Pancreatic Duct Stents for the Prevention of Post ERCP Pancreatitis: For All or Some?

GASTROENTEROLOGY 2012;143:493–500

SELECTED SUMMARIES Philip S. Schoenfeld, Section Editor John Y. Kao, Associate Section Editor

STAFF OF CONTRIBUTORS Nuzhat A. Ahmad, Philadelphia, PA Darren M. Brenner, Chicago, IL Andrew T. Chan, Boston, MA Francis K. L. Chan, Hong Kong, China Lin Chang, Los Angeles, CA Tsutomu Chiba, Kyoto, Japan Massimo Colombo, Milan, Italy B. Joseph Elmunzer, Ann Arbor, MI Alex Ford, Leeds, United Kingdom

Timothy B. Gardner, Lebanon, NH Lauren B. Gerson, Stanford, CA Colin W. Howden, Chicago, IL W. Ray Kim, Rochester, MN Paul Y. Kwo, Indianapolis, IN Edward V. Loftus, Rochester, MN Josep M. Llovet, New York, NY Julian Panes, Barcelona, Spain Joel Rubenstein, Ann Arbor, MI

PANCREATIC DUCT STENTS FOR THE PREVENTION OF POST ERCP PANCREATITIS: FOR ALL OR SOME? Sofuni A, Maguchi H, Mukai T, et al. Endoscopic pancreatic duct stents reduce the incidence of post-endoscopic retrograde cholangiopancreatography pancreatitis in high risk patients. Clin Gastroenterol Hepatol 2011;9:851– 858. Pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP), occurring in 3%–7% of cases, with the risk being as high as 20%– 40% in certain high-risk populations (Am J Gastroenterol 2007;102:978 –983; Am J Gastroenterol 2007;102: 984 –986). Most cases of post-ERCP pancreatitis (PEP) are mild with resolution of symptoms within 24 –72 hours. Severe PEP is rare, but can be life threatening. There has been significant interest in identifying interventions that can reduce the risk of PEP. Various pharmacologic interventions for prophylaxis of PEP have been investigated (Am J Gastroenterol 2007;102:978 –983; Am J Gastroenterol 2007;102:984 –986; Pancreas 2011;40:181– 186; Chin Med J Engl 2010;123:2600 –2606; Gut 2008;57: 1632–1633). However, most of these have been found to be either ineffective or impractical. In a recent, multicenter, placebo-controlled, double-blind clinical trial, a single dose of rectal indomethacin was found to be associated with a lower rate of PEP in high-risk patients (suspicion of sphincter of Oddi dysfunction; N Engl J Med 2012;366:1414 –1422). Similarly, a precise technique employed during endoscopic cannulation and endotherapy alone may not be sufficient to prevent pancreatitis in high-risk cases. Currently, pancreatic duct (PD) stent is the only nonpharmacologic intervention which has been reproducibly demonstrated to be effective for prophylaxis of PEP (Gastrointest Endosc 2011;73:275– 282). The mechanism by which the risk of PEP is lowered is not clearly understood. Nevertheless, there is substantial evidence in randomized, controlled trials that place-

Sameer Saini, Ann Arbor, MI Shiv K. Sarin, New Delhi, India Shamita B. Shah, Stanford, CA Amit Singal, Dallas, TX Jan Tack, Leuven, Belgium Michael L. Volk, Ann Arbor, MI Akbar Waljee, Ann Arbor, MI Kenneth K. Wang, Rochester, MN Alastair J. M. Watson, Norwich, UK

ment of a PD stent reduces the risk of PEP in high-risk patients (Gastrointest Endosc 2003;57:291–294; Gastrointest Endosc 2005;62:367–370; Clin Gastroenterol Hepatol 2007;5:1339 –1346; Gastroenterology 1998;115:1518 – 1524). These studies have included a heterogeneous patient population with various high-risk groups, including known or suspected sphincter of Oddi dysfunction, precut sphincterotomy, pancreatic sphincterotomy or endotherapy, endoscopic biliary balloon dilation of an intact papilla, endoscopic ampullectomy, and pancreatic brush cytology (Gastroenterology 1998;115:1518 –1524; Clin Gastroenterol Hepatol 2011;9:851– 8; Gastrointest Endosc 1993;39:652– 657; Gastrointest Endosc 2008;67:255–261). Expanding on these data, Sofuni et al have conducted a multicenter, randomized, controlled trial to evaluate whether the placement of a pancreatic spontaneous dislodgement duct stent would prevent PEP in patients with any risk factors (Clin Gastroenterol Hepatol 2011;9:851– 858). Their second aim was to identify risk factors for PEP. A total of 426 consecutive patients from 37 highvolume centers in Japan were randomized to 2 groups: A stent group with placement of a 5F ⫻ 3-cm stent without an internal flange and a no stent group. The endoscopists participating in the study were highly experienced, with a volume of ⬎300 ERCP cases per year. As per Japanese guidelines, all patients were administered ulinastatin (a protease inhibitor) immediately after ERCP and thereafter every 12 hours. In addition, prophylactic antibiotics were also administered. Stent dislodgement was confirmed by daily radiography until day 4, at which time a retained stent was removed endoscopically. Pancreatitis was defined by characteristic abdominal pain and hyperamylasemia to ⬎3 times the upper limit of normal within 24 hours after the procedure. Severity of pancreatitis was classified by previously defined criteria (Gastrointest Endosc 1991;37:383–393). The primary endpoint of the study was the frequency and severity of PEP in patients with risk factors. The authors performed an intention-totreat analysis. In addition, they also performed a full analysis set (FAS) of all cases except the excluded ones.

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The researchers reported that PD stent placement was successful in 88.3% of cases. The overall rate of PEP was 11.9%: 9.4% in the stent group versus 14.6% in the nonstent group in the intention-to-treat (ITT) analysis (P ⫽ .076), although the lack of significance could be partly because of the relatively small sample size. The FAS yielded a frequency of PEP in the stent group and nonstent group to be 7.9% and 15.2%, respectively (P ⫽ .021). There was no difference in the frequency of severe pancreatitis between the stent and no stent group. The majority of patients in both groups had mild pancreatitis. The rate of spontaneous stent dislodgement by day 3 was 95.2%. The mean duration to dislodgement was 1.8 days. No major complications were reported. Of those randomized to stent placement (n ⫽ 213), there were 25 unsuccessful PD stent placements; 12% of these developed mild pancreatitis. In multivariate analysis, risk factors for PEP were pancreatography first, nonplacement of stent after ERCP, procedure time ⬎30 minutes, pancreatic tissue sampling by any method, pancreatic intraductal ultrasound, and difficulty of cannulation (⬎15 minutes). There was a significant risk of PEP in patients with ⬎3 risk factors. The authors concluded that placement of a PD stent reduces the incidence of PEP. They also identified several risk factors for PEP. Comment. Pancreatitis continues to be a serious complication of ERCP, and can be associated with substantial morbidity. Various mechanisms of injury have been proposed, including mechanical injury to the papilla and pancreatic sphincter from cannulation, chemical injury owing to ionic contrast agents within the pancreas, hydrostatic injury as a result of excessive contrast injection into the pancreas, thermal injury from electrocautery, and enzymatic injury by activation of pancreatic enzymes. The relative contribution of each mechanism to the overall process is unclear. However, once initiated, the pathways of inflammation in PEP are similar to other forms of pancreatitis with inflammation localized to the pancreas, involving extrapancreatic tissues, or leading to a systemic inflammatory response. The risk of PEP is determined by a combination of patient- and procedure-related factors that have been well described (Gastrointest Endosc 2001;54:425– 434; Gastrointest Endosc 2004;59:845– 864). Female gender, age ⬍60, suspected sphincter of Oddi dysfunction, prior history of PEP, PD injection, endoscopic balloon dilation of an intact sphincter, precut sphincterotomy, difficult cannulation, and pancreatic sphincterotomy have been found on multivariate analysis to be independent risk factors for PEP. Furthermore, these risk factors are additive. Therefore, patients with ⱖ1 risk factors for PEP are at an even higher risk for PEP. To date, a number of pharmacologic interventions for prophylaxis against PEP have been studied (J Clin Gastroenterol 2011;45:170 –176; Pancreas 2010;39:1231–1237; Gastrointest Endosc 2007;66:1126 –1132; J Gastroenterol

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Hepatol 2008;23:e11–16; World J Gastroenterol 2009;15: 3999 – 4004; Gastrointest Endosc 2011;73:700 –706.e1–2). Most of these agents are targeted to interrupt the inflammatory cascade described. The results have been disappointing. Most recently, a multicenter, double-blind, placebo-controlled, randomized, controlled trials of 602 patients with suspected sphincter of Oddi dysfunction demonstrated a significant reduction in the rate of PEP in those that were given preprocedure rectal indomethacin (9.2% vs 16.9% in placebo; N Engl J Med 2012;366:1414 –1422). These results are indeed encouraging; however, thus far placement of a PD stent is the only nonpharmacologic intervention that has demonstrated efficacy for prophylaxis against PEP. Although the exact mechanism by which the stent prevents PEP is not well understood, it is thought to work by allowing drainage of the duct that may otherwise be compromised by intentional or unintentional manipulation of the pancreatic sphincter. There are several published studies in the literature that provide substantial evidence of the efficacy of pancreatic stents in preventing PEP, including a recent meta-analysis (Gastrointest Endosc 2011;73:275–282). It comprised a summary of 8 randomized, controlled trials and reported that prophylactic PD stents significantly decreased the risk of PEP (odds ratio, 0.22; 95% confidence interval, 0.12– 0.38; P ⫽ .010). A major limitation of these studies has been the lack of an ITT analysis, whereby patients in whom pancreatic stent placement fails are excluded. This is a significant omission, because failure of pancreatic stent placement has been demonstrated to be associated with a high pancreatitis rate (Gastrointest Endosc 2004; 59:8 –14). Despite the substantial data supporting the efficacy of pancreatic stent placement in various clinical scenarios, there continues to be some debate among endoscopists on exactly which cases merit a stent (Gastrointest Endosc 2006;64:45–52). Equally important, there is debate about whether all endoscopists should have proficiency in placing these stents. The study by Sofuni et al (Clin Gastroenterol Hepatol 2011;9:851– 858) provides additional, valuable data to the growing body of literature in this field. The study is well designed and conducted. In contrast with earlier studies, the study population included consecutive patients undergoing ERCP who met the inclusion criteria, regardless of the degree of risk. This is important to evaluate if we are to determine whether the spectrum of patients considered candidates for PD stenting is to be expanded. Second, the authors performed an ITT analysis, where all exclusion cases, once randomized, were included in the analysis. In addition, they also performed a FAS of all cases except the excluded cases, which is more reflective of the actual clinical situation. In addition, unsuccessful stent placement cases were not excluded from the analysis. This is an important consideration, because this group has higher rates of pancreatitis (Clin Gastroenterol Hepatol 2011;9:851– 858). The study results demonstrate that pancreatic stent placement is successful and safe in expert hands. The

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technical success rate was 88% without any major complications. The study also makes a case for using stents without internal flanges, because the majority of these stents dislodged spontaneously within 0 – 4 days mitigating the need for a second look endoscopy. Second, in the ITT analysis, there was a strong trend toward a significant benefit in the stent group, although the difference did not attain significance. This is likely reflective of the sample size of the study, and it is probable that with a larger sample size, the difference in the PEP rates would have reached significance. The authors have drawn their conclusions from the FAS data, which demonstrated a significant difference in the PEP rate between the stent and no-stent groups. Interestingly, 4 of the cases excluded from the stent group in the FAS data had PEP in the ITT analysis. Although we agree with the authors that the FAS findings are relevant and echo actual clinical settings, there should have been clarification as to whether the FAS analysis was planned a priori or was a post hoc analysis. Also, the PEP rates varied (0%– 60%) significantly among study institutions, which is interesting given that all the centers were high-volume centers. This reflects the reality that there is variation in results and expertise even amongst experienced endoscopists. Nevertheless, a PEP rate of 60% is exceedingly high, particularly in expert hands. As the authors correctly suggest, this may have influenced the findings of the study. In addition, the failure rate of pancreatic stent placement was 12%, which is higher than the previously reported rates of 4%–10% (Gastrointest Endosc 2003;57:291–294; Gastrointest Endosc 2005;62:367–370; Gastrointest Endosc 2004;59:8 –14; Clin Gastroenterol Hepatol 2007;5: 1354 –1365). One can easily assume that these rates would be higher in less experienced hands. Third, in contrast with previous studies that have suggested that guidewire cannulation as opposed to contrast injection may be associated with lower rates of PEP, the current study demonstrated a significantly high rate (34.6%) of PEP in cases where pancreatic guidewire was placed to achieve selective biliary cannulation. This is indicative of what most endoscopists suspect (ie, wire manipulation in the PD is itself a risk factor for PEP). Finally, the authors defined risk factors for PEP, all of which were procedure-related, and none of which would be unexpected or improbable to an endoscopist. So, how does one translate all these findings into clinical practice? Although there remains debate about the details of technique (type, size, and length of stent) in pancreatic stent placement, the evidence for efficacy of stents in preventing PEP in high-risk patients is substantial. Most of this evidence is from expert endoscopists in high-volume centers. What remains unclear is whether PD stenting is performed outside these centers, and if so, with what prevalence and outcomes. In addition, the question that continues to be discussed is whether all endoscopists who perform ERCP should develop proficiency in PD stenting or should high-risk patients undergo ERCP only at regional tertiary care centers where the necessary exper-

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tise is available to mitigate procedure-related complications. A published survey of community and tertiary care endoscopists (Endoscopy 2010;42:503–515) provides important insight into these questions. Fewer than 50% of those surveyed reported attempting prophylactic PD stent placement in ⱖ75% of cases clearly identified as high-risk ERCP cases. Twenty-one percent of respondents did not perform PD stenting in any of the circumstances listed and this was ascribed to lack of experience. Interestingly, some of the respondents reported placing 7F and 10F stents in the pancreas, which, considering the normal diameter of the PD, are excessively large and likely to cause duct injury. The lack of enthusiasm for PD stenting needs to be considered in the context of the technique required to place a PD stent and the potential risk of inducing PD injury by placement of one. The technique and equipment for PD instrumentation has nuances that are different from those required for biliary access and stenting. In addition, the anatomy of the PD can be highly variable. Hence, placement of a PD stent can be quite challenging even in expert hands. There have also been reports of serious injury resulting from duct perforation (either from a guidewire or the stent itself), inward migration of stents, or inadvertent delivery of a stent all the way into the duct. Despite these caveats, and given that regionalization of ERCP services is both impractical and unpopular with patients and providers, there is a growing consensus among opinion makers that the ability to place a prophylactic pancreatic stent be a part of the skill set of the endoscopist in practice performing ERCP (Gastrointest Endosc 2001;54:425– 434; Gastrointest Endosc 2006; 64:45–52; Gastrointest Endosc 2007;65:960 –968). The risk of PEP is a strong reminder to remain diligent about establishing a clear indication for performing ERCP. When ERCP is performed, it is imperative that the endoscopist be aware of patient and procedural risk factors, and is prepared to place a prophylactic PD stent when appropriate. The ability to place a pancreatic stent is an essential skill that should be acquired by those performing ERCP. The expectation is that all advanced endoscopy fellows acquire this skill at the end of their year of advanced training. For the practicing endoscopist, proficiency in pancreatic stenting requires education in indications for stents, understanding the anatomy of the PD, familiarity with equipment, training in technique, and awareness of potential complications and their management. There remain many aspects of prophylactic PD stenting that require further investigation. The prevalence, efficacy, and outcomes of pancreatic stent in a spectrum of practices need to be evaluated. The ideal stent design, material, and configuration needs to be defined. The optimal timing of placement of stent and the duration of stent placement for prevention of pancreatitis needs to be clarified. Finally, there is strong interest and ongoing research in pharmacoprophylaxis for PEP. Whether an effective agent will change the complexion of how ERCP is performed

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remains to be seen. Recent results from a randomized clinical trial on the use of preprocedure rectal indomethacin appear to be promising in the reduction of PEP (N Engl J Med 2012;366:1414 –1422). Continued investigation into these issues will provide us with much needed answers to these unresolved questions. BRINTHA K. ENESTVEDT NUZHAT A. AHMAD Perelman School of Medicine Hospital of University of Pennsylvania Philadelphia, Pennsylvania

MESENTERIC FAT AS A SOURCE OF CRP AND TARGET FOR BACTERIAL TRANSLOCATION IN CROHN’S DISEASE Peyrin-Biroulet L, Gonzalez F, Dubuquoy L, et al. Mesenteric fat as a source of C reactive protein and as a target for bacterial translocation in Crohn’s disease. Gut 2012; 61:78 – 85. C-reactive protein (CRP) has long been used as a nonspecific marker of inflammation and an important biomarker of disease activity in Crohn’s disease (CD) J Biol Chem 2004;279:48487– 48490). The liver was originally thought to be the only source of CRP synthesis. However, recent evidence has suggested human adipocytes as an extrahepatic source of CRP (Annu Rev Immunol 2010;28: 157–183). Interleukin (IL)-6 (a potent inducer of hepatic CRP expression) and tumor necrosis factor (TNF)-␣ are the main proinflammatory cytokines secreted by adipose tissue, suggesting inflammation in mesenteric fat may contribute to increased levels of CRP in CD (Gastroenterology 1999;117:73– 81). In this study, the authors investigated mesenteric adipocytes as a source of CRP expression in patients with CD and correlation with serum CRP concentrations. The impact of inflammatory and bacterial challenges on CRP expression by mesenteric adipocytes using an adipocyte cell line (3T3-L1 cells) was examined. Furthermore, bacterial translocation to mesenteric fat was studied in experimental models of colitis and ileitis and in patients with CD. The authors prospectively recruited a cohort 22 patients with CD, 17 with ulcerative colitis (UC) and 21 controls (with colorectal malignancy [n ⫽ 19] or diverticulitis [n ⫽ 2]). Biopsies of mesenteric and subcutaneous adipose tissues and healthy and inflamed colonic tissue were taken during surgery. Histologic examination was performed to confirm the absence of inflammation on intestinal biopsies and to select fat specimens at a distance from mesenteric lymph nodes. Using real-time polymerase chain reaction, levels of CRP mRNA expression were 105-fold greater in mesenteric adipose tissue of patients with CD compared with the UC and control groups. There was no observed difference between mesenteric CRP mRNA expression in the UC and control groups or in CRP mRNA expression in

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subcutaneous adipose tissue of all groups. To further investigate over-expression of CRP in mesenteric adipose tissue in CD, paired mesenteric and adipose tissue samples in the same patient were compared (n ⫽ 6). Unlike in UC and control groups subjects (where observed CRP mRNA levels were similar in mesenteric and subcutaneous adipose tissues), CRP mRNA was over-expressed 140-fold in mesenteric fat compared with subcutaneous fat in patients with CD. To investigate whether the adjacent intestine was a source of local CRP, they compared intestinal and mesenteric adipose tissue CRP mRNA levels in patients with and without CD. Observed CRP mRNA levels were significantly higher in mesenteric adipose tissue than in the intestinal tissue of the same patients and were 217,500 ⫾ 67,500 times higher in the CD patients, owing to mesenteric adipose tissue hyperplasia in this group. They confirmed mesenteric adipocytes as a source of CRP at the protein level using Western blot analysis, suggesting intestinal tissue is not a local source of CRP. To confirm whether mesenteric adipose tissue CRP overexpression is a potential source of CRP in the serum of CD, the authors examined the ability of mesenteric adipose tissue to release CRP by comparing mesenteric CRP levels with paired serum CRP levels in patients with CD. They observed a strong positive correlation between mesenteric CRP transcript levels and plasma CRP levels, whereas no correlation was observed in UC and control subjects. This suggests that CRP released by mesenteric fat may be in part responsible for elevated plasma CRP levels in patients with CD. To examine the mechanisms by which mesenteric adipocyte CRP expression is triggered, the authors measured CRP mRNA levels according to differentiation and activation states of adipocytes. A 21 ⫾ 2.5-fold induction of CRP mRNA expression was observed during differentiation of 3T3-L1 pre-adipocytes, paralleled by an increase in aP2 mRNA levels (a well-established marker of terminal adipocyte differentiation). This indicates that CRP expression depends on adipocyte differentiation. Furthermore, independent treatment of mature adipocytes with TNF-␣, IL-6, Escherichia coli infection and lipopolysaccharide (a structural component of the outer wall of gram-negative bacteria) resulted in a significant increase in CRP mRNA levels. In comparison, stimulation with a control grampositive lactobacillus strain lead to no observed significant increase in CRP synthesis by adipocytes. Finally, the authors used the dextran sulphate sodium (DSS) mouse model of colitis to investigate bacterial translocation from the gastrointestinal tract to mesenteric lymph nodes. Bacterial translocation to mesenteric adipocytes occurred spontaneously in 15% of control mice, but was enhanced in all mice with DSS-induced colitis. Furthermore, significantly higher rates of bacterial translocation to mesenteric lymph nodes were observed in mice receiving DSS compared with control mice. However, rates of bacterial translocation to mesenteric adipose tis-