Post-ERCP pancreatitis prophylaxis: is it really that complex?

Acute pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP), occurring in about 3.5 % of unselected patients [1]. High risk patients should undergo pharmacological or mechanical measures to decrease post-ERCP pancreatitis (PEP), as PEP occurs in up to 25 % – 30 % of these patients [2]. Pharmacological approaches include rectal administration of indomethacin or diclofenac, sublingual administration of nitrates, and intravenous hydration [2]. The only mechanical approach recommended to prevent PEP is pancreatic duct (PD) stenting [2]. However, manipulation of the PD using wires and injection of contrast represent high risk interventions for the development of PEP [2]. Therefore, studies that investigate whether a pure pharmacological approach is equivalent to pharmacological intervention plus PD stenting in preventing PEP are of much interest. This is exactly what Sotoudehmanesh et al. from the Tehran University set out to investigate [3].

The authors performed a prospective, randomized study enrolling a total of 414 patients categorized as high risk for the development of PEP. The patients were randomized to a group receiving either pharmacological prophylaxis alone or pharmacological prophylaxis plus a PD stent. Pharmacological prophylaxis was identical in both groups and consisted of 100 mg indomethacin given rectally and 5 mg sublingual isosorbide dinitrate, plus Ringer’s lactate [3]. All procedures were performed by fellows-in-training supervised by endoscopists who were ERCP experts. The primary outcome was the rate of PEP.

The authors found no difference in PEP between the two groups (15.9 % vs. 12.6 %), concluding that the difference was not strong enough to show noninferiority of the approach using only pharmacological prophylaxis. Interestingly, the incidence of moderate and severe PEP was low in both groups (2.9 % vs. 1.9 %).

Do the results of this study indicate that endoscopists should maximize the prophylactic approach to include pharmacological intervention with additional PD stenting? My answer is a clear “No” and the rationale for my opinion is explained below.

“…I also share the authorsʼ hypothesis that additional stenting of the PD may not be as advantageous as presented by some experts endorsing this approach.”

The study has several advantages. First, it comes from a group of ERCP experts highly dedicated to the study of PEP prophylaxis [4] [5]. Second, the study was relatively large, prospective, and well designed, assuming a 10 % incidence of PEP; 10 % is a decent assumption compared with other studies expecting much higher incidences (e. g. 35 %), which of course does not represent general practice. Third, the results have wider applicability to current ERCP practices around the world compared with other tertiary center studies that recruit mainly patients with uncommon diagnoses including sphincter of Oddi dysfunction. Fourth, and most importantly, the authors compared the “best possible” medical prophylaxis with the best possible combined prophylaxis (medical plus PD stenting).

I must admit that I also share the authors’ hypothesis that additional stenting of the PD may not be as advantageous as presented by some experts endorsing this approach. In the study, there was no difference in the incidence of severe PEP in patients who received the PD stent and those who did not. I want to remind readers that placing a stent into a previously nonmanipulated PD automatically adds a high risk to the procedure. Indeed, the European Society of Gastrointestinal Endoscopy (ESGE) guidelines clearly state that wire and contrast manipulation of the PD entails a high risk [2]. Thus, I would mainly insert a plastic stent into the PD only when the wire accidentally entered the PD, as is also endorsed by ESGE. In the Sotoudehmanesh et al. study, plastic stents passed spontaneously within 72 hours in only a minority of patients (11.3 %). Almost 89 % of patients required a follow-up esophagogastroduodenoscopy to remove the PD stent, adding additional burden to the patient and cost to the procedure.

There are several potential drawbacks of the study. First, only about 1 in 5 patients (414 out of 2114) could be recruited. However, this is often the case in studies evaluating PEP. Nevertheless, in our practice we also need to make a decision on what type of PEP prophylaxis we should use for those patients using nonsteroidal anti-inflammatory drugs, or with creatinine higher than 1.4 g/dL or heart failure greater than New York Heart Association (NYHA) class 2. Therefore, the study should be interpreted only in the context of patients investigated. Of course, this does not decrease the validity of the results, but the use of PEP prophylaxis should not be expanded to all comers.

Second, the authors used criteria modified from existing PEP criteria, although these were still quite similar to the criteria listed by the ESGE [2]. In future studies, however, some of these criteria may need to be revisited, as (early) precut sphincterotomy, especially using the technique of fistulotomy, is now considered as safe or safer than ongoing attempts at bile duct cannulation with traditional bile duct sphincterotomy [2] [6].

Third, although the results come from a tertiary medical center, they may not apply to many of those centers worldwide. Most of the included patients suffered from biliary duct stones (72 %) and very few had tumors of the pancreas (about 3 %) [3]. Cannulation of patients with distal bile duct strictures is more difficult than those with an intact distal bile duct lumen.

Fourth, some technical factors of the procedure are not well described in the paper, such as how long the fellows were allowed to attempt cannulation, the diameters of the common bile duct, use of balloon or basket, and type of pancreatic stent. This latter aspect is quite important. The authors mention that it was a 5-Fr single-pigtail plastic stent from Endoflex (Germany). I am not familiar with this stent; it appears to have an inner flap, which may have been the reason for its low spontaneous passage. I recommend using 5-Fr single-pigtail stents without an inner flap so that spontaneous passage is possible, in accordance with ESGE guidelines [2]. In addition, and more importantly, PD stents are not commonly available in most endoscopy units around the world. This lack of availability of plastic stents may also be a reason for low acceptance of this method as prophylaxis of PEP [2].

In summary, although this study did not show that a pure pharmacological approach was noninferior to pharmacology plus PD stenting, it also did not demonstrate that it was inferior. What does this mean for ongoing ERCP practice? I will continue to give PEP prophylaxis with diclofenac or indomethacin suppository plus intravenous hydration to all high risk patients. A PD stent appears reasonable in patients who already have wire passage into the duct, but should not be aggressively pursued in others. A study comparing pure pharmacology vs. PD stent may be of interest, but I doubt it will have a higher impact that the current study because of the aforementioned limitation of PD stent availability. Future studies should attempt to include a higher number of patients and aim at finding superiority.

• References

• 1 Kapral C, Mühlberger A, Wewalka F. et al. Quality assessment of endoscopic retrograde cholangiopancreatography: results of a running nationwide Austrian benchmarking project after 5 years of implementation. Eur J Gastroenterol Hepatol 2012; 24: 1447-1454
• 2 Dumonceau JM, Andriulli A, Elmunzer BJ. et al. Prophylaxis of post-ERCP pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Guideline – updated June 2014. Endoscopy 2014; 46: 799-815
• 3 Sotoudehmanesh R, Ali-Asgari A, Khatibian M. et al. Pharmacological prophylaxis versus pancreatic duct stenting plus pharmacological prophylaxis for prevention of post-ERCP pancreatitis in high risk patients: a randomized trial. Endoscopy 2019; 51: 915-921
• 4 Sotoudehmanesh R, Khatibian M, Kolahdoozan S. et al. Indomethacin may reduce the incidence and severity of acute pancreatitis after ERCP. Am J Gastroenterol 2007; 102: 978-983
• 5 Sotoudehmanesh R, Eloubeidi MA, Asgari AA. et al. A randomized trial of rectal indomethacin and sublingual nitrates to prevent post-ERCP pancreatitis. Am J Gastroenterol 2014; 109: 903-909
• 6 Mariani A, Di Leo M, Giardullo N. et al. Early precut sphincterotomy for difficult biliary access to reduce post-ERCP pancreatitis: a randomized trial. Endoscopy 2016; 48: 530-535