ACUTE CHOLANGITIS AS a result of an occluded

Digestive Endoscopy 2017; 29 (Suppl. 2): 88 93 doi: 10.1111/den.12836 Current status of biliary drainage strategy for acute cholangitis Endoscopic treatment for acute cholangitis with common bile duct stone and stent occlusion Management of acute cholangitis as a result of occlusion from a self-expandable metallic stent in patients with malignant distal and hilar biliary obstructions Hideyuki Shiomi, 1 Kazuya Matsumoto 2 and Hiroyuki Isayama 3 1 Division of Gastroenterology, Department of Internal Medicine, Graduate School of Medicine, Kobe University, Kobe, Hyogo, 2 Department of Gastroenterology, Tottori University Hospital, Tottori, and 3 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Acute cholangitis as a result of common bile duct stones can be managed; however, cholangitis caused by occlusion with a biliary self-expandable metallic stent (SEMS) in patients with an unresectable malignant biliary obstruction has not been fully discussed. The acute cholangitis clinical guidelines (Tokyo Guidelines 2013) recommend following the same procedure as that used for cholangitis; however, the patient s condition, including performance status, tumor extension or staging, and prognosis must be considered. Most physicians manage cholangitis from a SEMS occlusion using a two-step procedure. They insert endoscopic drainage with a plastic stent or insert a nasobiliary drainage tube, which does not exacerbate sepsis. Addition or replacement of a biliary SEMS is required in many cases depending on the cause of the occlusion. Tumor ingrowth through the stent mesh is common in uncovered SEMS and requires placement of another stent in an in-stent method. However, covered SEMS tends to be occluded by sludge, so it must be replaced because of the bacterial biofilm that forms on the covering membrane. The location of the biliary stricture (hilar or distal) should also be considered. Strategies for managing cholangitis as a result of occlusion by a biliary SEMS remain controversial, so prospective clinical trials are needed. Key words: biliary stent, biliary stricture, endoscopic biliary drainage, obstructive jaundice, self-expandable metallic stent INTRODUCTION MANAGEMENT OF ACUTE cholangitis as a result of common bile duct stones has been comprehensively discussed. However, the appropriate management for acute cholangitis as a result of an occluded self-expandable metallic stent (SEMS) remains controversial. Because this is a common emergency situation, treatment strategies should be established for this type of cholangitis. Patients who undergo a SEMS procedure are always in poor physical condition from an unresectable malignancy with or without chemotherapy. The treatment strategy can differ depending on whether a distal or a hilar stricture is causing the stenosis. In this review, we discuss strategies to treat cholangitis as a result of a SEMS occlusion. Corresponding: Hiroyuki Isayama, Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Email: isayama-tky@umin.ac.jp Received 18 December 2016; accepted 2 February 2017. MANAGEMENT OF CHOLANGITIS AS A RESULT OF A SEMS OCCLUSION ACUTE CHOLANGITIS AS a result of an occluded SEMS can rapidly progress to a severe stage accompanied by organ dysfunction; thus, early detection is necessary for appropriate management, including emergency biliary drainage and medical treatment. These patients are advised to seek immediate medical attention when they have symptoms, such as fever and jaundice. Medical personnel are also educated to contact experts for immediate consultation when patients with symptoms call or visit. Patients with acute cholangitis receive blood biochemical testing at regular intervals and early stent replacement and re-drainage should be considered if biliary system enzyme levels are higher than normal. Furthermore, computed tomography (CT), magnetic resonance cholangiopancreatography (MRCP) and abdominal ultrasonography (US) are useful for pre-procedural planning to evaluate and manage targeted biliary ducts for stent replacement before endoscopic re-intervention, and endoscopic procedures can be carried out in a short time. 88

Digestive Endoscopy 2017; 29: (Suppl. 2): 88 93 Management of occluded biliary stent 89 Management of cholangitis and the SEMS are the two main considerations in these cases. Cholangitis is managed according to guidelines, but the patient s condition, performance status, chemotherapy, myelosuppression, cancer stage, and expected prognosis should also be considered. Endoscopic biliary drainage is mandatory depending on the timing, stent type, and procedure. Strategies to exchange a SEMS or place a new stent through the initial one are not well defined. In addition, if acute cholecystitis occurs after SEMS placement, it is sometimes difficult to diagnose which biliary infection occurred: cholangitis with or without cholecystitis, or cholecystitis without cholangitis. We should take blood tests and dynamic CT to distinguish the status. DISTAL BILIARY OBSTRUCTION A DISTAL SIDE biliary obstruction is caused by different types of malignant tumor, including pancreatic cancer, biliary tract cancer, gallbladder cancer, and lymph node metastasis. Endoscopic biliary drainage has been widely accepted as a palliative procedure for patients with an unresectable distal malignant biliary obstruction (MBO). Some studies have shown the superiority of SEMS compared with that of plastic stents (PS). Both covered and uncovered SEMS are used for distal MBO cases, but these two types of SEMS remain controversial. However, the superiority of uncovered SEMS for patency has not been elucidated, and these two types of SEMS have similar complication rates. Many endoscopists choose a covered SEMS for an MBO because of similar efficacy and the benefit of removability. CASE PRESENTATION AN 81-YEAR-OLD male patient had distal biliary tract cancer and was at tumor stage IB (T2, N0, M0 UICC). Initially, we placed a PS before surgical treatment (Fig. 1). However, acute cholangitis as a result of PS occlusion occurred 2 weeks later, so the PS was exchanged for endoscopic nasobiliary drainage (ENBD) (Fig. 2). We exchanged the ENBD for a covered SEMS 4 days later because of the patient s wish for the best supportive care (Fig. 3). He was admitted 5 months after placement of the fully covered SEMS because of recurrent grade II cholangitis according to Tokyo Guidelines 13. Clogging was diagnosed by endoscopic retrograde cholangiopancreatography (ERCP), and we cleared the clog with a balloon catheter. No re-occlusion was detected after 7 months (Fig. 4). DISTAL BILIARY OBSTRUCTION CASES WE CLEARED THE clog with a balloon to re-canalize the initial covered SEMS and manage the cholangitis. We used this approach because this case was not severe (a) (b) Figure 1 Cholangiogram and placement of a plastic stent for distal biliary tract cancer. (a) Distal biliary stricture (white arrows). (b) Placement of plastic stent (7 Fr Flexima stent; Boson Scientific Corp., Waltham, MA, USA). Bile juice flowing from the stent.

90 H. Shiomi et al. Digestive Endoscopy 2017; 29: (Suppl. 2): 88 93 Figure 2 Endoscopic nasobiliary drainage tube (pig-tail type) was re-placed to the occluded plastic stent. and the patient s condition was good. Placing an ENBD tube was another option, as these tubes can be used to check drainage status, bile juice volume, and the causative bacteria by culture. In addition, the tube can be washed if it becomes occluded. Indication for placing an ENBD tube has not been established, but we recommend this procedure in patients with severe acute cholangitis. No subsequent procedure was carried out in this case, and the covered SEMS was patent with no complications until the patient died. Replacing a covered SEMS after it becomes occluded with sludge has been recommended by some authors; however, the initial stent can be left in place to be cost-effective and reduce the number of procedures. 1,2 Another approach would be to place a PS inside the initial covered SEMS. No controlled comparative study has included this approach, and strong evidence is needed to manage this condition using this strategy. The utility of replacing a SEMS may be identified in the future when the prognosis of patients with pancreatobiliary tract cancer is improved by further advances in chemotherapy. 2,3 An uncovered SEMS is another viable option to treat distal MBO. Tumor ingrowth is the most common reason for occlusion of an uncovered SEMS, and cleaning is not appropriate in this situation. A PS or placing an ENBD tube can be used to manage cholangitis, and an additional stent (a) (b) Figure 3 Placement of a fully covered self-expandable metallic stent. (a) X-ray image after endoscopic placement across the papilla. (b) Endoscopic view.

Digestive Endoscopy 2017; 29: (Suppl. 2): 88 93 Management of occluded biliary stent 91 (a) (b) (c) (d) (e) Figure 4 Removal of sludge with a balloon catheter. (a) Cholangiogram showed occluded stent (white arrows). (b) Cleaning a stent with a balloon catheter. (c) Endoscopic view of sludge coming out of a stent. (d) Balloon catheter. (e) After cleaning a covered self-expandable metallic stent. should be placed inside the initial uncovered SEMS. Togawa et al. reported a retrospective comparative study of occluded uncovered SEMS and inserted covered SEMS in a stent-in-stent method, resulting in longer patency than that of an uncovered SEMS and PS. 4 No prospective data have established the management procedure for an occluded SEMS in cases of distal MBO. HILAR BILIARY OBSTRUCTION SEVERAL STUDIES HAVE shown that technical placement success rates for PS and SEMS in patients with distal MBO are similar, but the occlusion rate of a PS is higher than that of a SEMS. 5,6 Managing hilar MBO is technically more complex than that of distal MBO because of variations in hilar bile ducts. Mukai et al. reported a prospective randomized controlled trial in which SEMS were associated with longer stent patency, fewer complications, and better cost-effectiveness than those of a PS in patients with hilar MBO. The authors suggested that SEMS are more advantageous than PS for hilar and distal MBO. 7 Recent advances in chemoradiotherapy for unresectable pancreatobiliary malignancies have contributed to prolonged survival. SEMS dysfunction occurs in 20 27% of patients 8 and an occluded SEMS is associated with the development of acute cholangitis. High-risk patients with cancer and the elderly have an often-fatal complication of acute cholangitis, which requires emergency drainage. However, no evidence supports re-intervention for an occluded SEMS in patients with unresectable hilar MBO. The number of stents, choosing the drainage area, and the stenting configuration (side-by-side or stent-in-stent) are somewhat controversial in cases of hilar stenting with a SEMS. The re-intervention procedure is influenced by these factors, and this information should be considered before a re-intervention. CASE PRESENTATION THE INITIAL SEMS was placed using the stent-in-stent technique. After selective biliary duct cannulation, a guidewire was inserted into the target biliary duct through the SEMS and a small volume of contrast medium was injected (Fig. 5a). Two guidewires were inserted into the bilateral biliary duct (Fig. 5b), and an ENBD tube was placed through the occluded SEMS along the guidewires (Fig. 5c,d). If the stent would not pass through the SEMS mesh, the mesh was dilated using a dilator and a balloon catheter. After the cholangitis improved, the occluded SEMS and the extent of the stricture were evaluated with contrast medium injected into the ENBD tube (Fig. 6a). A wire-

92 H. Shiomi et al. Digestive Endoscopy 2017; 29: (Suppl. 2): 88 93 (a) (b) (c) (d) Figure 5 Emergency endoscopic drainage for acute cholangitis caused by occluded self-expandable metallic stent (SEMS) using the stent-in-stent technique. (a,b) Two guidewires were advanced into each of the two targeted intrahepatic bile ducts through the occluded SEMS. (c) Two nasobiliary drainage tubes were simultaneously advanced into the targeted intrahepatic bile ducts through the occluded SEMS. (d) After withdrawing the endoscope. (a) (b) (c) 1 1 2 2 Figure 6 Replacement of nasobiliary drainage (NBD) tube with a plastic stent (PS) in a stent-in-stent fashion. (a) Self-expandable metallic stent (SEMS) occluded by tumor ingrowth or sludge (white arrows) was evaluated with contrast medium injected from the NBD tube. (b) Sludge was cleaned from the SEMS using a wire-guided retrieval balloon catheter. Tumor ingrowth was confirmed by intraductal ultrasonography. (c) A PS was advanced and placed along each guidewire in targeted intrahepatic bile ducts through the occluded SEMS. guided retrieval balloon catheter was used to clear debris, an inflated balloon was pulled through the biliary duct, and tumor ingrowth was confirmed by intraductal ultrasonography (Fig. 6b). A PS was inserted through the occluded SEMS for the tumor ingrowth (Fig. 6c). HILAR OBSTRUCTION TWO APPROACHES HAVE been used for endoscopic or percutaneous transhepatic biliary drainage (PTBD) when the initial SEMS is occluded in a hilar MBO. The endoscopic biliary drainage is usually preferred as the first choice because it is less invasive and preserves patient quality of life. However, PTBD should be considered an alternative approach if the endoscopic approach fails. However, no evidence supports endoscopic management strategies for acute cholangitis caused by occlusion of a hilar SEMS. If an occluded SEMS is suspected based on symptoms and blood test results, emergency ERCP should be carried out. An occluded SEMS increases intraductal pressure, which eventually leads to cholangiovenous and cholangiolymphatic reflux. Translocation of bacteria into the bloodstream causes septicemia, which is often a fatal complication. Patients with cholangitis have infected bile juice and sludge in the biliary duct. If a large volume of contrast medium is pushed into the biliary duct, bacteremia is induced by cholangiovenous reflux. The targeting of bile duct which should be drained was required in hilar MBO and determined by MDCT or MRCP before ERCP. Three-phase (arterial,

Digestive Endoscopy 2017; 29: (Suppl. 2): 88 93 Management of occluded biliary stent 93 portal, and equilibrium) contrast-enhanced CT is required in hilar MBO cases and the arterial phase suggests the areas of inflammation. 9 A PS or an ENBD tube are placed for emergent biliary drainage. The advantage of ENBD is that it allows the monitoring of infected bile juice, washing out of debris by saline injection, and measurements of tumor ingrowth after a contrast medium injection. In contrast, the disadvantage is that it causes stress to patients and confers the risk of self-removal of the tube. After cholangitis improves, another stent should be inserted to prevent the biliary obstruction due to tumor ingrowth. A PS is generally used more commonly as the second stent. Placing a PS is simple, has a high success rate, and is easy to carry out as a re-intervention. A recent systematic review of 10 retrospective studies revealed that placing a PS may be as effective as placing a second SEMS. 10 In contrast, Inoue et al. reported that the median time to a recurrent biliary obstruction of a revisionary stent is significantly longer for placing a SEMS than that for placing a PS. 11 The Tokyo Criteria use the term recurrent biliary obstruction rather patency. 12 CONCLUSION IN CONCLUSION, We described management strategies for acute cholangitis caused by occlusion of both distal and hilar SEMS. Management of cholangitis and consideration of drainage strategies differ between distal and hilar cases. Many problems emerge regarding the drainage area, placement method, and optimal stent type for the appropriate approach to endoscopic palliation. Furthermore, re-intervention strategies for occluded SEMS should be individualized, considering patient condition or initial drainage, until more acceptable results are found in randomized controlled trials that further evaluate these issues. CONFLICTS OF INTEREST AUTHORS DECLARE NO conflicts of interest for this article. REFERENCES 1 Togawa O, Isayama H, Tsujino T et al. Management of dysfunctional covered self-expandable metallic stents in patients with malignant distal biliary obstruction. J. Gastroenterol. 2013; 48: 1300 7. 2 Kida M, Miyazawa S, Iwai T et al. Endoscopic management of malignant biliary obstruction by means of covered metallic stents: primary stent placement vs. re-intervention. Endoscopy 2011; 43: 1039 44. 3 Lee BS, Ryu JK, Jang DK et al. Reintervention for occluded metal stent in malignant bile duct obstruction: a prospective randomized trial comparing covered and uncovered metal stent. J. Gastroenterol. Hepatol. 2016; 31: 1901 7. 4 Togawa O, Kawabe T, Isayama H et al. Management of occluded uncovered metallic stents in patients with malignant distal biliary obstructions using covered metallic stents. J. Clin. Gastroenterol. 2008; 42: 546 9. 5 Isayama H, Komatsu Y, Tsujino T et al. A prospective randomized study of covered versus uncovered diamond stents for the management of distal malignant biliary obstruction. Gut 2004; 53: 729 34. 6 Kitano M, Yamashita Y, Tanaka K et al. Covered selfexpandable metal stents with an anti-migration system improve patency duration without increased complications compared with uncovered stents for distal biliary obstruction caused by pancreatic carcinoma: a randomized multicenter trial. Am. J. Gastroenterol. 2013; 108: 1713 22. 7 Mukai T, Yasuda I, Nakashima M et al. Metallic stents are more efficacious than plastic stents in unresectable malignant hilar biliary strictures: a randomised controlled trial. J. Hepatobiliary Pancreat. Sci. 2013; 20: 214 22. 8 Dumonceau JM, Tringali A, Blero D et al. Biliary stenting: indications, choice of stents and results: European Society of Gastrointestinal Endoscopy (ESGE) clinical guideline. Endoscopy 2012; 44: 277 98. 9 Kiriyama S, Takada T, Strasberg SM et al. TG13 guidelines for diagnosis and severity grading of acute cholangitis (with videos). J. Hepatobiliary Pancreat. Sci. 2013; 20: 24 34. 10 Shah T, Desai S, Haque M et al. Management of occluded metal stents in malignant biliary obstruction: similar outcomes with second metal stents compared to plastic stents. Dig. Dis. Sci. 2012; 57: 2765 73. 11 Inoue T, Naitoh I, Okumura F et al. Reintervention for stent occlusion after bilateral self-expandable metallic stent placement for malignant hilar biliary obstruction. Dig. Endosc. 2016; 28: 731 7. 12 Isayama H, Hamada T, Yasuda I et al. The Tokyo Criteria 2014 for transpapillary biliary stenting. Dig. Endosc. 2015; 27:259 64.