CHOLEDOCHOLITHIASIS IN PATIENTS WITH ACUTE GALLSTONE-RELATED DISEASE: RISK FACTORS, IMPACT OF ADMISSION DAY AND TREATMENT STRATEGY

Transcription

1 ARISTOTLE UNIVERSITY OF THESSALONIKI SCHOOL OF HEALTH SCIENCES FACULTY OF MEDICINE CHOLEDOCHOLITHIASIS IN PATIENTS WITH ACUTE GALLSTONE-RELATED DISEASE: RISK FACTORS, IMPACT OF ADMISSION DAY AND TREATMENT STRATEGY A thesis submitted in fulfillment of the requirements for the degree of Master of Science in Medical Research Methodology By Eleftherios Gialamas Thessaloniki, December, 2016

2 CHOLEDOCHOLITHIASIS IN PATIENTS WITH ACUTE GALLSTONE-RELATED DISEASE: RISK FACTORS, IMPACT OF ADMISSION DAY AND TREATMENT STRATEGY A MSc thesis submitted in fulfillment of the requirements for the degree of Master of Science in Medical Research Methodology At The School of Health Sciences Faculty of Medicine Aristotle University of Thessaloniki By Eleftherios Gialamas Thessaloniki, December, 2016 Supervisor: Prof. Georgios Tsoulfas Co-supervisor: Prof. Christian Toso Advisory committee: Prof. Dimitrios G. Goulis, Prof. Spiridon Miliaras Word count:

3 AKNOWEDGMENTS First and foremost, I would like to express my sincere gratitude to my thesis advisor Prof. Christian Toso for the continuous support of my MSc study and research, for his patience, motivation, enthusiasm, and immense knowledge. His guidance helped me in all the time of research and writing of this thesis and steered me in the right direction whenever he thought I needed it. I would also like to thank Prof. Georgios Tsoulfas and Spiridon Miliaras for their encouragement, insightful comments and valuable input throughout this thesis. Moreover, I am fully indebted to Prof. Dimitrios Goulis, who is also one of my thesis advisors. Since my first year in Medical School, he has been providing me with direction, assistance and support and became more of a mentor and friend, than a professor. It was through his persistence, understanding and kindness that I completed my undergraduate and MSc degree and I owe him my full appreciation. Additionally, I would like to express my deepest appreciation and gratitude to Dr. Fani Apostolidou-Kiouti, surgical resident in Thessaloniki and instructor of Statistics during this MSc program. Her contribution during the whole procedure of the statistical analysis of this thesis was immense and valuable and I am extremely grateful to her for the great amount of hours spent for the accomplishment of this study. Last but not the least, I would like to thank my parents, who encouraged me during for the fulfillment of this MSc program and have always supported me with their understanding, wisdom and patience

4 INDEX AKNOWEDGMENTS INDEX ABSTRACT ABBREVIATIONS GENERAL PART A. Introduction to biliary tree Anatomy Intrahepatic biliary tree Extrahepatic biliary tree Gallbladder Physiology Bile formation and composition Gallbladder and sphincter of Oddi B. Gallstone disease C. Choledocholithiasis Definition, epidemiology and classification Clinical image Diagnosis Predictive risk factors Complications Cholangitis pancreatitis Management of confirmed choledocholithiasis Treatment strategy according to the risk of choledocholithiasis Low risk Intermediate risk High risk Impact of weekday admission

5 SPECIAL PART Aim of the study Patients and methods A. Study type, Setting, Design B. Patients C. Statistical analysis Results A. General features B. Predictive risk factors C. Impact of weekday admission D. Treatment strategy for intermediate risk patients Discussion A. Predictive risk factors B. Impact of weekday admission C. Treatment strategy for intermediate risk patients REFERENCES APPENDICES

6 ABSTRACT Word count: 298 Background: Choledocholithiasis occurs in 8-20% of patients with gallstone-related disease. The aim of this thesis was: to define predictive factors of choledocholithiasis in patients with acute gallstone-related disease, (b) to investigate the impact of admission day on the length of hospital stay and postoperative morbidity and (c) to define the best treatment strategy for patients at intermediate-risk for choledocholithiasis. Patients and methods: It is a retrospective cohort study of prospectively collected data for patients admitted in the emergency unit with acute gallstone-related disease, during 26 months. Results: (a) Significant factors associated with the presence of common bile duct (CBD) stone are advanced age, right upper quadrant pain, cholecystitis, increased concentrations AST, ALT, ALP, γgt, total and conjugated bilirubin and CBD dilation (p<0.05). The best fitting multivariate model for absence of choledocholithiasis (dependent variable) included cholecystitis, AST, ALT, γgt and CBD dilation (independent variables) with an area under curve of (b) No difference was found for length of stay or complication according to the day of admission. A shorter length of stay by 1 day was found in patients admitted in the Weekend group as compared to Weekday group (p=0.028). (c) Length of stay was shorter by 3 days (p<0.001) in the cholecystectomy-first group than in the endoscopic ultrasound ± endoscopic retrograde cholangio-pancreatography (ERCP)-first group, but no difference was found regarding complications. Conclusions: Age, right upper quadrant pain, cholecystitis, abnormal liver function tests and CBD dilation are independent risk factors for choledocholithiasis. The proposed multivariate model can predict the absence of CBD stone with an accuracy of 85%. Admission day does not have a significant effect neither on length of stay nor presence of complications. Finally, the cholecystectomy-first approach in intermediate-risk patients is associated with a shorter length of stay and fewer CBD investigations with similar postoperative morbidity

7 ABBREVIATIONS ALP: Alkaline phosphatase ALT: Alanine aminotransferase AST: Aspartate aminotransferase ASGE: American Society for Gastrointestinal Endoscopy AUC: Area under the curve BMI: Body mass index CBD: Common bile duct CCK: Cholecystectomy CI: Confidence interval ERCP: Endoscopic retrograde cholangio-pancreatography EUS: Endoscopic ultrasound ggt or γgt: Gamma-glutamyl transferase IOC: Intraoperative cholangiography IQR: Interquartile range LFTs: Liver function tests LoS: Length of stay MRCP: Magnetic resonance cholangio-pancreatography OR: Odds ratio PTC: Percutaneous transhepatic cholangiography ROC: Receiver operator characteristic - 7 -

8 RUQ: Right upper quadrant SAGES: Society of American Gastrointestinal and Endoscopic Surgeons SD: Standard deviation US: Ultrasound - 8 -

9 GENERAL PART - 9 -

10 A. INTRODUCTION TO BILIARY TREE 1. ANATOMY The biliary tree contains three different parts: (a) the intrahepatic biliary tree, (b) the extrahepatic biliary tree and (c) the gallbladder. Each part will be separately described below. INTRAHEPATIC BILIARY TREE The intrahepatic bile ducts are branches of the corresponding hepatic ducts that enter the liver via the Glisson s capsule and are situated above the corresponding branches of the portal vein. In general, they follow the corresponding arterial branching pattern inside the liver (1). As shown in Figure 1, the right hepatic duct drains the bile ducts from segments V, VI, VII, and VIII, which constitute the right liver. More precisely, usually, the bile ducts from segments V and VIII join firstly and form the anterior sectoral duct, and the bile ducts from segments VI and VII form the posterior sectoral duct. The two sectoral ducts join and form the right hepatic duct. The right anterior hepatic duct usually enters the liver above the hilar plate, whereas the right posterior duct dives behind the right branch of the portal vein. The left hepatic duct, which normally has a longer extrahepatic course before giving off its segmental branches, directly drains the bile ducts from segments II, III, and IV, which constitute the left liver. The caudate lobe (segment I) is drained by several small bile ducts that usually end into both the right and left duct systems (2). In 30-40% of cases, there may exist variations in the intrahepatic biliary tree, regarding either the right or the left hepatic duct. Figure 1: Usual pattern of intrahepatic biliary tree (3)

11 EXTRAHEPATIC BILIARY TREE The extrahepatic biliary tree (Figure 2) consists of the right and left hepatic ducts, the common hepatic duct, the cystic duct, and the common bile duct (CBD) or choledochus. The cystic and common hepatic ducts join to form the common bile duct. The common bile duct enters the second part of the duodenum through the sphincter of Oddi (4). Figure 2: Anterior aspect of biliary anatomy. a = right hepatic duct, b = left hepatic duct, c = common hepatic duct, d = portal vein, e = hepatic artery, f = gastroduodenal artery, g = left gastric artery, h = common bile duct, i = fundus of gallbladder, j = body of gallbladder, k = infundibulum, l = cystic duct, m = cystic artery, n = superior pancreatoduodenal artery (1) The cystic duct arises from the infundibulum of the gallbladder and extends to join the common hepatic duct. The length of the cystic duct is quite variable. The cystic duct may have variations in the drainage into the common bile duct. The surgeon should be familiar and expect these variants, as it can lead to potential injury during cholecystectomy or hepatic resection (1). The common bile duct is formed by the common hepatic duct and the cystic duct. It is approximately 8 to 10 cm in length and 0.4 to 0.8 cm in diameter and is divided into three

12 segments: supraduodenal, retroduodenal, and intrapancreatic. The supraduodenal segment is located in the hepatoduodenal ligament laterally to the hepatic artery and anteriorly to the portal vein (1,2). The retroduodenal segment follows a posterior course to the first portion of the duodenum (D1), anteriorly to the inferior vena cava, and laterally to the portal vein (2). The lower third (intrapancreatic) portion is located behind the head of the pancreas in a groove, or inside it, and enters the second part of the duodenum (D2) (1). The distal portion of the duct is covered by smooth muscle that forms the sphincter of Oddi. The common bile duct may enter the duodenum directly (25%) or join the pancreatic duct (75%) to form a common channel, called the ampulla of Vater (Figure 3). Arterial blood supply of the common bile duct is done by branches of the cystic, hepatic, and gastroduodenal arteries, whereas the venous drainage forms a plexus that enters the portal system. The lymphatic drainage follows the course of the hepatic artery to the celiac nodes (2). The mucosal epithelium of the bile ducts varies from cuboidal in the ductules to columnar in the main ducts (5). Figure 3: Common bile duct and the sphincter of Oddi (1) GALLBLADDER The gallbladder is a pear-shaped reservoir for bile located on the surface under the liver at the confluence of the right and left lobes of the liver (2). It varies in size (usually between

13 cm long), has a volume capacity of about ml and consists of four anatomic parts: fundus, body, neck and infundibulum or Hartmann s pouch 9 (Figure 2). The fundus projects 1 2 cm below the hepatic edge and can often be palpated when the cystic or common duct is obstructed (i.e. Courvoisier s sign). Arterial blood reaches the gallbladder via the cystic artery, which usually (>90%) originates from the right hepatic artery (5). Calot's triangle or hepatocystic triangle is an area of paramount importance in biliary surgery, as it represents the area where the cystic artery normally follows its course (3). It is bounded by the common hepatic duct on the left, the cystic duct inferiorly, and the liver margin superiorly. There exist several known variations in the origin and course of the cystic artery. The venous drainage of the gallbladder is directly into the liver parenchyma or into the common bile duct plexus. Lymph drainage is done into the lymph nodes of the neck. In many cases, we can meet a lymph node in the insertion of the cystic artery into the wall of the gallbladder, called the Mascagni s or Lund s lymph node. The gallbladder wall consists of a single epithelium that contains cholesterol, a lamina propria, a muscle layer and the serosa. The gallbladder differs histologically from the rest of the gastrointestinal tract as it lacks muscularis mucosa and submucosa. The mucus secreted into the gallbladder originates in the tubule-alveolar glands found in the mucosa of the infundibulum and neck (1). The innervation of the whole biliary tree is done by branches of the parasympathetic and sympathetic system. The afferent fibers in the sympathetic nerves mediate the pain of biliary colic. 2. PHYSIOLOGY The physiology of the gallbladder and sphincter of Oddi is regulated by a complex interplay of hormones and neuronal inputs designed to coordinate bile release with food consumption. BILE FORMATION AND COMPOSITION Approximately 500 to 1500 ml of bile is produced every day by the liver and is secreted in the intrahepatic biliary canaliculi. The secretion of bile is regulated by neurogenic stimuli

14 More precisely it is promoted by vagal stimulation and decreased by splanchnic sympathetic nerve stimulation (1,5). The main composition of bile is water, various electrolytes, lipid acids, bilirubin, bile salts, phospholipids, and cholesterol, with a ph of the hepatic bile neutral or slightly alkaline (6). During its passage through the ductules, hepatic bile is modified by the absorption and secretion of electrolytes and water (5). The yellow color of the bile is linked to the presence of the pigment bilirubin diglucuronide, which comes from the metabolism of hemoglobin, and in healthy patients is present in bile in concentrations 100 times greater than in plasma (7). When the sphincter of Oddi is open, bile flows from the liver through to the intrahepatic biliary ducts, into the common hepatic duct, through the common bile duct, and finally into the duodenum. When the sphincter of Oddi is closed, the bile flows into the gallbladder (7). GALLBLADDER AND SPHINCTER OF ODDI There are three factors of paramount importance in the regulation of bile flow: (a) hepatic secretion, (b) gallbladder contraction and (c) resistance of the sphincter of Oddi. The main function of the gallbladder is the concentration and storage of bile and its deliverance into the duodenum in response to a meal. During the fasting period, this storage represents approximately 80% of the bile secreted by the liver. It is possible thanks to the significant absorptive capacity of the mucosa of the gallbladder (1). The sphincter of Oddi creates a pressure gradient between the bile ducts and the gallbladder, thus facilitating the gallbladder filling. In response to a meal, the sphincter of Oddi relaxes and the gallbladder contracts and empties, forcing bile into the duodenum. The hormone cholecystokinin, released in the bloodstream from the intestinal mucosa, is the major physiologic stimulus for postprandial gallbladder contraction (8)

15 B. GALLSTONE DISEASE Gallstone disease is one of the most common pathologic entities of the gastrointestinal tract, affecting more than 20 million people in the USA. It is the reason for more than operations performed annually, with at least 6000 deaths resulting from its complications or treatment (5). The incidence of gallstones is affected by many factors, such as age, gender and ethnicity. Risk factors for gallstone disease include obesity, pregnancy, dietary factors, Crohn s disease, terminal ileal resection, gastric surgery, hereditary spherocytosis and thalassemia (9). The incidence of gallstones is higher in older ages and women are affected three times more than men (10). The 5-F rule refers to risk factors for the presence of gallstones: (a) Fair (more prevalent in Caucasian population), (b) Female, (c) Fat (BMI >30 kg/m 2 ), (d) Fertile (one or more children), (e) Forty (age 40) (11,12). The pathogenesis of gallstones lies in the failure to maintain certain biliary solutes, primarily cholesterol and calcium salts in a solubilized state. Gallstones are classified by their cholesterol content as either cholesterol (75%) or pigment stones (25%). Pigment stones are further classified as either black or brown (2). Figure 4: Cholesterol (left) and pigment (right) gallstones Despite their varying composition, all gallstones present with similar clinical symptoms (5). In the great majority of cases (almost 95%) gallstones remain asymptomatic and are

16 discovered incidentally during ultrasonography or CT scan for another reason. The reason why asymptomatic gallstone progress into symptomatic biliary disease remain still unknown (1). Approximately 1% to 2% of asymptomatic individuals with gallstones per year will develop symptoms, usually biliary colic, or complications related to their gallstones (2,5,13). The most usual symptom of symptomatic gallstone disease is postprandial biliary colic pain in the right upper quadrant (RUQ) associated sometimes with nausea or vomiting. The pain is caused by the mechanical effect of a gallstone against the walls and can be felt in the epigastric area or the right scapula. This condition is described by many authors as chronic cholecystitis. Complications of the simple symptomatic gallstone disease are (1): Acute cholecystitis Choledocholithiasis Cholangitis Biliary pancreatitis The present study focuses and will further elaborate on choledocholithiasis

17 C. CHOLEDOCHOLITHIASIS 1. DEFINITION, EPIDEMIOLOGY AND CLASSIFICATION Choledocholithiasis is defined as the presence of gallstone in the common bile duct. The prevalence of choledocholithiasis in patients with gallbladder stones is 5 12% (1,14,15) and in patients undergoing cholecystectomy 8 20% (16,17). The vast majority (>85%) of CBD stones are secondary, formed in the gallbladder and passed through the cystic duct into the common bile duct. Primary CBD stones originate de novo in the bile ducts and are associated with biliary stasis (due to various reasons, such as bile duct strictures, stenosis of the ampulla of Vater and tumors) promoting bacterial overgrowth. They are more frequent in the Asian population (1,2). 2. CLINICAL IMAGE Clinical manifestations of choledocholithiasis depend on the grade of obstruction of the CBD. In many cases (even >50%), CBD stones remain asymptomatic and are incidental findings during abdominal imaging for another purpose or in intraoperative cholangiography during cholecystectomy. The main symptom caused by CBD stones is pain. Progressive CBD occlusion as it happens in malignancies will rarely produce the same type of pain (5). Pain might be accompanied by nausea and vomiting. Another frequent symptom, depending on the grade of CBD obstruction, is jaundice accompanied by darkening of urines and pruritus (1,5). Symptoms may be transient if the CBD stone spontaneously makes its way through the ampulla (1). Finally, the clinical image of choledocholithiasis is sometimes associated with severe conditions of septic shock in case of cholangitis, or with pancreatitis, that remain the two most frequent complications of CBD and will be further described below. 3. DIAGNOSIS The initial paraclinical evaluation of a patient with suspected choledocholithiasis should include serum liver function tests (alanine aminotransferase, aspartate aminotransferase,

18 alkaline phosphatase, gamma glutamyl-transferase, total and conjugated bilirubin) as well as an abdominal ultrasound (15). Laboratory findings: Although elevated serum bilirubin, alkaline phosphatase (ALP), and transaminases are commonly seen in patients with choledocholithiasis, more than 30% of patients have normal LFTs (1). The elevation of serum bilirubin whose level usually does not exceed 10mg/dL occurs within 24 hours after the beginning of symptoms, and its direct fraction is higher than the indirect (5). Levels of ALP and bilirubin usually become normal in a few days after the removal of the obstacle. Due to the fact that the CBD obstruction is transitory and incomplete in most cases of choledocholithiasis, the rise in bilirubin levels is lower than the one observed in cases of tumoral CBD occlusion (1,2,5). Imaging findings: o Abdominal ultrasound (US): The first radiological approach towards a patient with suspected choledocholithiasis is abdominal US, which can show stones in the gallbladder and the presence or not of dilated CBD. Even though US is very sensitive for the diagnosis of gallbladder stones, it lacks sensitivity for the detection of CDB stones, as the interference of duodenal and/or colonic gas in the last portion of the common bile duct may cause difficulties in its visualisation (2). This sensitivity varies in different studies from 15% to 55% (2,18,19). On the other hand, US can effectively detect CBD dilation with a relatively high sensitivity (77-87%), which can be associated with choledocholithiasis (1,2,20,21). Despite the fact that mild CBD dilation >6mm has been related to advanced age, a dilation >8 mm found in the US in a patient with gallbladder stones could be an indication of CBD obstruction by stones (22,23). o Abdominal CT scan: Helical CT has shown a better sensitivity and specificity over abdominal US for the detection of choledocholithiasis, even if its expense and the irradiation exposure have put limits in its use as a first-line diagnostic tool of CBD stones (24 26). o Magnetic Resonance Cholangio-Pancreatography (MRCP): In several studies, MRCP has demonstrated high rates of sensitivity (85-95%) and specificity (93-100%) in the detection of CBD stones with a diameter larger than 5 mm

19 (27 29). It is a non-invasive imaging procedure that provides excellent biliary anatomic details, with the cost as main disadvantage (1,2). Figure 5: Magnetic resonance cholangiopancreatography (MRCP) shows a 5 -mm distal bile duct stone (arrow). o Endoscopic retrograde cholangio-pancreatography (ERCP): ERCP remains the gold standard for the diagnosis of CBD stones. Multiple studies attribute to ERCP high rates of sensitivity and specificity (89-93% and % respectively) (30,31). It provides a therapeutic option at the same time of diagnosis of choledocholithiasis and skilled, experienced endoscopists can successfully cannulate the ampulla of Vater and perform a diagnostic cholangiography in more than 90% of cases (Figure 6). ERCP has an associated morbidity <5% (in most cases pancreatitis, infection, haemorrhage) (1,2,32,33). Contra-indications or reasons for an unsuccessful ERCP may be previous gastric surgery (Billroth II or Roux-en-Y reconstruction), periampullary diverticula, or tortuous biliary duct (2)

20 Figure 6: ERCP: A. Schematic picture showing the endoscope in the duodenum and a catheter in the CBD. B. An endoscopic cholangiography showing stones in the common bile duct (arrowheads). (1) o Percutaneous Transhepatic Cholangiography (PTC): It may be used if ERCP is unsuccessful and is usually performed in cases of primary CBD stones rather than the secondary ones. o Endoscopic ultrasound (EUS): EUS has similar rates of sensitivity and specificity as ERCP for detection of CBD stones (92-100% and % respectively). However, it lacks possibility for therapeutic intervention (1,2,34). It can be performed similarly to a standard endoscopy with ultrasound imaging of the extrahepatic bile duct done through the duodenum. o Figure 7: EUS image of a gallstone (arrow) impacted into the papilla of Vater (35)

21 4. PREDICTIVE RISK FACTORS Until now, there is no single clinical risk factor, completely accurate in predicting the presence of CBD stone in patients with symptomatic gallbladder stones (2,15). A number of studies have tried to establish prognostic factors or scores, in an effort to predict the probability of choledocholithiasis before cholecystectomy. This is of major significance, as it can help the surgeon decide if an intraoperative cholangiogram (IOC) should be performed during cholecystectomy. According to a meta-analysis for predictive factors of choledocholithiasis, the presence of cholangitis, CBD stones on US and jaundice are the strongest indicators of CBD stones, with positive likelihood ratios of 18.3, 13.6 and 10.1 respectively (36). In 2010, the American Society for Gastrointestinal Endoscopy and the Society of American Gastrointestinal and Endoscopic Surgeons (ASGE/SAGES) published guidelines to categorize the risk of choledocholithiasis in patients with symptomatic gallbladder stones. This assignment was based on various clinical factors (such as age, LFTs and abdominal US findings), which were stratified in very strong, strong and moderate ones (Table 1). Patients are classified in high risk of choledocholithiasis (>50%) if at least one very strong or both strong predictors are present. Low risk of choledocholithiasis (<10%) includes patients without any of these predictors, whereas all other patients belong to the intermediate risk category (10-50%) (15). The detection of a CBD stone on abdominal US is found to be the most accurate predictor of choledocholithiasis prior to ERCP or cholecystectomy (15,36,37). On the contrary, a patient without jaundice and without CBD dilation on US has a low probability (even less than 5%) of choledocholithiasis (16,38)

22 Table 1: Risk of choledocholithiasis in patients with symptomatic gallbladder stones based on clinical predictors (15) Predictors of choledocholithiasis Very strong predictors CBD stone on abdominal US Total serum bilirubin > 4 mg/dl Clinical ascending cholangitis Strong predictors Total serum bilirubin 1.8 4mg/dl CBD dilation on abdominal US (>6 mm with gallbladder in situ) Moderate predictors Abnormal LFT other than total bilirubin Clinical biliary pancreatitis Age > 55 years old Risk for choledocholithiasis High High Low Intermediate Clinical predictors Presence of any very strong predictor Presence of both strong predictors Absence of any predictor All other patients

23 5. COMPLICATIONS CHOLANGITIS Acute cholangitis is a morbid condition of ascending bacterial infection in association with partial or complete obstruction of the bile duct. Choledocholithiasis is its primary cause (39). The clinical image varies from mild symptoms to septic shock. Main symptoms include RUQ pain, jaundice and fever (Charcot s triad), sometimes accompanied by hemodynamic instability and mental status fluctuation (Reynold s pentad) (1,2,5). However, according to the updated Tokyo guidelines for diagnosis and management of cholangitis, the new diagnostic criteria include jaundice and fever without pain, but with radiologic findings compatible with biliary obstruction (CBD dilation, stone visualisation, etc.) (40). Treatment includes intravenous administration of antibiotics, fluid resuscitation if required, and rapid biliary drainage (either by ERCP or by PTC) (1,2,5,40). PANCREATITIS Gallstone pancreatitis is the second most common complication of choledocholithiasis. In spite of the fact that the exact mechanism remains unclear, the impaction of a CBD, or a stone CBD migration into the duodenum might lead to an obstruction of the pancreatic duct, causing pancreatitis. According to the revised Atlanta classification, the diagnosis of acute pancreatitis requires at least two of the following three criteria: (a) acute onset of epigastric abdominal pain usually irradiating to the lumbar region, (b) serum lipase elevation at least three times the upper normal limit and (c) radiologic findings compatible with acute pancreatitis in the contrast abdominal CT (less commonly in the MRI or US) (41). If the symptoms are persisting and choledocholithiasis is proved by imaging, an ERCP with sphincterotomy should be performed, followed by a cholecystectomy during the same hospital stay

24 6. MANAGEMENT OF CONFIRMED CHOLEDOCHOLITHIASIS Various studies have shown that up to 80% of CBD stones will migrate spontaneously to the duodenum, and can eventually cause pancreatitis or cholangitis (42,43). These two complications of choledocholithiasis can lead to severe, even life-threatening conditions. It is, thus, generally accepted that CBD stones should be removed once discovered, even incidentally (44,45). Treatment of confirmed choledocholithiasis includes several options, depending on factors as the laparoscopic surgeon s and the endoscopist s skills as well as the individual patient s situation (2). Removal of choledochal stones, if detected during endoscopic cholangiography, can be achieved by sphincterotomy and a ductal stent can be placed to maintain drainage in case of incomplete CBD clearance (1,2,46). ERCP should then be followed by laparoscopic cholecystectomy. Figure 8: An endoscopic sphincterotomy. A. The sphincterotome in place. B. Endoscopic picture of completed sphincterotomy. (1) Choledocholithiasis can also be detected during an intraoperative cholangiography (IOC) at the time of cholecystectomy (47). In this case, there exist two options: (a) same time laparoscopic CBD exploration via the cystic duct (choledochoscopy with stone removal) or with laparoscopic choledochotomy and insertion of a T tube, and (b) endoscopic sphincterotomy as soon as possible after cholecystectomy. In case ERCP and sphincterotomy are not feasible, an open common bile duct exploration is required and a T tube should be placed if a choledochotomy has been performed (1,48)

25 7. TREATMENT STRATEGY ACCORDING TO THE RISK OF CHOLEDOCHOLITHIASIS LOW RISK As mentioned above, low-risk patients with symptomatic gallbladder stones have a probability less than 10% of choledocholithiasis. These patients should be treated directly with laparoscopic cholecystectomy without further CBD investigations (15). It stills remain controversial whether routine IOC should be performed or not (49 51). INTERMEDIATE RISK In patients that belong in the intermediate risk category (probability for choledocholithiasis 10%-50%), guidelines propose two valid options: either initial cholecystectomy or preoperative CBD exploration (15). A recent randomized controlled trial demonstrated superiority of the cholecystectomy-first approach (with IOC) compared to the preoperative EUS and ERCP with subsequent cholecystectomy in terms of length of hospital stay and total number of endoscopic or radiologic procedures per patient (52). HIGH RISK High-risk patients (probability of CBD stones >50%) require preoperative endoscopic exploration of the bile duct (15). Typically, preoperative ERCP is performed followed by laparoscopic cholecystectomy. There exists, however, the possibility to perform intraoperative CBD exploration. 8. IMPACT OF WEEKDAY ADMISSION It is true that ERCP can be simultaneously a diagnostic and therapeutic procedure requiring the coordination of a health-care team that includes a specialized endoscopist, a trained nurse and in some cases, anesthesiologists (53,54). Due to all these requirements, ERCP is not always easy to obtain during weekends and holidays, in the exception of urgent cases of severe cholangitis. It is also generally acceptable that in many departments of Abdominal Surgery, even the realization of laparoscopic cholecystectomy can be differed in time, if patients are admitted during the weekend and their clinical condition allows it

26 On the other hand, many studies have been referring to the so-called weekend effect for various acute conditions. Indeed, it has been shown that weekend hospital admission and realization of procedures has been associated with worse outcomes, as the staff is often reduced during weekends (55 57). Weekend effect has been demonstrated for acute myocardial infarction (58), stroke (59) as well as gastrointestinal pathologies (upper gastrointestinal bleeding (60,61), urgent surgery for complicated bowel inflammatory disease (62)). In regards to ERCP, two recent retrospective studies showed absence of weekend effect in cases of acute cholangitis, with patients having similar clinical outcomes irrespective of the weekday they were admitted (53,56), even if difference was found in the time from admission to ERCP. However, a third similar retrospective study taking into account all ERCPs (and not only for cholangitis), demonstrated a significant decrease in length of hospital stay and a trend towards decrease in inpatient charges for patients undergoing ERCP during weekend (54)

27 SPECIAL PART

28 AIM OF THE STUDY This study refers to adult patients admitted in the emergency unit of a tertiary university hospital with acute gallstone-related disease. It has four main goals, which are analytically described below: a) Demographic data and general features of the patients will be described. Patients will be categorised in groups regarding the risk of choledocholithiasis as well as the treatment strategy followed in each of them. b) An effort will be done to define possible risk factors that could predict the presence of choledocholithiasis upon admission of the patient in the emergency unit. c) The impact of the admission day of the patient on the length of hospital stay will be investigated as well as the presence of postoperative complications. d) The best treatment strategy in terms of length of stay, overall outcome and complications will be defined for those patients belonging to the category at intermediate risk for choledocholithiasis, as this is defined upon admission in the emergency unit. The comparison will be made between the cholecystectomy-first strategy vs the EUS/ERCP-first strategy

29 PATIENTS AND METHODS A. STUDY TYPE, SETTING, DESIGN It is a retrospective cohort study, including adult patients that were admitted at first in the Emergency Unit, then in the Division of Visceral Surgery at the Geneva University Hospitals, Geneva, Switzerland. The study period was 26 months, from the 1 st November 2012 till the 31 st December All patients were studied prospectively and their records were screened for extraction of the desired data that will be described analytically below. B. PATIENTS INCLUSION CRITERIA All patients 16 years old admitted through the Emergency Unit with an acute gallstonerelated disease from November 2012 to December 2014, and having undergone a cholecystectomy during their hospitalization. Presence of gallstones was confirmed by abdominal ultrasound in all patients. More precisely, patients included in the study were: a) Patients with persistent biliary colic pain, as defined by sudden right upper quadrant (RUQ) pain with duration of more than 6 hours and ultrasonographic evidence of gallstones. b) Patients diagnosed with acute cholecystitis, based on clinical criteria (fever 38.5 C, positive Murphy sign) as well as ultrasonographic criteria (gallbladder wall thickness >4 mm, striated gallbladder wall, perivesicular fluid). c) Patients diagnosed with acute cholangitis, as defined by the revised in 2013 Tokyo guidelines (40). d) Patients with suspect CBD stone migration (sudden RUQ and/or epigastric pain, associated with elevated LFTs). e) Patients with acute mild biliary pancreatitis, as defined by the revised Atlanta classification (41). EXCLUSION CRITERIA Patients were excluded of the study based on the following criteria:

30 a) Patients having previously undergone cholecystectomy (including acute cholangitis or pancreatitis due to a residual CBD gallstone). b) Patients with modified gastro-duodenal anatomy interfering with endoscopic assessments (in cases of Roux-en-Y gastric bypass or Billroth II procedures). c) Patient or legal caretaker refusal to undergo cholecystectomy or incapacity to provide informed consent. d) Patients with a previous ERCP failure. e) Indications for delayed cholecystectomy (including acute cholecystitis with a symptoms duration more than seven days). f) High-risk patients for whom the decision was taken upon admission, after preoperative medical assessment, to differ cholecystectomy (during another hospitalization). g) Patients with acute moderate and severe biliary pancreatitis, as defined by the revised Atlanta classification (41), since the main concern of their treatment is resuscitation, stabilization and in many times, iterative surgical operations for debridement of necrotic tissue, differing thus the time of cholecystectomy (even if this last was performed in some cases during the same hospitalization). h) Patients with associated hepatic or bilio-pancreatic malignancy. C. STATISTICAL ANALYSIS GENERAL FEATURES All statistical calculations were done using the R version for Microsoft Windows TM. Normality was assessed in every case using either the Kolmogorov-Smirnov test (if the sample size was 50) or the Shapiro-Wilk test (if the sample size was less than 50). Data were summarized using the mean values (with standard deviation) in case of normal distribution, or the median values (with the interquartile range) in case of non-normal distribution. A p-value 0.05 was considered significant. Collected data included demographic data and general features of patients (age, gender and body mass index [BMI]), clinical features (presence or absence of fever and right upper quadrant [RUQ] pain upon admission), detailed LFTs values on admission (aspartate

31 aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP], gamma-glutamyl transferase [γgt], total and conjugated bilirubin) and lipase values. Data was also collected concerning the presence of a bilio-pancreatic history, including previous episodes of jaundice, cholangitis or pancreatitis. As far as total and conjugated bilirubin are concerned, a conversion factor of 17.1 was applied in order to convert mmol/l to mg/dl. Additionally, ultrasonographic findings on admission were collected, including common bile duct (CBD) diameter measurement and presence of associated acute cholecystitis. As CBD dilation we considered a diameter 6 mm. Assessment of presence of acute cholecystitis was based on the criteria described in the Patients section. We also recorded the final number of CBD explorations per patient in the exception of IOC (EUS, ERCP, and MRCP) performed during the same hospital stay, as well as the presence or absence of a CBD stone in the end of investigations. Postoperative complications including all surgical and medical adverse events were assessed using the Clavien-Dindo classification (63), with severe adverse events defined as a score III. Patients were classified into three groups according to the risk of choledocholithiasis (low, intermediate and high risk) and based on the ASGE/SAGES guidelines (15). Based also on the same guidelines, patients with mild gallstone pancreatitis are considered at intermediaterisk for CBD stone. However, due to the need for delaying cholecystectomy during the same hospitalization until the patient has been resuscitated and stabilized, these patients were considered as high-risk patients for choledocholithiasis. Based on the ASGE/SAGES recommendations (15), low-risk patients were treated with initial laparoscopic cholecystectomy with intraoperative cholangiography (IOC), followed if needed by endoscopic ultrasound and stone extraction (EUS/ERCP). Based on the same recommendations, high-risk patients, as previously defined, were treated with initial CBD investigations (either EUS or MRCP), followed if required by ERCP. Subsequent laparoscopic cholecystectomy with IOC was performed during the same hospital stay. The same treatment strategy was also opted for patients with mild acute biliary pancreatitis, who were, as per local policy, classified in the high-risk category for choledocholithiasis. Finally, for intermediate-risk patients, the treatment strategy incorporated the recommendations of a prospective randomized clinical trial having taken place in the same Department, demonstrating superiority of the cholecystectomy-first strategy for this category of patients, in terms of length of stay (52). Consequently, these patients were treated with initial

32 laparoscopic cholecystectomy with IOC, followed if needed by endoscopic ultrasound and stone extraction (EUS/ERCP). PREDICTIVE RISK FACTORS Predictive risk factors were used for univariate and multivariate analysis using logistic regression. The results were expressed using OR and 95% CI. P-values <0.05 were considered statistically significant. A multivariate model was then built after backward variable selection using the Akaike's criterion (AIC). Included variables in the model had to demonstrate a p <0.2 in the univariate model. P-values <0.05 were considered statistically significant in the final multivariate model. The goodness of fit was assessed with the R- squared value. IMPACT OF WEEKDAY ADMISSION At first, statistical analysis was performed to check if there is an impact of each weekday admission separately on the length of hospital stay (primary outcome) and the presence of postoperative complications (secondary outcome), for all patients included in the study, irrespective of the treatment strategy followed. Kruskal-Wallis test was used for the first and Fisher s exact test for the second purpose, respectively. P-values < 0.05 were considered statistically significant. Dunn s test with Bonferroni correction was used for multiple comparisons using rank sums. A second analysis was performed for three groups of patients according to the treatment strategy that was followed (cholecystectomy only, cholecystectomy followed by EUS/ERCP, EUS/ERCP followed by cholecystectomy). Kruskal-Wallis test was used for the investigation of impact on the LoS and Fisher s exact test for the investigation of impact on the presence of postoperative complications. Again, p-values < 0.05 were considered statistically significant. A third analysis was then performed, pooling patients in two weekday groups, according to their day of admission, as defined below: Weekday group A: Tuesday, Wednesday, Thursday, Friday Weekday group B (or weekend group): Saturday, Sunday, Monday The pooling in these two weekday groups was based on the observation that in our institute, the realization of an emergent ERCP or cholecystectomy is more difficult to take place during

33 the weekend. This is the reason why we made the hypothesis that patients admitted during the second weekday group were more likely to obtain an ERCP or CCK rapidly (early the following week) than those admitted in the first weekday group. In this third part, we investigated only the primary outcome, length of stay, and repeated the analysis for all patients as well as for the three groups according to the treatment strategy followed. Mann- Whitney test was used and p-values less than 0.05 were considered statistically significant. Finally, subgroup analysis was performed in order to detect any differences among the two weekday admission groups for the times between various interventions, using Mann-Whitney test. More precisely: For the cholecystectomy only group: time from admission to cholecystectomy (t 1 ), time from cholecystectomy to exit (t 2 ). For the cholecystectomy followed by ERCP group: time from admission to cholecystectomy (t 1 ), time from cholecystectomy to ERCP (t 2 ), time from ERCP to exit (t 3 ). For the EUS/ERCP followed by cholecystectomy group: time from admission to EUS/ERCP (t 1 ), time from EUS/ERCP to cholecystectomy (t 2 ), time from cholecystectomy to exit (t 3 ). Table 2: Schematic presentation of the various times studied according to the strategy followed Strategy Time t 1 Time t 2 Time t 3 CCK Admission to CCK CCK to exit - CCK /ERCP Admission to CCK CCK to ERCP ERCP to exit EUS ± ERCP / CCK Admission to EUS±ERCP EUS±ERCP to CCK CCK to exit * CCK = cholecystectomy, EUS = endoscopic ultrasound, ERCP = endoscopic retrograde cholangiopancreatography TREATMENT STRATEGY FOR INTERMEDIATE RISK PATIENTS For this part of the analysis, only patients that belonged to the intermediate risk category for choledocholithiasis (as defined above) were selected. It overlaps some part of a previously

34 published study (64), but the proposed thesis material has been built and analyzed from the original raw data. At first, sample size calculation was made. The sample size calculation was based on a prospective clinical trial having taken place in the same hospital (52) and showing a shorter length of stay by 3 days (median LoS 5 days vs 8) in favour of the cholecystectomy first strategy. In order to detect a similar reduction in the length of stay by 3 days, when requiring a 2-sided level of significance α = 0.05 and to achieve a statistical power of 80%, the necessary sample size of each group is 45 patients. Following that, patients were pooled in two groups according to the strategy followed: the first with all patients treated initially with laparoscopic cholecystectomy and intraoperative cholangiography (followed, if needed, by postoperative CBD clearance by ERCP) and the second with patients treated initially with endoscopic CBD exploration and clearance, followed by laparoscopic cholecystectomy. Student s t-test and chi-squared test was used in order to assess the similarity in general features of the two groups. As also mentioned previously, length of hospital stay was the primary outcome. Secondary outcomes were the presence of postoperative complications, the presence or absence of CBD stones as well as the final number of CBD explorations in the exception of IOC (EUS, ERCP, and MRCP) performed during the hospital stay. Mann-Whitney test was used for the assessment of the primary outcome and the categorical secondary outcomes, and chi-squared test or Fisher s exact test for the rest (with the results expressed in OR with 95% CI)

35 RESULTS A. GENERAL FEATURES During the study period (26 months), the records of 637 patients were assessed. Of them, 56 patients did not meet the inclusion criteria and were excluded (Table 3). So, the study population was 581 patients. Table 3: Patients excluded from the study according to the predefined exclusion criteria Exclusion criteria Number of patients Previous cholecystectomy 15 Patient s refusal for cholecystectomy 2 Previous ERCP failure 1 Indication for delayed cholecystectomy 10 Contra-indication to cholecystectomy 15 Associated malignancy 13 Total 56 All general features and demographic data of patients included in the study are summarized in Table 4. Median age was 54 years and median BMI 27.2 kg/m 2. Male:female ratio was 1:1.3. Further details regarding patient assessment upon admission (LFTs, US findings, clinical findings) are included in the same table (Table 4). After investigation and treatment of patients, choledocholithiasis was found in 22.4% of the included patients. As explained above, patients were categorized in three risk group for choledocholithiasis: low risk with 278 patients, intermediate risk with 161 patients, and high risk of CBD stone with 142 patients. Finally, based on the criteria of treatment strategy followed, the majority of patients were treated only with laparoscopic cholecystectomy

36 (57.8%), whereas in 57 patients cholecystectomy was followed by ERCP and in 188 patients, EUS and ERCP were performed at first, followed by cholecystectomy. Table 4: Demographic data and general features General features n=581 Age, median (IQR) [years] 54 (30.0) BMI, median (IQR) [kg/m 2 ] 27.2 (7.3) Gender, n (%) Male 254 (43.7) Female 327 (56.3) Bilio-pancreatic history, n (%) Positive 21 (3.6) Negative 560 (96.4) Fever on admission, n (%) Yes 61 (10.5) No 520 (89.5) RUQ pain on admission, n (%) Yes 481 (82.8) No 100 (17.2) Cholecystitis on admission US (*), n (%) Yes 387 (66.7) No 193 (33.3) Liver function tests (LFTs) ASAT, median (IQR) [IU/l] 44 (184.5)

37 ALAT, median (IQR) [IU/l] 57 (197.0) ALP, median (IQR) [IU/l] 81 (69.5) γgt, median (IQR) [IU/l] 88 (305.5) Total bilirubin, median (IQR) [mg/dl] 1.2 (1.5) Conjugated bilirubin, median (IQR) [mg/dl] 0.2 (0.6) Lipase, median (IQR) [IU/l] 30 (25.0) CBD dilation on admission US (**) (>6 mm), n (%) Yes 114 (32.8) No 234 (67.2) CBD investigations per patient (***), median (IQR) [number] 0 (1.0) CBD stone presence, n (%) Yes 130 (22.4) No 451 (77.6) Risk category Low 278 (47.9) Intermediate 161 (27.7) High 142 (24.4) Strategy Cholecystectomy 336 (57.8) Cholecystectomy/ERCP 57 (9.8) ERCP/Cholecystectomy 188 (32.4) (*) Missing data for one patient, (**) Missing data for 233 patients, (***) Except intraoperative cholangiography

38 Table 5 shows the total postoperative adverse events rate during the first postoperative months (4.5%). A total of 2.4% of patients presented a severe complication classified with Grade III. Median length of hospital stay for all patients was 7 days. Diagrams of LoS are analytically presented in the Impact of weekday admission section, whereas diagrams of postoperative adverse events are presented in the Appendix. Table 5: Postoperative complications and length of stay Postoperative complications, n (%) Yes 26 (4.5) No 555 (95.5) Severe postoperative complications (*), n (%) 14 (2.4) Length of stay (LoS), median (IQR) [days] 7 (5) (*) Clavien-Dindo Grade III B. PREDICTIVE RISK FACTORS Factors that could possibly be used as predictors for the presence of choledocholithiasis upon patient admission were assessed by logistic regression, after having been categorized in two groups: (a) general or demographic factors, and (b) specific factors. More precisely: General factors: Age, Gender, BMI Specific factors: Bilio-pancreatic history, RUQ pain, Fever, Cholecystitis, LFTs (AST, ALT, ALP, γgt, Total bilirubin, Conjugated bilirubin), Lipase, CBD dilation (>6 mm) Univariate analysis after logistic regression showed that factors associated in a statistically significant way (p<0.05) with the presence of CBD stone are: age, RUQ pain, cholecystitis, AST, ALT, ALP, γgt, total bilirubin, conjugated bilirubin and CBD dilation (Table 7). Table

39 6 shows the detailed analysis of categorical factors that were found to be statistically important in the univariate analysis. Table 6: Statistically significant categorical predictive factors for choledocho lithiasis (univariate analysis) Predictive factors CBD stone, n (%) p-value Yes RUQ pain Yes 95 (16.4) 386 (66.4) No 35 (6.0) 65 (11.2) Cholecystitis <0.001 Yes 55 (9.5) 332 (57.3) No 75 (12.9) 118 (20.3) CBD dilation <0.001 Yes 68 (19.6) 46 (13.2) No 38 (10.9) 196 (56.3) No A multivariate model was built after backward variable selection using the Akaike's information criterion (AIC). As previously mentioned in the Patients and Methods section, the included variables in the model had to demonstrate a p < 0.2 in the univariate model. Both total and conjugated bilirubin demonstrated a p < 0.05 in the univariate analysis. However, due to the fact that these two variables are dependent (one can be predicted from the other), only total bilirubin was included in the multivariate analysis in order to avoid colinearity in the model. Therefore, variables included in the multivariate analysis were: age, gender, RUQ pain, cholecystitis, AST, ALT, ALP, γgt, total bilirubin, conjugated bilirubin and CBD dilation. The best model fitting to our data contained the following variables: cholecystitis, AST, ALT, γgt and CBD dilation (Table 7). The three last factors showed a p<0.05 in the multivariate

40 analysis. Missing data, especially concerning CBD dilation, were omitted. Further details for the omitted patients are provided in the Appendix (Table 14). The exact predictive model is given by the equation below: Based on this, a ROC curve was constructed trying to reflect the predictive value of the abovementioned model for the absence of CBD stone on admission (Figure 9). The AUC is Therefore, the rate of cases of absence of CBD stone that could be predicted by this model is 85%. Figure 9: ROC curve of the predictive model for the absence CBD stone

41 Table 7: Univariate and multivariate analysis for factors associated with choledocholithiasis. Predictive factors Univariate analysis Multivariate analysis OR 95% CI p-value OR 95% CI p-value General factors Age Gender BMI Specific factors Bilio-pancreatic history RUQ pain Fever Cholecystitis < LFTs AST < ALT < ALP <0.001 γgt < Total bilirubin <0.001 Conj. bilirubin <0.001 Lipase CBD dilation < <

42 C. IMPACT OF WEEKDAY ADMISSION A. Analysis for all patients Most patients (124 patients, 21.4%) were admitted on Monday and the least on Saturday (56 patients, 9.6%). The rest of the weekdays had similar number of admissions (Table 8). There was no statistically significant difference of LoS for every weekday of admission, when taking into account all patients, irrespective of the treatment strategy followed (p=0.065). Moreover, there is no statistically significant difference for presence of postoperative complications for every weekday (p=0.154). Table 8: LoS and postoperative complications for all patients, for every weekday admission LoS [days] Postoperative complications Weekday n (%) Median (IQR) Yes n (%) No Monday 124 (21.4) 6 (6.0) 4 (0.7) 120 (20.6) Tuesday 86 (14.8) 8 (6.0) 3 (0.5) 83 (14.3) Wednesday 79 (13.6) 6 (5.0) 3 (0.5) 76 (13.1) Thursday 82 (14.1) 8 (6.0) 9 (1.6) 73 (12.6) Friday 79 (13.6) 7 (6.0) 1 (0.2) 78 (13.4) Saturday 56 (9.6) 7 (5.0) 2 (0.3) 54 (9.3) Sunday 75 (12.9) 6 (5.5) 4 ( (12.2) p=0.065 p=0.154 Total 581 (100.0) 26 (4.5) 555 (95.5)

43 Figure 10: LoS for all patients B. Analysis according to the treatment strategy followed As mentioned above (Table 4), patients treated with cholecystectomy only were 336 (57.8%), with cholecystectomy followed by ERCP 58 (9.8%) and with EUS±ERCP followed by cholecystectomy 188 (32.4%). For patients treated with cholecystectomy only, there was a statistically significant difference for LoS among all weekdays of admission (p=0.047). After pairwise comparisons using Dunn s test with Bonferroni correction, a statistically significant difference was found only between patients admitted on Wednesday (median LoS 4.5 days) and those admitted on Thursday (median LoS 6 days). There was no statistically significant difference for LoS for every weekday in patients treated, with cholecystectomy followed by ERCP (p=0.917) and with EUS±ERCP followed by cholecystectomy (p=0.592)

44 Table 9: LoS for every weekday admission according to treatment strategy followed Weekday LoS [days], Median (IQR) CCK CCK / ERCP EUS ± ERCP / CCK n (%) Monday 5 (5.0) 6 (6.5) 10 (7.0) 124 (21.4) Tuesday 6 (4.0) 10 (4.0) 11 (3.5) 86 (14.8) Wednesday 4.5 (2.0) 9 (6.5) 9 (5.0) 79 (13.6) Thursday 6 (4.3) 8.5 (1.3) 10 (4.8) 82 (14.1) Friday 5.5 (3.0) 8.5 (2.3) 12 (7.0) 79 (13.6) Saturday 5 (3.0) 8 (2.0) 10 (3.3) 56 (9.6) Sunday 5 (4.5) 6 (4.0) 10 (4.0) 75 (12.9) p=0.047 p=0.917 p=0.592 Total, n (%) 336 (57.8) 57 (9.8) 188 (32.4) 581 (100.0) Figure 11: LoS according to treatment strategy followed

45 In addition, there is no statistically significant difference in presence of postoperative complications among weekdays admissions, for the three strategies followed (p=0.170 for cholecystectomy only, p=0.949 for cholecystectomy followed by ERCP and p=0.189 for EUS±ERCP followed by cholecystectomy). Table 10: Complications for every weekday of admission according to strategy followed Weekday Postoperative complications, n (%) CCK CCK / ERCP EUS±ERCP / CCK Yes No Yes No Yes No Monday 0 (0.0) 76 (22.6) 1 (1.8) 9 (15.7) 3 (1.6) 35 (18.6) Tuesday 1 (0.3) 47 (14.0) 1 (1.8) 6 (10.5) 1 (0.5) 30 (16.0) Wednesday 1 (0.3) 37 (11.0) 1 (1.8) 9 (15.7) 1 (0.5) 30 (16.0) Thursday 2 (0.6) 42 (12.5) 2 (3.5) 6 (10.5) 5 (2.6) 25 (15.3) Friday 0 (0.0) 46 (13.7) 1 (1.8) 11 (19.3) 0 (0.0) 21 (11.2) Saturday 1 (0.3) 36 (10.7) 0 (0.0) 3 (5.3) 1 (0.5) 15 (8.0) Sunday 3 (0.9) 44 (13.1) 1 (1.8) 6 (10.5) 0 (0.0) 21 (11.2) p=0.170 p=0.949 p=0.189 Total 8 (2.4) 328 (97.6) 7 (12.5) 50 (87.5) 11 (5.7) 177 (94.3) C. Analysis of LoS after creation of two weekday groups As mentioned above, patients were pooled in two weekday admission groups: Weekday group A: Tuesday, Wednesday, Thursday, Friday Weekday group B (or weekend group): Saturday, Sunday, Monday

46 When all patients were taken into account, there was a statistically significant difference for LoS between the two weekday groups (p=0.028). LoS was shorter in patients admitted during the second weekday group than those admitted during the first, by 1 day. Figure 12: LoS for the two weekday groups (g1 corresponds to weekday group A: Tuesday, Wednesday, Thursday, Friday and g2 corresponds to weekday group B: Saturday, Sunday, Monday) However, when analysis was performed according to the treatment strategy followed, there was no statistically significant difference for LoS for every weekday group (p=0.308 for cholecystectomy only, p=0.296 for cholecystectomy followed by ERCP and p=0.587 for EUS±ERCP followed by cholecystectomy)

47 Table 11: LoS among the two weekday admission groups for all patients and according to treatment strategy followed Group A Group B Strategy n (%) LoS [days] n (%) LoS [days] Total N Difference p-value Median (IQR) Median (IQR) (%) [days] CCK (3.0) (4.0) (30.3) (27.5) (57.8) CCK / 37 9 (3.0) (5.3) ERCP (6.4) (3.4) (9.8) EUS±ERCP (5.0) (5.5) /CCK (19.5) (12.9) (32.4) All patients (6.0) (5.0) (56.1) (43.9) (100.0)

48 Figure 13: LoS for the two weekday groups, for the CCK-only strategy (g1 corresponds to weekday group A: Tuesday, Wednesday, Thursday, Friday and g2 corresponds to weekday group B: Saturday, Sunday, Monday) Figure 14: LoS for the two weekday groups, for the CCK/ERCP strategy (g1 corresponds to weekday group A: Tuesday, Wednesday, Thursday, Friday and g2 corresponds to weekday group B: Saturday, Sunday, Monday)

49 Figure 15: LoS for the two weekday groups, for the ERCP/CCK strategy (g1 corresponds to weekday group A: Tuesday, Wednesday, Thursday, Friday and g2 corresponds to weekday group B: Saturday, Sunday, Monday) Finally, after main analysis, subgroup analysis was performed in order to detect any differences among the two weekday admission groups for the times between various interventions, as defined in Table 2. For the cholecystectomy only group: There was a statistically significant difference in time from admission to cholecystectomy (t 1 ) among the two weekday admission groups (p = 0.01). Even though the respective medians are equal, as shown in the diagram (Figure 16), there is a tendency for a slightly shorter t 1 time in the Group B (Weekend Group). No statistically significant difference was found in time from cholecystectomy to exit (t 2 ) among the two weekday admission groups. For the cholecystectomy followed by ERCP group: There was no statistically significant difference in times t 1, t 2 and t 3 among the two weekday admission groups (p = 0.93, 0.28 and 0.81 respectively). For the EUS±ERCP followed by cholecystectomy group: There was no statistically significant difference in times t 1, t 2 and t 3 among the two weekday admission groups (p = 0.62, 0.59 and 0.56 respectively)

50 Table 12: Time between various interventions among weekday admission groups A and B t 1 [days] Median (IQR) t 2 [days] Median (IQR) t 3 [days] Median (IQR) A B p-value A B p-value A B p-value CCK 1 (1.0) 1 (1.0) (2.0) 3 (3.0) CCK/ERCP 1 (1.0) 1 (1.0) (2.0) 1 (0.0) (4.0) 3 (4.5) 0.81 ERCP/CCK 2 (2.0) 2 (1.0) (3.0) 3 (3.0) (4.0) 4 (3.0) 0.56 Figure 16: t 1 time (admission to CCK time) for the two weekday groups ( g1 corresponds to weekday group A: Tuesday, Wednesday, Thursday, Friday and g2 corresponds to weekday group B: Saturday, Sunday, Monday)

51 D. TREATMENT STRATEGY FOR INTERMEDIATE RISK PATIENTS There were 161 patients belonging to the intermediate risk category. Patients were pooled in two groups according to the strategy followed: the first (n=114) with all patients treated initially with cholecystectomy (either with or without ERCP following) and the second (n=47) with patients treated initially with EUS±ERCP followed by cholecystectomy. Regarding power size calculation, in order to find a difference of 3 days (as explained in the respective part of Patients and Methods ), with a power of 80% and a level of significance at 0.05, we should have 90 patients (45 in each group). There was a statistically significant difference in presence of choledocholithiasis between the two groups (OR 0.31, 95% CI , p<0.05). Patients treated by cholecystectomy first had 69% lower odds for choledocholithiasis than those treated by EUS±ERCP first. Length of stay was significantly shorter in the cholecystectomy first group than in the EUS±ERCP first group by 3 days (p<0.001) (Figure 18). Moreover, the number of CBD investigations per patient in the exception of IOC was significantly lower in the cholecystectomy first group (median number 0 in the CCK first vs 1 in the EUS first group, p<0.001). However, there was no statistically significant difference in presence of postoperative complications between the two groups (p=1.00) (Figure 17). More details concerning the adverse events rates for the patients belonging to the intermediate risk category, according to each treatment strategy followed can be found in the Appendix (Table 15)

52 Table 13: LoS and postoperative complications in intermediate risk patients Patients with intermediate risk (N = 161) Groups Cholecystectomy first EUS first p-value n=114 (70.8%) n=47 (29.2%) Age, mean (SD) [years] 51.6 (20.2) 56 (19.8) 0.21 BMI, median (IQR) [kg/m 2 ] 27.1 (6.4) 26.6 (8.5) 0.89 Gender, n (%) 0.32 Male 46 (40.4) 23 (48.9) Female 68 (59.6) 24 (51.1) CBD investigations per patient, 0 (1.0) 1 (1.0) <0.001 median (IQR) [number] CBD gallstone, n (%) Yes 17 (14.9) 17 (36.2) No 97 (85.1) 30 (63.8) Postoperative complications, n (%) 1.00 Yes 7 (6.1) 2 (4.3) No 107 (93.9) 45 (95.7) Length of stay (LoS), 6 (5.0) 9 (4.0) <0.001 median (IQR) [days]

53 Figure 17: Postoperative complications for intermediate-risk patients according to the treatment strategy Figure 18: LoS for intermediate-risk patients according to the treatment strategy

54 DISCUSSION A. PREDICTIVE RISK FACTORS In an effort to determine an optimal approach towards suspected choledocholithiasis, many studies have been trying to establish accurate predictive risk factors and prognostic models in this direction. A great majority of them either lacked methodological accuracy, or had important selection bias (65). Recently, the ASGE/SAGES guidelines stratified patients in three risk categories, based on factors as age, LFTs and abdominal US findings (15). In addition, CBD dilation on US, ascending cholangitis, and serum bilirubin levels higher than 4 mg/dl were considered very strong predictors of choledocholithiasis. In our study, we showed that the age, the presence of RUQ pain or cholecystitis, all LFTs and the presence of CBD dilation >6 mm are independent predictive factors for choledocholithiasis. Gender wasn t found to be statistically significant. We also defined a model to predict the absence of choledocholithiasis, containing the following independent factors: presence of cholecystitis, AST, ALT, γgt and dilation of CBD. Our model has a predictive value of 85% for excluding choledocholithiasis in patients admitted with acute gallstone-related disease. It is generally admitted that choledocholithiasis in patients with symptomatic cholecystolithiasis cannot be predicted accurately by a single factor and it has been shown that the combination of more than one variable could predict consistently the presence of CBD stone (15,37,65). Barkun et al. proposed a predictive model using age, elevated bilirubin, CBD dilation and suspected CBD stones on US, but their analysis was mainly retrospective (even though a prospective validation was performed but in a small number of patients) (37). In another study, Prat et al. provided three independent predictive and noninvasive factors for choledocholithiasis according to patient s age (γgt concentrations, CBD dilatation and pathologic image of gallbladder on US or fever for patients > 70 years-old) (65). In our study, we also provide a predictive model containing most the abovementioned factors, whose combination could exclude the presence of CBD stone. A meta-analysis showed various independent risk factors for prediction of choledocholithiasis (mostly cholangitis, CBD stones on US and jaundice) (36). However, the heterogeneity of included studies and the fact that no practical instruction was provided in the end, reduce

55 significantly its power and its external validity. The same meta-analysis showed that the presence of a dilated common bile duct on US has a sensitivity and specificity of 42% and 96% respectively with a positive likelihood ratio of 6.9. The results of our study concerning the same independent factor are comparable, with a sensitivity and specificity of 64% and 81% respectively and a positive likelihood ratio of 3.4. On the other hand, even if serum LFTs and especially γgt and total bilirubin levels, have been associated with choledocholithiasis, in the univariate analysis these variables showed an OR almost at one, even if there was a statistically significant difference. Consequently, based on our results, we cannot advocate for an effect positive or negative of these two independent predictive factors on the risk of choledocholithiasis. The main limitation of this part of our study is the important number of omitted data for CBD dilation in the multivariate analysis (233 patients). However, we performed a second univariate analysis in this omitted subgroup for the independent risk factors found to be important in the genuine univariate analysis, and show a similar direction of ORs. Thus, the omission of these patients couldn t have possibly affected the results, and couldn t have extended the risk of selection bias. Furthermore, our multivariate analysis model predicts the absence of choledocholithiasis and not the presence. Therefore, multivariate analysis should be carefully taken into account in this part of the study. Finally, the retrospective nature of this study makes of importance the need for a prospective external validation of this model. It could be interesting to perform a new prospective analysis, observing eventually the alteration in LFTs during hospitalization and before the intervention, to check if it could play a predictive role for choledocholithiasis. In conclusion, independent predictive factors for choledocholithiasis are the presence of RUQ pain, the presence of cholecystitis, the presence of a dilated common bile duct and serum LFTs. A predictive model using the presence of cholecystitis, AST, ALT, γgt and dilation of CBD on US can exclude the presence of choledocholithiasis with an accuracy of about 85%. Finally, these results need further prospective external validation in order to use them securely in the daily clinical practice and treatment of patients with an acute gallstone-related disease and suspected choledocholithiasis

56 B. IMPACT OF WEEKDAY ADMISSION We tried to evaluate the impact of the weekend admission, which theoretically could prolong hospitalization due to limited access to specialized technical platforms, as ERCP or emergent cholecystectomy, during the weekend. The main finding of this study is that the admission weekday doesn t play a significant role in terms of main outcomes, which were length of hospital stay and presence of postoperative adverse effects. Consequently, our study doesn t support the so-called weekend effect for the treatment of patients admitted with an acute gallstone-related disease. Even if patients admitted during weekend or Monday had overall a shorter length of stay by one day, this statistically significant result wasn t reproduced when patients were categorized according to the treatment strategy followed. Generally, patients treated initially by EUS+/-ERCP followed by cholecystectomy had longer length of stays; however, weekday admission doesn t seem to play an important role. Conversely to the other studies evaluating the presence of weekend effect in patients admitted with acute cholangitis (53,54,56), in our study we made the hypothesis that patients admitted during the weekend or on Monday were more probable to obtain an ERCP or cholecystectomy rapidly (early the following week) than those admitted in the rest of the week. This hypothesis was based on the observation that in our institute, even if it is a tertiary university hospital, the access to an emergent ERCP or cholecystectomy during the weekend is more difficult, leaving more time to organize these procedures early the following week. It is true that our analysis showed statistically significant difference in length of stay among all weekdays of admission, for patients treated with cholecystectomy only. Nevertheless, this difference was observed only between admission on Wednesday and Thursday, and obviously doesn t have clinical significance. We also tried to investigate if there exists any difference in the time of realization of various procedures (cholecystectomy, EUS ± ERCP) between patients admitted on weekend or not. We found that these times are similar for all patients, in the exception of patients with only cholecystectomy, in which the time from admission till operation had a trend to be shorter when the admission was made during the weekend. Our results differ from those of Parikh et al. (54) suggesting shorter LoS and lower complication rates if patients were admitted during the week and not weekend. However, we performed our analysis not only regarding ERCPs but also including cholecystectomy as interventions

57 The main strength of the present study, which is based on a cohort of patients admitted with an acute gallstone-related disease, is that it includes more than one procedures (not only ERCP) in the analysis and that the population is not limited only in patients suffering from cholangitis. We advocate, thus, that weekend admission is not associated either with longer length of stay, or with higher adverse events rate. One of the limitations of this study is its retrospective nature, increasing risk of inherently biased population and making almost impossible the establishment of causal associations. Therefore, it would be useful to perform a prospective cohort for the validation of these results. Another possible limitation is that our study refers to a tertiary hospital, where emergent ERCP and cholecystectomy are available even during weekends, whereas in the big majority of hospitals this is not the case. This fact could possibly reduce the external validity of our study. Future research could eventually include different categories of patients according to their specific biliary pathology (cholecystitis, cholangitis, choledocholithiasis, biliary pancreatitis, gallstone migration, etc.) as well as investigation and statistical analysis for the impact of weekday admission on inpatient hospital charges and overall cost. Another possibility would be to take into account in the statistical analysis various holidays, such as Christmas or Easter, during which access to procedures as ERCP is more difficult in the vast majority of hospitals, as is during weekends. In summary, the day of admission does not seem to have an impact either on the length of stay or in the complication rate in patients admitted with acute gallstone-related disease. Even when comparing weekend vs non-weekend admissions, there is no statistically significant difference on these main outcomes. Finally, no difference is found in intervals between various interventions performed, for patients admitted during weekend or the rest of weekdays. However, prospective validation of the abovementioned results is needed, so that they could lead to safe conclusions and associations. C. TREATMENT STRATEGY FOR INTERMEDIATE RISK PATIENTS The main finding of our study is that a cholecystectomy-first approach in patients with intermediate risk for choledocholithiasis is associated with a shorter length of hospital stay

58 and fewer CBD investigations per patient, compared to a CBD exploration-first approach. Additionally, it is not associated with increased postoperative morbidity. As mentioned in the General Part, the ASGE/SAGES 2010 guidelines recommend a CBD exploration in patients belonging in the intermediate risk group (10-50% risk for CBD stone) and consider both options (cholecystectomy-first and CBD exploration-first) valid in the management of these patients (15). Costi et al. showed in 2009 that the laparoscopy-first approach is superior in terms of reducing duration of hospitalization by almost 3 days (66). A prospective randomized controlled trial published recently by Iranmanesh et al. suggests that initial laparoscopic cholecystectomy with IOC and, if required, postoperative ERCP is associated with a shorter length of stay and lower number of CBD investigations with similar morbidity in patients of intermediate risk for choledocholithiasis (52). The latter was validated prospectively by a new study undergone in the same hospital that confirmed the results and developed a new algorithm for the treatment of patients with suspected choledocholithiasis (64). Consequently, it is proposed that patients fulfilling the criteria of intermediate-risk for choledocholithiasis ought to be treated directly by laparoscopic cholecystectomy and mandatory intraoperative cholangiography, followed if needed by postoperative CBD exploration. Despite the fact that this thesis overlaps some part of the abovementioned study, the analysis has been performed from the original raw data and evidently confirms the superiority of the cholecystectomy-first approach. These results are of great significance in the treatment of this specific category of patients, for whom no consensus exists so far. Indeed, there has been already an effort to avoid unnecessary preoperative CBD investigations, so as to reduce anesthetic, procedural and irradiation morbidity for patients as well as the inpatient stay. Several studies support the one-stage approach by intraoperative CBD clearance in the management of diagnosed choledocholithiasis (67 69). On the other hand, in cases of an emergency setting, Poh et al. recently showed that laparoscopic CBD clearance is not as effective as postoperative ERCP, even if it is related to fewer CBD investigations and shorter hospitalization. In our institute, intraoperative CBD exploration is not performed generally, and when choledocholithiasis is diagnosed on the IOC, patients are treated either with intraoperative or postoperative ERCP. However, this fact that depends clearly on local preferences and expertise, doesn t affect the primary results of our study, underlying the superiority of a cholecystectomy-first approach when risk of choledocholithiasis is estimated as intermediate

59 One possible limitation of this study could have been its retrospective nature. However, the majority of raw data was collected prospectively. Moreover, as previously mentioned, statistical analysis might overlap the study of Iranmanesh et al. (64), which was performed in an effort to prospectively validate the initial clinical trial of the same institute (52), and not in order to export genuine conclusions. On the other hand, this study was undertaken in the Geneva University Hospitals, a tertiary university hospital, where specialized technical platforms (for instance, ERCP) are rapidly available. This might not be the case in peripheral hospitals and could eventually reduce the external validity of the study. Nonetheless, choledocholithiasis was found in 21.1% (34 patients) of the intermediate-risk category patients, so the rest 80% didn t require postoperative CBD exploration. It could be, thus, beneficial even for smaller hospitals to introduce this cholecystectomy-first approach, with the condition that postoperative ERCP could be available and performed shortly after the operation. Finally, cost analysis wasn t the aim of this study. Even if it could be supposed that lower length of stay is related to lower inpatient hospital cost, a more detailed study in this direction could be useful in the future. In conclusion, we propose that patients at intermediate risk for choledocholithiasis should be treated by initial laparoscopic cholecystectomy with intraoperative cholangiography, followed if needed by postoperative CBD investigations, as it is related to lower length of stay and fewer CBD explorations. This approach is not associated with higher morbidity and could eventually change the treatment of this category of patients, for whom no general consensus exists till now

60 REFERENCES 1. Pham TH, Hunter JG. Gallbladder and the Extrahepatic Biliary System. In: Schwartz s Principles of Surgery, Tenth Edition. 10th ed. McGraw-Hill Education; Mulholland MW. The Greenfield s Surgery: Scientific Principles and Practice. 4th ed. Lippincott Williams & Wilkins; Skandalakis JE, Colborn GL, Weidman T a., Foster RSJ, Kingsnorth AN, Skandalakis LJ, et al. Skandalakis Surgical Anatomy. Paschalidis Medical Publication Ltd.; Scott-Conner CEH, Dawson DL. Operative anatomy. Third. Lippincott Williams & Wilkins; Doherty GM, Way LW. Current Surgical Diagnosis & Treatment. 12th ed. The McGraw-Hill Companies; O Leary JP, Tabuenca A. Liver, biliary tract, and pancreas. In: Physiologic basis of surgery. 4th ed. Williams and Wilkins; Chari RS, Shah SA. Biliary System. In: Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice. 19th ed. Elsevier Saunders; Geoghegan J, Pappas TN. Clinical uses of gut peptides. Ann Surg. 1997;225: Al-Jiffry BO, Shaffer EA, Saccone GTP, Downey P, Kow L, Toouli J. Changes in gallbladder motility and gallstone formation following laparoscopic gastric banding for morbid obestity. Can J Gastroenterol. 2003;17: Nakeeb A, Comuzzie AG, Martin L, Sonnenberg GE, Swartz-Basile D, Kissebah AH, et al. Gallstones: genetics versus environment. Ann Surg. 2002;235: Bass G, Gilani SNS, Walsh TN, Leader F. Validating the 5Fs mnemonic for cholelithiasis: time to include family history. Postgrad Med J. The Fellowship of Postgraduate Medicine. 2013;89: Pavel S, Thijs CT, Potocky V, Knipschild PG. Fair, and still a sun lover: risk of gallstone formation. J Epidemiol Community Health. 1992;46: Beckingham IJ. ABC of diseases of liver, pancreas, and biliary system. Gallstone disease. BMJ. 2001;322: Ko CW, Lee SP. Epidemiology and natural history of common bile duct stones and prediction of disease. Gastrointest Endosc. 2002;56(6 Suppl):S Maple JT, Ben-Menachem T, Anderson MA, Appalaneni V, Banerjee S, Cash BD, et al. The role of endoscopy in the evaluation of suspected choledocholithiasis. Gastrointest Endosc. 2010;71:

61 16. Liu TH, Consorti ET, Kawashima A, Tamm EP, Kwong KL, Gill BS, et al. Patient evaluation and management with selective use of magnetic resonance cholangiography and endoscopic retrograde cholangiopancreatography before laparoscopic cholecystectomy. Ann Surg. 2001;234: Koo KP, Traverso LW. Do preoperative indicators predict the presence of common bile duct stones during laparoscopic cholecystectomy? Am J Surg. 1996;171: Einstein DM, Lapin SA, Ralls PW, Halls JM. The insensitivity of sonography in the detection of choledocholithiasis. AJR Am J Roentgenol. 1984;142: O Connor HJ, Hamilton I, Ellis WR, Watters J, Lintott DJ, Axon AT. Ultrasound detection of choledocholithiasis: prospective comparison with ERCP in the postcholecystectomy patient. Gastrointest Radiol. 1986;11: Lapis JL, Orlando RC, Mittelstaedt CA, Staab E V. Ultrasonography in the diagnosis of obstructive jaundice. Ann Intern Med. 1978;89: Pedersen OM, Nordgård K, Kvinnsland S. Value of sonography in obstructive jaundice. Limitations of bile duct caliber as an index of obstruction. Scand J Gastroenterol. 1987;22: Bruneton JN, Roux P, Fenart D, Caramella E, Occelli JP. Ultrasound evaluation of common bile duct size in normal adult patients and following cholecystectomy. A report of 750 cases. Eur J Radiol. 1981;1: Bachar GN, Cohen M, Belenky A, Atar E, Gideon S. Effect of aging on the adult extrahepatic bile duct: a sonographic study. J Ultrasound Med. 2003;22: Soto JA, Alvarez O, Múnera F, Velez SM, Valencia J, Ramírez N. Diagnosing bile duct stones: comparison of unenhanced helical CT, oral contrast-enhanced CT cholangiography, and MR cholangiography. AJR Am J Roentgenol. 2000;175: Anderson SW, Rho E, Soto JA. Detection of biliary duct narrowing and choledocholithiasis: accuracy of portal venous phase multidetector CT. Radiology. 2008;247: Tseng C-W, Chen C-C, Chen T-S, Chang F-Y, Lin H-C, Lee S-D. Can computed tomography with coronal reconstruction improve the diagnosis of choledocholithiasis? J Gastroenterol Hepatol. 2008;23: Magnuson TH, Bender JS, Duncan MD, Ahrendt SA, Harmon JW, Regan F. Utility of magnetic resonance cholangiography in the evaluation of biliary obstruction. J Am Coll Surg. 1999;189:

62 28. Romagnuolo J, Bardou M, Rahme E, Joseph L, Reinhold C, Barkun AN. Magnetic resonance cholangiopancreatography: a meta-analysis of test performance in suspected biliary disease. Ann Intern Med. 2003;139: Verma D, Kapadia A, Eisen GM, Adler DG. EUS vs MRCP for detection of choledocholithiasis. Gastrointest Endosc. 2006;64: Tseng LJ, Jao YT, Mo LR, Lin RC. Over-the-wire US catheter probe as an adjunct to ERCP in the detection of choledocholithiasis. Gastrointest Endosc. 2001;54: Zidi SH, Prat F, Le Guen O, Rondeau Y, Rocher L, Fritsch J, et al. Use of magnetic resonance cholangiography in the diagnosis of choledocholithiasis: prospective comparison with a reference imaging method. Gut. 1999;44: Loperfido S, Angelini G, Benedetti G, Chilovi F, Costan F, De Berardinis F, et al. Major early complications from diagnostic and therapeutic ERCP: a prospective multicenter study. Gastrointest Endosc. 1998;48: Masci E, Toti G, Mariani A, Curioni S, Lomazzi A, Dinelli M, et al. Complications of diagnostic and therapeutic ERCP: a prospective multicenter study. Am J Gastroenterol. 2001;96: Amouyal P, Amouyal G, Lévy P, Tuzet S, Palazzo L, Vilgrain V, et al. Diagnosis of choledocholithiasis by endoscopic ultrasonography. Gastroenterology. 1994;106: Frossard JL, Morel PM. Detection and management of bile duct stones. Gastrointest Endosc. Elsevier Inc.; 2010;72: Abboud PC, Malet PF, Berlin JA, Staroscik R, Cabana MD, Clarke JR, et al. Predictors of common bile duct stones prior to cholecystectomy : a meta-analysis. 1996;44: Barkun AN, Barkun JS, Fried GM, Ghitulescu G, Steinmetz O, Pham C, et al. Useful predictors of bile duct stones in patients undergoing laparoscopic cholecystectomy. McGill Gallstone Treatment Group. Ann Surg. 1994;220: Yang M-H, Chen T-H, Wang S-E, Tsai Y-F, Su C-H, Wu C-W, et al. Biochemical predictors for absence of common bile duct stones in patients undergoing laparoscopic cholecystectomy. Surg Endosc. 2008;22: Kimura Y, Takada T, Strasberg SM, Pitt HA, Gouma DJ, Garden OJ, et al. TG13 current terminology, etiology, and epidemiology of acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. Springer Japan; 2013;20: Takada T, Strasberg SM, Solomkin JS, Pitt HA, Gomi H, Yoshida M, et al. TG13:

63 Updated Tokyo Guidelines for the management of acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2013;20: Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, et al. Classification of acute pancreatitis 2012: revision of the Atlanta classification and definitions by international consensus. Gut. BMJ Publishing Group Ltd and British Society of Gastroenterology; 2013;62: Oría A, Alvarez J, Chiapetta L, Fontana JJ, Iovaldi M, Paladino A, et al. Risk factors for acute pancreatitis in patients with migrating gallstones. Arch Surg. 1989;124: Frossard JL, Hadengue A, Amouyal G, Choury A, Marty O, Giostra E, et al. Choledocholithiasis: a prospective study of spontaneous common bile duct stone migration. Gastrointest Endosc. 2000;51: Williams EJ, Green J, Beckingham I, Parks R, Martin D, Lombard M, et al. Guidelines on the management of common bile duct stones (CBDS). Gut. 2008;57: Maple JT, Ikenberry SO, Anderson MA, Appalaneni V, Decker GA, Early D, et al. The role of endoscopy in the management of choledocholithiasis. Gastrointest Endosc. 2011;74: Tranter SE, Thompson MH. Comparison of endoscopic sphincterotomy and laparoscopic exploration of the common bile duct. Br J Surg. 2002;89: Hamy A, Hennekinne S, Pessaux P, Lada P, Randriamananjo S, Lermite E, et al. Endoscopic sphincterotomy prior to laparoscopic cholecystectomy for the treatment of cholelithiasis. Surg Endosc. 2003;17: Lilly MC, Arregui ME. A balanced approach to choledocholithiasis. Surg Endosc. 2001;15: Massarweh NN, Flum DR. Role of intraoperative cholangiography in avoiding bile duct injury. J Am Coll Surg. 2007;204: Metcalfe MS, Ong T, Bruening MH, Iswariah H, Wemyss-Holden SA, Maddern GJ. Is laparoscopic intraoperative cholangiogram a matter of routine? Am J Surg. 2004;187: Nickkholgh A, Soltaniyekta S, Kalbasi H. Routine versus selective intraoperative cholangiography during laparoscopic cholecystectomy: a survey of 2,130 patients undergoing laparoscopic cholecystectomy. Surg Endosc. 2006;20: Iranmanesh P, Frossard J-L, Mugnier-Konrad B, Morel P, Majno P, Nguyen-Tang T, et al. Initial cholecystectomy vs sequential common duct endoscopic assessment and

64 subsequent cholecystectomy for suspected gallstone migration: a randomized clinical trial. JAMA. 2014;312: Inamdar S, Sejpal D V, Ullah M, Trindade AJ. Weekend vs. Weekday Admissions for Cholangitis Requiring an ERCP: Comparison of Outcomes in a National Cohort. Am J Gastroenterol. Nature Publishing Group; 2016;111: Parikh ND, Issaka R, Lapin B, Komanduri S, Martin J a, Keswani RN. Inpatient weekend ERCP is associated with a reduction in patient length of stay. Am J Gastroenterol. Nature Publishing Group; 2014;109: Zapf MAC, Kothari AN, Markossian T, Gupta GN, Blackwell RH, Wai PY, et al. The weekend effect in urgent general operative procedures. Surgery. 2015;158: Tabibian JH, Yang JD, Baron TH, Kane S V., Enders FB, Gostout CJ. Weekend Admission for Acute Cholangitis Does Not Adversely Impact Clinical or Endoscopic Outcomes. Dig Dis Sci. Springer US; 2016;61: Bell CM, Redelmeier DA. Mortality among patients admitted to hospitals on weekends as compared with weekdays. N Engl J Med. 2001;345: Kostis WJ, Demissie K, Marcella SW, Shao Y-H, Wilson AC, Moreyra AE, et al. Weekend versus weekday admission and mortality from myocardial infarction. N Engl J Med. 2007;356: Palmer WL, Bottle A, Davie C, Vincent CA, Aylin P. Dying for the weekend: a retrospective cohort study on the association between day of hospital presentation and the quality and safety of stroke care. Arch Neurol. 2012;69: Shaheen AAM, Kaplan GG, Myers RP. Weekend versus weekday admission and mortality from gastrointestinal hemorrhage caused by peptic ulcer disease. Clin Gastroenterol Hepatol. 2009;7: de Groot NL, Bosman JH, Siersema PD, van Oijen MGH, Bredenoord AJ, RASTA study group. Admission time is associated with outcome of upper gastrointestinal bleeding: results of a multicentre prospective cohort study. Aliment Pharmacol Ther. 2012;36: Ananthakrishnan AN, McGinley EL. Weekend hospitalisations and post-operative complications following urgent surgery for ulcerative colitis and Crohn s disease. Aliment Pharmacol Ther. 2013;37: Dindo D, Demartines N, Clavien P-A. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:

65 64. Iranmanesh P, Tobler O, De Sousa S, Frossard J-L, Morel P, Toso C. Prospective validation of an initial cholecystectomy strategy for patients at intermediate-risk of common bile duct stone. Gastrointest Endosc. 2016; Prat F, Meduri B, Ducot B, Chiche R, Salimbeni-Bartolini R, Pelletier G. Prediction of common bile duct stones by noninvasive tests. Ann Surg. 1999;229: Costi R, Mazzeo A, Tartamella F, Manceau C, Vacher B, Valverde A. Cholecystocholedocholithiasis: a case control study comparing the short- and longterm outcomes for a laparoscopy-first attitude with the outcome for sequential treatment (systematic endoscopic sphincterotomy followed by laparoscopic cholecystectomy). Surg Endosc. Springer-Verlag; 2010;24: Dasari BVM, Tan CJ, Gurusamy KS, Martin DJ, Kirk G, McKie L, et al. Surgical versus endoscopic treatment of bile duct stones. Cochrane database Syst Rev. 2013:CD Alexakis N, Connor S. Meta-analysis of one- vs. two-stage laparoscopic/endoscopic management of common bile duct stones. HPB. 2012;14: Rogers SJ, Cello JP, Horn JK, Siperstein AE, Schecter WP, Campbell AR, et al. Prospective Randomized Trial of LC+LCBDE vs ERCP/S+LC for Common Bile Duct Stone Disease. Arch Surg. 2010;145:

66 APPENDICES APPENDIX 1: UNIVARIATE ANALYSIS FOR PREDICTIVE FACTORS IN OMITTED PATIENTS In the main analysis, there was no information concerning the presence or absence of CBD dilation upon admission US in 233 patients. These patients were omitted during univariate and multivariate analysis. Due to the fact that the number is important (40.1% of all patients), a supplementary univariate analysis was performed in these patients, in order to control if their omission of the initial analysis could have possibly affected our results. Predictive factors having shown statistical significance in the initial univariate analysis were controlled in the 233 patients omitted due to unavailable information for CBD dilation and the results are shown in Table 14. All factors, except age, have a p<0.05 and the odds ratios have the same direction as in the initial univariate analysis. Consequently, the omitted 233 patients were unlikely to affect the results of our analysis, regarding the predictive factors for choledocholithiasis. Table 14: Univariate analysis for predictive factors in omitted patients Predictive factors Univariate analysis OR 95% CI p-value Age RUQ pain Cholecystitis <0.001 LFTs AST ALT <0.001 ALP <

67 γgt <0.001 Total bilirubin <0.001 Conjugated bilirubin <0.001 APPENDIX 2: TOTAL ADVERSE EVENTS RATES FOR INTERMEDIATE RISK PATIENTS The following table and Figure 21 show the adverse events rates for the patients belonging to the intermediate risk category, according to each treatment strategy followed. More precisely, patients are not pooled in two groups as was performed in the main analysis, but in three groups (cholecystectomy only, cholecystectomy followed by ERCP and EUS±ERCP followed by cholecystectomy). Table 15: Postoperative complications in intermediate risk patients according to treatment strategy followed Postoperative complications, n (%) Strategy Yes No Total CCK 2 (2.5) 79 (97.5) 81 (100.0) CCK / ERCP 5 (15.2) 28 (84.8) 33 (100.0) EUS ± ERCP / CCK 2 (4.3) 45 (95.7) 47 (100.0) Total 9 (5.6) 152 (94.4) 161 (100.0)

68 Figure 19: Postoperative complications for all patients according to the treatment strategy Figure 20: Postoperative complications for low-risk patients according to the treatment strategy

69 Figure 21: Postoperative complications for intermediate-risk patients according to the treatment strategy Figure 22: Postoperative complications for high-risk patients according to the treatment strategy