Total Pancreatectomy with Islet Autotransplantation: Pancreatic Disease

Welcome back. Welcome back to managing the Disease Pancreas and Children. What have we learned? So our final session here, uh, we're going to be talking about total pancreatectomy with eyelid auto transplantation. Uh, we have a, uh, most of the members of our team here, endoscopy, GI colleagues, pain. Uh, and endocrine, uh, and, uh, this just highlights, uh, how multidisciplinary this patient population, uh, uh, really, uh, uh, really requires in terms of approach. And so, uh, we'll start here. There is, um, off label, uh, discussion, uh, of medications by Doctor Goldschneider. Uh, overall, where are we going to go? So we'll talk about indications for total pancreatectomy with eyelid auto transplantation. Uh, we'll talk about our approach to evaluation. Uh, we'll go through the operation and perioperative and postoperative management, and then we'll finish up with, uh, outcomes and how, how do we follow these patients, uh, over the long term. So we'll start with a polling question. So that question is, how likely are you to refer a chronic pancreatitis patient for a TPIT evaluation? 1, highly likely. I think that TPIT is a very reasonable approach in the appropriate clinical setting. 2, somewhat likely. 3, not very likely. 4, never. I don't feel there's a role for TPIAT. 5, I don't know enough about TPIAT to say. So go ahead and log answers, please. All right, and then we'll, uh, turn things over, uh, to start, uh, to, uh, Joe Palermo. We will start us with the case. Thank you, Jamie. And so, um, I just want to echo Jamie's sentiment. I think this is really a true multidisciplinary team approach, and selecting the right patient is probably as critical as doing the surgery itself. And so I'll take you through a case of a recent patient that we've had, a 13 year old female with chronic pancreatitis. She does have a double heterozygosity, one CFTR mutation. And one sphinx mutation. She is exocrine insufficient, uh, with low fecal elastase as well as, uh, low direct pancreatic function testing on her ERCP and and imaging, she is found to have Davisum, and she did have a minor sphincterotomy by Doctor Lynn, I believe, at the time. Um, repeated ERCP, uh, showed mildly dilated, uh, and irregular dorsal duct, and, um, she started having more frequent flares, uh, over the year prior to her evaluation, um, and they were now happening about monthly. Um, and her pain attacks, uh, between episodes, uh, were also occurring, and she was on opioids regularly. Um, and because of all this, she had missed numerous days of school. So her testing included, uh, with her recurrent, uh, acute pancreatitis episodes, she did have documented elevated lipases, um, so she certainly was having episodes as well as her, her pain in between her flares. Uh, her pancreatic function testing, as I noted above, she'd had normal CBC, CMPs, sweat chloride testing, um, and as I mentioned, her genetic testing. Um, and then, uh, we'll show you, uh. And Dr. Trout will show you his, uh, the recent MRCPs and ERCPs. Dr. Trout, is Dr. Trout on this? Oh, he is not on this one. OK, so I'm going to do the MRCP. All right, so with the MRCP or Tom, do you want a radiologist, Tom, do you want to talk about it because you can talk about your ERCP as well? Yeah, yeah, sure. So the uh the MRCP here, um, we see the blue arrow kind of indicating the, uh, the biliary tree, the extra hepatic biliary tree that doesn't appear to be abnormal in any type of way, um, looking at the pancreatogram that's shown on this. Uh, on the, the, the pancreatic duct that shows on this image, um, there's some mild prominence in terms of diameter wise. There's some irregular subtle irregularity too as well on that left image and, uh, similar type of findings, um, with the, the right image too as well. Moving on to the ERCP, uh, that was performed one month later again, as Doctor Palermo had pointed out, this child has had a complete pancreas divism and so this is cannulation through the minor papilla. Uh, with our scope in the long position and we see that there appears to have been a progression, at least comparatively from the MRCP to the, the pancreatic pancreatic gram ERCP image that her ducts appears to be more dilated than it had been on the MRCP. Um, still some ductal irregular irregularity as well, um. And um I, I want to say that she had, uh, I think Doctor Palermo, you presented that she had two ERCPs, the second one. I, I believe this is probably the second one with the top right image showing that um there was a dilation of her ampula rather than doing a, a, a sphincterotomy that was performed at the initial ERCP, so there was no room to extend that, that sphincterotomy, so dilation of the ampula, um, and, uh, then placement of a, um, a pancreatic duct stent. Uh, so because of her, she's obviously had increasing frequency and severity of her pancreatitis episodes despite our medical and endoscopic approaches, impaired quality of life, and continued opioid requirement. And so let's go back to our polling question and see what our follow up was. You see that. So the need for this course. Wow, yeah, I don't know, no. OK, that's fair, very fair. Uh, not very likely, somewhat likely, at least there are no nevers, what folks are considering. So, um. We'll go on with what the indications are for TPIAT um so as you're going to surmount from what we just talked about, the main indication is chronic pain, unresponsive to optical, medical, and endoscopic approaches um or surgical approaches and significantly impaired quality of life with repeated AP episodes, repeated admissions, missed school or work, um, and so, and these are obviously things that we have to, we want to document over a period of time and not just for one or two months. So what's our evaluation? And as you've heard so far, it's very multidisciplinary. So, um, gastroenterology, surgery, endocrine, pain team, human genetics, uh, our ID team, as well as our social workers and other ancillary services, um. The GI visit is really a global assessment. It's our initial meeting with the family. We talk about obviously their overall course of their disease, but we also do a very extensive nutritional evaluation. We obviously are reviewing their previous imaging and testing. We have regular pancreas radiology meetings where we go over all the cross-sectional and ERCP imaging on our patients in a multidisciplinary fashion as well. And then we also do review any previous exocrine and endocrine function testing they've had. Um, our human genetics colleagues will review or obtain outside genetic testing, uh, review or obtain new genetic testing if it hasn't been obtained yet. Um, and then they'll also be counseling the families and not just about this patient, but what about the rest of the families? How does this affect the other family members? Who else might need to be tested? What is the best course of action for the other family members? And are there other family members who are known to be positive for mutations that need genetic counseling, or we're welcome them in as well, and they're happy to see them and talk with them at that visit or separately if needed. And as I mentioned, our social workers play a very important role because obviously chronic pancreatitis is a tremendous stress on families, but going through the process of the TPIT evaluation and the TPIT itself is another stressor on the families. So they work to assess the support structures for the family, assess what their resources are. They assist obviously with. School and work issues to the best of our ability because our goal is for these patients to have as normal a life as possible and then certainly they're helping us with planning the TPIT if we go down that route because the families are away from home for at least 6 to 8 weeks and so that obviously is another significant stress on families. Our ID team works with us because of the splenectomy and all these patients, as Doctor Nathan will point out down the road. We make sure that their immunizations are up to date. We talk about osteoprophylaxis and management and how we manage them post splenectomy, and then we also evaluate them for MRSA colonization to see if they need any additional management prior to surgery. Um, with that, I'm gonna hand off to Doctor Elder to really start talking about our endocrinology, um, uh, component because it's really, it is really a significant component component leading up to the TPIT, um, and then helping the families understand what's involved with the TPIT itself. That So endocrinology, uh, gets involved, uh, with, with these patients, um, at a very pivotal time in, in decision making, you know, the, the family is now having to make a, a huge decision on behalf of their child, in essence trading one chronic illness for another, and so we, we meet and talk about the benefits of TPIT, which, um, as Joe mentioned, is improved quality of life and reduction of pain, less missed days of school, participation in activities and titration of. Pain medications, but we also have to talk about what lies ahead of them after the procedure, and that is an insulin dependent form of diabetes that you hope, um, there's recovery and insulin independence over the course of a year, but immediately postoperatively they will need insulin. We talk about the frequency of blood glucose monitoring, the different modes of. of insulin, whether it's subcutaneous injections or the use of an insulin pump, the risk of diabetic ketoacidosis and long term complications. So my role is not to talk them out of this procedure, but really to show them what Children's Hospital in Cincinnati has to offer. We have a very large diabetes center and we care for nearly 2000 patients with insulin dependent form of. Diabetes and we have a large educational staff to help them with this transition including 9 diabetes educators, um, 8 registered diabetes nurses, and 6 social workers, not so much to help with social problems, but with the transition back into school. Um, we have a large expertise in technology, specifically using continuous glucose monitoring. And insulin infusion pumps and so all of the patients that um go through our pancreatic center, we want to know what their baseline uh glucose tolerance is and their insulin secretory uh capacity is and so the recommendations are to perform an oral glucose tolerance test or a mixed meal test using standard protocols, um, and what we do is we place an IV and do timed samples collected at 0, 30, 60, 90 minutes, not only. To look at the glucose trend, but look at the ability of that pancreas to make insulin and so, uh, in terms of diagnosing diabetes, we utilize the, um, American Diabetes Association criteria for normal glucose tolerance, impaired glucose tolerance, impaired fasting glucose, and those are defined in the table there, and diabetes and specifically if we diagnose diabetes in this patient population, there is a term called type 3C diabetes. Specifically, uh, describing a pancreatic form of diabetes, unlike type 1 diabetes, which is autoimmune, um, related, or type 2 diabetes, which describes an insulin resistant form of diabetes. And so type 3C, you have to match the ADA criteria for diabetes. It's an insulin deficient form of diabetes, and the islets antibodies are negative. The choice of therapy in a type 3C diabetes is insulin and not oral hypoglycemic agents. Um, this represents the mixed meal tolerance test of the patient that was initially presented. It was performed in March of 2015. Um, the top row is glucose, second row, insulin and C-peptide, and, um. My interpretation, and I'll walk you through this, is that although she did not meet any ADA, uh, defined criteria for impaired glucose tolerance, there are some subtle abnormalities identified. I don't know if I have an error on here, but a fasting glucose greater than 100. Is considered abnormal, and this patient's fasting glucose was 96, so it was at the upper limits of normal range, and if you look at enough oral glucose tolerance tests, any blood sugar greater than 140 is higher than anticipated, and she got to 150 at the 60 minute mark. A normal peak insulin in face of oral glucose tolerance load is typically at 30 minutes, and this patient's peak glucose was at 60 minutes, which allowed for that blood sugar to rise a little bit. So the overall assessment of this mixed meal tolerance test was that the fasting glucose was in the high normal range. There was higher anticipated blood glucose at 60 minutes, and there was a slight delay in insulin secretion. So already with her chronic pancreatitis, she was showing some subtle. Abnormalities that may or may not help families with decision making. Deb, really simple for those of us who never do this. What's in the mixed meal? What are we challenging them? So we use a standard boost preparation. So it's, it's not only carbohydrates, it's also fats and proteins. So it supposedly mimics a mixed meal, more physiologic. The oral glucose tolerance test is a carbohydrate challenge only. Yeah, I think, um, Deb, you bring up a very good point regarding the progressive nature of, uh, the endocrine component, the endocrine portion of the disease, and, uh, you know, clearly as we'll go through the, uh, rest of the, the, uh, presentation here, you know, we don't really know for any one given patient when is the right time to offer a TPIET. Um, but you know, all of us will, will say that, you know, if they've gotten to the point where they've burnt out all their islets, then you've sort of missed the boat unfortunately, um, but this is a, this is, this is a question, and this is, uh, um, one of the questions that we'll be hopefully answering in the coming years as part of a, a, a TPIT consortium, uh, that's recently been funded, uh, and I think that these are going to provide a lot of good answers ultimately. So we're gonna switch gears from endocrine to uh pain uh and turn things over to uh to Ken. All right. Let's start with a poll question uh regarding pain. What expectations do you set with the patients ahead of time in, in those patients, of course, that are gonna be going through a TPAIT, um, so what do you tell them to expect afterwards? And one is, you know, I, you play it by ear because everyone's different. The patients should expect to be pain-free and jump right back into a normal life after. The pain should be reduced and function should return to normal, perhaps with a lot of effort, or the patients should start to work on function now, meaning preoperatively, and they plan to continue this postoperatively regardless of how much pain they may or may not have at that time. We'll come back to that. So preoperative pain management is really an extension of the whole multidisciplinary process, and I'm gonna draw a quick aside that uh Joe talked a little bit about the, the radiologic reviews and so on. We meet on a weekly basis, the whole team. And so communication is really what helps guide this process through because we don't know exactly what the timing is. Should I do should I do an interventional pain block? Should I use opioids? Should we proceed with, you know, faster or slower depending on our endocrinologic status? So I just want to emphasize that there is a lot of discussion that goes on a very frequent basis. So as part of that. Um, our multidisciplinary evaluation and plan is as similar to uh described in session two, where we have psychology doing a cognitive behavioral therapy and they work on coping, anxiety management, and planning. We identify barriers, so are there any safety concerns, any history of mismanagement of opioids in the family, uh, suicidality, that kind of thing? What's the psychosocial situation? Um, we provide a lot of education. We hope to make people pain free, but you can't promise them that or you set up for expectations that you can't promise to meet. We set those expectations and goals. This is going to be a lot of work if they're sitting on the couch now and not learning to cope with discomfort and multiple medications, if they're not practicing their coping skills, they're not going to be prepared to go through a very big perioperative process and a rehabilitation phase which will hopefully get them back to their normal lives. So we start prepping them, preparing them now, and obviously there's medication management. And opioids are the things that are most talked about, and as I mentioned earlier, they're tools to do a job, but you can select them, and we didn't have time before, but now we'll talk a little bit about why one versus another. Well, for moderate pain, mild to moderate pain, something like tramadol is useful because it doesn't generally slow the gut motility very much, so some of the GI slowing that you get with conventional opioids can be avoided. Now there are times where that's not enough and we move on. But standard opioids are then would be considered second line, at least in our practice. Now that said, you know, there's not a lot of experience and certainly no FDA approval for some of these medications in kids, so it's something that we have to do very thoughtfully and carefully as we go along. Now that obviously brings up legal and logistical issues which we won't have time to go into because they can be extensive depending on local law practice and social pressures. Now we bring in a bunch of medications which we call neuropathic medications, things like tricyclic antidepressants. We use gabapentin, and the idea is that we think there's sensitization that goes on in both the enteric and central nervous system from all the repeated inflammatory insults, and so that can lead to things like pain when all the enzymes are normal. And that's just frustrating. That's like having somebody with a Crohn's disease who the scopes show nothing. The fecal calprotectin is normal, and yet their abdomen hurts just as badly as if they're having a full flare. And we think that that is more of a neurologic neuroprocessing issue, and we treat it as such, and we don't treat that kind of pain with opioids. So, um, we'll go back to our, our polling question. While we're showing that, Ken, can I ask you a quick question? We get, we get asked by a gastroenterologists from around the nation, our colleagues, are you successful and from your experience, uh, in weaning opioids once the patient is, um, on a good regimen of TCAs or gabapentin? It varies. Those who have repeated, um, episodes of active inflammation. They're going to need things during those times, but what we work towards is people with recurrent episodes as opposed to something that's continuous. We try to limit the use of opioids to when there's active inflammation there's some sort of evidence of a somatic process. Now in the post-op period, we'll talk about that sort of towards the end. We'll come back on that. Uh, I'm sorry, did we, there's that pulse. There we go. 66% pain. It should be reduced and function should return to normal, perhaps with a lot of effort. And then the other, the rest were start now and start working. You know what the truth is, it does shade towards that latter answer, but both are extremely reasonable. Um, the emphasis on this is going to take a lot of effort. This is one of those times I look at the kids and I say this is all about you, which means you have to do a bunch of work. All right, all right, so we're going to the slides to switch gears. We're going to talk now about the surgical, uh, approach, surgical evaluation. So as, uh, Ken mentioned earlier and as Joe has mentioned, as, as we've all mentioned, you know, this is really, um, uh, you know, this is, this is not like taking an appendix out. It's not like taking a gallbladder out. It's not even like taking a spleen out. Um, it's really a complex process, um, a lot of moving parts, and so this is very much, uh, um, extremely multidisciplinary, and everyone's, uh, input is critically important to the eventual, uh, uh, outcome of the patient. Ah, from the perspective of this subgroup of patients, um, again, this is a very highly selected subgroup of patients that we offer TPIT to, uh, patients with intractable chronic pain or incapacitation due to the frequency of their acute recurrent attacks, uh, who have either no surgical, uh, conventional surgical option, uh, or have failed prior conventional surgery, uh, and again, of course, assuming they've also failed all medical and endoscopic approaches as well. So what are the goals? So the, the number one goal, the goal that we have to keep in mind here, what's the reason for this operation, uh, is to relieve the incapacitating pain or the the debilitation of acute recurrent pancreatitis. Uh, you know, we, we often get asked, uh, you know, quote unquote, how did the transplant go? It's not really about the transplant. Yes, we would love for everyone to be insulin independent. Ah, but really what we would love more is for everyone ultimately if possible, or as many as possible can, uh, to be to, to achieve pain-free status and to be fully functioning. That is the number one goal. Uh, the goal of the IAT, of course, is, is to preserve the alpha and beta cell mass as well as pancreatic polypeptides secreting, ah. Uh, cells as well in the islets, uh, so that, uh, you can prevent or minimize, uh, otherwise, uh, potentially challenging diabetes. Historically, the term brittle was used. I don't know, Deb, if you want to comment on, on the use of the term brittle. That has historically been the concept of, of surgical pancreatitis or surgical, um, diabetes. Yeah, this is a term that describes a form of diabetes that. Translates into being unpredictable extreme highs, extreme lows for no reason. There's thought that it's due to lack of contraregulatory hormones, specifically when you remove the alpha cells, the glucagon response is gone or impaired, um, but when you actually look at the, the definition of brittle diabetes and apply it to the type one patient population, it's only reported in. A small subset of patients, less than 1%, and there's been recent studies that compare the total pancreatectomy population head on head with the complications described in the type 1, and there doesn't seem to be a difference. And so the question of brittle diabetes is, is that really a phenomenon in and of itself, or are there multiple. Other factors that go into a patient having a blood sugar liability whether it's poor compliance and not checking blood sugars and not following glucose trends and not making appropriate decisions, the effects of exercise, the effects of gastroparesis and not absorbing calories, so I, I tend not to use that term only because. I almost think look at it as a crutch and it and it prevents you to stop looking for the answer as to why you're having problems with blood glucose and so although it may represent a real phenomenon, I don't think it's um should be applied. You know, to, to a population, you know, that's that's struggling with blood glucose problems, OK, so. Uh, but certainly without the IAT portion, uh, diabetes would be, uh, inevitable regardless of how challenging to control or not. So what are our criteria here, uh, for total pancreatectomy and eyelet autotransplantation? Uh, so clearly diagnosis of either ARP or chronic, uh, chronic pancreatitis, uh, combination of, um. Uh, imaging modality, uh, exocrine pancreatic insufficiency evidence, uh, genetics, etc. Chronic pain of greater than 6 months, uh, duration with, uh, either daily opioid use or severely impaired quality of life with having had adequate interventions by her pain team to try to mitigate these absence of reversible cause of pancreatitis, a failure again of medical or endoscopic intervention. from the IAT portion, uh, adequate beta cell function, and obviously it's a big operation. We have to make sure there are no physiologic or psychosocial, contraindications. What are contraindications to IAT, uh, pre-existing insulin dependent diabetes mellitus Challenges with liver disease, um, and so a lot of patients, uh, uh, that we see, um, tend to have, uh, fatty infiltration of the liver. Uh, and, uh, the, the concern there is that you're placing these eyelets into Amelia that, uh, potentially, uh, uh, you're creating some additional, uh, risk, particularly in the setting of patients that have some other liver disease etiology, uh, and have developed portal hypertension or portal vein thrombosis, and so those are really contraindications to IAT. Who are patients, what patients don't do as well after TPIT? So again, uh, Ken, um, alluded to this. So patients that have a central sensitization of pain or functional pain disorders, certainly patients that have drug seeking behavior or, uh, severe psychosocial maladaptation. What other things do we consider from a surgical perspective preoperatively? So again, cardiopulmonary comorbidities, any bleeding or clotting disorders? How's that nutritional status? Uh, we presented a patient, uh, earlier on, uh, that, uh, really had some challenges in terms of us, uh, being able to get adequate nutrition in her and ultimately ended up on TPN for quite a while. But for her TPIAT, uh, immunizations up to date, and that speaks to, uh, the splenectomy, and I'll get into that in a second. Any prior abdominal surgery, prior pancreatic surgery, any presence of pseudocysts, any other, uh, uh, local complications that may, uh, make, uh, a dissection challenging? And then of course what's the patency of the portal vein and splenic vein junction and then what's the hepatic arterial anatomy. So and this patient, uh, fortunately this patient didn't have to head to TPIT, but this patient had a completely replaced right hepatic artery that actually went through the head of the pancreas, uh, which obviously would have been a challenge, or would be a challenge in the future if we have to take that pancreas out. We'd have to preserve that and it goes right through the head of the pancreas. Um, pain management as we head toward the operation, Ken. All right. Um, just briefly, this is something that we designed as as seamless as possible, um, where the chronic pain team from the outpatient side signs out to the perioperative team and they go through a protocol and they see the patient the night before. They'll start a dose of gabapentin if they're not already on it, um, and we, we're trying to use that for preemptive purposes. Our inpatients team is to get an ECG prior to starting methadone, although that's a whole separate discussion as to where the evidence is pro and con on that. Intraoperative methadone is started, ketamine infusion is used during the case and continues post-op, as I'll explain. Lidocaine infusion is used for the 1st 8 hours. Dexamethaamidine is started as an infusion, and that's prior to transport up to the intensive care unit, and we're not using any epidurals or nerve catheters because of heparinization. Excellent. So the actual procedure, so it certainly, uh, it involves a total pancreatectomy and uh near total duodenectomy. We actually do preserve a D1. Uh, and, uh, the reasons being that, um, our reconstruction, as you'll see in a few slides, uh, really, um, uh, the GI reconstruction, uh, we perform in an effort to, uh, reduce consequences or reduce, uh, bile reflux, and so, uh, we actually create a ro limb and we preserve the pylorus, uh, to reconstruct the, uh, uh, enteral side of the tract, uh, and you'll show, show some pictures in a second. Uh, splenectomy. We do perform a splenectomy, uh, uh, routinely for our TPIATs. There are some institutions that attempt to preserve the spleen. Uh, the risk with preserving the spleen or trying to preserve the spleen is, is, um, uh, there's risk for warm ischemia to those eyelets as you're trying to dissect. The splenic artery, splenic vein off the back of the pancreas, uh, and frankly, uh, if you try to preserve the spleen, uh, and, uh, sacrifice those vessels and thereby, uh, um, uh, let the spleen live off of the short gastrics, uh, there's certainly, uh, um, risk for a spleen, uh, uh, not, uh, ultimately surviving. Uh, based on just the short gastrics, uh, we do perform, of course, a cholecystectomy. Um, we do take out the appendix. The last thing a child needs after DPIT is to have appendicitis down the line, so we take out the appendix, and we do place a gastroduodenal feeding tube for the period of time that the patients do have delayed gastric emptying, which is a consequence, uh, of how we reconstruct the GI tract. Uh, there are often, uh, are typically significant adhesions and scarring. Uh, the key here is that we do preserve the blood supply to the pancreas as long as possible, really up till the very end. Uh, you'll see here in this image we've, uh, looped the gastroduodenal artery with a blue loop here. Uh, the red one is on the splenic artery, and we've really freed the entire duodenum and, uh, uh, pancreas up, uh, and those are the, uh, last, uh, vessels, the last, uh, portion of the operation, and that's when we get our eyelet team, uh, to the room. The goal of, uh, eyelet, uh, isolation, of course, is to digest the pancreas and, uh, break away all the exocrine, all the er tissues, uh, to, uh, release relatively pure eyelets in as small a tissue volume, as we can, uh, that we can safely then, uh, uh, send into the portal vein. This is a. Yeah, sorry, uh, this is, uh, a combination mechanical and collagease digestion, uh, and, uh, uh, density gradient centrifugation, so the recording method that is well, uh, uh, established, uh, the pellets are assessed for viability, purity, and, uh, endotoxin. There is a relationship between yield and severity of a pan of chronic pancreatitic changes by imaging or if you happen to have histopathology, um, uh, prior to, uh, or certainly thereafter, uh, predicting eyelet yield is, is very difficult, uh, but we do know that insulin independence is dependent on the number of islet equivalents, uh, uh, transplanted. There is of course data as we described earlier that prior ductal drainage procedures and distal pancreatic resection, so distal pancreatectomies, do compromise eyelet yield. And so again, as we talked about in the last session, we do tend to avoid surgical drainage procedures in patients that we really anticipate to require, future TPIT, so particularly those with genetic etiologies. This is what the field looks like after we have the pancreas out, um, as you'll see here, uh, this is the, uh, end of the bile duct right here that we'll, uh, reconstruct. This is the end of the duodenum, so we've preserved the pylorus here. So this is D1 right here, uh, and then you see the, the portal vein, uh, right here as the SMV and the splenic vein. So we leave a little splenic vein stump so that we can, uh, put a little cannula into that splenic vein to infuse the eyelets, and so all the pancreas, duodenum, uh, are, are gone. This is how we reconstruct the GI tract and the bile duct, and so we do have a Roy hepatocojuginostomy, and then we have a second roe limb up to the duodenum up to D1. And so, you know, the consequence of this is that the consequence of another roe limb up here as well as preserving the pylorus, is that patients do have delayed gastric emptying. And it really is quite like clockwork. By about 345 weeks, uh, their gastric emptying improves, uh, and we're able to advance them on their nutrition by mouth as tolerated. But in the meantime we do have a need for feeding downstream and so we do place a gastroduodenal feeding tube that ultimately does come out within a couple, a handful of months. The eyelid infusion is via the splenic vein stump in our practice. Uh, certainly you're, uh, I like to describe to families if you've ever seen a snow globe shaken a snow globe, that's what these eyelids, this is what this looks like, and you're putting all this into the the uh portal vein. And so there is going to be an increase in portal pressure as this is occurring and so, and that may lead to portal vein thrombosis. So we do anticoagulate with heparin intraoperatively as well as for a week postoperatively. We do measure portal vein pressures. There is of course data that demonstrates that pressures exceeding 25 centimeters of water pressure are associated with higher risk of portal vein thrombosis post TPIAT. And so if those pressures do rise, we, uh, allow, we stop the infusion temporarily and we allow some, uh, auto regulation of the pressures in the portal vein and then go ahead and, uh, proceed with continued infusion. If the portal vein pressures do remain elevated and we feel we can't safely put all the rest of all of the eyelets into the portal vein, we'll, uh, disperse them into the peritoneal cavity. Insulin fusion, we have to highlight this very significantly. This has started early on in the case in the operation. Uh, and it's critical to maintain, uh, glycemic control, uh, uh, post TPIAT, uh, as we, uh, as you, uh, it's very clear, we're disrupting all of the vasculature to the islets, and there are all sorts of stresses, and there are all sorts of pro apoptotic, uh, pathways that, uh, are exacerbated or are incited. Uh, and these eyelets do not resume function, uh, immediately. Uh, they really rely on just diffusion of nutrients and oxygen to the core of the eyelet until there's neovascularization that's occurred, which takes weeks to months. And really tight glucose control is very critical, uh, to, uh, protect from, uh, uh, toxic hyperglycemia. Uh, and what does this require? Very intensive insulin therapy. What do we do in the ICU thereafter? Uh, we do, uh, monitor for complications of, uh, portal vein thrombosis with Doppler ultrasounds. We do maintain, uh, heparin infusions. Uh, we do, uh, utilize a dexedrine infusion for the 1st 2 days to decrease the instant blood mediated inflammatory response which, uh, potentially, uh, which has a potentially detrimental effect on the islets as well. Uh, our glucose infusion, uh, uh, process, I'll have Deb talk about that in a little bit, um, but we do maintain tight glucose control between, uh, 80 and 120. And we utilize a continuous glucose monitor. Patient's on some antibiotics. We do advanced tube feeds over the course of the first week, and then, uh, by the end of that first week we're transitioning from an insulin infusion to subcutaneous dosing, uh, typically after we've advanced on tube feeds and of course pain management per our pain team. So with that I'll let Ken just describe that the infusions that were started in the operating room are continued at least for the 1st 24 hours or so while the patient's intubated and then are are turned off. They go on a patient controlled analgesia pump where they can hit the button and control their own pain, assuming they have the developmental and intellectual capability to do that. We'll continue the methadone. It's sort of a basal, and especially that'll account for any preoperative opioid that they were on. Um, as soon as the oral capacity resumes, we start, we resume the medications that they were on preoperatively. Um, we do not use any acetaminophen because some of our continuous glucose monitoring, um, will read falsely with that. So if we need to use it for some reason, we make sure that that's a conversation that's had before that's prescribed. Great, thanks again. After the ICU, uh, they do go to the surgical ward for several days to sometimes up to a week for a continued, post-surgical, um, recovery. We continue to advance tube feeds if necessary. We do advance PO diet as tolerated. We do sometimes utilize Augmentin or other agents for, um, uh, helping to promote improved gastric emptying, although, frankly, I, I think most of it is really tincture of time. Uh, and then finally the last, uh, stop is on the endocrinology ward, uh, and that's where really all of the intense teaching, uh, goes on in terms of, uh, insulin infusion pumps, diabetes education, uh, and pump, uh, enteral, uh, pump teaching. Patients are discharged locally for several weeks, and we have a follow up over the every 3 months for that first year, and then it's weaned thereafter, and tight glucose control remains critical weaning of opioids, and, uh, attention to nutritional issues and vitamin deficiencies. And then we also have to maintain. Control of, uh, uh, some of the, um, platelet issues and so what we have noted and others have noted is a significant thrombocytosis after this operation that likely is not necessarily just related to the splenectomy, um, but may have, uh, uh, some, um, mechanism based on increased thrombopoietin levels that we, uh, have seen in our patients post TPIT Thrombopoietin, of course, produced by, uh, the liver, uh, by the hepatocytes. What's the complication rate? About 15 to 20%. Uh, bleeding, uh, 5 to 7%. Abscesses, wound infections, bowel obstructions can occur, portal vein thrombosis and a handful of percent. Of course, any anastomosis can leak, bile leaks, enteral leaks. Uh, really every patient gets a systemic inflammatory response. Uh, and so they do have fevers for several days. Uh, and, uh, typically these do resolve, um, uh, by about post-op day 6 or 7, if not sooner. Uh, really, all patients because of that, uh, GI reconstruction do have delayed gastric emptying and have a requirement for a tube feed, uh, support, uh, and then the longer term issues that can occur is the presence of an anastomotic ulcer or gastritis. So what are the outcomes in kids? So, uh, it's clearly, uh, there is, uh, data now, um, for, for those that, um. Uh, haven't encountered TPIT, uh, patients and outcomes, uh, that really in up to 85-90% of patients, uh, uh, can achieve opioid independence. Uh, there's a reduction in pancreatis pancreatitis type pain and severity of pain. Really, most of the improvement occurs over the first several months. There's clearly a decrease in lost school days. These effects are sustained over time, but the important considerations, as has been alluded to already, is lifelong need for pancreatic enzyme replacements, daily multivitamins, and really this speaks to how we really have to discuss pre-op. having realistic expectations, trading one disease for another, glycemic control, 40% of patients, uh, uh, do achieve insulin independence, and this is in children, and typically this has occurred over the 1st 12 months. Uh, 30% have partial graft function, uh, uh, which, uh, requires just basal insulin requirement, and then 30% will require basal bolus requirements. Um, uh, data, uh, now has, uh, uh, come out, out of Minnesota that, uh, you know, the best outcomes, ah, have been seen in patients under 12, ah, and that, uh, is, uh, up to about 55% insulin independence rate for patients, uh, under 12. Uh, and why does this happen? Uh, it might, uh, there is some evidence that, um, there's a higher, uh, replicatory, uh, capacity of islets in the younger kids. There's also some evidence, uh, in some models that there's some eyelet, uh, neogenesis that occurs that's of ductal, uh, origin. Uh, and eyelet function, uh, has been shown to be durable in, in, uh, uh, children for as long as 10 years post TPIAT and is especially good for, uh, patients who have undergone TPIT who are under 21 or with a short history of, uh, uh, pancreatic disease. This is our experience, uh, thus far, um, uh, through 8 cases. Uh, we have had, uh, no significant surgical, uh, complications. Uh, I will mention that all these patients do have delayed gastric emptying. Uh, that does resolve in several weeks. Uh, we have, uh, 4 that are off of opioids, 2 are actively weaning, and 2 are still early post-op in the last, uh, 5 weeks. Uh, 1 patient is off of exogenous insulin, 4 are aggressively, uh, uh, uh, weaning at this point. So I'll turn this over for the last bit to Ken and to Deb for some of the other outcomes post TPIT. All right, I think one more polling question for me, and that is what is the role for opioids post TPIT? And that's 1, I expect patients to be on high dose opioids for a long time, or 2, I expect them to be on low doses for a long time. 3, I expect they'll wean off over a long period of time. 4, I expect they will wean off over a short to medium length of time. Or 5, I expect patients to be off opioids in the immediate post-op period. We'll come back. Now our approach to pain management we've gone through, and I just want to emphasize that it is really an emphasis on functioning that in the chronic pain management world is the bottom line because we may not be able to cure all pain, but we should be able to help them have their lives back and everything that we planned starting well in advance of the procedure continues through. So week one and thereabouts, we're converting the opioids from IV form to oral form. We resume the basal medications as I mentioned. We can advance oral analgesic medications as needed, um, and we begin our wean even within the first week, again, mostly from the the large rise in opioid need in the immediate post-op period. We encourage getting out of bed. We really push them to be functional. And then after about a week, the surgical, uh, we're, we're blessed to have more than one inpatient pain team. That's what makes things a little more complex here, but on the other hand, we can hand off to the medical team which will then hand off to the outpatient team uh in time. So, let's see what you guys thought about um the role of opioids post TPAIT. And it looks like uh either a long wan or short to medium wan. Good. That's extremely realistic. All right, um, we'll get back our slides. All right. We follow these patients very, uh, not only regularly as, as, uh, Jamie explained, but actually fairly frequently at first because we're making relatively rapid adjustments, uh, at first in the opioids. So you see them about every 2 weeks. Um, we really push for a return to normal function. Our goal is to wean them off of the opioids, and that's part of the expectations we set preoperatively. All right. Because as I talked about with the sensitization, the visceral hyperalgesia, if we're not going to treat that with opioids, it's not appropriate, and there is no pancreas to have acute inflammatory disorders, we expect to wean them off. They're going to need a lot of psychological and social support, and if they're really physically debilitated, physical therapy. We have just one couple of comments from uh Doctor Elder with regard to, uh, what we, how we manage glucoses. I think this is really important. I'll be very quick, very quick. So I need my slides. All right, so the role that endocrine plays in this transition is to help protect the patient from hypoglycemia and also keeping the blood sugars in this tight range of 80 to 120, and that's no small feat. Insulin is one of those medications that if it's in the wrong hands, there's high risk for complications. There's a couple of mechanisms that we have put in place to do this, and I'm not going to go through these in detail, but just to go through. The slide that we have an insulin titration protocol that's used in the ICU that doses the units to the thousands of a unit and we're titrating blood sugars on the every 30 minutes to 1 hour. We also have a hospital policy to use continuous glucose monitoring throughout the hospitalization that's used as a tool. It's not to replace blood sugar monitoring. We also have a nursing driven insulin administration policy. Allows the nurse to assess the blood sugar and administer insulin without losing valuable time and calling the resident, waiting for the resident to put in an insulin order and so based on parameters, the nurse can dose insulin every 3 hours and so that has been a nice piece of this puzzle. And lastly, we do have a hospital insulin infusion pump program. The pump in this patient population. is extremely valuable because as the surgeons want to start building in windows within the enteral feeds, the pump allows you to have a higher basal rate overnight, lower basal rate during the day. If there's a hypoglycemic event, you can turn the insulin off and so these are a couple mechanisms that we instituted in our program to to address the safety issue when you're keeping this tight blood glucose profile. All right, thanks, Deb. So. I think we'll conclude with that, so, uh, we're actually, um, I have to, if it's OK with you, I want to give a little summary here. Is that OK or do you have more? OK, so, uh, as someone who doesn't do any of this stuff, this was one of the best sessions that I've been involved with. I, I'm excited to bring this back to my group. I will say that the eyelet cell auto transplant is something that I am completely unfamiliar with and what I learned the most is when to refer. And what I'm gathering from this is basically when medical therapists fail, the importance of the, the pain is the chronic pain is the major indicator. Um, this is, this is the big important thing that I think we've finished off with, and you can see how the comments totally dropped off because all of us are completely ignorant to ISL auto transplant. No one, no one has a strong opinion on this, but I think what everyone learned here is, as they're writing now, is that that's we now know who and where to refer to. Um, and even the, the resective pancreatic operations, I mean, that's where you cross a fine line where is that something that most of the pediatric surgeons around the world can do on their own, or should they be sending that to a referral center? Me, I, I probably would send that to you because that's not something I've done. Ah, so, uh, I think that's what we've learned from this, and. Um, I think this was a fantastic session. Um, the, this is, by the way, this is, and we have to, the reason we're being so we, we always go over, but this time we have to be exactly on time is that we have another event following this for those of you online, the, the fetal event which we invite everyone to, to stay on and watch. Um, they have to, we have to go to a new mark. They have to go back to and re-log in or can they just stay on? No, it's a totally different thing. So get log out and come back in, um. This is CME, so, uh, all of you can, uh, get your CME credit if you take the post test, uh, which will be what's that? If you go to the links box at the top, you can then take the post test to get your CME credit. A certificate will be emailed to you, um, and this will all be available online in about 48 hours you'll be able to search any of these topics. All these people would, I'm sure be very happy to answer, uh. Ah, any of your specific questions, um, about the more simple stuff and also the more complex stuff that we finished off with, um, and we have the number here, ah, which we posted before, and we'll repost it again. The number is 513-803-2123. That's the pancreas Center, pancreas Care Center. Uh, so as you can see this fantastic team is not so simple. It's not something that most of us can do at our own institutions. Uh, you need a team of endocrinologists, of pain doctors, anesthesiologists, gastroenterologists, radiologists, adult gastroenterologists, yeah, and surgeons too. Uh, so this is, this is why we have places like, uh, like you guys and, uh, places that we can send patients that most of us can't manage on our own. So I thank you for teaching us all about this today and, and, uh, answering future questions in the future. So thank you very much for a great show today. Thanks for having me pleasure. So we'll, we'll be back, uh, we, uh, in about, it'll be actually in an hour, yeah, yeah, so in an hour we invite everyone to join the fetal show. Just go to the website and sign on up. Thanks.