This study shows that transcystic guide wire assisted rendezvous cannulation at ERCP can be done in conjunction with bile duct stone clearance without increasing post-procedural leakage of pancreatic enzymes. This observation supports the hypothesis that rendezvous cannulation can prevent the risk of PEP. In fact, inadvertent contrast injection into the pancreatic duct during conventional ERCP was the factor most clearly associated with leakage of pancreatic enzymes into the systemic circulation, which we interpret as indicating risk of developing PEP.
The correlation between ERCP and PEP can be difficult to study, owing to the large number of patients required to ensure sufficient statistical power. In order to overcome these methodological difficulties, we utilised two biochemical markers, proCAPB 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[21,22
]. ProCAPB and trypsinogen-2 have also been shown to discriminate pancreatitis from non-pancreatic disorders with an accuracy of 95% to 99%[19,21
]. This distinction is essential, since two of our three study groups were subjected to additional surgical trauma in the form of laparoscopic cholecystectomy, which might increase unspecific inflammatory responses.
A potential weakness of the study is the lack of randomisation. Indeed, our original intention was to perform a randomised controlled trial. However, based on the promising results of our previous attempts with rendezvous ERCP[23
], we considered it ethically indefensible to perform conventional ERCP intraoperatively. First, the operating theatre during ongoing surgery is poorly suited for conventional ERCP and endoscopy under suboptimal circumstances would expose the patient to an unnecessary risk of pancreatic injury. Second, a study design where patients are randomised to postoperative ERCP could increase the risk of cannulation failures that would necessitate additional surgical exploration of the common bile duct. Therefore we considered this alternative study design more appropriate to address our research question. The present case-control design opens for selection bias, e.g
., in that patients selected for laparoscopic cholecystectomy with or without rendezvous ERCP were younger than those selected for conventional ERCP, of whom most had already their gallbladder removed, in some cases years earlier. However, this is to some degree counterbalanced by the fact that young age has repeatedly been found to be an independent risk factor for PEP[3,4,24,25
] whereas older patients may be protected, e.g
., by age-related pancreatic atrophy[26
]. These factors would be more likely to underestimate than overestimate the associations we found.
We observed only three cases of the clinically relevant outcome, PEP, all in the group subjected to conventional ERCP group and none in the rendezvous group. This difference did not reach statistical significance, most likely due to low statistical power. Previous trials have proposed a relationship between rendezvous cannulation and a decreased risk of PEP but to date these studies have been either too small or not adequately designed to address this pertinent question. A recent systematic review by La Greca et al[10
] concluded that intraoperative ERCP and bile duct clearance during laparoscopic cholecystectomy was associated with low risk of PEP and could be recommended. Scrutiny of the cited papers reveals that in cases involving complete transcystic bile duct cannulation, where the guide wire was brought into the duodenal lumen, the incidence of PEP was even lower, ranging from 1.7% to 2.2%[27,28
]. This contrasts to studies in which cannulation was not complete, where the corresponding incidence of PEP ranged from 3% to 7.6%[29-32
]. Our data confirm to these previous findings and highlight the relevance of completing the rendezvous guide wire based cannulation to minimise PEP.
In most conventional ERCP procedures, biliary cannulation is easy, completely uneventful and antegrade cannulation can be regarded as redundant. Our definition of difficult cannulation is arbitrary and subjective; however, even the most experienced endoscopist cannot predict whether a cannulation is going to be difficult or not until an attempt has been made, and each attempt at cannulation is potentially harmful. This is one of several arguments in favour of making rendezvous cannulation routine during laparoscopic cholecystectomy: regardless of the appearance of the papilla, the success rate of single-pass biliary cannulation approaches 100%. Repeat interventions, use of precut incision and so on should be kept to a minimum to diminish the risk of a variety of procedure-related complications.
Opacification of the pancreatic duct is another significant sign associated with difficult cannulation and the development of pancreatitis[3,8,24,25,33
]. In our series, we found a significant correlation between elevated levels of amylase (P
< 0.001) or proCAPB (P
= 0.002) and inadvertent cannulation and injection of contrast material into the pancreatic duct. Moreover, all three of our patients who developed PEP had had contrast medium injected into the pancreatic duct. Clearly, many of the risks associated with difficult cannulation, inadvertent pancreatic duct cannulation and contrast injection can be circumvented with rendezvous cannulation.
Current clinical evidence suggests that the risk of pancreatitis can be reduced, at least among high-risk patients, by temporary placement of a pancreatic stent that dislodges spontaneously[34,35
]. At the time we began our study there was no routine of using prophylactic pancreatic stents at our institution and we have therefore not offered this option during the study. Such stenting could clearly have affected the outcome for patients who were allocated to the conventional ERCP group and had a guidewire or minimal contrast injection into the pancreatic duct. Nonetheless, we firmly believe that it is preferable to use a technique that completely avoids cannulation of the pancreatic duct.
Transient asymptomatic hyperamylasemia has very little clinical significance and is usually not recognised as a complication. In the present study the levels of amylase after conventional ERCP were increased at 4, 8 and 24 h compared with levels in the rendezvous and the control group. These results are in line with other reports[36
], where a majority of the ERCP procedures involving cannulations that were characterised as difficult were associated with hyperamylasemia and PEP.
A few prospective studies[16,18,37
] demonstrate that patients affected by PEP have significantly elevated concentrations of trypsinogen-2 in urine six and 24 h after the index procedure, even in if the pancreatitis is mild. Our study confirms these findings: we found higher concentrations of trypsinogen-2 in plasma at 24 h in the conventional ERCP group than in the rendezvous and control groups. Taken together the surrogate markers we have used to detect early signs of PEP appear to be of high clinical relevance.
An additional advantage of the rendezvous approach, one of utmost clinical relevance, appeared when we analysed the CBDS clearance rate. Even though all stones were eventually cleared in both study groups, there was a significant advantage for the rendezvous technique during the index procedure. This finding is in line with the compilation of 21 reports by La Greca et al[10
] which demonstrated an overall success rate of 92.3% for rendezvous ERCP.
In conclusion, combined laparo-endoscopic transcystic guidewire rendezvous cannulation of the CBD minimizes the risk of unintentional pancreatic duct engagement and subsequent inflammatory damage to the gland. In addition, more complete CBDS removal can be offered. Thus, intraoperative ERCP with rendezvous cannulation technique shall be recommended to manage CBDS in conjunction with cholecystectomy.