if you are continually improving. albeit slowly, and you're not really hitting any sort of ceiling in terms of worsening bilirubins or multiple septic episodes and things, then keep going and I, and I would say too that it would not be unusual that depending on the length of the intestine that it would take a year or two. Let me take you through some patients here and help guide me on what goes through your head here. So. Uh, let's first start off with, what would you say are the most common reasons that children develop shortcut syndrome? So, um, I think the top ones would be necrotizing enterocolitis, uh, gastroschisis, uh, mid gut volvulus. And atresias and uh and then you know further on down would be, you know, trauma and inflammatory bowel disease, those types of things. OK, let's say, um, Brad, now you have a patient that had a closed gastroschisis. They have short gut. They had a primary anastomosis. Let's say they had two open ends that had through the umbilicus they were closed primarily or. Uh, reastomos and you have, let's say a G tube in, um, what goes through your head? What do you consider now? How do you start with this baby that you know has shortcut. With the medical management of this child and advancing their fees and all these different things. Well, the most important thing is you've got to provide sufficient calories for growth. And so originally that would start with nutrition by vein and you know, I think probably with regard to the TPN we shoot for about 100 to 120 calories per kilo per day. For total calories, about 50% of that's going to be glucose calories and Um, and then the remainder will be fat and protein. Generally shoot for about 2 to 3 g of protein per kilo per day and about 2 to 3 g of fat per kilo per day. Um, when you're advancing on the, uh, or when patients are on long-term TPN, I think some of the things that we want to try to do is begin enteral feeding as soon as. It's feasible, and that would be, you know, after your resection and reastomosis and they start stooling, that would be the time to initiate, and I generally start with a slow continuous drip as opposed to bolus feeds. I think that with a continuous drip, and this is kind of my more opinion, but I think the nutrient transporters are up regulated, and I think your ability to get more nutrition in may be advantageous. The people that sort of push for oral feedings, I think it's equally valid that you can stimulate a lot of gastrointestinal secretions and things that are vaguely mediated that might also help absorb and digest better. So I sort of get a combination. I generally, most of their calories ally are through a continuous drip, but I do allow the babies to feed orally whatever they can. The things that I would be continually doing then would be. making sure that they're gaining weight and you want a baby to gain about 20 to 30 g a day. That sort of approximates in utero aggression for a newborn and lack of weight gain or weight loss is concerning to me that we're not getting enough calories in. And so I would increase the calories by TPN and obviously keep pushing the enteral calories. And if you achieve a stool output that's greater than Uh, 40 per kilo per day you've got to back down, but constantly keep pushing that and, and I also am watching carefully the bilirubin levels and um if they should start to get jaundiced, um, then I think you've got to, you've got several options to consider. And one of those would be, and I think in the United States now we tend to do a lipid reduction strategy where we take them from 2 to 3 g per kilo per day of fat that's given every day down to about 1 g per kilo per day delivered twice or 3 times a week, and that's, um, I think, been very effective in reducing the. A cholestasis that occurs in association with TPN. The downside of that is, uh, you know, you're really taking away the amount of essential amino acids that they're getting, and babies that are growing obviously are laying down a lot of myelin and brain and and not having those amino or not having that type of fat is potentially disadvantageous. So there's been a new um um sort of approach, uh, not particularly new, been around for probably 8 or 9 years, is the use of omegavin, which is a fish oil-based fat. The usual intralipid that we use is soybean based, and that's primarily omega 6 fatty acids, and those are felt to be pro-inflammatory. The fatty acids that are in the fish oil or the omegave are primarily omega 3 fatty acids, and those are considered to be more anti-inflammatory. So there has been a lot of push to use omegaven, and it's actually used in countries outside of the United States instead of fish, instead of the soy-based formulations. And when you introduce those to children that are getting jaundiced, there has been demonstrated significant fall in their jaundice levels getting the fish oil. Now the downside of fish oil is it doesn't contain the essential fatty acids that are felt to be important for for babies that are growing. And so kind of in the middle has been something that I understand has recently been approved by the FDA for use in the United States. Is this Smoth lipid SMOF and that actually has a combination of a lot of things. So the S stands for soybean based lipid which contains the essential fatty acids. The M is medium chain triglycerides, which are more easily digested. Uh, the uh SM and the O is olive oil and the F is fish oil. And so that combination of those four elements then I think may be the most ideal circumstance to provide not only essential fatty acids but medium chain triglycerides, better digestible as well as the omega 3 and omega 6 combination that I think probably is a little bit more physiologic and the smoth, I think, has actually become the most commonly used. Lipid modality for children in Canada and I think now recently it's become FDA approved in the United States and so I think we might be hearing more and using more of that in the future. OK, so I want to see if I can recap what you just said. Uh, number one, so the babies comes up from surgery. Once they're recovered from surgery and have return of bowel function, you will start a continuous drip starting at a slow rate, probably at 1 cc an hour or something like that, and, and you go up at a frequency of, of how often? Um, I would probably go slow, probably, uh, double that in a, in at least in a couple of days, and, uh, and then double that again, um, or maybe go up by 50%, um, after another couple of days, really guided by the stool output, and I really wanna find out where we're, we're hitting the ceiling and once we do I back down a little bit, let their stool output chill, and then I give them a week or two. And then try again and constantly keep trying to see because I do know that they're undergoing this process of intestinal adaptation and that's very, very important and you know we see it structurally that they're growing taller villi and deeper crypts and they're increasing the absorptive and digestive surface area per unit length of their intestine and we know this is occurring not only structurally but it's occurring physiologically. And that babies that stool out at 2 mils an hour are now up to 6 mils an hour a few months later and not stooling out. So that's, I think, both the structural and functional features of adaptation. Yeah, that's a good point. OK. So, and I, and I do like the number use of 40 ccs per kilo of stool output as your gauge of you need to back off a little bit, right, right, OK, um, and then your formula of choice. I know you mentioned the Omegavan or the Smoth, but what about your the other formula? You know, I think breast milk is, uh, uh, if you know, if you're in a newborn situation, is probably the very best because it not only contains what the baby needs in terms of the proper fat and all of that, but it's, it has other things in there that are really, um, I think from an investigative standpoint, very rich to explore. One of which are the growth factors that are present, such as epidermal growth factor and insulin, insulin-like growth factors, and all of those things that really probably do promote adaptation, which is very, very important. Also, there are some milk oligosaccharides that are being demonstrated now to enhance adaptation. They have a lot of other features that I think improve nutrient digestion, absorption, and and things that are important for the neonatal gut. So there's a lot of things that are in breast milk that I think make it my number one choice if it's available for neonates. Otherwise, I don't use elemental formulas for older kids or anything like that. I think that. Uh, in theory, you, you may have a better ability to absorb the elemental, but I think also there is evidence to suggest that complex, uh, um, Formulas fed ally may actually stimulate adaptation a little bit better. So you know they they cause you to secrete enterotrophic hormones to a greater extent and that may be more that may be much better for promoting adaptation so. I tend to not use, you know, these very minimalist type of dipeptide types of things, and I tend to use more complex. Interesting. It's good to sort of challenge the gut a little bit. Absolutely. I want to ask you a question about something that we've encountered is as you're trying to start enteral feeding and let's say you haven't reached that 40 cc per kilo stool output, so in theory they're tolerating what you're giving them. But you're not seeing growth, uh, and now you, you sort of have to decide. So you sort of have to go up on your TPN, uh, but how do you deal with the volume now because you're giving them, do you back off the enteral feeding or keep both guys? No, I definitely keep that going. And in fact, if they haven't hit the 40, in stool output, I would do that first before going up on the uh parenteral nutrition. Um, I mean, you, you obviously want to support growth and you can do that with. TPN or Enril, and I would prefer Enr as long as they're tolerating it to keep pushing that because I think the advantages of the Enril is that um you're you're reducing the amount of TPN that's needed and therefore if there's any injurious component of TPN you're reducing and mitigating that and I think there is a threshold, although I don't know. The exact number of what percent of enteral calories prevent the onset of liver damage from the TPN, and I know there is a certain percentage, and I know if you're on, you know, 90% enteral feeding versus 10% enteral feeding, you're going to have a far less risk of, um, you know, TPN related cholestasis if you're at 90% enteral. So I always always push the enteral first. OK, let's say now, let's say 6 months have passed and you've got the baby on probably half of their goal of enteral feeding, the other half on TPN. At what point do you start thinking of surgical intervention? That's a great question. So at 6 months you still are in the phase at which they could be continuing to adapt and so um. I would say keep pushing with your enteral feeds and as long as you're able to slowly increase and reduce your TPN amount, then you're headed in the right direction and as I said before, I'd give that if you're on that, you know, the curve is upward, keep pushing it and anticipate that that could take a year or two. Um, my time that I would be starting to think about doing lengthening procedures or intervening surgically would be is if you hit a point rally and now you start backing away. In other words, if you were tolerating 50% enter, um, a month ago, but now you're down to 20%, uh, that if you're going backward rather than forward, that would be the time that I would start thinking about. Uh, an intervention. The other would be if there was multiple episodes of sepsis along with abdominal distention and evidence of really dilated bowel loops, and that would be another sort of reason to think about it. And then the third would be is if the child is starting to get jaundiced. Now you can mitigate that by the altering the lipid intake in their. Uh, you know, parenteral nutrition, but I think there's also a role to evaluate the gut when they're starting to get these jaundiced episodes because there could be some subclinical portal bacteremia and things that arise as a consequence of the dilated bowel loops. So I think probably dilated bowel loops are one central theme here. That can be responsible not just for the sepsis episodes but for inability to tolerate enteral feeding. They get bacterial overgrowth and they actually have diarrhea. It's a secretory diarrhea that has really not as much to do with how they're progressing in terms of their digestion absorption capacity, but because they've got dilated bowel loops and bacterial overgrowth, their enzymes are not able to work as well, so. That's the point I would sort of stop and say, OK, now it's time to interrogate the bowel, and I would start with the plain abdominal radiographs. And I think with that you can get a sense of whether there's a lot of dilated bowel loops with gas, and you know if it's a gasless abdomen that's very different than, you know, a bunch of balloon animals versus a focally big dilated bowel loop. And then I think after that you want to interrogate them both from above and below with contrast studies, so. I would do an enema from below and make sure that they don't have something kind of simple going on like an adhesive band, an obstruction, and an anastomosis. Those are the things that will prevent you from, you know, obviously moving up on your enteral feeding and those types of things also promote bowel dilation and potential sepsis, so. You know that would be something easily correctable that you don't want to go in thinking you're going to do a lengthening procedure and find just an adhesive band or something. So, uh, and then study them from above to get a gauge of what their transport time is and get a sense of kind of what their length looks like. Um, so if I saw a child in those circumstances that was starting to get jaundiced or a kid who was actually backing up on the amount of ventral feeding that they were tolerating. Then I would study them if they had dilated bowel loops, and what I generally would use is more than 44 to 5 centimeters of bowel dilation, and they're they're really going nowhere with advancing natural feeds or they're going backward, I think that would be the time to intervene surgically, OK? And I just wanted to clarify, so in a child who, let's say is now 3 years old. And is not backing, backing, going the wrong direction at all, but just not progressing, you don't move on to lengthening procedures in them typically if it's really been 3 years and they're they're completely stable, I would interrogate their bowel and if they had dilated bowel. Um, I think I would take advantage of that to go forward with trying to lengthen them to hopefully get them off of TPN. Great, got it. OK, so that helps. So again, so it's jaundiced, abdominal distension with dilated loops, or actually going backwards in their. Enteral feeding or just someone who after several years is just not progressing and happens to see that they have dilated loops on X-ray, is that a good summary? OK, good, perfect. All right, so let's say you have that child, let's say they're 2 years of age, they're starting to go backwards and they're feeding. And starting to develop some cholestatic jaundice and you get an X-ray and you see, let's say a couple of dilated bowel loops and you get your contrast study from below which shows no point of obstruction and your contrast study from above shows confirms dilated loop with somewhat areas of delayed motility, but things go through fine. Now what? So at that point I would offer the family a laparotomy and you know I would sort of make my determinations intraoperatively what I would do. But in general I think if you're going in with the intent of doing a lengthening procedure, you sort of have to have some ideas in your mind what you think is adequate amount of bowel length and what's worth lengthening and what's not, so. In terms of bowel length, I believe that if you go in and you find a child has over 100 centimeters of intestine, we know that less than 5 or 10% of those patients should require TPN. And so it would start making me think that there might be some other underlying problem that no matter what their length is, they're, they're maybe not going to have enough and that there's maybe a motility problem or a mucosal. A neuropathy type of thing going on, so I keep that in the back of my mind. With 100 centimeters of intestinal length and the bowel not being super dilated, I'm, I'm not completely convinced that there's a lot that you can do surgically for those kids. But let's say you get in there and you find less than 100, let's say less than 50, and you've got bowel that's at least 4 to 5 centimeters of intestinal length, I think then you've got an option. Of either doing a Bianchi intestinal lengthening procedure or a step procedure, the serial transverse enteroplasty. Now before you continue, let me make sure I understood one thing. So you go in and you see, let's say 70, 6060 centimeters of bowel, and when you said the 4 to 5 centimeters, you're talking about how dilated the bowel is. That's right, got it. OK, so you go in and you see it's dilated. OK, sorry. Yeah, so um. You know, it's dilated, it's short, and I think at this point you have a couple of options the serial transverse enteroplasty or the SEP procedure or a Bianchi procedure. I think honestly the SEP procedure has emerged to be the most commonly performed operation in these circumstances now. Um, the Bianchi, um, is a little bit more technically challenging to do, um, although the last two lengthening procedures I've done have been Bianchi's, and, uh, I can't sincerely tell you why I felt like I wanted to do Bianchi versus a step. So a Bianchi procedure takes advantage of the fact that the blood supply coming to the bowel wall from the mesentery actually bifurcates before it gets to the intestine. So there's a V going to the base of the bowel containing each arm, the blood vessels, and in the crotch of that V, therefore, is an area that's avascular right underneath the bowel, and you're able to staple across that as well as the top of the bowel to create two tubes of bowel. Each tube then is supplied by one arm of that V, that branching blood supply. And um I think the, uh, it's, it's, it's a little bit more difficult to get into the proper plane. Of the bowel when you're using a stapling device and doing a longitudinal division of the bowel, but once you're in it, it actually is not incredibly difficult. And then you sew the two ends of those two new tubes together to essentially double the length of the bowel for as long as you've stapled it. And Brad, do you start your Bianchi at where the bowel starts becoming dilated? Yes, yeah, I start it proximally and you curve in from one side and then curve out the other side and then do a single anastomosis, otherwise you can completely transect the bowel at the proximal and distal ends and then make your two tubes that way and then do two anastomosis, OK, got it, and more frequently I. Try to do the one and end up doing the 2 because I get confused, but regardless, that's, that's the longitudinal lengthening procedure, the Bianchi procedure. The step procedure is really an ingenious procedure that HB Kim came up with now at Boston Children's came up with this, I think, when he was in medical school, but basically it's cutting, uh, partially across the bowel on one side. And cutting partially across the bowel from the other side and alternating that so that you create these channels within the bowel and it actually effectively reduces the caliber of the bowel also, but it also increases the length that the nutrient would come into contact with the mucosal surface, so it's going down these channels that are zigzagging as opposed to a straight tube of dilated bowel. Um And people, I think, have had way more experience with the Bianchi recently because or with the step procedure because it is very easy to do. There's less risk of injuring the blood supply to the mesentery and things because you're really only cutting across at right angles, partially across the bowel. So I think most people are doing those. I tend to, I've had a few instances. Where a step procedure had been done previously and we know that the step can redilate and that you have to redo a step and um and I think when when that happens, the outcomes overall long term are not as good as if you never have to redo a step. So I think that's an issue that, uh, you know, really sort of warrants a little bit of of work um. You can do a Bianchi and then go back in and do another step on top of a Bianchi. You can't do a Bianchi once a step has been done. I was waiting for you to say that because I think that's a huge point to make. Yeah, yeah, yeah, OK. Although having said that, we did a Bianchi. Recent where a step had been done, but it hadn't been done adequately. In other words, it didn't go across even 50% of the bowel. So you were still able to do a Bianchi. We were able to do a Bianchi through that area, but that bowel was very dilated. And the other thing that I've seen with some steps is that they have dismotility, and I think of a child who had a step procedure done. Um, at the neonatal period, and, uh, this child had had a, uh, a, an ileal atresia, and she actually had a reasonable amount of intestinal length, but had that dilated bulb of ileal atresia, which was stepped and she was put into continuity and she honestly was on TPN for years. She had no good ability to tolerate enteral feeding. Her bowel proximally was very dilated, and the gastroenterologist who referred to me said that, uh, you know, we needed that she had a primary disc motility and that, uh, you know, so we explored her, and I'll never forget in the operating room looking at this step which looked like a bunch of gnarled up hamburger in the distal bowel, and the bowel proximal was very dilated. And it was of sufficient length and so the GI folks came into the OR and we really debated because they wanted me to remove the proximal dilated bowel thinking that that was the source of the sepsis and problems and dysmotility. And I really made it a point to say that I think it's the step that is acting as a brake, you know, and they ended up letting me take out the distal bowel. Well, they didn't let me. We all agreed, you know, cooperatively for me to remove the distal bowel, and I did, and she completely weaned off of TPN. So that makes me feel like steps are not as innocuous as as we think they are, and because of that, I, I don't know, I tend to lean a little bit more as a primary to do a Bianchi, and if I have to redo something, I might, I might do it as a step then I'm really glad you're you're saying that, and I. I, I think that you're right, the easiness of the step makes it an appealing procedure, but I think a lot of advantages to Bianchi. And so what can you tell us? What are, if people are going to try a Bianchi, what are the pitfalls? How can you mess it up? Well, obviously not getting in the proper plane. So if you are stapling down and you're not and you're off the midline of the under surface of the bow. You really can mess up the blood supply to that other tube of bowel. Now, having said that, there is, I believe, a case report in the literature whereby that happened, and unfortunately, you know, you make two tubes of bowel, you have to take out the other tube because it died. But when they reastomosis that single tube remaining, the patient actually improved. Oh really? So yeah, so it makes you wonder, is it the bowel dilation and reducing that, or is it really that you're doubling the length? Yeah, so it's, it's really not known, but I think that is a very important thing. The other thing is, you know, when you're doing your, uh, reastomosis of the bowel, it can be, um, a little more tortuous, um, if you tend to do the anastomosis in a. You know, end to end, way above the mesentery. So some little tricks have been to create a window in the mesentery to bring the bowel underneath the more proximal bowel and do your anastomosis, sort of transmesenteric, and that can sometimes take away an acute angulation and make it look a little bit more neat, I guess the other thing is you can get really disoriented and so an isoperistaltic segment to an antiperistaltic. And I think that could really be a problem. So you have to be careful to mark your ends so you know which is proximal distal. Absolutely. And the final thing is it's a long staple line and if the bowel is real thick, you might, and I haven't done this um. Often, but, um, you know, I tend to squeeze stuff along the staple line, and if there's any leak, I reinforce that with some Lambert's and uh yeah, so those are the caveats from my standpoint for that. So the case that you just talked about where that one case report where they removed the ischemic segment and the patient got better, is there, does that make an argument for tapering? You know, that's a great, great point. I would, I would taper a child who had dilated bowel who had at least 90 to 100 centimeters of intestinal length. If it was just dilated and appears to be of sufficient length, then that's an absolute time that I would taper. OK, absolutely. Brad, you had talked earlier about TPN related cholestasis and some strategies you can use to try to minimize that or mitigate the risk of that. What about once it's developed, what strategies can you use to improve the cholestasis? Well, I think some people have used bile salts, kenodeoxycholic acid, as a means to improve bile flow. Other things that we talked about, you know, changing the lipid composition that you're delivering, um, increasing the amount of enteral feeds, obviously, um, there's really not a lot of good data. I know Dan Teitelbaum. A rest his soul, actually did a trial of providing cholecystokinin as a way to promote bile flow and mitigate TPN cholestasis, and unfortunately that didn't work. So I think those are the major things, and I think the other big thing would be to consider the fact that if the bowel is dilated, that that's a nitis for infection. And that that is probably encouraging translocation of bacteria and you know, a lot of endotoxin and things like that into the portal circuit, which is damaging the liver and that's contributory. So I think, you know, if, if the bowel is dilated and they're starting to get jaundiced, I think that would be an indication to. To taper that bowel or lengthen it, how do you medically manage or prevent or minimize the chance of bacterial overgrowth? That's a great question, and I don't think that there's a lot of good data. People will try oral antibiotics, giving them Cipro and Flagyl or singly or in combination. Others have tried probiotics as a means to feed the or as a means to really provide. You know, lactobacilli and things that are felt to be beneficial and knock out the enteropathogenic types of organisms in the bowel, and there's maybe a role for prebiotics, administration of things that feed the good bacteria and and, you know, not feed the bad bacteria. Um, there might be a role for fecal transplantation. In other words, taking, you know, stool from a healthy baby with normal gut length and instilling that into the GI tract of a baby that's having overgrowth type issues. I think getting to the root of the cause of the overgrowth, and that to me is the dysmotility and the dilated bowel is, is probably more important. What we're learning too, it's interesting that the bacteria that change in the gut in patients with short gut syndrome really becomes a, uh, I would hate to, you know, I don't really want to cast this as me saying this is exactly what happens, but it is, is it like an obesogenic microbiome. In other words, the bacteria that change in these babies with shortcut syndrome. The gut bacteria become more efficient and are able to help adapt by encouraging greater absorption digestion. Interesting. Yeah, so I do think there's a role potentially for manipulating the gut microbiome in these patients to mitigate bacterial translocation and things. We actually had a couple of papers recently, and this is in our animal work, but If you do bowel resections in mice and follow them long term, they start to get steatosis in their liver, and we provided them with oral vancomycin to knock out the gram positive organisms that tend to bloom in patients with short gut syndrome, and we completely prevented the bacterial or the hepatic steatosis in the mice that were fed oral vancomycin. That did not absorb the bank. It's it's completely rally limited. Now, in contrast with that, we had a paper at AAP this past year that the same effect was true in mice that had TLR-4 deficiency, which is the receptor for endotoxin. If you knock that out, it also prevents them from getting bacterial or hepatic steatosis associated with intestinal resection. So I think there's a role for both gram positive and gram negative organisms, uh, so I think that's the, that's sort of the, the confusing sort of thing, but a lot of work, yeah, yeah, a lot of stuff in the OR or in the, uh, uh lab for us to sort out. Yeah, I'm glad you're doing it. You talked about the gut microbiome. What about, um, any work of regarding growth factors? We are, um, fortunate in that there has been a, uh, a new agent, um, that is, um, basically it's a GLP-2 analog. It's called GDX or to do glutide. And this is a growth factor that's been sort of recently described, and it's actually been subjected to randomized prospective clinical trials in adults and administration of this growth factor in adults has been demonstrated to wean the amount of TPN significantly that the adults with short gut syndrome required. It took away about 1 L or 2 per week of TPN that they required, and so. I think that really is opening the door for the consideration of growth factors. It's not yet approved for children in the United States. There are some trials that are going to start looking at this. I think some of the concerns with growth factor administration to children is potentially the malignancy risk because many of these growth factors promote proliferation, and the question always becomes then how long do you administer it, what's the best way to give it. Is there a way to target it just to the gut? And if you, if you did that, are you promoting potential neoplasia in the gut and those types of things? I think those are the big concerns. But to do glutide, GLP-2 analog has been the biggest one. We've been able to demonstrate, not just us, but other laboratories have been able to demonstrate that administration of several growth factors actually promote a better adaptation response, at least in animal studies. And these include things such as epidermal growth factor. Gail Bessner's demonstrated it with HB EGF. We've seen it with several of the interleukins. We've seen it with growth hormone, glutamine combinations in patients. The growth hormone glutamine is probably the most old growth factors that have been administered, and I think the results of that are primarily mixed. It hasn't been a Huge advance in the amount of TPN that you can wean and and it's expensive, so. We've been actually working with a uh um. Uh, Plant Science Center here at Danforth Plant Science Center at Washington University, and they've developed for us a transgenic soybean that overproduces EGF and so, uh, potentially we might have an EGF formulation, uh, like a formula, enteral tube feeding formulation that may promote adaptation with this growth factor in that, so. Hopefully more to come on that. Yeah, yeah. Still a lot of work though. Absolutely. So the last thing I want to ask you is, uh, if all of these interventions fail and the patient does seem to be not progressing and may be a candidate for intestinal transplantation, what do you tell the parents is the prognosis and the long term survival with that? Right now, the survival for small bowel transplant is about 50 to 60% at 5 years. So the early outcomes have been markedly improved. I think one year survivals now are above 70 to 80%, which is really very, very good. But, um, you know, the intestine itself is such an immunogenic organ. It's filled with all kinds of white cells and macrophages and all sorts of things that mount a huge graft versus host response to the recipient. And so you have to really put these patients on really industrial strength dosages of immunosuppression, which then makes them at higher risk for, you know, malignancies and and really reduces their ability to fight infections and so then it's sort of this balance between GVH versus rejection. And that's what really I think is the most difficult thing. So a lot to be learned in that regard. Yeah, I didn't, I didn't realize that the that the results were that poor. I mean, so, so given that touching on something you'd hit on before, when should we be considering that and calling our transplant surgeon for evaluation for a transplant? You know, I would say it's probably uh regionally dependent, um, you know, if you're in a community where intestine transplantation is not being performed and uh it would require the family driving to a center and being evaluated and everything, um, versus, you know, being part of your medical center already and having them just dropped down. I'd say if they're close by, probably. Early just to talk about it and so that the family can understand and you know it's sort of like prenatal consultations that it's good to sort of give them some of the facts and things while they're of sound mind and not having to make decisions under duress. I think that's always helpful. So probably at any point you start thinking about it is probably a reason to at least get them into the discussion and get, get them to meet. I, I would not go to transplant without, I think you want to try to do everything you can to avoid transplantation. I do think that with the role for intestinal lengthening procedures and the various sort of things that we can do for mitigating liver damage, the other thing that we didn't talk about yet, but a very important component is controlling the sepsis catheter sepsis, and I think Ethanol locks for central lines, I think, is a very important thing that has reduced significantly the number of episodes of sepsis in patients with short gut syndrome that have Broviac catheters and things. I think that's really been a nice improvement. Brad, do you do that prophylactically or only for treatment? We've been doing it prophylactically for kids that are on home TPN. OK, I just want to hit on this again one more time just to make sure I got it. What I'm hearing, what I've learned here is, you know, I have, for example, I have patients who are in their teens who are dependent on TPN, and I always wonder, you know, at what point do I say, It's OK to just exist on TPN or we should consider small bowel transplant, and that's always been tough for me and yeah, I think that's, I could see that is a very tough thing. I think if they're doing well. Um, and they're not jaundiced, um, doing it for the sake of getting them off of TPN may be a bit premature if they're, if they're otherwise doing well, and I say that because you're taking someone who's stable and doing fine and now putting them in a category of 50% 5 year survival. Exactly, and then that's the big thing I learned today from you is uh. That is really only if there's a real problem, last ditch resort. Yes, yes, that should be the last ditch, and I think lengthening procedures, doing all the things that we talked about ethanol locks, everything you can do from a rehabilitation standpoint is really key. And I think the other important thing is that this is a multidisciplinary effort. This is a team sport in taking care of these patients. So having pharmacists, having nutritionists, having surgeons, having GI doctors, really all together, ID folks, you know, radiology and everything, interventional radiology is really key for improved survival, and I think it's been demonstrated in many series Boston. Michigan, Texas, that these multidisciplinary teams really do improve the survival of these kids. So one person trying to do all of that is probably not going to be as good. I think there's always value in having many different disciplines weigh in. Well, uh, I think of all the points you made that was probably the most important is get your team involved, so, uh. Brad, I really appreciate you, uh, spending this, uh, this hour with us going over something that's not easy for, for a lot of us and has a lot of complexity to it and uh my pleasure. I hope I helped absolutely certainly helped me uh well thank you again and uh I hope you enjoy the rest of your day. We hope you enjoyed this episode of Stay Current in Pediatric Surgery. You can listen, watch, or read all content by downloading the Stay Current and Surgery app. Please send questions or comments to us attacurrent podcast@gmail.com. We'll see you next time.
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