B. R. Poh 1,S.P.S.Ho 3, M. Sritharan 1,C.C.Yeong 1,M.P.Swan 2,D.A.Devonshire 2,P.A.Cashin 1,3 and D. G. Croagh 1,3

Transcription

1 Randomized clinical trial Randomized clinical trial of intraoperative endoscopic retrograde cholangiopancreatography versus laparoscopic bile duct exploration in patients with choledocholithiasis B. R. Poh 1,S.P.S.Ho 3, M. Sritharan 1,C.C.Yeong 1,M.P.Swan 2,D.A.Devonshire 2,P.A.Cashin 1,3 and D. G. Croagh 1,3 1 Upper Gastrointestinal/Hepato-Pancreato-Biliary and General Surgery Unit and 2 Gastroenterology and Hepatology Unit, Monash Health, and 3 Department of Surgery (School of Clinical Sciences at Monash Health), Monash University, Victoria, Australia Correspondence to: Mr D. G. Croagh, Monash Health, Monash House, Suite 9, 271 Clayton Road, Clayton, Victoria 3168, Australia ( daniel.croagh@monashhealth.org) Background: Various minimally invasive approaches exist for the management of choledocholithiasis at the time of laparoscopic cholecystectomy. The aim of this study was to compare endoscopic retrograde cholangiopancreatography (ERCP) with laparoscopic bile duct exploration (LBDE) and test the hypothesis that intraoperative ERCP is no different to LBDE in terms of rate of bile duct clearance or retained stones. Methods: Eligible patients with choledocholithiasis undergoing emergency laparoscopic cholecystectomy were randomized to intraoperative ERCP or LBDE in a 1 : 1 ratio. The primary outcomes were rates of bile duct clearance and retained stones. Secondary outcomes were postprocedure complication rate, mortality rate, postoperative length of hospital stay, conversion to open surgery rate, procedural time and total duration of surgery. Results: Some 104 patients were randomized, and 52 patients in each group were included in an intention-to-treat analysis. Duct clearance rates were 87 per cent for patients who had intraoperative ERCP and 69 per cent for those in the LBDE group (P = 0 057). The rate of retained stones was lower in the ERCP group than in the LBDE group: 15 versus 42 per cent respectively (P = 0 004). Median postoperative length of stay was shorter with ERCP (2 days versus 3daysforLBDE;P = 0 015). Conclusion: Intraoperative ERCP is more effective than LBDE in terms of minimizing the rate of retained stones in patients with choledocholithiasis undergoing emergency laparoscopic cholecystectomy. Registration number: ACTRN ( Paper accepted 5 April 2016 Published online 15 June 2016 in Wiley Online Library ( DOI: /bjs Introduction Various minimally invasive approaches exist for the management of choledocholithiasis at the time of laparoscopic cholecystectomy, comprising laparoscopic or endoscopic methods, or a combination of both. Generally, these include laparoscopic transcystic common bile duct exploration, laparoscopic choledochotomy, laparoscopic endobiliary stent placement and endoscopic retrograde cholangiopancreatography (ERCP) with stone extraction, which may be performed before, at the time of, or after laparoscopic cholecystectomy 1,2. Previous trials comparing laparoscopic bile duct exploration (LBDE), via either a transcystic or a transcholedochal approach, with endoscopic methods of stone clearance, either preoperative, postoperative or intraoperative ERCP, have collectively failed to demonstrate the superiority of one approach over the other, although there is some suggestion that LBDE may be associated with a lower rate of retained stones compared with ERCP in the postoperative setting 3. A retrospective study 4 of the management of choledocholithiasis in emergency laparoscopic cholecystectomy found that postoperative ERCP resulted in significantly better rates of duct clearance compared with laparoscopic clearance. This prompted the present authors to design a randomized trial with the aim of comparing LBDE with intraoperative ERCP in a similar patient population BJS Society Ltd BJS 2016; 103:

2 1118 B. R. Poh, S. P. S. Ho, M. Sritharan, C. C. Yeong, M. P. Swan, D. A. Devonshire et al. The aim of this study was to compare the two single-stage approaches using laparoscopy and endoscopy in patients undergoing emergency laparoscopic cholecystectomy with choledocholithiasis, in line with recommendations from a recent Cochrane review 3 that further randomized clinical trials are needed to validate existing data on the topic. Single-stage approaches may shorten length of hospital stay and be more efficacious 5 7. It was hypothesized that intraoperative ERCP would be no different to LBDE in terms of rates of bile duct clearance or retained stones in patients undergoing laparoscopic cholecystectomy. Methods This was an open-label randomized clinical trial with two parallel arms: LBDE, by either transcystic exploration or laparoscopic choledochotomy, versus intraoperative ERCP with endoscopic sphincterotomy and stone extraction. Ethical approval was granted by the Monash Health Human Research Ethics Committee on 13 March 2013, and the trial was carried out in accordance with the principles of the Declaration of Helsinki 8.Thetrialwasregistered retrospectively with the Australian New Zealand Clinical Trials Registry (ID ACTRN ) on 9 July Patients Patients between the ages of 18 and 99 years who were admitted to the acute surgical unit, or referred to the unit, with a diagnosis of biliary colic, choledocholithiasis, acute cholecystitis, ascending cholangitis and/or gallstone pancreatitis, and listed for emergency laparoscopic cholecystectomy, were approached for potential trial recruitment by the attending resident or registrar (not involved in the study). Biliary colic was defined as presentation with typical biliary-type pain and imaging findings of gallstone(s), and choledocholithiasis when common bile duct stones were found on imaging, with or without symptoms of biliary-type pain or obstructive jaundice. The definitions and classifications outlined in the Tokyo guidelines 2013 were used for acute cholecystitis and acute cholangitis 9,10, and the 2012 revision of the Atlanta classification for acute pancreatitis 11. The following patient groups were excluded: private and elective patients, pregnant women, children (patients under the age of 18 years), patients with postsurgical anatomy precluding routine endoscopic access to the ampulla of Vater (Billroth II reconstruction, any form of Roux-en-Y reconstruction), and patients with severe pancreatitis or severe cholangitis. All patients who consented to trial participation proceeded to undergo laparoscopic cholecystectomy as scheduled. Upon visualization and confirmation of the presence of choledocholithiasis (by a consultant) during intraoperative cholangiography (IOC), a saline flush with intravenous administration of glucagon or butylscopolamine was administered if the stones were judged small enough to attempt flushing. Enrolled patients in whom this was not possible were randomized to one of the two study arms. Randomization Allocation concealment was carried out by means of sequentially numbered, sealed and signed opaque envelopes containing letters generated by randomization software for simple randomization in a 1 : 1 ratio. The randomization sequence was generated months before trial commencement by an investigator not involved in patient enrolment or care. The allocation sequence was deleted after preparation of the randomization envelopes, and thus was effectively concealed from investigators and proceduralists. Randomization envelopes were drawn and opened by the circulating nurse upon consultant confirmation of choledocholithiasis at the time of IOC. Laparoscopic bile duct exploration LBDE was performed by one of the 12 consultant surgeons in the unit, or by a registrar or fellow under consultant supervision. All 12 consultant surgeons had performed between ten and 40 LBDE procedures before trial commencement, in addition to other complex laparoscopic procedures. When a patient was randomized to LBDE, this was performed immediately after IOC, via either the transcystic route or choledochotomy, at the attending surgeon s discretion. Transcystic exploration was performed under fluoroscopic guidance and/or direct vision with a 2 7-mm flexible choledochoscope, if available. A 5-mm flexible choledochoscope was sometimes used if the cystic duct anatomy permitted. Choledochotomy was undertaken using a longitudinal incision and exploration under direct vision using a 5-mm flexible choledochoscope. Stone extraction was usually performed with a Nathanson (Cook Medical, Bloomington, Indiana, USA) or Zero Tip (Boston Scientific, Natick, Massachusetts, USA) basket; Fogarty balloon catheters were employed only occasionally. Electrohydraulic lithotripsy was occasionally used for difficult stones. Laparoscopic endobiliary Fanelli stents (Cook Medical) were deployed for biliary drainage by the operating surgeon as indicated, and were generally placed whenever laparoscopic choledochotomy was performed.

3 Intraoperative endoscopic retrograde cholangiopancreatography versus laparoscopic bile duct exploration in choledocholithiasis 1119 Enrolment Assessed for eligibility n = 1206 Randomized n = 104 Excluded n = 1102 Did not meet inclusion criteria n = 475 No trial consent available n = 252 No stones on IOC n = 359 Stones flushed n = 16 Allocation Allocated to intraoperative ERCP n = 52 Received intervention n = 47 Did not receive intervention n = 5 Endoscopist failed to attend n = 4 Duct cleared by IOC catheter n = 1 Allocated to LBDE n = 52 Received intervention n = 48 Did not receive intervention n = 4 Randomization letter misread n = 1 Choledochoscope not available n = 1 IOC misinterpreted n = 2 Follow-up Lost to follow-up n = 9 Died n = 4 Uncontactable n = 5 Discontinued intervention n = 0 Lost to follow-up n = 6 Died n = 2 Uncontactable n = 4 Discontinued intervention n = 0 Analysis Analysed n = 52 Excluded from analysis n = 0 Analysed n = 52 Excluded from analysis n = 0 Fig. 1 CONSORT diagram for the trial. All randomized patients were included for analysis in their respective groups on an intention-to-treat basis regardless of follow-up, as one of the primary outcomes was independent of follow-up. IOC, intraoperative cholangiography; ERCP, endoscopic retrograde cholangiopancreatography; LBDE, laparoscopic bile duct exploration Intraoperative endoscopic retrograde cholangiopancreatography Intraoperative ERCP was performed by one of four endoscopists accredited in ERCP techniques, three of whom were gastroenterologists and one surgeon with a subspecialty interest in hepatopancreatobiliary surgery. Endoscopists were generally given advance notice that they might be needed in theatre to perform ERCP. If the patient was randomized to intraoperative ERCP, the endoscopist would be notified to present in theatre. Following cholecystectomy, intraoperative ERCP was performed using standard techniques with a side-viewing duodenoscope. Intraoperative rendezvous facilitation of cannulation via a guide-wire passed during IOC was not employed, however residual contrast from the IOC often served to facilitate cannulation. Endoscopic sphincterotomy was performed using a bow-string sphincterotome (Cotton Cannulatome II (Cook Medical) or Dreamtome RX (Boston Scientific)). Balloon sphincteroplasty was performed when indicated using the CRE Balloon Dilator (Boston Scientific). Stone extraction was achieved using balloon or basket catheters under fluoroscopic guidance. Biliary or pancreatic drainage stents were deployed if indicated. Postoperative care Patients received routine postprocedural care and were monitored for complications on the ward by the treating team and trial coordinators. Post-ERCP complications were classified according to the grading system proposed by Cotton and colleagues 12. At discharge, patients were advised to re-present to the authors institution in the event of any recurring symptoms or suspected complications to facilitate follow-up. Patients were informed after the procedure of the intervention they had been assigned to. Postinterventional assessments were generally carried out in a non-blinded fashion. Outcome measures The primary outcomes monitored were rates of bile duct clearance and retained stones. Bile duct clearance was defined as a clear intraoperative cholangiogram, choledochoscopy or occlusion cholangiogram after the procedure. Retained stones were defined as any biliary tract stones detected within 2 years of the index procedure. This included expected (following failed duct clearance) and unexpected symptomatic and asymptomatic presentations for biliary stones.

4 1120 B. R. Poh, S. P. S. Ho, M. Sritharan, C. C. Yeong, M. P. Swan, D. A. Devonshire et al. Table 1 Characteristics of participants Intraoperative ERCP (n = 52) LBDE (n = 52) Age (years)* 53 9(22 6) 53 4(19 7) Sex ratio (F : M) 31 : : 23 Preoperative bilirubin (μmol/l) 31 0 (24 50) 44 5 (26 98) No. of stones 1(1 2) 1(1 2) Maximum stone size (mm)* 7 3(3 1) 6 5(3 2) Minimum stone size (mm)* 6 1(3 0) 5 2(2 7) CBD diameter (mm)* 10 6(2 8) 10 6(3 3) Cystic diameter (mm)* 5 0(1 6) 5 0(1 7) ASA fitness grade I 15 (29) 13 (25) II 21 (40) 22 (42) III 13 (25) 12 (23) IV 3 (6) 5 (10) Preoperative diagnosis Biliary colic 7 (13) 13 (25) Choledocholithiasis 10 (19) 10 (19) Acute cholecystitis 5 (10) 3 (6) Ascending cholangitis 24 (46) 26 (50) Gallstone pancreatitis 4 (8) 0 (0) Cholangitis with pancreatitis 2 (4) 0 (0) Preoperative imaging Ultrasonography 49 (94) 50 (96) CT 10 (19) 7 (13) MRCP 11 (21) 9 (17) Values in parentheses are percentages unless indicated otherwise; values are *mean(s.d.) and median (95 per cent c.i.). Values based on 38 and 40 patients. ERCP, endoscopic retrograde cholangiopancreatography; LBDE, laparoscopic bile duct exploration; CBD, common bile duct; ASA, American Society of Anesthesiologists; MRCP, magnetic resonance cholangiopancreatography. Secondary outcomes were postprocedure complication rate, perioperative mortality rate, postoperative length of hospital stay, conversion to open surgery rate, procedure time and total duration of surgery. Postoperative length of stay was measured in days from the day of operation to the day of discharge. Procedure time for LBDE was measured in minutes from randomization to LBDE until performance of completion cholangiography. Procedure time for intraoperative ERCP was measured in minutes from scope introduction until performance of occlusion cholangiography. Total duration of surgery was the time in minutes from beginning to end (skin closure for LBDE, and withdrawal of scope for intraoperative ERCP). Follow-up Data were collected in the operating theatre, on the ward and in the office. Follow-up data for patients re-presenting to the unit were tracked and recorded by the treating team and trial coordinators in a non-blinded fashion; otherwise all randomized patients were followed up by telephone at 3-month intervals. Any other required information was obtained (with consent) from the patient s general practitioner, attending private specialist (consultant) or treating healthcare facility. A standard pro forma was used for follow-up calls, and included enquiry about related signs and/or symptoms and whether further care or procedures related to gallstone disease had been required or sought. Statistical analysis Sample-size determination was based on estimates from the authors own institutional data 4 to detect a two-sided difference for superiority of intraoperative ERCP. Using both expected bile duct clearance rates of 60 per cent in the laparoscopic group and 85 per cent in the endoscopic group, and retained stone rates of 40 and 15 per cent respectively, in order to detect a 25 per cent difference (α=0 05, power 80 per cent) in the rate of bile duct clearance or retained stones, it was calculated that 49 patients per arm would be required. Data were analysed using GraphPad Prism 6 0 (Graph- Pad Software, San Diego, California, USA). Continuous variables were compared using Student s t test (for normally distributed variables) or Mann Whitney U test (for non-normally distributed variables). Categorical data were compared with Fisher s exact test. P < was considered statistically significant. Results Between 18 March 2013 and 12 May 2015, 52 patients were randomized to intraoperative ERCP and 52 to LBDE (Fig. 1). All patients were included for analysis on an intention-to-treat basis. Follow-up was conducted until November 2015; median length of follow-up was 13 (range 6 26) months. Fifteen patients were lost to follow-up, six of whom died during the follow-up interval, from congestive cardiac failure, metastatic renal cell carcinoma, stroke, vascular dementia, metastatic prostate carcinoma and necrotizing fasciitis. There were nine protocol deviations. Five patients in the ERCP group did not receive the intended treatment, four owing to failure of an endoscopist to attend to perform ERCP leading to an overall failure to attend rate of 8 per cent. (Transcystic exploration was attempted for 3 of these patients, but failed in 2, and 1 was an elective patient who had been wrongly recruited.) In the fifth patient, stones were initially demonstrated in the duct but were cleared incidentally by the IOC catheter, and thus no further intervention was required.

5 Intraoperative endoscopic retrograde cholangiopancreatography versus laparoscopic bile duct exploration in choledocholithiasis 1121 Table 2 Primary and secondary outcomes Intraoperative ERCP (n = 52) LBDE (n = 52) P# Retained stones 8 (15) 22 (42) Duct clearance 45 (87) 36 (69) Morbidity 14 (27) 20 (38) Procedure time (min)* 20 (15 27) 28 (24 40) 0 003** Total duration of 112 ( ) 110 (95 140) 0 590** surgery (min)* Postoperative length of stay (days)* 2 (2 3) 3 (2 4) 0 015** Values in parentheses are percentages unless indicated otherwise; *values are median (95 per cent c.i.). Values based on 46, 43, 48 and 45 patients. ERCP, endoscopic retrograde cholangiopancreatography; LBDE, laparoscopic bile duct exploration. #Fisher s exact test, except **Mann Whitney U test. Four patients in the LBDE group did not receive the intended treatment. One patient mistakenly received intraoperative ERCP after the randomization letter was misread by the circulating nurse. Another patient did not have LBDE owing to unavailability of a choledochoscope. In a further two patients intraoperative cholangiograms were misinterpreted and, after randomization but before intervention, proved not to be stones. Two patients in the LBDE group received intraoperative ERCP. In one, this occurred after failure of LBDE; as the operator was also proficient in ERCP techniques, ERCP was attempted. In the other, intraoperative ERCP was performed owing to concern regarding a common bile duct injury that may have occurred during the attempted LBDE. ERCP later showed no bile duct injury. Both participants were considered treatment failures and were analysed as part of the LBDE group. Table 1 shows patients baseline characteristics. Of the 48 intraoperative ERCP procedures performed (47 intended ERCP procedures plus the patient in the LBDE group who mistakenly received ERCP), 41 were completed in the supine position, five in the prone position, one in the left lateral position and one was initially attempted in the supine position but the patient was subsequently turned prone owing to difficulty in cannulation. Table 2 shows the primary and secondary outcomes. There was no perioperative mortality or conversions to open surgery. Duct clearance rates were 87 per cent in the ERCP group and 69 per cent for LBDE (P = 0 057). The rate of retained stones was lower with ERCP: 15 per cent versus 42 per cent for LBDE (P = 0 004). Intraoperative ERCP was unsuccessful owing to failed cannulation in only one patient. Endoscopic sphincterotomy was performed in all patients who received intraoperative ERCP. Biliary stents were deployed in three after ERCP, because of known or suspected residual duct stones. Table 3 Morbidity Intraoperative ERCP (n = 52) LBDE (n = 52) P Unexpected retained 1 (2) 8 (15) stone Post-ERCP pancreatitis 4 (8) 2 (4) Mild 1 (2) 1 (2) Moderate 3 (6) 1 (2) Postsphincterotomy bleed 4 (8) 1 (2) Mild 2 (4) 0 (0) Moderate 2 (4) 1 (2) Bile leak 0 (0) 2 (4) Wound complications* 0 (0) 2 (4) Pneumonia 0 (0) 2 (4) Other 5 (10) 4 (8) Total 14 (27) 20 (38) Total with Clavien Dindo 5 (10) 11 (21) grade III or above 13 Values in parentheses are percentages. *Included wound sinus and port-site haematoma; included pleural effusion, hypotension, atelectasis, acute urinary retention and atrial fibrillation. One patient had both unexpected retained stone and pneumonia. ERCP, endoscopic retrograde cholangiopancreatography; LBDE, laparoscopic bile duct exploration. Fisher s exact test. No pancreatic stents were deployed. Balloon sphincteroplasty was used in one patient in addition to standard sphincterotomy. ERCP achieved duct clearance in 43 of the 48 patients who received intraoperative ERCP per protocol. Only one patient was found on follow-up to have an unexpected retained stone (which remained asymptomatic as the patient had a biliary stent in situ). Transcholedochal exploration was performed in five patients in the LBDE group, successfully in all instances. Laparoscopic endobiliary stents were placed following laparoscopic choledochotomy in these five patients, two of whom were found to have retained stones on follow-up; one presented unexpectedly 15 months later with cholangitis. Some 43 patients in the LBDE group had transcystic exploration per protocol. Duct clearance was achieved in 29. Laparoscopic endobiliary stents were used in five patients, and electrohydraulic lithotripsy in two. On follow-up, 20 patients who had undergone transcystic exploration were found to have retained stones; these were unexpected in six patients. In four instances the retained stones led to complications. Table 3 summarizes the morbidity experienced in each group. Of the nine patients who had unexpected retained stones (7 symptomatic, 2 asymptomatic), four presented with abdominal pain associated with raised liver function test results, two had pancreatitis and one cholangitis. All nine proceeded to ERCP for stone clearance. ERCP-related morbidity was also experienced in the

6 1122 B. R. Poh, S. P. S. Ho, M. Sritharan, C. C. Yeong, M. P. Swan, D. A. Devonshire et al. LBDE group as these patients often required ERCP as salvage therapy for retained stones. There were no cases of ERCP-related perforation. Patients who had post-ercp pancreatitis were distinct from those who presented with gallstone pancreatitis. All five patients who had a postsphincterotomy bleed required endoscopic therapy to stop the bleeding, and three needed blood transfusions. Two patients in the LBDE group had bile leak, compared with none in the ERCP group; both leaks were managed endoscopically by ERCP and biliary stenting, and neither required open surgery for repair. Although the proportion of patients with Clavien Dindo grade III (or above) complications 13 was more than double in the LBDE group compared with that in the ERCP group, this was not significantly different (P = 0 173). Discussion In this study, the proportion of retained stones was significantly different following intraoperative ERCP and LBDE. The presence of retained stones is probably a better indicator of procedural efficacy than duct clearance, as it relies less on interpretation of duct clearance at the end of the procedure, which may be subject to greater interobserver variability. Duct clearance and retained stone rates in both groups were comparable to those for historical controls in an emergency cohort 4 : 86 and 15 per cent respectively for postoperative ERCP in the historical cohort (compared with 87 and 15 per cent in the present intraoperative ERCP group); and 63 and 43 per cent for LBDE in the historical cohort (versus 69 and 42 per cent respectively in the present LBDE group). Although improved duct clearance and retained stone rates were anticipated in both groups in the trial setting (compared with historical controls), this was apparent only for duct clearance in the LBDE group and any real improvement was likely offset by the technical difficulties and failures experienced in both groups. The relatively high rate of ERCP cannulation may have contributed to the presence of a residual cholangiogram before initiating ERCP, which would have provided the endoscopist with a road map to facilitate cannulation. A relatively high proportion (almost half in both groups) of patients with a preoperative diagnosis of suspected or definite acute cholangitis (as per Tokyo guidelines 2013 criteria 10 ) were included in the study. Because of the strategy to attempt laparoscopic or endoscopic clearance of the bile duct at the time of laparoscopic cholecystectomy, preoperative use of magnetic resonance cholangiopancreatography to confirm or diagnose choledocholithiasis was relatively low (19 2 per cent). This strategy may allow a reduction in the preoperative length of hospital stay. Only two previous studies 14,15 have compared LBDE with intraoperative ERCP. Hong and colleagues 14 randomized 234 patients with choledocholithiasis diagnosed by preoperative ultrasonography or IOC and found similar duct clearance rates for both groups: 89 per cent for the 141 patients having LBDE and 91 per cent for the 93 undergoing intraoperative endoscopic sphincterotomy. ElGeidie et al. 15 randomized 226 patients with choledocholithiasis on IOC and similarly found no significant difference in duct clearance between the groups: 92 per cent in 112 patients in the LBDE group versus 97 per cent in 107 undergoing intraoperative endoscopic sphincterotomy. The latter authors excluded patients with signs of cholangitis, gallstone pancreatitis, and American Society of Anesthesiologists fitness grade IV and V, whereas Hong et al. 14 did not specify any exclusion criteria. The present trial is the only study comparing LBDE with intraoperative ERCP in the acute care surgery/emergency setting. Although the duct clearance rates by intraoperative ERCP found here are comparable to those in other studies, the rate of successful clearance by LBDE is substantially lower. A number of factors could account for this. All patients had acute presentations and more than half had cholangitis. Inflammation in Calot s triangle and the hepatoduodenal ligament may have increased the difficulty of transcystic bile duct exploration, and this may also have discouraged the use of choledochotomy, which is often more effective, especially for larger stones or stones above the termination of the cystic duct. For much of the study there was no access to a 2 7-mm choledochoscope. Direct visualization of stones greatly facilitates their removal and also allows more accurate assessment of duct clearance. The high rate of retained stones in the LBDE group suggests that, despite consultant review of the final intraoperative cholangiogram, a number of stones were missed with this technique. With the performance of endoscopic sphincterotomy in the ERCP group, it was possible that any stones missed on cholangiography could be allowed to pass asymptomatically (if small enough), whereas this was not possible with an intact sphincter of Oddi in the LBDE group. Lastly, a large number of surgeons were involved in the study. Although all surgeons were proficient with LBDE, there is inevitably a range of ability and interest in pursuing this technique. This may be more reflective of the real world environment compared with previous studies from centres with a special interest in this area. This may explain the persisting widespread reliance on ERCP in the wider surgical community 16, despite the

7 Intraoperative endoscopic retrograde cholangiopancreatography versus laparoscopic bile duct exploration in choledocholithiasis 1123 apparent attractiveness of LBDE, which allows clearance of the bile duct and cholecystectomy in a single procedure. This study was not powered to detect differences in procedural morbidity. Nonetheless, although the rate of post-ercp pancreatitis is consistent with reported rates, the incidence of postsphincterotomy bleeding was relatively high in the present population compared with the literature 17. The high proportion of participants with cholangitis may have increased the risk of this complication 18. Two patients developed bile leak; one had transcystic exploration and the other underwent laparoscopic choledochotomy. Transcholedochal exploration is known to have higher rates of bile leak than transcystic exploration or ERCP 19. Increasing use of choledochotomy may improve duct clearance rates by laparoscopic bile duct exploration, with the caveat that a higher incidence of bile leak may be observed; conversely, increasing use of ERCP would likely increase ERCP-related morbidity, including the postulated but unproven long-term consequences of performing endoscopic sphincterotomy, such as duodenobiliary reflux and bacterobilia, with the possibility of recurrent choledocholithiasis or even cholangiocarcinoma (although these have not been proven conclusively) The present study was limited by its non-blinded nature, and thus the potential for performance bias. However, given that duct clearance rates were similar to those in historical controls, performance bias was considered to be minimal. Potential imprecision could have occurred during the interpretation of cholangiograms, and this may have had some influence on study findings. It was considered that the duration of follow-up was adequate and sufficient in terms of detecting postoperative complications and outcomes. Nevertheless, this was a single-institution study limited to a cohort of patients undergoing emergency laparoscopic cholecystectomy, which may have some impact regarding its external validity. Further limitation in terms of applicability to the wider community include the ability of individual institutions to provide a timely ERCP service, particularly in the operating theatre setting (outside the endoscopy suite). However, within the setting of the acute surgical unit, the majority of procedures in this trial were performed during office hours, thereby facilitating the logistics required for on-table ERCP. Acknowledgements The authors acknowledge the contribution of the following people in the conduct of this study: M. Adams, M. Barnes, R. Berry, K. Bowers, M. Cullinan, A. Dhir, Z. Dubrava, J. Gribbin, G. Jones, L. Low, N. Naqash, D. Spilias and R. Workman. Disclosure: The authors declare no conflict of interest. References 1 Overby DW, Apelgren KN, Richardson W, Fanelli R; Society of American Gastrointestinal and Endoscopic Surgeons. SAGES guidelines for the clinical application of laparoscopic biliary tract surgery. Surg Endosc 2010; 24: Itoi T, Tsuyuguchi T, Takada T, Strasberg SM, Pitt HA, Kim MH et al.; Tokyo Guideline Revision Committee. TG13 indications and techniques for biliary drainage in acute cholangitis (with videos). J Hepatobiliary Pancreat Sci 2013; 20: Dasari BV, 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; (12)CD Poh B, Cashin P, Bowers K, Ackermann T, Tay YK, Dhir A et al. Management of choledocholithiasis in an emergency cohort undergoing laparoscopic cholecystectomy: a single-centre experience. HPB (Oxford) 2014; 16: Ding G, Cai W, Qin M. Single-stage vs. two-stage management for concomitant gallstones and common bile duct stones: a prospective randomized trial with long-term follow-up. J Gastrointest Surg 2014; 18: ElGeidie AA. Single-session minimally invasive management of common bile duct stones. World J Gastroenterol 2014; 20: Wild JL, Younus MJ, Torres D, Widom K, Leonard D, Dove J et al. Same-day combined endoscopic retrograde cholangiopancreatography and cholecystectomy: achievable and minimizes costs. J Trauma Acute Care Surg 2015; 78: World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013; 310: Yokoe M, Takada T, Strasberg SM, Solomkin JS, Mayumi T, Gomi H et al.; Tokyo Guidelines Revision Committee. TG13 diagnostic criteria and severity grading of acute cholecystitis (with videos). J Hepatobiliary Pancreat Sci 2013; 20: Kiriyama S, Takada T, Strasberg SM, Solomkin JS, Mayumi T, Pitt HA et al.; Tokyo Guidelines Revision Committee. TG13 guidelines for diagnosis and severity grading of acute cholangitis (with videos). J Hepatobiliary Pancreat Sci 2013; 20: Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG et al.; Acute Pancreatitis Classification Working Group. Classification of acute pancreatitis 2012: revision of the Atlanta classification and definitions by international consensus. Gut 2012; 62: Cotton PB, Lehman G, Vennes J, Geenen JE, Russell RC, Meyers WC et al. Endoscopic sphincterotomy complications and their management: an attempt at consensus. Gastrointest Endosc 1991; 37:

8 1124 B. R. Poh, S. P. S. Ho, M. Sritharan, C. C. Yeong, M. P. Swan, D. A. Devonshire et al. 13 Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004; 240: Hong DF, Xin Y, Chen DW. Comparison of laparoscopic cholecystectomy combined with intraoperative endoscopic sphincterotomy and laparoscopic exploration of the common bile duct for cholecystocholedocholithiasis. Surg Endosc 2006; 20: ElGeidie AA, ElShobary MM, Naeem YM. Laparoscopic exploration versus intraoperative endoscopic sphincterotomy for common bile duct stones: a prospective randomized trial. Dig Surg 2011; 28: Croagh DG, Devonshire D, Poh B, Berry R, Bowers K, Spilias D et al. Management of CBD stones in patients having laparoscopic cholecystectomy in a private setting in Australia. ANZ J Surg 2015; 85: ASGE Standards of Practice Committee, Anderson MA, Fisher L, Jain R, Evans JA, Appalaneni V et al. Complications of ERCP. Gastrointest Endosc 2012; 75: Freeman ML, Nelson DB, Sherman S, Haber GB, Herman ME, Dorsher PJ et al. Complications of endoscopic biliary sphincterotomy. N Engl J Med 1996; 335: Reinders JS, Gouma DJ, Ubbink DT, van Ramshorst B, Boerma D. Transcystic or transductal stone extraction during single-stage treatment of choledochocystolithiasis: a systematic review. World J Surg 2014; 38: Tanaka M, Takahata S, Konomi H, Matsunaga H, Yokohata K, Takeda T et al. Long-term consequence of endoscopic sphincterotomy for bile duct stones. Gastrointest Endosc 1998; 48: Macadam RC, Goodall RJ. Long-term symptoms following endoscopic sphincterotomy for common bile duct stones. Surg Endosc 2004; 18: Reinders JS, Kortram K, Vlaminckx B, van Ramshorst B, Gouma DJ, Boerma D. Incidence of bactobilia increases over time after endoscopic sphincterotomy. Dig Surg 2011; 28: