Dr. Christopher Duggan and Dr. Biren P. Modi - New Frontiers in Intestinal Failure

So I think we'll get going. Um, I asked for not to, not to introduce me since everybody in the room, I think probably knows me. I don't know. Is this working? Thanks, Chris. Um, so, uh, Farro asked us, uh, to present, uh, an update on intestinal failure. So, the purpose of, of this hour is really just to give you some updates and highlight some things that you are probably hearing about when you take care of these patients up on the floor, um, some sort of newer things that we're doing, um, and then hopefully tease some future directions in, in the care of our intestinal failure patients. Um, I have no conflicts of interest. Uh, Chris is the site PI for one of the study drugs that you'll be hearing about from him, um, and otherwise, no other, uh, significant financial relationships related to this talk. Uh, these are our learning objectives, which is also similar to our outline. Basically, we're gonna review the natural history of, uh, pediatric intestinal failure, uh, in 2018, um, and try to, uh, frame that in terms of our main goal, which is achieving in autonomy for these children, getting them off IV nutrition, um, and some newer therapies that are helping to do that. Um, I'm gonna then go into some, uh, comorbidities that we're starting to see in these patients and, and focus in on a couple that we're interested in studying, uh, and are studying currently. And then go into some future topics, uh, uh, for study. So, uh, many, many of you in the room know Chris Duggan. He's gonna, um, talk to us about the first half of the, uh, of the outline here. Um, for those that don't know him, Chris is, uh, uh, the director of the Center for Nutrition here at Children's and the medical director of our short bowel program, the Center for Advanced Intestinal Rehabilitation. Um, he was trained at Hopkins and then here for his GI fellowship and has been on staff here ever since. Um, he's a full professor of pediatrics at HMS as well as, uh, having secondary. Um, uh, assignments at the HSPH in nutrition and in global health. Um, he obviously has an interest in studying, uh, intestinal failure, but also has an interest in studying the effects of nutrition and malnutrition in the third world, uh, and has been pretty much continuously funded for that for, for decades, I think. Um, uh, yeah. And, uh, perhaps most notably, something that we're really proud of is that Chris just last month was named the editor in chief of the American Journal of Clinical Nutrition. Uh, which is the most widely circulated journal of nutrition in the world as far as I understand. Uh, so congratulations and welcome. Um, Thank you, uh, Baron, for the kind introduction and thanks always, uh, uh, for the Department of Surgery for hosting us. I was, uh, thinking about the first time that I lectured in this, uh, hall. It was about 25 years ago. I was a young enthusiastic, uh, faculty member, and, uh, Danny London and I spoke about medical surgical therapies for short bowel syndrome. And, uh, during, after the Lecture, uh, Doctor Hendron, Doctor Murray were sitting in the front row, and they had some laudatory things to talk about our, our, our talk, which was nice, but I'd, I actually embarrassingly didn't know who Dr. Murray was. And after the lecture, Steve Fishman, who at that time was also a young and enthusiastic faculty member, said, hey, it's a, it's a nice day when a Nobel Prize winner thinks you're doing good work. Uh, so, um, I think we're on to something. I think we're doing some good work and it's a pleasure to speak at this, uh, forum with, with Bern. Um, as he, as he mentioned, uh, uh, the first kind of section of the talk will be talking about the, what we know about the natural history of intestinal failure. Um, and so, before we look at the future, it's important to, I think, to review where we have been in the past. And Tom and I wrote this review article to the New England Journal of Medicine a couple of years ago, and in it, we put together a really, um, great table. We thought it was great. The editors. Though it should live in the supplementary, uh, part of the journal. So you had to go online to see this table. Uh, but it's a nice review of kind of the natural history of survival, purely just looking at mortality rates in children with intestinal failure. Um, before, um, the home parenteral nutrition and even inpatient parenteral nutrition, uh, became the mainstay of therapy for children. Short bowel syndrome. This is what the epidemiology of the of shortcut looked like. This was from uh Doug Wilmore's 1972 paper in which he reviewed um 50 cases in the English medical literature, all of which had been presented almost as single case reports. And he pointed out that on the Y axis you have, uh, residual bowel length. And he has two groups of children, those for whom ileocecal valve was intact and those for whom ileocecal valve was resected. And I'll just call to your attention the fact that at that point in the early 1950s, 1960s, and early 1970s, if your residual small bowel length was 40 centimeters or less, you had a 100% mortality rate. Um, so this degree of Linking, uh, anatomy with outcome was really obvious when you're talking about short bowel patients. Uh, but the, the good news is that from that time, from the 1970s to 1980s, there was a progressive increase in, um, survival rates. So this was Wilmore's case series of 50 patients published in 1972. Um, in, uh, 19, um. 99, a medical student, David Andorsky, reviewed children's hospital experience and defining parental defining intestinal failure as parenteral nutrition use greater than 90 days and limiting our study to infants. Uh, we had a 30% mortality rate, which is really, uh, quite striking, uh, certainly an improvement from the 1970s. As the decades went on, uh, subsequent centers published their results. Uh, Dan Teitelbaum's group published a 73% survival rate. Uh. Ending in 2003, um, Biron Modi, when he's a research fellow, updated our, our survival rate and showed that it had an increase to 89%, really with no significant changes except for the introduction of our multidisciplinary team. And then, um, the, the, the largest case series is the so-called Pediatric Intestinal failure Consortium, a case series of nearly 300 children, and that's one I'll harken back to because that's one of the largest data sets that's been involved in. Children with infants with intestinal failure, and as you can see, the mortality rate was still stuck at about 26%. Um, Brenna Fullerton updated our care data, uh, more recently and found a greater than 95% survival rate at, at 5 years, which is really, um, as good as it gets. So I will say that even in my, uh, getting longer but still relatively short career, there's been a substantial improvement in survival rates in these children, which has really been, uh, quite, quite heartwarming. Getting back to the, uh, the PIFCON data set, um, this is a, a cohort of about 14 different academic medical centers, some of which offer intestinal transplantation, some of which emphasize intestinal rehabilitation, and essentially one of the demographic points that they, they made was the fact that many different Uh, gastrointestinal diagnoses lead to the diagnosis of short bowel syndrome. They used the diagnosis of short bowel syndrome as dependence on parenteral nutrition for 60 days, somewhat more conservative measure than 90 days, but I would say that these data generally reflect our, uh, our demographic splits in our care patients. I think one of the papers, one of the points this paper made, however, is that Nearly more than 25% of these patients have multiple single diagnoses. So, uh, obviously, it's quite well known that children with gastroschisis can have complications with intestinal atresias. Um, we also know that children with intestinal atresias can have ischemic bowel disease as well. So it really gets, becomes, uh, very important to understand the underlying physiology and pathophysiology of malabsorption in these children. And my point to the students and residents who rotate through us is that under the hood, it looks very different. Outside, uh, the patients, they look very much the same. So they're young infants, they often have a central line in place, they often have a gastrostomy too, but that really masks the interindividual complexity that occurs, um, between patients. That has a large effect on outcomes, of course. One piece of data that really we've seen, uh, clinically has been the rising prevalence of gastroschisis in our country. So this is a report from the CDC, uh, which showed several things. Number one, the trends was substantially higher. There's been about a 20% increase in the prevalence of infants born with gastroschisis throughout many different states in which this data is collected. The other The interesting thing is that there's a huge age disparity. So maternal young maternal age is a very high risk factor for developing, for delivering a child with gastroschisis. You can see the top curve is mothers who are less than 20 years, um, bottom curves are, are older women. So, this is really a big conundrum that needs to be figured out, the specific etiology of gastroschisis and how we can take care of these infants, uh, better. But the main outcomes of the PIFCON data set were as follows. Um, the, the data was collected between the years of children born between the years 2000 and 2004, so you can quarrel that it's a little bit outdated. But if you look at the cumulative incidence of three important outcomes, number one being enteral autonomy, number two being death, and number three being transplantation, you can see a couple points. Number one is that enteral autonomy, the rate at which children are weaned from parental nutrition. Really, uh, increases very quickly in the first year of life, but it doesn't end as some commentators would suggest. Uh, enteral autonomy can increase substantially over years 23, and even 4 and 5. So, this was a really important take-home message because it pointed out that we shouldn't be in a rush to transplant children who don't meet transplant criteria, that we should do all we can to improve rates of ventral autonomy. The number, the 2nd An important factor is that death is not an uncommon outcome. I mentioned that 73% was the overall survival rate, um, so you can see that back in 14 years ago, uh, mortality rates were still hovering at the 25% rate. Now this includes death both pre and post-transplantation, so it's a little bit tricky to know whether children would have done better with earlier transplantation or later transplantation, but it's as a benchmark, it's a helpful national cut point. Uh, Mark Pooter, Erica Fallon, Kathy Gurra, Paul Mitchell, and others contributed to, uh, another important study in which they evaluated the natural history of children born at our, at our institution. These were 63 infants born, uh, in a more recent time period than the PIFCON data set. 63% achieved full enteral autonomy. There were still about 20% who underwent intestinal transplantation or died. Um, and interestingly, independent factors for achieving natural autonomy, not surprisingly, were residual small bowel length, were achieving all follow-up at one center, namely Boston Children's Hospital, and not undergoing intestinal lengthening procedure. And, um, the graphics in this paper are really quite well done. One graph that I thought was very striking was the cumulative incidence of weaning from parenteral nutrition. Uh, and you can see that there was a various cut point. If you use 50 centimeters as the residual small bowel length, you can see a, a, a dichotomy in that children with greater than 50 centimeters of residual small bowel length were much more likely to wean in the first two years after resection than those who had less than 50 centimeters of residual small bowel length. Another graph that was quite nice evaluated the probability of weaning depending on the residual small bowel length. This Y axis shows the number of patients. Who were in each category. This Y axis shows what percentage based on a logistic regression curve would be weaned from parenteral nutrition, and this X axis shows the small intestinal length that's residual. And you can see that the 50% cut point, the point at which you would flip a coin to predict whether someone comes off parenteral nutrition or not, uh, at this point comes. Between 10 and 20 centimeters of small intestine. And keeping that number in, in your, uh, brain is important because if you compare the Fallon data from Children's Hospital in 2014 with the Andorski data published just 13 years earlier, you can see that there's a substantial shift to the left, that when we compared our rates of weaning and our chances A weaning with residual bowel length. In the earlier case series, the residual bowel length was about 30 to 40 centimeters, at which we would tell a parent, well, your child is likely or not to come off parental nutrition, whereas the, the shift of the curve to the left has really improved, shown substantially improved outcomes in our ability to achieve ventral autonomy at very short residual bowel lengths. And I think that's important for us as a community to learn and appreciate, and I don't think the national community has appreciated as much as we would like. And I say this based on a survey that Patrick Javit and colleagues in Seattle recently published, and they essentially surveyed pediatric surgeons and neonatologists who were largely part of academic hospitals. 80% or more and who um largely were either at hospitals that were training hospitals or who had intestinal rehabilitation programs at that hospital. So you would think that this would be the, uh, these would be the survey respondents who would have an updated version of how aggressive medical and surgical therapy. be pursued in children with short bowel syndrome. So this is sort of a complicated slide, but they gave the respondents several case scenarios, including children with prematurity, 25 weeks gestational age, with neck or with neck and a variety of morbidities, a 32 week gestational age infant with neck alone, or a full-term infant with volvulus. And then they said, the residual bowel length is as small to read, less than 30 centimeters of residual, less than 20 centimeters, less than 10 centimeters. And then they would ask, would you, would you, uh, never recommend comfort care? In other words, would you be aggressive in your medical and surgical therapy? And so, it's one of these glass half full, half empty approaches. So 44% of uh Respondents, these are academic neonatologists and surgeons, would recommend comfort care if a child with 25 weeks gestational age and substantial neck presented to them with less than 20 centimeters of bowel. So basically, they would say, you know, there's really nothing we should do about these children, and I think that's really selling them short. Um, and if you look at the Data, only a third of surgeons and only 20% of neonatologists would, would never recommend comfort care. So more than half, more than three quarters of academic practitioners would back away from carrying a child with 25 weeks gestational age and neck only with no other morbidities. I think that's really not the best attitude. Similarly, if you ask them what would they do with a full-term infant in volvulus, half of the surgeons said they would never recommend comfort care, so the implication is the other half would say we should back off on a full-term infant with uh intestinal volvulus. And about 1/3, 2/3 of the neonatologists, uh, said they might recommend it, recommend, uh, comfort care only. So I think that those attitudes are really uh behind the time and really don't, are not supported by the current literature with respect to survival, and as Baron will talk about morbidity and quality of life. So, um, the route to enteral autonomy, I've already pointed out is can be a long one, but the good news is we have a lot of different techniques in which we can achieve that, and they are generally broken down in terms of nutrition, medical, or surgical. We're not gonna talk about surgical today, but I will talk about nutritional and medical therapies. And when one thinks about the process of intestinal adaptation, It's important to realize that animal studies and human studies dating back more than 50 years have identified this compensatory practice that process that occurs normally after extensive bowel resection. And this idea is that it includes both structural structural and functional changes to the intestine to improve nutrient and fluid absorption. Kelly Tappendon has put this out uh in a nice review recently in JP in which she talks about structural changes of the bowel, hyperplasia, angiogenesis, bowel dilatation, elongation, as well as functional measures in which epithelial cells act more efficiently to improve absorption, to differentiate more quickly, and to reduce transit time. So, we think of achieving enteral autonomy as basically achieving the holy grail. Coming off of parenteral nutrition obviously improves these children's uh quality of life as well as risk factors for sepsis. And when we took the PIFCON data set and analyzed what the predictors were of achieving enteral autonomy, and we did this with a multivariate regression analysis, We found a number of important findings. Number one, children with necrotizing enterocolitis were more than twice as likely to wean from parenteral nutrition over time than compared to children without neck, and this presumably relates to the fact that as premature infants, they are further down on the intestinal rehabilitation curve and have more capacity to regrow and test in both length and mucosal surface area. Interestingly, if you were cared for at a site that did not offer intestinal transplantation, you were nearly 3 times more likely to wean from parenteral nutrition than not. And this probably speaks to cultural norms that might influence practitioners' decisions about whether they should push for rehabilitation or push for transplantation. If you had a preserved ileocecal valve, you were nearly 3 times more likely to come off parental nutrition, uh, than to stay on parental nutrition. And if you had a residual bowel length, obviously higher residual bowel lengths are also related to improved outcomes in this large cohort. So, this is an interesting component of where we take kids from on depending on parental nutrition to coming off of parental nutrition. Um, uh, Brad Warner, Bram Raphael, and colleagues, um, put together a position statement that basically summarized the literature with respect to the impact of intestinal rehabilitation sites, and they really pointed out that optimal outcomes, not surprisingly, are achieved when children are taken care of at centers with a large volume and a large experience. Uh, my colleague Allie Carey published a poster at the Pittsburgh Intestinal Rehabilitation Program this past fall, where she highlighted the fact that some children are unable to wean appropriately as outpatients and need to be admitted to the hospital. And we see this often when, when, uh, advances in natural nutrition are difficult to be, uh, tolerated as an outpatient. Sometimes inpatient admission is really important to do. Um, there are a large variety of studies that highlight different components of nutritional therapy that might have an impact on achieving enteral autonomy, and I don't really have time to go through all of them, but I do want to concentrate on the second one, which is the root of enteral nutrition. And I do that because I think it Justifies a lot of what we do up on the floors and as the outpatient side of things. I'm gonna skip this slide just in the interest of uh time. The, um, Olivier Goulet is a pediatric gastroenterologist in Paris, and he has a very strong feeling that oral nutrition is really the best route to achieve enteral nutrition. Um, but he understands that it's a matter of debate without a lot of hard data. Uh, he cites a group of experts saying that they should promote as much oral feeding as possible, allowing the maintenance of sucking and swallowing with the interest and enjoyment associated with eating. This is a typical French approach that we should concentrate on the enjoyment of life and meals. Um, and, and we're all for that too, and in fact, we have a Speech and language pathologist who's an integral part of our team, but I do believe that oral feeds are not necessarily the best approach, uh, to achieving internal autonomy, that I think we should moderate that approach. And, um, this is a study in adults with short bowel syndrome that essentially explains why our approach is what it is with respect to a tube and oral feeding. So this is. A small study, this is 15 subjects. These are all adults, so the reference, the relevance to pediatrics might be a bit stretching it, um, but they had a variety of different residual small bowel lengths. Um, they had remaining colon that varied from 0 to 86%, and they had these underlying, uh, diagnoses of intestinal failure, which are obviously somewhat different than what we might see in infancy. But the study was a crossover study in which they were, they uh took chil took adults and either gave them exclusive continuous tube feeds for 24 hours, or oral feeding, ad-lib oral feeding for 24 hours, or a combination approach in which oral feeds were uh provided during the day and tube feedings were provided at night. And the graphical representation of the data in this paper are as follows. Uh, 1, there was a net zero of absorption versus excretion of nutrients. The total intake was measured in the gray and light gray bars, and the total output was in the black bar. So, the net absorption was measured in the gray bar, i.e., the difference between intake and output. And among the three groups, there was a consistent finding in that Continuous enteral tube feeds, 24 hours of continuous tube feeds, uh, on the far left. was associated with some improvement in absorption compared to oral feeds, but the the best approach was really a combination. So, if the gray bar is net absorption, you can see that this really had the best approach in terms of increasing intake, increasing absorption, and not really increasing output substantially. Um, so this is the approach, and if you measure the outcome in terms of energy absorption, if you measure it in terms of lipid absorption, or if in terms of protein absorption, the same approach, the same findings are seen. Um, so this is essentially why we commonly employ an approach that uses both modalities, continuous feeding at night and bolus feedings during the day. It takes advantage of the enterocytes absorptive capacity during the during the night, um, and the oral bolus feeding has a lot of physiologic uh implications as well. I don't think um it it matters. We've published kind of our feeding advancement protocol. I'm not sure it matters what feeding advancement protocol you have as long as you have a protocol, so you can stick with it. This is a before and after study from Johns Hopkins, where they compared two cohorts of infants, both before and after feeding guidelines were initiated in 2013. Um, and, uh, in terms In terms of its impact on intestinal failure, liver disease, the introduction of a feeding protocol reduced intestinal failure associated liver disease by substantial amounts, as well as improved rates of achieving enteral nutrition and weaning from parenteral nutrition. So I do believe that we've come a long way in terms of recognizing that objective measures of feeding intolerance should be made on the wards. In terms of medical therapies for achieving enteral autonomy, this is really an exciting and new area. The intestinal enteroendocrine cell secretes a hormone called proglucagon, and intestinal enzymes digest this long enzyme this long protein into a variety of different uh smaller uh proteins, and GLP-2 has long been known to be an important component of intestinal trophism. And why do we know that? If you take GLP-2, if you take newborn pigs and feed them newborn pig milk, they actually have very nice developed villi and crypts. If you take the same newborn pig and don't provide them any enteral nutrition, but provide them with parenteral nutrition, you have a substantial degree of mucosal. Atrophy with a very blunted villi and shortened crypts. Uh, but if you give the same animal model nothing by mouth or parenteral nutrition and provide an exogenous hormone in high concentrations, you can see a very substantial increase in villi, and I should point out an increased absorptive capacity. Um, I've been, um, at this group to develop a pediatric trial for nearly decades, and I'm happy to say that we finally have some preliminary data. The timeline for the trials of tadulatide, uh, really has been quite delayed, and unfortunately, this is kind of the classic problem that happens in pediatric medicine development, is that even if you have a drug that would be better used in children, because children with intestinal failure make up a large component of children of subjects nationwide, uh, it's easy. to study adults. And so this happened uh here with this drug that even though we had data showing very high mortality rates in the 1990s, the first studies were done in adults. We made decades of attempts to start the drug trials in children, but it really wasn't until 2013 that a multi-site trial in children was entertained. And as you can see, the sample size was really quite substantially less. We were only studying the first study in 23 children across several different sites. Um, this is an example of the adult literature. If you look at the volume of parental nutrition used per week, if you look at two different, uh, doses of the drug, which is also called Gatex, you can see essentially regardless of the dose of the drug, there's a dose dependent and time dependent effect of weaning from parenteral nutrition with the addition of Gatex. I should say that Gatex is a GLP-2 analog whose enzyme, whose amino acids have changed to resist peptidase breakdown, so its half-life is much longer than GLP-2. Um, if you look at the data for children, a shorter underpowered study was really done initially to prove safety. A further follow-up study was done and it does seem to show efficacy. This was data presented uh by Shire at the September uh intestinal failure meeting in Pittsburgh, the current standard of care was provided to one group of patients, but 2 groups were randomized to receive 2 doses of Gatex, and this was an open label allocation, uh, study. This was, uh, people who elected to be in the treatment arm versus people who elected to be in the standard of care arm. Their primary outcome was a 20% reduction in parental support after 24 weeks, and 54 and 69% of participants in the active treatment group achieved that outcome, uh, but only 11% achieved it in the standard of care group. Uh. 2 and 3 patients respectively achieved dental autonomy, weaned completely from parental nutrition in the treatment groups, but none did in the standard of care. So these data are being brought to the FDA and the company is optimistic that they'll have licensure of this drug sometime in the spring. Um, I think I've done something in 28 minutes, so Bar and, let me turn it over to you to talk about morbidities. Thanks, Chris. So, um, yeah, as Chris highlighted, you know, one of the things that's happened over the last couple of decades is that we've shifted from talking about survival to now really talking about comorbidities. And, um, and that's become important, especially in light of some of that data that, uh, that Chris showed from Patrick's group, where there really are discrepant, um, ideas about what to do with children with short bowel syndrome, um, specifically in the extremes of short bowel syndrome. Um, part of it is, I think that, uh, some of the practitioners that are responsible for the early care of these children, especially in the neonatology, uh, world, don't necessarily get the privilege of taking care of them long term and see how they do years down the road. Um, so, I actually make it a point in clinic of often trying to ask our parents to take their kids back up to the NICU, um, to, to show them what their, uh, children look like 345 years down the road, where they've gone from a child that was on the oscillator, um. You know, Mark and I were talking about a child this morning who came up from another institution with a diagnosis of neck totalis, was on the oscillator, was, uh, written off at the other hospital, and if it wasn't for the mother, uh, demanding a transfer here, um, probably would have been, uh, made comfort care only. And after transfer here, I think, I think it was Terry. It was during my fellowship that took the child to the OR, um, had 55 centimeters of bowel that were, uh, that were found, put back together, and the kid now is in our clinic on a backpack for, uh, G tube nutrition, but is off PM. Um, and the NICU doesn't get to see that patient very often. Um, unfortunately, some of our colleagues in surgery also don't get to see that, that patient often. And so, um, part of what I think our responsibility is, as, as people that are in the world of intestinal failure is to educate our, our colleagues about that. That doesn't mean that all children are, uh, doing great, and it also doesn't mean that their, uh, their life is completely, uh, complication-free. And I think it's upon us to To study what those comorbidities are that we're trying to, that we're starting to see in these children long term. As they, um, as they are, are now surviving more. So, this is just a list of some of the comorbidities that we're seeing in children and the organ systems that are involved. Chris obviously talked about PN dependence, um, uh, uh, just, uh, a few minutes ago, and I'll try to just highlight some of the other ones and focus in on, on liver health and, um, some studies we're doing to look at that as well as quality of life. Um, so just to flash through some of these surg, uh, the burden of disease is something we're really recognizing. Uh, this is a study that Ferraz did when he was with us in our, um, in our group and, uh, looking at surgical burden, um, using the same cohort of patients that Chris mentioned in the pediatric intestinal failure consortium. Um, and so, uh, essentially looking at almost 300 patients. Um, remarkably, in that 3-year follow-up, the average 3-year follow-up they had, those children had an average of almost 5 abdominal operations. And these weren't simple operations. They were significant. They were, uh, bowel resections and ex-lapse and, uh, uh, operations for adhesive bowel disease, uh, funduplications, etc. And so, uh, a significant burden of disease that imparts, uh, a lot of, um, uh, burden on the patients, as well as their families to be in the hospital and to recover from these. Oh boy. All right. That didn't go well. That's my very well organized desktop, Doctor Chamber. Sorry, bear with me. Yeah, just to review what Chris said. I can, uh, summarize in 10 seconds. She's a lot of slides, Chris. All right. So, the other, um, really, um, fascinating thing that we're really starting to get into is, is neurodevelopment. Um, a lot of our patients are premature infants, as you saw from Chris's data, about a third of our patients are, uh, patients with necrotizing enterocolitis. Uh, it's obviously in the premature category. Um, and it's interesting to see what's going on with their neurodevelopment, um, at a, uh, at a time interval away from their, uh, neonatal period. Um, that maybe is over and above what we would expect for their simple, simple, their prematurity. And so, uh, these are a couple of studies that were done for the Neonatal Research Network out of the NICHD, um, looking at, uh, neurodevelopmental, um, uh, Uh, impact in survivors. And you can see that, um, in survivors, necrotizing enterocolitis, as compared to age and, uh, and, uh, prematurity matched controls has a significant, um, increase in, in having, um, decreased neurodevelopmental outcomes. In survivors. So, uh, the top paper is, uh, looking at sort of the whole network, uh, and had about, um, I believe like, uh, 9500 patients, only, um, 450 in, in each group, and, uh, and you can see that they had an odds ratio of, uh, 2, basically doubling their risk of having neurodevelopment impairment that was defined as, uh, uh, low Bailey developmental scores or cerebral palsy, blindness, deafness, etc. Um, this is, oh man, OK, it's a bad thing. Sorry. Chris, I don't know if this is a crystal here. And we'll do this without the Presentation view. It's just a memory issue with my computer, or is this? It's just I just do this without. I can just do this without putting a presentation view, yeah. OK. OK, we'll give it another go. Uh, so these are data that, uh, Bretta Fullerton, um, looked at with us, uh, along with the Vermont Oxford Network, um, and looking at basically, uh, somewhere around 9000 ELBW, so less than 1 kg birth weight and about 450 patients that were medical and surgical neck. Counter to the, um, to this, uh, study from the Neonatal Research Network, which noted no difference between medical neck, surgical neck, and, uh, and SIP, our data actually, um, in a slightly larger cohort that encompassed perhaps more of the, um, the nation's ELBW patients, um, demonstrate actually an incremental increase in neurodevelopmental impairment based on the severity of the disease. So, Um, you see the, the black bar is 17%, which would be sort of our baseline children that were the same ELBW, um, but did not have any type of neck, as opposed to those in the slightly, uh, lighter shade of 24% with medical neck alone, and those with surgical neck, which had a nearly 40% risk of neurodevelopmental impairment at 18 to 24 months. So, significant, uh, problem, uh, still being teased out, I think we'll, we'll hopefully get some more longer term data in terms of five-year follow-up data to really be able to look at what the, what these children are doing as they enter, enter the school age period. Um, metabolic and bone disease. So, uh, we've noticed that children with, uh, intestinal failure long term start developing problems with their kidneys, start developing significant difficulties with bone mineral density. Um, the top paper there from Kozar and, and Wales in Toronto demonstrated that patients with, uh, intestinal failure have nearly a, uh, 50%, I think it was like 44% risk of having abnormalities in their kidneys on ultrasound. So, that would be either echogenicity of the, uh, cortex or actual nephrocalcinosis. Um, and this was associated with obviously higher excretion of calcium that likely has to do with, um, management of calcium, um, related to receiving a bulk of their, their, uh, calcium intake via the IV route. And in fact, more PN exposure was associated with a risk of having renal abnormalities on ultrasound. Um, the other two studies are from our group looking at metabolic bone disease. Uh, so, Farage showed that, in fact, the risk of metabolic bone disease is quite high in these patients. Um, about 40% had vitamin D deficiency. Uh, nearly a third had actual, uh, what we defined as, uh, metabolic bone disease, uh, based on a bone mineral density less than -2 of standard deviation. Uh, away from the norm based on a DEXA scan. Um, Sam, then, uh, just recently, Sam Hann, who's in our group now, uh, just looked at these data, uh, longer term and looking over serial DEXA scans, uh, and demonstrated that, uh, a risk of, um, decreasing bone mineral density over time is associated with low vitamin D status. Uh, and in fact, the pathologic fractures are related, uh, interestingly enough, to an elevated parathyroid hormone level, um, despite, uh, a lack of true hyperparathyroidism as far as we can tell. So, you know, these, these, uh, few comorbidities sort of highlight a shifting focus, as I mentioned, uh, as mortality has steadily fallen. However, we really need to understand these comorbidities more so we can try to mitigate, uh, their risks to the children. And I wanna sort of focus in on a couple. One is, um, the study of liver health and understanding liver health a little more long term, and the other is gonna be quality of life, which really ties in a lot of the comorbidities as well as the, uh, the move towards enteral nutrition that, that Chris highlighted. So, um, this group knows, uh, pretty well what intestinal failure associated with liver disease is. There really are no consensus definitions. As you know, we use a definition that really is a, uh, a marker of liver injury, which is cholestasis, um, and typically define a direct bilirubin over 2 mg per deciliter as a, uh, as true intestinal failure associated with liver disease. There are a lot of etiologies, um, recent data and, and all of Mark's work have really focused on the lipid source and parenteral nutrition. Um, but there are other, uh, uh, sources as well. There are other components of parenteral nutrition that seem to be harmful both in the, uh, their actual components as well as the way that they're delivered. Uh, but there is clearly an interplay with the microbiome, with the anatomy in terms of, uh, altered, uh, enterohepatic circulation. Um, obviously, we know the premature liver is more prone to liver disease, and then inflammation and recurrent sepsis clearly, uh, go on to harm the liver. Uh, and you've seen that up on the floors with these kids who come in with clapsies or that have clamsies during their neonatal period, uh, and the effects that that has on their, um, on their liver function. The classic, of course, is a lack of enteral nutrition. Um, providing calories through the enteral route clearly has a salubrious effect on the, uh, liver. These are data that, uh, that Patrick showed when he was here demonstrating sort of a curve of, uh, resolution of cholestasis once the child achieves full enteral nutrition. You'll see a very similar slide if you were to look at the effects of Omegaveen. Um, institution, uh, provided, uh, uh, providing sort of a, uh, 100% fish oil-based lipid source and about 2 to 3 month, uh, time course to resolution of cholestasis. So why does it matter? Well, um, It's clearly a survival issue. Uh, Children with cholestasis and as a marker of liver disease have a significantly decreased survival expectation, but also, uh, long term, 25% of these patients go on to develop end-stage liver disease. It's the leading indication for transplantation in our patient population and, uh, historically it has been the greatest contributor to morbidity and mortality. It likely also significantly decreases quality of life, uh, because of the complexity of care that's associated with, uh, with having liver disease. Um Why we need to monitor it and what, what I'm sort of getting to is, is a newer way of looking at liver disease, um, is that we know that there, the, the time course is long and yet, uh, the liver sustains ongoing injury. Um, while a lot of the newer ways of treating liver disease or at least, um, masking it perhaps, um, show a resolution of the lab markers that we have, what we believe, what we have seen is that there is still an ongoing continuation of, uh, of liver disease that can progress, potentially long term to, uh, to, uh, eventual liver failure. And One of the goals of, of our monitoring is to, um, is to evaluate for complications. We want to see that there's development of cirrhosis and the complications thereof, such as portal hypertension and liver failure. Um, obviously, you know, the things we look at in terms of looking for those, but understanding the progress of liver disease allows us to inform the timing and referral for transplantation. Um, and can also help us catch, um, catch the problem before it happens or before further deterioration occurs and potentially allow us to escalate therapy in terms of being more aggressive about weaning parenteral nutrition, etc. So our ideal tests are um gonna have a high sensitivity so we can pick up that deterioration, but also we're gonna be minimally invasive uh and not uh subject the children to additional risk as we have serial monitoring. occurring over there, uh, pro and obviously cheap and, uh, and be reliable in our patient population. That's something I'll touch on in a few minutes and we want them to be accurate and precise. I want them to show, uh, liver disease when it's happening, shows uh worsening of it when it happens, and also, um, be reliable to continuously do that. There's not a great, uh, consensus in terms of what the best options are. Um, we obviously use direct hyperbilirubinemia alone as a marker, but there are other scores out there and there, uh, are sort of, um, uh, other options. Liver biopsy, I'll touch on. The APRI is something that's been touted, but we have not really found to be clinically very useful. Uh, it's an index looking at the AST and the, uh, platelets. Um, and there's significant variability in the way that these actually pick up liver disease. So, if you take one cohort of patients in this group did this, uh, and apply different, uh, uh, definitions of liver disease to them, um, the range of actually finding liver disease in the same cohort, the same patients ranges from 5 to 40%. So, clearly, the definitions matter and the, uh, actual testing matters. I've highlighted histopathology here and in that color on purpose because histopathology is not really a gold standard, but it's more a, uh, a bronze standard, uh, in the sense that, um, and I'll touch on this in a few minutes, uh, that it doesn't perfectly pick up liver disease. I've highlighted in blue the methionine breath tests which were developed, uh, which Tom has been working on. Um, here and is, is still being developed and hopefully will become clinically useful as an actual marker of, uh, true, uh, hepatocyte function. It actually directly measures, um, uh, mitochondrial function within the liver. Uh, and then elastography is what I'm gonna touch on here, uh, A newer, um, uh, testing modality, uh, that is used in other arenas of liver disease, but not in intestinal failure yet. You, uh, you all may have heard of it as FibroScan. Um, that's the brand name of the, uh, of the testing mechanism that we use that uses listography. So, liver biopsy, the fellows know this needle well. Um, it, uh, is, uh, you know, 14 gauge core needle biopsy. The problem with liver biopsy is that it, um, it's great at looking at the piece of liver that you take out, right? Uh, and we use a fibrosis staging, uh, uh, system called Mavvir that looks at, uh, basically a totally normal, all the way to true cirrhosis with nodular formation and everything in between. You know, um, functionally, in our world, we consider the 1st 4 to be reversible. Uh, but once we, uh, see cirrhosis, we don't really consider that to be reversible, and then it's about seeing what the long-term implications of that cirrhosis are. The difficulty with liver biopsy is it's invasive. It requires an operation or a procedure, uh, in IR. There's clearly a complication risk that's associated with it, um, and it doesn't really provide us functional data, uh, but just looks at the actual architecture and the, and the histopathology. It also samples somewhere um around 15,000 to 1/10,000 of the liver. And we know the fibrosis in the liver is, is not diffuse but it's patchy and focal and so we could easily miss, um, uh, bad fibrosis even though it's uh developing elsewhere in the liver. Elastography is, uh, basically an ultrasound machine or it looks like an ultrasound machine. It shoots a shock wave at the liver. It measures the rate of speed at which that shock wave comes back and it converts that into a liver stiffness measurement that's measured in kilopascals. It's not invasive. There's really no risk to the patient. It's done the same way an ultrasound does. It takes seconds, um, and it's been validated in other hepatic injury states. So, um, this is a nomogram that the hepatologist in the adult world, as well as our pediatric hepatologists use. To look at um what the liver stiffness score, which is down here on the bottom, um, how that correlates to uh the level of injury, level of fibrosis within the liver based on that uh that histogram. So, uh, for example, if you have a Kilopascal of 9 on the on the uh elastography and you have hepatitis C, then you see that you're in the orange and you have somewhere on F2 to F3 liver fibrosis. Um, uh, conversely, if it's, uh, uh, an alcoholic liver disease, that actually correlates with less fibrosis, uh, in the liver. We don't have something like this for pediatric intestinal failure because we haven't really looked at it. Uh, and that's really what we're interested in doing. Uh, the group in, uh, uh, Columbus has started to look at this using a different modality of elastography called, um, called ARFI, uh, and in their initial, uh, study looked at 11 patients with matched liver biopsies and demonstrated that they were able to discriminate mild from moderate to severe fibrosis, uh, with an area under the curve of 0.833. Um, our data here on a slightly larger cohort again demonstrated discrimination using transient ostography or the fiber scan. Uh, you can see from this box plot that there's a, a nice separation of patients between the mild and the moderate to severe, uh, fibrosis. And if you look at the area under the curve, um, this performs slightly better, essentially the same as the, um, ARFI modality used in Columbus. Um, and we, uh, noted a cutoff point if we use 6 kilopascals as giving us a sensitivity of 80% and the specificity of 100% of moderate to severe fibrosis. If you look at this elastogram though, and then look at that number of 6 kilopascales, you can see that in pretty much all adult states, that would suggest that the patient has zero or nearly zero fibrosis. So, really a demonstration that our patient population is different and then we need to work on creating a, a nomogram like this for us, and that's some future work that we're gonna be doing. To shift focus really quickly to quality of life. Um, as I mentioned, this really is something that ties together all of the comorbidities that these patients experience over the first few, few years of their life. And so it's become an area of, uh, of focus for us. And we're just starting to analyze, um, health-related quality of life as it applies to our patients. Um, this is a group in Finland which has the, uh, benefit of having a national patient cohort. Uh, so they had a built-in, uh, control, uh, and so they compared their patients with intestinal failure in their one intestinal failure, um, center in the, uh, in the country to 400 control patients throughout the country that were, uh, obviously matched to the patients, uh, to the, uh, uh, disease patients. And they demonstrated, although not striking, that there was a significantly lower, um, Quality of life in, in, uh, intestinal failure patients compared to their national controls, um, both in patient self-reporting as well in proxy as in proxy. Um, this, uh, group used something called the PESQL, which is a, uh, uh, commercially and sort of academically, uh, available, uh, validated scoring system, uh, or survey instrument that we're also using here. Uh, it was also used by Patrick's group in Seattle a few years ago. Um, both of these groups compared, uh, basically, um, intestinal failure patients here and, and Patrick's group is 23 patients, um, to, uh, sort of, um, Published norms or to control. So, the Finland group used their, uh, national database controls here. Uh, Patrick used, uh, published norms from the group that, uh, sort of validated the PSQL and you can see a significantly lower, um, quality of life in basically all domains and all age groups, uh, for patients with intestinal failure. One thing that Patrick's group did was survey the patient's parents about whether they thought the PDSQL was useful. And, and an important piece that came out of that was that the majority of the patient's parent sets actually stated that the, the PESQL was too generic. It didn't really um touch on On the kinds of things that affected their quality of life, um, and, uh, specifically things that were disease-specific like, uh, diarrhea, like the number of times a child goes to the bowel, you know, goes to the bathroom during school, uh, the number of times they have to get up to change the child's diaper uh in the middle of the night. Um, stress about devices that, as Chris showed you that picture of the, the infant with intestinal failure, there's a lot of, uh, tubes that are attached to these children. Um, and so, one of the things we did when we started developing our, um, quality of life assessment here was to add a sort of, uh, well, unvalidated, but, uh, an investigator-created instrument that we, uh, uh, developed with the help of, um, the clinical trials group, uh, looking at, um, things that we thought would be important for our patients. We also added the PHQLGI module, which is also uh academically available uh for free, thankfully, um, to our patients. We've, we've been now controlling, continuously enrolling patients for about 2 years. We're up to 53 patients that have agreed to, to do the assessment with us and we're really just now looking at this data, um, and now analyzing it to prepare it for publication. So, um, just to share some of that data with you that are unpublished, but, um, one of the things we did was similar to the other groups compared to the, um, to the sort of published norms. And we, we compared to both the healthy patient as well as to patients with chronic GI diseases over on the right. And you can see that we're starting to see some signals. Obviously, our numbers are somewhat limited, and I'll, I'll get to that in a second. Um, in order to really compare to a, uh, to a big group and pick up subtle differences in quality of life within these different domains of life. Um, but some of the things that we're really starting to see that are that, uh, the children's emotional function, as well as their, um, school functions, really how they get along with peers, how they, um, function in school, uh, seems to be limited. One of the things that we were able to do because we had slightly larger numbers was look at PN patients versus non-PN patients. And what I found really interesting, and in fact, we went back and had to look at the numbers again and crunch the, the, the qual the PSQL involves sort of a transformation of the data. Want to make sure we didn't reverse what we were doing because we found that PN patients actually reported higher quality of life than non-PN patients. That doesn't make a lot of sense until maybe we look into it a little deeper and think, what is it that's impacting our patient's quality of life? And that's really where we're, where we're going with our next set of sort of ongoing studies, um, because, uh, I might hypothesize, uh, without any real data that this really has to do with, um, you know, what the child's quality of life is. is having attachments to tube feedings or trying to, um, perhaps overeat to compensate for their short bowel and having 3 or 4 bowel movements while they're at school or having a stoma appliance with, um, with high output while they're at school. And so, those kinds of things, I think are really impacting these children's quality of life, and that's what we're, uh, at the stage of looking into next. Um, one of the things I'll sort of talk about the bottom point here is that, um, with, uh, support from the Research executive Committee of our department, um, I was fortunate enough to get one of the first grants, and we're, uh, we're using that money towards developing a multi-institutional consortium. Um, we're up to 10 centers now, um, and have another 5 that have been invited, um, so that we can hopefully turn our 53 patients into 500 patients and really be able to get, um, the numbers needed to, to find some of these signals in terms of what's going on with these patients' quality of life. As I mentioned, we're also gonna keep looking at elastography. We're now sort of prospectively collecting data on that as we move forward to try to build a larger cohort of patients that have undergone elastography. And then things as Chris mentioned, um, are sort of evaluating better ways to achieve general autonomy, um, how to best support these patients and wean their parental support over time, um, and what, what these newer nutrition therapies are doing to things like not just weight gain, but also body composition. Um, and, uh, and those kinds of things. And finally, the role of hormonal treatment as Chris touched on, GLP-2 is really an exciting sort of, um, advancement, and we're hoping that it's gonna be something that, that bears fruit, uh, in the near future. So, with that, this is, uh, an older picture of, uh, of our group, uh, and we welcome any questions. Thank you. Well, Christen Beer and I. I'm not a Nobel laureate, but I'll thank you anyway for bringing a uh great summary of, of where you've come over the last uh several decades. I think it was impressive, the, the table that they wouldn't let you put in the primary article in the New England Journal of Medicine showed uh very nicely how Children's care program had the highest survival sort of by each time interval that you, you went, went through. I have, I have a couple of questions and I'm sure there'll be more from the audience. Chris, on your early scale where you showed the, the leftward shift in improved, uh, survival and, and function in the kids more recently compared with historic, what, what do you think are the dominant factors that have, have led to that change and, and what can be. Expanded on that even further. Sure, no, I, I appreciate the question and comment, Bob. I think the, um, so much has changed, uh, over the course of the last two decades in the care of these patients. I, I, I think there are reasonable data to suggest that the, uh, establishment of multidisciplinary programs for the Care of these patients has improved communication among providers and has reduced um adverse events. Clearly the development of Omegavan has had a huge impact on the progression, the, the ability to uh keep children on parental nutrition for longer periods of time and has clearly had an effect on mortality. Um, I think we've been more aggressive with treating and preventing central line infections. Uh, we've had appropriate increased use of diagnostic tests, including endoscopy, to diagnose and effectively treat morbidities of intestinal inflammation. Um, so there are, there are many different factors. It's, it's hard to tease them all out. It's been nice to be in an institution that has, uh, pioneered many of them. And Biron, it's interesting that on the quality of life, and that's great work that you're doing and clearly questions that need to be answered for those patients. I was fascinated, and you pointed out how the kids with PN rated their parents rated their quality of life, or at least the parents' quality of life, better than the kids when they were on. Oral, and yet the whole. The rest of the program is to get them over to oral feed so that they don't have continued liver injury. How can you address those issues to make it less of a problem for the families, or is there anything? Yeah, I mean, that's a great point. And, um, and something we're gonna have to tackle in the next few years. I think if, if those, if those data really ring true with a larger cohort, um, there really will be sort of a, uh, as you mentioned, sort of a disparity between our overall goal, which clearly is important for survival, which is to get children off of parental nutrition, um, versus some of the more balanced goals of quality of life. And You know, with individual patients, we do see that, um, in clinic. We have patients that whose parents don't want to push to get off parental nutrition and You know, it's a balancing act because some of those patients are meticulous about their central-line care. Their children have not come in with a central line infection in years. They've not had some of the devastating consequences that we see of patients with parenteral nutrition. And so, you know, it's hard to push those parents, um, to make huge leaps and advances in internal nutrition when they'd rather be on a slower train because they're not experiencing the difficulties, and they see the real-life benefits from a quality of life standpoint. Um, in some instances of, of having some parental nutrition support because they keep a central line. If the child gets dehydrated from an acute illness, they have the ability to give extra IV fluids and not have to come into the hospital, um, to treat that. And, and, you know, taking time out from work, the child out of school and being in the hospital for 3 or 4 days for IV hydration while their diarrheal illness settles out, that's a real quality of life impact. So, um, I, I don't think we have an answer to that yet other than we know that we need to get children off parental nutrition from a survival standpoint. So, so the answer then is going to be how to make their quality of life better, uh, as they progress to enteral nutrition. Additional questions. Uh, uh, thank you very much. Uh, uh, that was a tremendous, uh, talk, Chris and Beer, and, uh, and, uh, uh, if I could just thank everyone in the room, uh, particularly our, uh, uh, uh, dietitians and inpatient and outpatient nurse practitioners who care for these patients because they're certainly not an easy cohort to take care of. And I think one of the major reasons that we have such excellent survival and such reasonable quality of life is, uh, uh, everyone's work on their behalf. Uh, I do have a, a question for Bern. You know, although we say that perhaps the quality of life is worse, according to this, uh, there seems to be no happier day in a, uh, uh, intestinal failure patient's, uh, uh, uh, and family's life than the day you pull out their central line. So, I'm wondering how you uh uh weigh the that dichotomy. Yeah, well, I mean, I think, I think for most of the patients, it has to do with the fact that we've been pushing them towards that for years often, uh, and, and touting how important that is. And, and, and it is. I mean, I think, um, especially patients who have had to deal with an admission for fever and rule out, uh, for the central line infection, uh, or who have been admitted with an actual bacteremia, uh, those patients see the real-world implications of having a central line. And, and I think Um, you know, are willing to, to deal with the quality of life issues that they know can get better over time. Hopefully we'll show that, um, in order to, to get rid of the, you know, what I, uh, Uh, often spend time in clinic doing is, is stressing how important it is to get the central line out. Uh, so hopefully that, that means that the parents are hearing that message, yeah. Doctor Fisherman. Well, it is a pleasure to see the changes have come over those 25 years. Um, this is a surgical grand rounds, and it's fascinating how we talk very little about surgery, given all the improvements that have been made in multidisciplinary management, Omegavin, understanding microbiome, etc. etc. Is intestinal lengthening dead? Is there a role for intestinal lengthening anymore? Yeah, there is. I mean, there, so, you know, I purposefully left that out because it's something that we've talked about quite a, quite a few times, uh, in this forum. Um, but there is, uh, and, and, uh, even contemporary data would suggest that. We've talked about it at length in Pittsburgh. Um, there are 2 or 3 talks about it. The, the issue is that it's, it's one of the arrows in our quiver, right? And there are, uh, there are patient selection issues that are really sort of now coming to light. Um, I don't think intestinal lengthening is something to embark on on a patient who's on 0% centrally. Um, it's not gonna get them off off PN and go from 0 to 100. Um, but there are children who clearly have maximized medical therapy and plateaued with their advancement in enteral nutrition who are close. Um, and those are the kids who seem to be the best cohort, um, for intestinal lengthening options. And those are the ones in our practice, those are the ones we offer it to. Um, and that we see the most benefit from. And that seems to be, um, the consensus if you talk to the surgeons at the, at the intestinal failure meetings. That's where we're all sort of going. Um, certainly, some centers are more aggressive than others, but, um, I think part of that probably speaks to local environment in terms of how good the medical therapy is, uh, versus not. And I, and I, and I think, uh, just as an addendum, it'll be real interesting to see if kids who uh normally would plateau with our medical therapies might get a lot better with an approach that includes uh hormonal therapy such as Gatex. Additional questions for Chris and Bear. No, thanks for a great presentation highlighting all the progress. Thank you. Good job. It's awesome. Thanks, man. Sorry about the uh, mechanical, uh, I don't know. I think it just, uh, it seemed like this was, was loose. 00 jeez. All right, cool. Thank you very much. Um, yeah, thanks. What are you, uh, when you, you're here tomorrow, right, in the clinic, OK. Isn't it I'm biased. Oh. Yeah red line with that. I I did that. Thank Well, uh, I had forgotten that. Oh, you're 25 years somebody mentioned something in you something about that. I know. Right Yeah. Yeah I don't Oh, I see, I see. Yeah I Oh No. I I people Yeah. Right. To This OK The question the question yeah. you guys. I Yeah Yeah Yeah. I that's. Yeah. It's, OK. Of course, yeah. OK, I'll um I'll talk to her. Or I just thought I wanted to. O That's Oh yeah she may not take. And yeah, yeah. Is very good. OK. It's like a path it's a pathway. That was. I We have of course. You say it like. Oh, I know. Is to detailed. Yeah No. I really, I Test 12. Test, test