Advancements in Pediatric Intestinal Failure: Innovative Therapies and Improved Outcomes

Hi everyone, I'm Lizzie Lee from Cincinnati Children's Hospital Medical Center. Today we will hear from Cincinnati Children's pediatric surgeons, Doctor Stephanie Oliveira and Doctor Paul Wales about advancements in pediatric intestinal failure. Let's start with what exactly is intestinal failure and how is it defined? The reduction of functioning. Intestinal mass below that which can sustain life, resulting in dependence of supplemental parental support for a minimum of 60 days within a 74 consecutive day interval. So what causes the majority of intestinal failure in kids? More than 50% of the cases that we see are related to short bowel syndrome, some mucosal enteropathies and some dysmotility disorders. And how does short bowel syndrome lead to intestinal failure exactly? There are different causes of short bowel syndrome in pediatrics. Most of them happen during the neonatal period, so babies that have gastroschisis that may lead to necrotizing choralism and lead to bowel atresia like other malformations and intestinal vaults. Over the past decades, treatment has improved so much that more children now survive, shifting the focus to managing long-term complications. The field is starting to focus on neurocognitive outcomes, quality of life, and caregiver burnout. But now you're seeing chronic. Intestinal inflammation in these patients, often resembling Crohn's disease. They require management alongside intestinal failure with inflammatory bowel disease therapies like biologics. Why does this happen? It's not known why this happens. These kids are surviving and not having so much other complications. What is driving this improved care and survival? Is it intestinal rehabilitation? So that's the treatment strategy that we use in these patients with intestinal failure. We don't have a clear-cut guideline because every patient is extremely unique, born in a different gestational age, had a different bowel resection, has a different anatomy, different set of comorbidities. So what is intestinal rehabilitation and what is its goal? The goal is to optimize intestinal function and adaptation before the development of irreversible complications. We strive. To give patients better quality of life like any other sort of rehabilitation like physical rehabilitation. Some injury happened, you try to regain function of the organ. As part of that rehab, we're trying to encourage intestinal adaptation. Intestinal adaptation is an active process, is a compensatory process that starts happening right after bowel resection. What are some things that enhance intestinal adaptation? Food, bacteria and hormones in the gut is important. We are trying to regain function of the bowel, so eventually the person doesn't need TPN anymore. And what can we do to try to avoid a transplant? Venteral nutrition, parental nutrition, medications, surgical procedures, feeding therapy, and central line locks. These treatments have improved the patient's quality of life significantly in the past 20 years. One of the major milestones is internal autonomy. Can you tell us more about it? Internal autonomy is getting off TPN, having all your nutrition. Going to your gut, either by mouth or by a feeding tube. A research report published by the Pediatric Intestinal Failure Consortium in 2012 showed that 50% of the intestinal failure patients achieved internal autonomy, and 25% of them either passed away or had an intestinal transplant. From 2010 to 2015, that study was repeated with double the number of patients and still about 50% reached enter autonomy. But the number of transplants significantly decreased as well as death. One of the things that changed the outcome is the establishment of multidisciplinary teams. Other studies from Canada, Michigan, and Spain have similar findings showing that a multidisciplinary intestinal rehab team improves survival. What are some predict? of reaching internal autonomy. The residue is more about length, the more about, the better. Follow up on an institution that has an IR program and no-step procedure. So, having an intestinal rehab program available is really important for helping them achieve internal autonomy. Who should be referred to these programs? If any physician has a patient with intestinal failure, we can consult at any point and provide support. But definitely, patients that are not making progress, that are on prolonged TPN have significant comorbidities, you wanna make sure you refer them sooner than later. OK. Is there a time when you should not refer? You don't want to refer them when several complications. Already happened and now there's not a lot we can do other than transplant. At what point do you consider intestinal transplantation? We transplant when we have irreversible complications, or we have so many things to do to avoid that. The number of transplants has significantly decreased over the last several decades. Next, we will talk with Cincinnati Children's Intestinal rehab surgical director, Doctor Paul Wales, about innovative therapies and improved outcomes. Doctor Wales, what is the spectrum of liver disease associated with intestinal failure? They go anywhere from mild cholestasis to more profound steatosis, which we see in older children or adolescents and adults, with ongoing inflammation, fibrosis, and ultimately cirrhosis leading to death or the need for transplantation. And what are the risk factors for intestinal failure? There's some patient factors related to prematurity, uh, lack of enteral feeding, the inability to feed because of the anatomy or recurrent infections, sepsis, which can affect the liver directly and indirectly. And the components of TPN. Although TPN is life saving for these patients, it needs to be managed carefully, as it can contribute to hepatic dysfunction. That's where your intestinal rehab team comes in to help manage these components. Can you tell us more about your program? The term intestinal rehab program was coined in the year. 2000 intestinal rehab teams improve the outcome of children because of integration of care, improved communication, better continuity. As we heard earlier from Doctor Oliveira, the goals of intestinal rehab are to optimize growth, bowel function, and try to provide the most normal feeding behavior as possible. Now, what other specialties do you rely on? We have a large reliance on speech, language, and occupational therapy. While our patients are on TPN, we're trying to mitigate the progression of liver disease, sepsis, vascular complications. Having a dedicated unit with dedicated staff all contributes to better outcomes. Once the patients return home, what is the role of the families? What we ask our Families to do at home is significant. These patients go home on TPN. The families run the pump, add vitamins to the TPN, program the pump, record ins and outs, manage the G tube, manage the stoma. That can be a huge caregiver burden. How do you support these families? We educate and empower our parents because we've all seen. High-quality families that over time demonstrate evidence of burnout. How has research shown that intestinal rehab programs are making a difference? There's literature that shows the improvement of outcomes with programs in general. You see an improved survival related to liver dysfunction, decreased septic episodes, reduction in central line complications, reduced ICU admissions, and the patients that were listed for transplant are coming off the list because of improved status. Mortality has gone down. Let's switch gears. You wanted to highlight alternative lipid strategies in parenteral nutrition. Why are lipids important for intestinal failure patients? Lipids are a source of essential fatty acids. They're a non-protein energy source important for growth. Fatty acids have a major role in cellular pathways. Can you tell us more about what lipid emulsions are and how they're made? Historically, most of the lipid emulsions in North America are soybean-based, so they have a high phytosterol content. A high omega 6 long chain polyunsaturated fatty acid content and low antioxidant content. Why is prolonged soybean-based liquid exposure harmful? It is associated with deterioration of liver dysfunction, i.e., cholestasis. Doctor Whale's team did a multiple variable analysis on this very topic in September 2011. It's called the role of parenteral lipids in the Development of advanced intestinal failure associated liver disease in infants. To read the full article, click the link in the description below. This is a paper that we wrote several years ago that showed that for every day that an infant is exposed to soybean lipid dosed at greater than 2.5 g per kilo per day, which is more conventional dosing. That is associated with a 3% increase in the odds ratio of developing advanced liver disease. So this explains why lipid emulsions needed to evolve over time. Here's a quick history lesson about how they've gotten better. The first generation were basically the soybean-based lipids, rich in omega 6UUFA. That would be intralipids, and that's been around for 40 years and it's saved a lot of lives. Next, 2nd generation mulsions try to reduce omega 6 exposure and dilute the soybean component. The 3rd generation lipids attempt to not only reduce the omega 6 component, but to change the omega 6 to the omega 3 ratio with the addition of omega 3 lipids. This balance matters because omega 6 fatty acids tend to promote inflammation, while omega 3s lead to a more anti-inflammatory response. Omega 6 lipids are metabolized to arachidonic acid. Which produce leukotrienes and prostaglandins of the more pro-inflammatory profile. The omega 3 lipids are metabolized through EPA and DHA and lead to the production of cytokines that have a less inflammatory profile. So what This all mean for the way that omega 3 lipids affect bile flow. Omega 3 lipids improve bile flow because they decrease lithogenicity of the bile. They decrease steatosis. They stimulate improved beta oxidation and clearance, and they lower oxidative stress and support immune function. So what are the main goals of improving the lipids in parenteral nutrition? One is lipid minimization, and then the second strategy is a change in composition. New alternative lipid emulsions change the omega 3 ratio to become less inflammatory. There's a lot of literature dating back even decades that show that if you restrict exposure to soybean lipid, you improve cholestasis. When you dose the lipid at 1 g per kilo per day or less. This sounds Promising. Is it safe to minimize lipids in parental nutrition for premature babies? The problem with this in preterm babies is that fat is important for growth, especially for neurocognitive development. So there is the risk of essential fatty acid deficiency if we restrict lipid dosing too much. In utero, babies receive significant amounts of DHA and arachidonic acid through the placenta. But when we use standard lipid emulsions and TPN, they. short. DHA and arachidonic acid are important for retinal and brain development. None of the lipid emulsions today were designed for premature babies. They were all designed for adults in a critical care setting. So there's a real need for innovation to individualize the lipid emulsions for preterm babies. We're currently in work with industry to create a lipid emulsion that's more specifically tailored to preterm babies that has a higher content of arachidonic acid. Beyond nutrition, these infants rely heavily on central lines, which I understand comes with their own set of dangerous complications. So our patients with central lines, it's literally their lifeline. And without venous access, we can't support our families. They are at risk for complications, infections, blockages, thrombosis, and breakage. The financial and human toll of central line associated bloodstream infections, also known as collapses, is staggering. In the United States, there's about 240,000 collapses in the United States on an annual basis. The cost of one of these is about $30,000 about $2 billion a year nationwide. I know ethanol locks were highly successful in reducing these infections initially, but there were supply issues. How did your team pivot when ethanol became too expensive and hard to get? We landed on 4% tetrosodium EDTA or kite lock as it's known in the trade name, which is an antithrombolytic, anti-fibrinolytic, and antimicrobial. So, it satisfies all three criteria that are important for a good lock solution. Lyne complications increased for patients on home TPN during the ethanol shortage. The alternative kite lock was able to address the three issues of complications. Number 1, the organisms, 2, the clot thrombosis, and finally, the biofilm. Is kite lock currently available for patients? It's licensed in Europe, it's licensed in Australia. It's not available in the United States. I'm happy to say that we have finally launched our multi-center randomized trial of kitelock versus heparin, which went live 4 weeks ago, and we're actively recruiting patients. In the next year, we'll have the results of the trial, and we can get the kitelock into the United States. This will be a major game changer. Let's shift our focus to the gut. Trophic peptides like GLP-2 seem to be opening new doors for children with short bowel syndrome. Let's review the types of short bowel syndrome really quick. In short bowel syndrome, we have 3 anatomical subtypes. Type 1 is the high L piginostomy. Type 2, where you've lost your distal small bowel, your ileum, and part of your colon, and there's a small bowel colonic anastomosis. And then type 3 where you've lost the mid-part of your small bowel, but you still have some retained ileum and an intact colon. So patients with type 3 have the best prognosis because they still have residual ileum. Which subtype is the most common? The most common anatomical subtype in pediatrics is type 2. These patients struggle. Type 1 and type 2 struggle because they lack an ileum. The ileum is where GLP-2 is naturally produced. So without it, these infants cannot generate the necessary hormone surge to drive their own intestinal adaptation. If they can't produce it, you have to give the hormone synthetically. But I understand that the native hormone has its limitations. The problem is that the native hormone has a half-life of 7 minutes. So it's not practical. So it's been altered, one amino acid alteration to an analog called taglutide. That has a half-life of 2 hours and it's given once a day subcutaneous injection. So you were part of this multi-center phase 3 study published in 2020 at Cincinnati Children's about the safety and efficacy of taglutide in intestinal failure due to short bowel syndrome. What were the results? What we see in patients that received taglutide, a 40% reduction in TPN fluid and calorie requirements over a six-month period. And 70% of patients that received the analog achieved the study endpoint, which was a 20% reduction in TPN requirements. Wow. So tarilutide has made a big difference in the past 5 years and has become more mainstream. It's licensed for children that are greater than 1 year of age. Already, it's made a big difference in our practice and even kids with very extreme anatomy have been able to get off TPN as a result of being able to replace this hormone. Are there any new products down the pipeline? Another GLP-2 analog, a proglutide, has a longer half-life and can be given once a week. That's currently being studied. And what we've shown is that it actually works even better than taglutide. You get more bowel lengthening with a proglutide compared to glutide. So it sounds like GLP-2 analogs show great promise, but it's still early. To wrap up, what's the big picture goal of optimizing lipids, preventing Lyme infections, and using these new peptide therapies? These interventions have led to a decrease in transplantation since 2008. In large part because of the successes of intestinal rehabilitation, the outcomes of transplant at 5 years are about 65%. Whatever we can do to avoid transplant and lifelong immunosuppression, that is our goal. In summary, children have a much greater adaptive potential than adults because of their inherent gut growth capacity. The proportion of children that are reaching internal autonomy has improved over the past 20 years. If we can control liver disease, we buy time. Omega 3-based lipid improvements, central line protection methods, and GLP-2 analogs are some of the innovations that can optimize adaptive potential and protect the liver. We have lots of exciting medical and surgical options available to us, but this should all be done under the umbrella of a multidisciplinary team. Multidisciplinary. intestinal rehab programs like the one at Cincinnati Children's are key to lowering transplant rates and reducing infections. Thank you for listening. We hope you liked this episode. Please follow Stay Current MD on social media. Give us a rating and subscribe to YouTube channel. And don't forget to download the Stay Current app to find more content.