Between April 2005 and November 2010 patients who fulfilled the inclusion criteria (Table 1) were recruited as they presented at the Department of Surgical Gastroenterology, Karolinska University Hospital. All patients had a physical examination, were screened for baseline serum markers and were examined with abdominal ultrasonography, CT-scan or MRCP to confirm cholecysto- and/or choledocholithiasis and to rule out ongoing pancreatitis and/or cholecystitis. Among these patients we identified three study groups. Regardless of suspicion of CBDS, patients with cholecystolithiasis who were fit for surgery, were prepared for a standard laparoscopic cholecystectomy. According to the results of the intraoperative cholangiography, patients were allocated to one of two groups: rendezvous ERCP group (positive finding of CBDS) or laparoscopic cholecystectomy only (negative finding of CBDS). The third group, which received conventional ERCP, included patients with high suspicion of choledocholithiasis who had already had a cholecystectomy and patients with cholecystolithiasis and CBDS who were unsuitable for surgery. All patients were hospitalised for a minimum of 24 h, had a clinical examination at 4, 8 and 24 h postoperatively, and had a 30-d follow-up interview by telephone. Post ERCP pancreatitis was defined as post-procedural onset of upper abdominal pain lasting more than 24 h and combined with pancreatic amylase concentration in serum of at least three times the upper reference limit[20].

Demographic and procedure-related data were collected prospectively before and after the procedure and follow-up data were noted at 4, 8 and 24 h postoperatively and at 30 d follow-up. All patients gave oral and written informed consent before they entered the study, which was approved by the Regional Research Ethics Committee of Stockholm.

Laparoscopic cholecystectomy was performed according to standard laparoscopic technique with pneumoperitoneum, introduction of four troachars and isolation of the cystic duct. All procedures included intraoperative cholangiography through a small incision of the cystic duct to check for CBDS and to delineate bile duct anatomy.

When cholangiography during laparoscopic cholecystectomy reveals CBDS, the endoscopist is called to the operating room. While waiting for the endoscopist to arrive, the surgeon inserts a transcystic guide wire (Jagwire™ 450 cm × 0.0635 cm or 450 cm × 0.0889 cm, Boston Scientific Corporation, Natick, MA, United States) through the existing cholangiography catheter and advances the guide wire through the choledochus, papilla of Vater into the duodenum. The pneumoperitoneum is deflated to facilitate transoral introduction and positioning of the duodenoscope. For rendezvous cannulation, the guide wire is captured with a polypectomy snare and pulled gently through the working channel of the duodenoscope (Figure 1). When the guide wire is in place, a sphincterotome is introduced over it and the rendezvous cannulation can be completed when the sphincterotome enters the common bile duct. After sphincterotomy, any stones are extracted with retrieval balloons or baskets. The first sweeping is done in choledochus along the transcystic guide wire. Then the guide wire is extracted (with the balloon catheter positioned in choledochus) and repositioned in the intrahepatic ducts to allow clearance of possible remaining supracholedochal stones. If there is any suspicion that stone clearance may be incomplete, a biliary stent is inserted.

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Figure 1 Laparo-endoscopic cannulation technique employing a transcystic guidewire, inserted by the surgeon through a cholangiocannula grasper and captured by the endoscopist with a polypectomy snare in the duodenum.

Conventional ERCP was performed with Olympus TJF-160R or TJF-160VR (Olympus Optical, Tokyo, Japan) and wire-guided cannulation (WGC) technique through a sphincterotome (Autotome™ RX 44 Cannulating Sphincterotome, Boston Scientific Corporation, Natick, MA, United States). The complexity of cannulation was rated subjectively by the endoscopist, based particularly on the difficulty of cannulation, the number of inadvertent pancreatic duct cannulations and contrast injections with pancreatic duct filling. If the cannulation required more than six attempts or precut technique, it was considered a difficult cannulation.

All procedures were performed by one of three senior endoscopists with 7-15 years’ experience of ERCP and with a present procedure rate of approximately 150-300 ERCP investigations per year. All patients were investigated under general anesthesia. Prophylactic antibiotics were administrated as a single intravenous dose of 4 g piperacillin and 0.5 g tazobactam (Tazocin^®, Wyeth AB, Solna, Sweden) prior to all procedures. Cholangiography was performed by using Iohexol (Omnipaque^®, GE Healthcare, Stockholm, Sweden) monomeric non-ionic contrast medium. Sphincterotomy was carried out with pulsating cutting and coagulation diathermy system (ERBE, Elektromedizin, Tübingen, Germany).

Blood samples were collected in ice-cold EDTA (ethylenediaminetetraacetic acid) tubes immediately prior to surgery or endoscopy (0-sample) and sampling repeated at 4 ± 1 h, 8 ± 2 h and 24 ± 4 h after laparoscopic cholecystectomy or ERCP. Plasma was obtained after centrifugation at 2200 r/min for 10 min and then frozen and stored at -70  °C until further analysis.

ProCAPB B and trypsinogen-2 levels in plasma were determined in-house with a double-antibody enzyme linked immunosorbent assay developed at the Department of Surgery, Clinical Sciences, Skåne University Hospital, Malmö[17,19]. Pancreatic amylase was measured by an enzymatic colourimetric modular analyser with the manufacturer’s reagents (Roche, Diagnostics Gmbh, Mannheim, Germany) at the Department of Clinical Chemistry at Karolinska University Hospital in Huddinge, accredited by the Swedish Board for Accreditation and Conformity Assessment. All samples were blinded at analysis.

This study was conducted with the approval of the Regional Research Ethics Committee of Stockholm, Sweden.

Power calculations assumed a pancreatic enzyme reaction rate of 14% with the use of the conventional ERCP cannulation technique. Assuming a reduction in pancreatic reaction rate to 1% in the rendezvous group and 1% in the control group, 40 patients in each study arm were required to determine this difference with a 95% probability and with a 75% power (χ² test of equal proportions). The variables pancreatic amylase, proCAPB and trypsinogen-2 were analysed using a mixed linear model with one between-group factor i.e., conventional ERCP, rendezvous ERCP and control group and one within-group factor, time (0, 4, 8 and 24 h) and the subsequent interaction between the factors. In case of significant interactions, simple main effect tests were performed, i.e., effects of one factor when the level of the other factor was fixed. Results are presented as mean, SD and 95% CIs. The distribution of some variables (e.g., proCAPB, trypsinogen-2, pancreatic amylase) was positively skewed and in these cases the variables were log-transformed before the formal analyses. The binomial response was subsequently analysed by fitting a generalised estimating equations model with the Genmod procedure in SAS^® System 9.1, SAS Institute Inc., Cary, NC, United States. These latter parameters are presented as OR and 95%CI. P-values less than 0.05 were considered statistically significant.

A total of 139 patients (41 men and 98 women) with a median age of 54 years were enrolled into the study. During the inclusion period 17 patients were excluded due to: acute pancreatitis immediately prior to ERCP (n = 3), conversion of the operation from laparoscopic to open cholecystectomy (n = 6), tumour (n=4), and retraction of informed consent (n = 4), leaving 122 participants for further analyses. Relevant preoperative demographic characteristics (Table 2) did not differ between the three study groups in terms of gender, BMI, physical status according to ASA-classification, baseline laboratory values for CRP, pancreatic amylase, proCAPB and trypsinogen-2. However, there was a difference in age, with the conventional ERCP group being somewhat older. In addition, there was an expected difference between the control group and the other two groups regarding bile duct width, alkaline phosphatase and bilirubin levels but no significant difference between the rendezvous and conventional ERCP group.

PEP emerged in three (7%) of the 41 patients cannulated with conventional ERCP, vs none of those cannulated by use of rendezvous technique (P = 0.24) (Table 3). According to the Cotton criteria[20], one of these cases was classified as moderate and two as mild. Cannulation of the biliary duct was scored as difficult in nine (22%) cases where conventional ERCP was used, and precut sphincterotomy was performed in six of these (15%). There were three (7%) cases of unsuccessful cannulation and these failures were not associated with juxtapapillary diverticula or other duodenal abnormalities. Contrast medium was inadvertently infused into the main pancreatic duct in 11 (27%) of the patients in the conventional ERCP group. In the rendezvous ERCP group, transcystic antegrade biliary rendezvous cannulation was successful in all 40 cases and no unintentional cannulation or opacification of the pancreatic duct occurred.

Complete CBDS clearance at the index procedure was achieved in 38 (95%) of the rendezvous ERCP procedures vs 29 (71%) patients in the conventional ERCP group (P = 0.01), even though there was no significant difference in stone size (P = 0.40) or procedure time (P = 0.11) between the two study groups. After an additional ERCP, all patients, including the three whose initial cannulation failed, had their bile ducts cleared of stones.

In the 41 control patients, no case of pancreatic duct opacification during cholangiography was noted, nor was acute pancreatitis or hyperamylasemia observed. Two major postoperative complications were recorded: one patient had postoperative intra-abdominal bleeding which did not need surgical intervention and one had postoperative bile leakage from the cystic duct, which was successfully treated by endoscopic placement of a temporary stent.

The post-procedural time course of pancreatic amylase showed no difference between the controls and the rendezvous ERCP group (Figure 2A). In those subjected to a conventional ERCP, amylase levels had already increased significantly at 4 h and remained elevated throughout the 24-h monitoring time. Virtually the same picture emerged concerning the plasma levels of proCAPB (Figure 2B). Plasma concentrations of trypsinogen-2 were also significantly increased at 24 h in patients subjected to a conventional ERCP (Figure 2C). CRP values rose as expected in the groups subjected to surgery (rendezvous and control group) at 24 h after the completion of the procedure.

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Figure 2 Approximative analysis and figure based on serum values at all times (0, 4, 8 and 24 h) using a mixed linear model. A: Pancreatic amylase before (0) and at 4, 8 and 24 h after the procedure; B: Procarboxypeptidase B before (0) and at 4, 8 and 24 h after the procedure; C: Trypsinogen-2 before (0) and at 24 h after the procedure. y-axis values are logarithmically transformed. Vertical bars denote 95% confidence intervals. Circles: Conventional endoscopic retrograde cholangiopancreatography (ERCP); Squares: Rendezvous ERCP; Diamonds: Laparoscopic cholecystectomy control.

We explored other possible confounders but were unable to demonstrate any relationship between these laboratory variables and procedure time, the number of cannulation attempts, age, gender, comorbidity, degree of CBD dilatation, number or size of CBDS or the need for precut cannulation techniques. However, if side branches of the pancreatic duct side had been filled with contrast medium, this was significantly associated with the plasma level of proCAPB (P = 0.009) and most likely pancreatic amylase (P = 0.051).

Endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy and stone extraction is a standard procedure in the management of common bile duct stones (CBDS). The method is, however, marred by complications like pancreatitis, bleeding and perforation. Intraoperative rendezvous ERCP during cholecystectomy with cannulation over a guidewire represents an alternative method to remove CBDS that theoretically may, due to a significantly reduced risk to cannulate the pancreatic duct, decrease the risk of procedural induced pancreatitis.

The concept of rendezvous cannulation involving a combined laparo-endoscopic approach and used in conjunction with intraoperative ERCP has been described previously. The question whether intraoperative rendezvous ERCP reduces the risk of post ERCP pancreatitis (PEP) rate or not is, however, not known mainly due to the fact that the incidence of PEP is rather low and large study groups are therefore needed in order to reach enough statistical power to investigate the impact of different ERCP techniques.

To overcome the methodological difficulties in studying the effects of intraoperative rendezvous ERCP on PEP the authors utilised two highly sensitive and specific biochemical markers, procarboxypeptidase B and trypsinogen-2, as surrogate variables of pancreatic inflammatory response. These have both been shown to be superior to lipase and pancreatic amylase as diagnostic markers of acute pancreatitis, especially if the objective is to distinguish mild from severe pancreatitis.

The study results have helped to obtain an increased knowledge of the beneficial effects that intraoperative rendezvous ERCP may have in reducing PEP. The proposed mechanism for this is that, due to cannulation over the guidewire, the risk of cannulating the pancreatic duct and thus injecting contrast in the duct is minimal.

ERCP: An endoscopic method to examine the bile- and pancreatic ducts as well as to, by intervention, remove, common bile duct stones or relieve bile duct obstruction. Pancreatic amylase, procarboxypeptidase B and trypsinogen-2: Biochemical markers that serve as surrogate variables of pancreatic inflammatory response.

The authors of this paper report that intraoperative rendezvous ERCP reduces the release of the pancreatic markers (pancreatic amylase, procarboxypeptidase B and trypsinogen-2) compared with conventional ERCP. As only a few papers have been published in this topic, this paper can provide additional data for the accumulation of the knowledge in this field. The case control design of the study, however, opens for selection bias which weakens the power of the conclusion.