Comparison of Two Management Strategies, "Endoscopy First" and "Laparoscopic Cholecystectomy First", for Patients with Gallbladder Stones and Intermediate Risk for Choledocholithiasis: Study Protocol for a Randomized Trial

Background: The optimal approach for patients with gallbladder stones and intermediate risk for choledocholithiasis still remains undetermined. Use of diagnostic endoscopic retrograde cholangiopancreatography should be minimized as it carries considerable risk of post-procedural complications. This study compares two different management strategies: intraoperative cholangiography and endoscopic ultrasound before laparoscopic cholecystectomy for patients with symptomatic cholecystolithiasis and intermediate risk for choledocholithiasis. • Methods: It is a prospective randomized single-centre clinical trial enrolling adult patients undergoing laparoscopic cholecystectomy due to symptomatic gallbladder stones with intermediate risk for choledocholithiasis. The risk for choledocholithiasis is calculated using an original prognostic score – Vilnius University Hospital Index. A total of 106 participants will be included and randomized into two groups. Evaluation of bile ducts using endoscopic ultrasound and endoscopic retrograde cholangiography on demand will be performed before laparoscopic cholecystectomy for one arm (“Endoscopy first”). Intraoperative cholangiography during laparoscopic cholecystectomy and postoperative endoscopic retrograde cholangiopancreatography on demand will be administered in another arm (“Cholecystectomy first”). Postoperative follow-up is 6 months. The primary endpoint is the length of hospital stay. Secondary endpoints will include accuracy of the different management strategies, adverse events of interventions, duct clearance and technical success of interventions (intraoperative cholangiography, endoscopic ultrasound, endoscopic retrograde cholangiography), costs of treatment. • Discussion: This trial is planned determine which strategy is better approach for a patient with intermediate common bile duct stones risk and to define a simple to calculate and safe algorithm on managing choledocholithiasis. • Trial registration: The trial is registered at ClinicalTrials.gov, identification number NCT03658863.

The hypothesis to assess is that LC with IOC ("Cholecystectomy first" strategy) will decrease both the length of hospital stay and morbidity by lessening the number of Informed consent will be obtained from all study participants.

Setting
Participants will be enrolled and the trial will be carried out in Vilnius University Hospital Santaros Klinikos, a tertiary referral centre. The institution has experience in endoscopic ultrasonography, ERCP and intraoperative cholangiography procedures.

Randomization
Eligible patients who provide informed consent will be assigned to the groups "Endoscopy first" or "Cholecystectomy first" randomly, according to a pre-made sequence. The sequence is generated by a site random.org (Randomness and Integrity Services Ltd). The sequence was created using block randomisation of two elements, A and B (A -"Cholecystectomy first", B -"Endoscopy first") in a ratio 1:1. According to the sequence, sheets with group's name are enclosed to opaque envelopes. Envelopes are numbered and the number of the envelope is patient's number in the trial. When a new participant of the trial is enrolled the topmost envelope is opened by one of investigators and the participant is randomised into the specified group.

Procedure
The participants of the trial will undergo CBD evaluation depending on the group assignment. For the group "Endoscopy first" EUS is used to evaluate bile ducts. If stones in extrahepatic bile ducts are seen ERCP and lithectomy is performed during the same anaesthesia. LC is performed after endoscopic procedures as soon as possible. In the group "Cholecystectomy first" LC with IOC is performed. If stones are found postoperative ERCP with lithectomy is applied (during cholecystectomy if common bile duct is completely blocked or as soon as possible).
EUS is performed with linear or radial Olympus ultrasound endoscopes. CBD, pancreatic head and adjacent structures are visualised from duodenal bulb and descending duodenum. EUS is considered positive for CBD stone(s) when a constant hyperechogenic lesion with acoustic shadowing is seen in CBD projection. ERCP procedures are performed by experienced endoscopists (each has more than 5 years of experience in ERCP and more than 500 procedures done). Olympus side-viewing endoscopes TJF-160VR are used. Primary deep selective cannulation of CBD is performed with sphincterotome or cannula and guidewire technique. Diatrizoate (Urografin) and iohexol (Omnipaque) are used as a contrast media. Endoscopic sphincterotomy is performed over a guidewire technique with Olympus pull-type sphincterotome. Papillary balloon dilation using a through-the-scope balloon catheter is applied when stricture is indicated. Stones are removed using a retrieval balloon catheter and/or a Dormia basket.
Complete clearance of CBD is documented with a balloon catheter cholangiogram at the end of the procedure. ERCP is considered positive when a filling defect(s) is seen in cholangiogram and/or a stone(s) evacuates from CBD. ERCP is considered unsuccessful when cannulation of bile ducts is technically impossible.
All patients will undergo a standard four-port LC: a 10-mm port at the umbilicus, a 10-mm port at the subxyphoid, a 5-mm port at the bottom of the gallbladder, and a 5-mm port at the right epigastrium. A 30-degree laparoscope is used for intra-abdominal visualization.

Statistical considerations
Sample size was calculated in reference to collected data on management of choledocholithiasis in the trial centre, Vilnius University Hospital Santaros Klinikos (11). In our previous study mean treatment duration for different management strategy groups (LC-IOC first and ERCP-first) were 5.37 and 7.13 days, with standard deviations 2.5 and 2.8 respectively, these findings were used to calculate requested sample size. α error probability was selected to be 0.05, power (1-β) 0.095. Calculated effect size for two independent groups is 0.663. Required sample size is two groups with 53 participants each.
The endpoints in different management groups will be analysed using chi-square test or Ttest for independent means. Two-sided hypotheses are to be checked and a P-value <0.05 will be considered statistically significant.

Discussion
In the era of minimally invasive surgery and personalized medical care the optimal cost-effective strategy for the management of patients with symptomatic gallstones and suspected choledocholithiasis is not categorically defined yet.
The whole approach to patient with gallbladder stones consists of a few steps: evaluation of probability of stones in CBD, visualisation and evacuation of the stones when present and treatment of cholecystolithiasis itself (18). There are a few main clinical dilemmas in the management of choledocholithiasis: which patients should be investigated for CBD stones and what is the optimal way to treat it -single-stage (LC with intraoperative CBD evaluation) or two-stage (preoperative ERCP followed by LC) technique.
First, it is essential to define the criteria for different risk groups. Whilst the majority of recent trials evaluating accuracy of choledocholithiasis prediction refer to ASGE guidelines we performed an analysis of seven different studies on this prognostic system and predictive values of high risk criteria were quite mediocre: general sensitivity was found to be 52.4%, specificity 60.8%, positive predictive value 65.6%, negative predictive value 47.4%, accuracy 55.9% (11). At the centre of this trial an original prognostic index (VUHI) is used for prediction of choledocholithiasis risk before LC since 1999. It is calculated by formula VUHI = A/30 + 0.4×B, where A -total bilirubin concentration (mcmol/l), B -CBD diameter measured by ultrasound exam. Results of our previous study showed that VUHI had comparable and, at some parameters, superior performance than the prognostic system of ASGE guidelines (11). The most modest measure was the specificity of VUHI (54%, whilst sensitivity was 80.5%). This implied that earlier threshold of the index was kind of weak spot in this evaluation system. Newly generated model for predicted probability of choledocholithiasis sets limits for intermediate risk group, i.e. determines which patients should undergo additional non-interventional investigation. We chose thresholds for intermediate risk group to be at 25 and 75% of probability for CBD stones considering that upper limit of 50% as in ASGE guidelines would still leave certain amount of patients who will receive unnecessary ERCPs. Latest EASL (The European Association for the Study of the Liver) guidelines also state that patients with intermediate probability should undergo further evaluation with EUS or MRCP but do not define what this intermediate probability is (19). Meta-analyses showed that these two diagnostic procedures are quite comparable but EUS has better diagnostic accuracy (20,21). Just one trial comparing EUS and IOC was found in PubMed database and showed better predictive values of IOC (22). Considering that this study was performed twenty years ago and imaging technologies have advanced since then it is worth to compare these two methods once again. When comparing IOC with ERCP as a diagnostic procedure, systematic review of ten trials by Gurusamy et al. showed slightly higher sensitivity of IOC with no difference in specificity (23). The next step is to choose optimal management strategy. In the aforementioned study we assessed effectiveness of different approaches (LC with IOC and ERCP "on demand" versus preoperative ERCP with sphincterotomy and necessary therapeutic interventions followed by LC). Some advantages in both strategies were found: there were less missed stones and false positive cholangiographies in ERCP-first group, meanwhile LC-IOC group had less ERCP related complications and mean length of hospital stay in this group was shorter, in most cases reflecting no need to wait for another procedure (11). Barreras González JE et al. also find these two strategies comparable in efficacy (24). Moreover, meta-analyses of various different trials show that there is no significant difference in the mortality, morbidity, retained stones, and failure rates between the single-stage and two-stage choledocholithiasis management (1,25). The main drawback of preoperative ERCP plus LC strategy against various single-session approaches (intraoperative ERCP, LC with laparoscopic bile duct clearance, open bile duct clearance) is the time: usually there is waiting period between two procedures which prolongs duration of hospital stay and slightly increases the risk to develop recurrent biliary events and cholecystitis (19,26,27).
The reduced length of hospital stay was the only significant advantage of intraoperative ERCP found by Cochrane systematic review when comparing single stage and two stages approach in another way -laparoscopic -endoscopic rendezvous versus preoperative endoscopic sphincterotomy (28). A recent meta-analysis by Ricci et al. of four laparoscopic and endoscopic techniques for managing gallstone disease with biliary duct calculi showed that safest and the most successful approach is combined LC with intraoperative ERCP (29). However, one of the biggest limitations to single-session ERCP and LC is difficult coordination of medical personnel, equipment and location of procedure (30,31). Despite these restraints a large survey of general surgeons in USA showed that the majority of respondents preferred ERCP to laparoscopic CBD exploration for the management of choledocholithiasis (32).
This trial is aimed to answer the question which one of the two strategies -preoperative EUS or LC with IOC is the optimal solution for intermediate risk of CBD stones. We intend to compare various aspects of two ways of choledocholithiasis management: from accuracy to cost and time efficiency. Thresholds of different risk groups also will be verified prospectively. This trial is planned to define a simple to calculate and safe algorithm on managing choledocholithiasis.

Availability of data and materials
The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
This trial was conducted with no external funding and is performed on the resources of the hospital as the trial is a part of PhD research of one of investigators (AA) and the centre of the trial is a university hospital. The approval to carry out the trial on resources of the hospital was obtained and signed as a contract between the hospital and investigators.
Authors' contributions GS and AA conceived the project, designed the study, drafted the manuscript, and approved the final submission. GS, AA, JS, TJ and MD arranged inclusion criteria, participates in patients' selection and enrolment. AA performed sample size calculation.
KS and JV helped design the study, revised the manuscript, and approved the final submission. All authors read and approved the manuscript.  If you had any of those symptoms, would you agree to arrive at Santaros Klinikos for additional investigation -abdominal ultrasound and blood tests? Figure 1 Flowchart of the study.

Supplementary Files
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