with the review of guidelines and basically clinical applications of some of the newest ASG guidelines that have been released lately. Who better than to start us off than Dr. Joseph Elmanzar coming to us from the Medical University of South Carolina. He's going to be putting some pep into our morning to start off our day talking to us about post-DRCP pancreatitis. Awesome. Another pep talk. So thank you to the ASG and the course directors for inviting me to be here. It's an honor to be with you and to kick off what will hopefully be an awesome course. So I always say this. I have no commercial conflicts of interest, but I almost certainly have an intellectual conflict of interest related to rectal NSAIDs for preventing post-DRCP pancreatitis, without which my career would not be nearly as far along. But having said that, I really do my very best to be mindful of this conflict. So everybody in this audience knows that post-DRCP pancreatitis is bad. And sometimes it can be really, really bad with innumerable local and systemic complications, prolonged hospitalization, ICU stay, and death. And this is why we've tried so hard in the last three decades or so to find meaningful ways of preventing this complication. So most experts agree that the prevention of post-DRCP pancreatitis involves five elements of care that should be accounted for in every case, almost like a quality checklist. Number one is appropriate patient selection. Number two is risk stratification and meaningful use of that risk stratification information in clinical decision making. Number three is atraumatic and efficient procedural technique. Number four is prophylactic pancreatic stent placement and appropriate candidates. And number five is pharmacoprevention, which includes rectal NSAIDs and IV fluid resuscitation. In the interest of time, because of time constraints, I'm basically going to highlight the main take-home messages for each of these elements. And I'm going to do so using this framework that divides interventions to reduce post-DRCP pancreatitis into three phases, before, during, and after the procedure. So before the procedure and overall, the single most important intervention to reduce the incidence of post-DRCP pancreatitis is thoughtful patient selection. This is when you consider the strength of the indication, the clinical objective, and when you risk stratify patients according to patient-related and anticipated procedure-related risk factors for post-DRCP pancreatitis. And the guiding principle here is in this era of widespread availability of highly accurate but safe diagnostic alternatives, namely MRCP and endoscopic ultrasound, ERCP should be and has become a near-exclusively therapeutic procedure that really should be restricted to patients who are most likely to benefit and whom the risk-benefit ratio is most favorable. Now, risk stratification, according to independent predictors of post-DRCP pancreatitis, which have been widely published and with which most of us are familiar, is not only important for deciding whether or not to even proceed with the ERCP and whether to send the patient to a referral center, if so, but also has implications in the next two phases, including whether or not to place a prophylactic stent, whether to give rectal endomethasin or NSAIDs, how aggressive to be with IV fluid resuscitation, and whether or not to watch the patient in the hospital overnight because you perceive them to have a really high risk of post-DRCP pancreatitis. Now, during the procedure, it's widely believed on the basis of relatively limited evidence that sound procedural technique does reduce risk. And this is a complicated discussion that's somewhat outside the scope of this presentation. But the highlights are to favor a guidewire-assisted cannulation approach and the early implementation of alternative access techniques in the event of a difficult cannulation. So start with a wire, but be ready to pivot relatively early on to something else, like the double-wire technique or cannulating alongside a prophylactic pancreatic stent, early needle knife, relatively early on in the process in the event you're having a hard time achieving biliary access or access in general. And these are evidence-based and supported by meta-analysis. Now, in contrast, there are procedural interventions that we try to avoid, the most important of which are aggressive or repeated injection of contrast into the pancreatic duct, short duration, so one minute or less duration, balloon dilation of an intact biliary sphincter. Both of these have been shown to significantly increase the risk of post-ERSP pancreatitis. And recently, we've become quite interested in ERSP skill as it relates to performance and outcomes, and specifically in the role of video analysis to better understand what a skillful ERSP actually is so we can do a better job coaching it. And we all know that coaching works. Professional athletes almost invariably have coaches, even though they're typically quite masterful at their craft. But a coach for every ERSPist is obviously not realistic. But what could be practical and potentially scalable are video-based coaching initiatives and video-based coaching platforms, which is something in which we in ASGE is very interested, and our surgical colleagues are way ahead of us on this. They've done a lot of preliminary work with initial success, particularly around training, but also in post-graduate practice and so forth. And this could be a viable solution to helping our ERSP colleagues, who don't do as many, who are lower volume in terms of their practice. But before we can coach, we have to have a better understanding of what technical skill actually is in ERSP. And importantly, can it be reliably captured on video? And ultimately, does it really matter? Or is ERSP too idiosyncratic in terms of complications? Because we've all either heard of or had the misfortune of a one-touch seamless cannulation, a very quick procedure in which terrible pancreatitis develops. But toward this goal, we spent some time, a few years, developing and validating an instrument for the objective video-based assessment of technical skill in ERSP known as the BSAT, or the Bethesda ERSP Skill Assessment Tool, and this is available. And now we're in the process of conducting a portfolio of clinical studies to help understand things like the discriminative and predictive validity of this tool with the ultimate goal of taking it out into the community, initially in the form of a randomized controlled trial, to see if feedback based on video can help, particularly the lower volume ERSPists improve their performance and ultimately their outcomes. Now switching gears to intraprocedurally, the prophylactic pancreatic stent. We know that pancreatic stents work because they preserve pancreatic duct drainage in the face of orifice edema that can develop during and after the ERSP, so they reduce the likelihood of intraductal hypertension, which can elicit the inflammatory cascade. To my knowledge, there are 12 randomized controlled trials and at least as many non-randomized studies that have consistently shown benefit, and perhaps the most important benefit associated with prophylactic stenting is what appears to be a profound reduction in severe and necrotizing pancreatitis. Now I'm personally a big proponent of prophylactic stents and I have a relatively low threshold to place one in my practice, but it is important to acknowledge that pancreatic stents are associated with several potential disadvantages. So first trying to place a stent and failing to do so seems to increase risk above baseline. Non-pancreatic stent complications, including internal migration of the stent into the pancreas, which can be a nightmare, can complicate up to 5% of patients' cases. If stents are left in place for more than a short period of time, patients can develop stent-related duct changes, and although we don't fully understand the implications of these changes, there's no doubt that mechanically relevant strictures can occur. And of course, stents are inconvenient to patients and costly to the healthcare system because every single patient requires an abdominal x-ray to ensure spontaneous passage, and in up to 20% of patients, a follow-up EGD is necessary to remove retained stents. And beyond this, there's still several uncertainties around prophylactic stenting, including the fact that I'm not certain that we have a precise estimate of the benefit of this intervention because all the randomized control trials were unblinded and done by highly expert endoscopists. Plus, from a clinical point of view, it's not clear how hard we should be trying to place a stent. There's no doubt that there's a point of diminishing returns after which additional attempts become counterproductive, but we don't have a lot of clarity around that balance. But nevertheless, despite these disadvantages and uncertainties, it's important to highlight the fact that prophylactic stents are guideline recommendation, recommended as a strong grade A recommendation by both the ASGE and our European counterparts for patients at high risk for post-CRSP pancreatitis. Now, in parallel, rectal NSAIDs have become quite popular for preventing post-CRSP pancreatitis, and this started with a meta-analysis and then a more definitive randomized control trial that showed that endomethicin was safe and effective for preventing this complication. And since then, there have been several other RCTs and seemingly as many meta-analyses that have consistently shown a 40 to 60% risk reduction in post-CRSP pancreatitis associated with either rectal endomethicin or rectal diclofenac. But one unintended consequence of this line of research has been the skyrocketing cost of rectal endomethicin in the United States. And we and others, including Andy Storm and his group at the Mayo Clinic, have sounded the alarm around this problem, which is affecting patients directly. Now, how a medication that, when we published our initial endomethicin RCT in 2012, cost $20 and now can cost in excess of $2,000 to $3,000, and the problem is that patients are incurring this cost because endomethicin is not yet FDA-approved for post-CRSP pancreatitis, so some insurers don't cover this, and so this is cost directly to the patient. How this escalation happened is complicated and interesting. Of course, outside the scope of this presentation, but the message is that this is a real problem that we need to be addressing as a field, as a society, and something that we all have to innovate around trying to figure out, and there are some, there is some movement in that direction. But based on available evidence, it's clear that endomethicin is effective in addition to prophylactic stent placement in high-risk cases. But given the disadvantages and uncertainties, perhaps the more salient clinical question is whether or not rectal endomethicin can replace or significantly, or eliminate the need for pancreatic stents in clinical practice. And in 2013, two hypothesis-generating studies suggested this possibility, suggested if you gave rectal endomethicin, or the patient received rectal endomethicin, perhaps they didn't need a stent. And this observation is biologically plausible because the very process of placing a stent, so accessing the pancreas, negotiating a wire through the pancreatic duct, occasionally injecting some contrast for a roadmap, and then actually getting the stent into the duct, are all, of course, mandatory for stent placement, but in and of themselves can induce injury to the pancreas. But the problem is that even though those studies were intended to be hypothesis-generating, as a field, we sort of embraced the concept that pancreatic stents are no longer necessary. And so within a year of the publication of those papers, you could see the rate of prophylactic stenting among high-risk patients dropped precipitously in the United States, natering down to 3%. Although this is a trend in clinical practice that is incongruent with clinical practice guidelines and with the existing evidence, and is, again, an unintended consequence of rectal endomethicin, the sort of advent and diffusion of rectal endomethicin. So that was the rationale behind the recently concluded SVI, or stent versus endomethicin trial, which was a multi-center, randomized, double-blinded, non-inferiority study of rectal endomethicin alone, versus a combination of endomethicin plus a prophylactic stent. We enrolled 1,950 patients across 20 referral centers in the United States and Canada, with a major emphasis on developing a biorepository to fuel translational research in this space. Now, I am happy to report that the paper was accepted for publication a couple days ago, but unfortunately it's embargoed, so no results today, but hopefully soon. But it's important to reemphasize that until the SVI results are available, it is the combination of rectal endomethicin plus a prophylactic stent that is guideline-recommended for high-risk patients. So what I do in my practice, which we should all be doing. So I'll spend the last couple of minutes discussing IV fluid hydration, as it pertains to prevention of posterior speed pancreatitis. Now, everyone in the room is familiar with the concept that IV fluids are considered to be the cornerstone of managing acute pancreatitis in general. And posterior speed pancreatitis is a particularly attractive target because the exact time of the injury is known. So in theory, it's possible to take more full advantage of the quote-unquote golden window during which IV fluids are thought to be most beneficial. On the basis of relatively strong preclinical data and one randomized controlled trial, it does look like lactated ringers is superior to normal saline in this context. And there's a body of evidence that shows that lactated ringers infusion does reduce not only the incidence, but also the severity of posterior speed pancreatitis should it occur. Now, all this enthusiasm was tempered recently by the publication of the FLUT trial by our friends and colleagues in the Dutch Pancreatitis Study Group. So the FLUT trial was a randomized controlled trial of relatively aggressive versus modest IV fluid in patients undergoing ERCP. It was a methodologically rigorous RCT, although open label. And in this study, they basically showed no difference in posterior speed pancreatitis between the groups. However, one could argue that they use smaller volumes than what we typically believe should be helpful in this context. Their eligibility criteria resulted in the enrollment of mostly average risk patients. But despite this, there was a possible trend toward benefit in secondary outcomes in the event the patient were to develop posterior speed pancreatitis. And importantly, they didn't show a signal toward harm in the patients who are in the aggressive group. But we still don't know what the appropriate or what the optimal infusion strategy is, what the right dosimetry is. And so until relatively recently, what I would say is that my, for better or for worse, non-evidence-based practice had been to give about three liters periprocedurally, especially to young, healthy patients who are at high risk for posterior speed pancreatitis. And then if they're admitted with pain, then I would typically give them another three to five liters over the first 12 hours. And my rationale for this level of aggressiveness is that if they go home from recovery and they come back at midnight with posterior speed pancreatitis, the likelihood is that they're gonna be under-resuscitated, and I'd like to be ahead of the eight ball. And if you're thoughtful about patient selection, if you really sort of pay attention to the possibility of volume and sodium overload, my observation is quite uncommon to overload a patient with this strategy. But having said that, it's becoming very clear, and there's a growing body of evidence, that more is not better with IV fluids, including the publication of the recent Waterfall trial. And I think overall, the evidence is becoming clear that IV fluids for pancreatitis in general, and maybe for posterior speed pancreatitis, does have a J-shaped curve, so there's a point after which additional fluids are likely causing net harm. Now keep in mind, prevention is not treatment, and the Waterfall trial was a treatment study, so we may be in a different context with prevention, but the bottom line is all of us are now rethinking our approach to IV fluids, and I was taught more and more and more until volume overload. And obviously that's not the right approach for patients, so we all need to be a little bit more thoughtful about how to move forward. So in conclusion, ERCP should be a near-exclusively therapeutic procedure. That's the most important thing you can get out of this talk. Cases should be risk stratified, but you gotta use that information. Sound procedural technique is important, and hopefully we'll find ways to improve that. Prophylactic stents, rectal endomethysin, and aggressive question mark lactated ringers are indicated in high-risk cases, and you should be considering rectal endomethysin in all patients who are at risk for pancreatitis, although the costing is a really important consideration that's become quite problematic. So thank you very much.

post-ERCP pancreatitis

patient selection

risk stratification

procedural technique

pancreatic stent placement