Incidence, Risk Factors, Recognition and Prevention of Post-ERCP Pancreatitis

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1 International Journal of Mevlana Medical Sciences Advanced Technology and Science ISSN: Review Article Incidence, Risk Factors, Recognition and Prevention of Post-ERCP Pancreatitis Huseyin Korkmaz *a, Tuncer TEMEL b Received 2 th May 2013, Accepted 15 th May 2013 DOI: /b000000x Abstract: Pancreatitis remains the most common severe complication of endoscopic retrograde cholangiopancreatography (ERCP), and typically develops in 5-7% of patients. Although most post-ercp pancreatitis (PEP) is mild, severe pancreatitis and its complications can occur, and in rare cases death can result. Intensive studies about pharmacological agents and mechanical methods are being made to prevent the development or attenuate the severity of PEP, but still no drug or mechanical method which can be used commonly throughout the world has been investigated. Instead of recent technical advances in ERCP and upgrading experience of endoscopists there is no dramatic reduction in the incidence of PEP. Today, still, to prevent or minimize the development of PEP, determination and reduction of risk factors that plays a role in the development of PEP are the main stand. This article reviews risk factors for PEP as well as pharmacologic and procedural means that can be used to reduce its incidence. Keywords: Incidence Risk Factors; Recognition and Prevention, Post-ERCP; Pancreatitis; Detection of Post-ERCP. 1. Introduction Currently endoscopic retrograde cholangiopancreatography (ERCP) is used in increasing amounts for diagnosis and treatment of hepatopancreaticobiliary system diseases. Acute pancreatitis is the most common and the most feared complication of ERCP that can cause significant morbidity and mortality [1]. The incidence of acute pancreatitis after both diagnostic and therapeutic ERCP is reported in the range of and % respectively. However, some authors report that post-ercp pancreatitis (PEP) incidence might rise up to 15% at high-risk patients [1]. Different incidence rates for PEP at the literature may be due to varied definitions. PEP is defined as worsening of pre-existing or newly emerged abdominal pain and elevation of serum amylase levels at least three fold from the normal range within 24 hours after ERCP [2]. As the rate of asymptomatic hyperamylasemia is 30-70% after ERCP, serum amylase or lipase levels should not stand as a guide for the decision of PEP occurrence alone [3, 4]. In addition, after ERCP, gastrointestinal smooth muscle dysfunction syndrome (short-term abdominal pain, elevated serum amylase levels and leukocytosis) which must not be confused with pancreatitis can develop either [3]. Increase in amylase and lipase levels due to non-pep reasons secondary to ERCP generate the need for cut-off values of pancreatic enzymes. In a study performed by Testoni et al. with 231 patients for separation of PEP from non-pancreatic abdominal pain have been performed, the second hour serum amylase and lipase values were reported as more accurate than a Selcuk University, Faculty of Medicine, Department of Internal Medicine, Division of Gastroenterohepatology, Konya/Turkey, b Eskisehir Osmangazi University, Faculty of Medicine, Department of Internal Medicine, Division of Gastroenterology, Eskisehir/Turkey * Corresponding Author: husein68@hotmail.com clinical evaluation. Serum amylase values greater than 276 IU/L and lipase values greater than 1000 I/L at the second hour after ERCP have 100% predictive value for PEP [5,6]. More recently, in another study, it has been found that at the 3rd hour after ERCP if serum amylase levels are normal, incidence of PEP occurrence is only 1% whereas if serum amylase levels are five times higher than the upper limit value incidence of PEP occurrence is 39% [7]. If abdominal pain persists longer than 24 hours and the diagnosis is suspicious the contrast-enhanced computed tomography can be useful for a definitive diagnosis. If the patient has pancreatic type abdominal pain, leukocytosis, and hyperamylasemia the case can be treated as acute pancreatitis without any radiographic imaging except direct abdominal plain film for excluding perforation. Severities of post-ercp pancreatitis are classified according to the length of hospital stay. If the length of stay is up to 3 days it s considered as mild, if the length of stay is between 3-10 days it s considered as moderate and if the length of stay is longer than 10 days it s considered as severe pancreatitis. More than 90% of post-ercp pancreatitis are observed as mild and about 10% of post-ercp pancreatitis are observed as moderate or severe forms [2]. Many risk factors associated with the patient, endoscopist, and ERCP technique contributes to the development of PEP (Table 1). The mechanisms that lead to the formation of PEP are complex and not yet fully understand. Rather than a single chemical, hydrostatic, enzymatic, mechanical and thermal condition, pathogenesis is multifactorial [8-10]. Pathogenesis of PEP are mechanical damage as a result of difficult cannulation of common bile duct, hydrostatic damage as a result of excessive contrast injection to pancreatic duct, allergic or chemical injury at the pancreas secondary to ionic contrast, enzymatic damage as a result of activation of intestinal enzyme content, damage This journal is Advanced Technology & Science 2013 IJMMS, 2013, 1(1),

2 secondary to the bacterial contamination of endoscopes and accessories. All factors joint on the common pathologic way; otodigestion of pancreas secondary to premature activation of pancreatic proteolytic enzymes. Local and systemic inflammatory response depending on otodigestion leads to the release of inflammatory cytokines which resulted with acute pancreatitis [2, 8-10]. Table 1. Factors that increase the risk of post ERCP pancreatitis Patientrelated factors: Factors associated with endoscopist: Factors associated with ERCP technique: Younger age, female gender, suspected or known sphincter oddi dysfunction (SOD), a small bile duct diameter, normal serum bilirubin levels, history of recurrent acute pancreatitis, history of previous PEP Inexperienced endoscopist, hard cannulation, cannulation without guide wire, abstain from pancreatic duct stenting at high-risk procedures. Contrast injection to the pancreatic duct, pancreatic sphincterotomy, precut access, balloon dilatation, oddi manometry and endoscopic ampullectomy. Intensive studies about pharmacological agents and mechanical methods are being made to prevent the development or attenuate the severity of PEP but still no drug or mechanical method which can be used commonly throughout the world has been investigated. Instead of recent technical advances in ERCP and upgrading experience of endoscopists there is no dramatic reduction in the incidence of PEP. Today, still, to prevent or minimize the development of PEP, determination and reduction of risk factors that plays a role in the development of PEP are the main stand [11, 12]. Several studies have been conducted over the last 10 years involving pharmacological agents and mechanical methods for preventing PEP or decreasing its severity. In this review, the results of these studies will be discussed. 2. Prevention of Post ERCP Pancreatitis 2.1. Patient Selection and General Precautions The incidence of PEP can be reduced with the appropriate selection of patients and abstaining from ERCP at high-risk patients or patients that will not benefit from the procedure. Patients with low probability of bile duct stone presence and abdominal pain can be evaluated with non-invasive or less invasive alternative imaging methods like magnetic resonance imaging (MRCP) and endoscopic ultrasound (EUS). The risk for occurrence of PEP is 10 fold higher at patients with sphincter oddi dysfunction (SOD) (normal bile duct, recurrent abdominal pain and normal bilirubin levels). If the process is indicated in patients at high risk for development of complications such as pancreatitis, these cases must be informed and referred to a specialized center [3, 11, 12]. In addition, to reduce the risk of PEP development; physicians must avoid from diagnostic ERCP as much as possible and alternative non-invasive or less invasive methods must be implemented, endoscopist and the assistant must have sufficient experience, appropriately disinfected endoscopes and accessories must be used, selective contrast injection to common bile duct without traumatization of papilla and pancreatic duct cannulation must be performed. If you need to display the pancreatic duct, pancreatic duct must be carefully cannulated and cannulation time - the amount of injected contrast material must be kept as low as possible [3, 11] ERCP Techniques to Reduce the Post ERCP Pancreatitis Pre-cut sphincterotomy Approach to the biliary tree after unsuccessful cannulation is obtained by needle-knife (pre-cut) sphincterotomy. This technique is an independent risk factor for PEP [13]. This risk may be related with numerous cannulation attempts before needle knife sphincterotomy or traumatic nature of pre-cut technique. In a recent meta-analysis while incidence of PEP development is 2.5% at patients with early needle knife sphincterotomy, incidence of PEP development is 5.3% at patients with prior failure cannulation attempts [14]. Another meta-analysis showed that the rate of PEP is significantly decreased from 5.4% to 2.5% with premature needle-knife sphincterotomy [15]. Rate of PEP after needle knife sphincterotomy is decreased at patients with 10 or less cannulation attempts than patients with 10 or more cannulation attempts in a recent retrospective study [16] Stent Application to Pancreatic Channel As it has been clearly showed that stent application to pancreatic channel to high risk patients significantly reduces PEP incidence, pancreatic stent application becomes a standard procedure at patients under high risk of PEP occurrence. Pancreatic duct stent placement is effective in preventing pancreatic duct obstruction caused by edema secondary to cannulation, improves pancreatic duct drainage and decreases excessive hydrostatic pressure resulting from the contrast injection to the pancreatic channel [17]. A recent meta-analysis of high-risk patients; prophylactic pancreatic duct stenting have reduced the risk of PEP development significantly [18]. At high-risk cases like SOD, hard cannulation, orifice biliary balloon dilatation and pre-cut syphincterotomy, typical un-falanged (edge flush) 3-5 French pancreatic stents are used. A randomized controlled trial comparing the two stents, no difference in the rate of PEP occurrence was observed between 3 and 5 French stents, but emplacement of 5 French stent is much easier. (11.1 and 9.2 min respectively) [19]. Besides the general acceptance-reliability of pancreatic stents and the general consensus in the literature is the reduction of PEP at high-risk patients with stent placement; prophylactic pancreatic stent placement is not recommended as a routine procedure. Prophylactic pancreatic stenting is recommended in high-risk patients, at the suspicion of ampullar trauma, accidental pancreatic duct contrast injections or other worrisome situations Guide-Wire Cannulation Application of radio contrast material during the deep biliary cannulation (DBC) may cause unintentional contrast leakage into the pancreatic duct and increases the risk of PEP. Guide-wire cannulation technique pave the way for endoscopic access to both biliary tree and pancreatic duct without contrast application. As the guide-wire does not create excessive hydrostatic pressure, insertion of guide-wire to pancreatic channel while biliary cannulation does not lead to PEP [20]. ERCP was performed to 400 patients by a single endoscopist in a study. While 8 PEP cases was observed at patients with common bile duct cannulation by contrast agent application technique under fluoroscopy no PEP cases was observed at patients with common bile duct cannulation by guide-wire technique (P <0.001) and the successful cannulation rates were close to each other at the contrast application (98.5%) and guide-wire techniques (97.5%) [21]. In a retrospective study with 822 ERCP cases performed by Adler et all, successful common bile duct cannulation rate is 97% and PEP incidence is 1% at guide-wire technique [20]. Although no diversity between two groups in a meta-analysis comparing contrast agent applied cannulation with guide-wire cannulation at 1413 patients was determined (p>0.05),

3 at a recent meta-analysis guide-wire cannulation seem to be reduce PEP incidence 62% when compared with contrast agent applied cannulation (p<0.001) [22,23]. There was no difference between two groups for PEP incidence but total procedure time was shorter with guide-wire technique (20 vs 35 min, p>0.05) at the only prospective study of the literature comparing contrast agent applied cannulation with guide-wire cannulation at 500 cases [24]. Most commonly used guide-wire techniques are single and double wire techniques. In a randomized controlled trial with 188 patients, PEP ratio was significantly higher at double-wire cannulation group than single-wire cannulation group (17% vs 8%; OR: 2.13; 95% CI: ) [25]. Hence; in a retrospective study with 2843 patients, no significant difference between two techniques was demonstrated for the incidence of PEP. (5.3% vs 6.1%) [26] Pharmacological Agents Used in the Prevention or Reduction of PEP Pharmacological agents that have been or being tested for prevention of PEP development are selected in accordance with the pathophysiologic mechanisms of PEP. Action mechanisms of pharmacological agents according to pathogenesis are: 1) reducing the pressure of sphincter oddi 2) diminishing stimulation of pancreas 3) inhibiting protease activity 4) attenuation of enzymes associated with pancreatic inflammation cascade 5) prevention of systemic inflammation [27,28] Drugs reducing the pressure of sphincter oddi Drugs intended to prevent development of PEP by increasing papillary dilation and pancreatic drainage are nifedipine, epinephrine, nitroglycerine and botulinum toxin. Nifedipine is found to be ineffective in preventing the development of PEP when administered systemically prior to the ERCP [29,30]. Likewise direct topical application of spray lidocaine, epinephrine [31,32] and injection of botulinum toxin [33] directly to the papilla in the course of ERCP was found unbeneficial. Glyceryl trinitrate (GTN) implementation before the ERCP decrease the incidence of PEP apparently in comparison with placebo (5.9% vs 9.8%, p<0.001) in a meta-analysis study consisting 1820 patients; but the route of administration, the timing and dosage of the drug was non homogeneous [34]. In a recent separate meta-analysis of 1814 patients GTN reduced the incidence of PEP significantly (OR.56; %95 CI ; p = 0.001) [35]. Hence at a third meta-analysis consisted of 856 patients; depending on the sub-analysis; GTN was not superior to the placebo (RR 0.6 8; 95% CI , p = 0.12) [36]. In addition to conflicting results for the efficacy of GTP in preventing the development of PEP, routine usage in PEP prophylaxis is not recommended because of side effects like head ache and hypotension [11] Drugs reducing pancreatic enzyme secretion Somatostatine and its long-acting synthetic octapeptide analogue octreotide are potent inhibitors of pancreatic secretion. Theoretically inhibition of exocrine pancreatic secretion may prevent the development of PEP. However, a meta-analysis consisting 9 randomized controlled trials showed that somatostatine have no impact on reducing PEP incidence [37]. On the other hand at a recent randomized controlled trial somatostatine have reduced incidence of PEP significantly in comparison with placebo (%3.6 vs %9.6, p = 0.02) [38]. In a recent meta-analysis covering the last 17 randomized controlled trials consisting 3818 patients; systemic high-dose bolus injection or more than 12 hours continuous infusions of somatostatine are efficient approaches for prevention of PEP [39]. Inconsistent results of meta-analysis, lack of clarity on route of administration and the dosage of somatostatine as well as all the high cost of the drug restricts the routine application. Octreotide is long-acting and easy to use (due to subcutaneous administration) analogue of somatostatine. According to a previous meta-analysis; besides decreasing hyperamylasemia incidence; octreotide has no effect on reducing pancreatic pain and incidence of PEP [40]. Meanwhile in a recent meta-analysis of 18 randomized controlled trial high dose octreotide (>0.5 mg) admittance has reduced the incidence of PEP in comparison with placebo (%3.4 vs %7.5, p = 0.001) [41]. In addition, two novel studies with high patient numbers indicated that octreotide inhibits formation of PEP. In a randomized controlled study with 414 patients at octreotide and 418 patients at control groups; incidence of PEP (2.42% vs 5.6%, p = 0.046) and hyperamylasemia (12.32% vs 17.42%, p = 0.041) was found significantly lower at octreotide group [42]. High dose (500 mcg t.i.d) and long term (24 h prior to ERCP) octreotide admittance has lessen PEP incidence significantly than placebo (2% vs 8.9%, p = 0.03) [43]. Authors indicated that long term and high doses of octreotide administration is effective in preventing PEP. However, admittance of this approach to all patients is not costeffective Protease Inhibitors: Protease inhibitors, gabexate mesilate (GM), nafamostat mesilate (NM) and ulinastatin inhibits pancreatic trypsinogen which may play a role in the development of acute pancreatitis. GM has antiinflammatory effect in addition to protease inhibition. Hence earlier randomized controlled trials have found GM was effective in reducing the incidence of PEP [44,45]; a meta-analysis with the GM fails to show the efficacy in preventing the development of PEP. [37,46]. Ulinastatin is investigated as an alternative to GM in the treatment of acute pancreatitis. Latest two meta-analysis with the ulinastatin have determined that it can reduce the incidence of PEP, but anti PEP effect is at only high dosages like 150,000 units (OR: 0.039, 95% CI: , p = 0.01) (OR: 0.53; 95% CI: , p = 0.02) [47,48]. Although GM and ulinastatin are widely used in order to avoid pancreatitis in Japanese patients; utilization of these two important agents has not been accepted extensively in the west. NM (half-life 22 min) reduces the incidence of PEP significantly in comparison with placebo when admitted as a continuous infusion for 1 hour prior and 6 hours after ERCP (1.8% vs 9.1%) [49]. Very recent subgroup analysis of 608 NM administered patients established that although NM reduces incidence of PEP at low risk patients (2.7% vs 11.9%; p = 0.007) it has no significant effect on high risk patients (5.9% vs 14.6% p = [50]. In general; protease inhibitor application has not been approved for use outside of Japan because of the high cost, post-ercp hospitalization requirement and high patient number demand for prevention of one PEP episode (NNT = 34.5) [46] Drugs that reduce inflammation Drugs that reduce inflammation consists non-steroid antiinflammatory drugs (NSAID), corticosteroids, antioxidants, antibiotics and immune-modulator drugs. So far, most promising results at pharmacological prophylaxis have been obtained with NSAIDs. Diclofenac or indomethacin admitted via rectal route before or IJMMS, 2013, 1(1), This journal is Advanced Technology & Science 2013

4 after ERCP have reduced the incidence of PEP without any side effects [51-53]. First of these studies examined 912 patients; after administration of NSAIDs relative risk factor for PEP was found as 0.36 (95% CI ). The last of these 3 meta- analysis has been reported a significant reduction in the incidence of mild PEP (RR=0.49; 95% CI ; p = 0.009) and a slight decrease in the incidence of moderate and severe PEP (RR = 0.13, 95 CI , p = 0.50) [52]. At a very recent double-blind placebo-controlled study; 100 mg indomethacin via rectal route have decreased PEP incidence at high-risk patients by approximately 50% [54]. Based on these findings, only pharmacological agents recommended for prophylaxis of PEP by Society of European Gastrointestinal Endoscopy are rectal NSAIDs [11]. This recommendation is not accepted in America and besides recommendations many of the endoscopists from Europe do not admit NSAIDs for PEP prophylaxis already (83.7%) [55]. Prospective studies with intravenous COX 2 inhibitor valdecoxib and intramuscular diclofenac have shown that both agents do not have any effect on preventing PEP [56,57]. Whereas in a prospective randomized controlled trial performed by administration of 2 g intravenous ceftazidime ½ hour before ERCP have shown that ceftazidime significantly decrease the incidence of PEP in comparison with placebo (2.6% vs 9.4%, p<0.001) [58]; there is need for studies that will be illustrated with larger number of patients. Corticosteroids was not superior to placebo in preventing PEP (10.8% vs 12%, p = 0.20) and hyperamylasemia (29.9% vs 31.3%, p>0.05) at two meta-analysis consisted of 7 and 6 randomized controlled trials respectively [59,60]. Neither prophylactic low-dose unfractionated heparin nor low molecular weight heparin admittance showed significant benefit in the prevention of PEP at a meta-analysis consisted of 1438 patients [61]. There is little evidence supporting the use of interleukin-10, nonionic contrasts, PDE inhibitor udenafil-5, and antioxidants such as allopurinol and N-acetylcystein for prevention of PEP [62-65]. Secretin is a gastrointestinal hormone that stimulates the secretion of bicarbonate from pancreas. In a randomized controlled trial of 869 patients receiving intravenous secretin before ERCP, the incidence of PEP was significantly decreased in comparison with placebo (8.7 vs 15.1%) [66]. Instead of questions about costeffectiveness of secretin, results of the study give permission to further studies that will be held with secretin. 3. Results The most effective methods in preventing PEP are carefully selection of patients and identification of risk factors before ERCP. Non-invasive techniques (EUS - MRCP) should be considered as the first procedure for examination of pancreaticobiliary system at high-risk patients. Guide-wire cannulation technique and pancreatic stenting are proven techniques to reduce the incidence of PEP at high risk patients. Despite ongoing efforts for identification of a pharmacological agent to prevent PEP, no agent with full compliance to this purpose has been demonstrated yet. Diclofenac seems to be the only drug to be used in the prevention of PEP and is recommended due to inexpensiveness, reliability and ease of use. Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. References [1] Arata S, Takada T, Hirata K, et al. Post-ERCP pancreatitis. J Hepatobiliary Pancreat Sci 2010; 17: [2] Freeman ML. Post-ERCP pancreatitis: patient and technique- related risk factors. JOP 2002; 3: [3] Sarıtas Ü, Üstündag Y, Baron TH. Prevention of post- ERCP pancreatitis. Turk J Gastroenterol 2011; 22 (5): [4] Aliperti G. 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