Early or delayed laparoscopic cholecystectomy after endoscopic cholangiopancreatography and papillotomy- does it make a difference? CURRENT STATUS: POSTED

Background Endoscopic retrograde cholangiopancreatography with endoscopic papillotomy (ERCP/EPT) followed by a cholecystectomy is a standard treatment of common biliary duct stones. It is unclear, however, what is the optimal time interval between ERCP/EPT and cholecystectomy. The primary aim of our study was to evaluate our current practice where patients are mostly operated one to three months after ERCP/EPT. The secondary aim was to determine the optimal timing for the cholecystectomy after ERCP/EPT. Methods A retrospective analysis of 117 patients who underwent a preoperative ERCP/EPT followed by a cholecystectomy was performed. Associations between demographic characteristics, type and duration of operation, conversion rate, postoperative complications and interval time were tested using multiple linear regression. The optimal interval was studied by drawing receiver operating curve (ROC) and studying the area under curve (AUC). Results The time interval between cholecystectomy and ERCP/EPT was not associated with the number of conversions to open surgery, duration of the operation or postoperative complications. There was no statistically significant association between any independent variable and time interval. No threshold interval could be found that would discriminate whether a patient had either operation conversion or complications or not. Conclusion No statistically significant associations between the timing of cholecystectomy after ERCP/EPT and the rate of conversions, complications or operation duration are seen in the group. Our current practice is safe, as the time interval in our study does not affect the rate of conversions, postoperative complications or operation duration. Based on the results of our study, no recommendations regarding the optimal time for the surgery can be given. Larger prospective randomized trials are needed.


Background
Up to 33% patients with gallstones have gallstones present in common bile duct (CBDS) as well. (1,2) There are no clear evidence-based recommendations for the management of patients with choledocholithiasis. (3) CBDS management includes clearance of both bile duct and gallbladder stones. Cholecystectomy as well as one of the methods of bile duct clearance have to be performed. The latter is done through endoscopic retrograde cholangiopancreatography (ERCP) or surgical common bile duct exploration. (2)(3)(4)(5)(6)(7)(8)(9) In our institution a current standard of care for treatment of patients with CBDS is ERCP with endoscopic papillotomy (ERCP/EPT) and extraction of stones followed by laparoscopic cholecystectomy. Operation date is scheduled after discussion at the multidisciplinary teem meeting (MDT). Patients are mostly operated on within three months from the index procedure (ERCP/EPT).
Nevertheless, the optimal timing of cholecystectomy after an ERCP/EPT remains unclear.
Despite the fact that an early cholecystectomy is recommended, there are no clear guidelines on how long the time interval should be. (2,(10)(11)(12)(13). Recommendations put forth in many guidelines are conflicting and often very unspecific, as is clearly shown in the review article, done by van Dyk and al. Literature recommendations for the time interval differ from a few hours to a few months, while some authors even favor a single-step management, where ERCP/EPT is done during the cholecystectomy. (2,3,7,12,14,15) Salman et al in their paper recommend a very short time interval (<72h), due to a presumably decreased risk of conversions, duration of surgery as well as length of stay and postoperative complications. Same approach is recommended by Borreca et al, mainly due to decreased risk of symptoms reoccurrence. An early cholecystectomy does seem to decrease the risk for reoccurrence of biliary complications. Postponing the operation for about 6 weeks, on the other hand, provides for better operating conditions, due to less inflammation in the gallbladder area. (11,14,16,17) Mann et al argue, that a 6-week delay is safe for the patients and does not increase the risk of symptoms reoccurrence, postoperative complications, operation duration or conversion rates. Contrary to this, Schiphorst et al believe that the operation, performed within the first week after ERCP/EPT, leads to a decreased rate of symptoms reoccurrence, length of stay and rate of conversion. This is backed by a study done by De Varies et al, which shows that patients operated in less than 2 weeks after ERCP/EPT have a lower conversion rate than those operated on within 2-6 week.
It remains unclear if a one-step approach, where ERCP/EPT is done during cholecystectomy, is superior to a two-step approach (therapeutic splitting). Some authors argue, that the former approach decreases the length of stay, costs and is more comfortable for the patients. On the other hand, others report no differences in length of stay and operation time, with most noting one-step approach being technically and organizationally more challenging, and therefore requiring high level of experience. (12,(18)(19)(20)(21)(22)(23)(24)(25) The primary aim of our study was to evaluate our current practice where patients are mostly operated on one to three months after ERCP/EPT. The secondary aim was to determine the optimal timing for the cholecystectomy after ERCP/EPT.

Participants
The electronic database of a tertiary referral medical center was searched for patients that underwent cholecystectomy between 1.    There was no mortality in our groupand the rate of postoperative complications in our sample was 9,4%, which is similar to those reported (5,3-14%) by other authors. (2,9,27,30). It is an established fact, that the rate of conversion to open cholecystectomy is higher (8-55%) in patients with a complicated gallstone disease (i.e. gallstones present, previous ERCP/EPT, urgent surgery) compared to the conversion rates (3-5%) in uncomplicated cholecystectomies. (7,17,(26)(27)(28)(29) In our study the conversion rate was 14,5%, which is comparable to the reported conversion rates in the literature. We found that the timing did not affect the rate of conversion, duration of the surgery or postoperative complication. It is hypothesized that ERCP/EPT causes inflammation in the gallbladder area thus making the subsequent cholecystectomy more difficult. Hence, surgery is often delayed, allowing the area presumably to cool off. Also, the delay allows the patient to recover from initial illness. (10,16,27) Such a delay, however, causes an increased risk of biliary symptoms reoccurrence and disease progression, hence complicating the following surgery. (12,17,27) Therefore two approaches to the timing can be considered, a very early cholecystectomy, avoiding the risk of symptoms reoccurrences or a delayed operation allowing for the gallbladder area to settle. Several published studies confirm equivalency of both therapeutic strategies (10,11,16,18,27), including the results of our study. Contrary to this, there are some studies that favour either one or the other approach. Our study has limitations. First of all, it has all of the inherent biases of a retrospective study. Second, only a few patients were (N=3) operated within a very short period of time (<72h), in an interval, that many authors argue decreases the rate of conversions, postoperative morbidity and length of stay, outweighing the risk of an early surgery. (2,12,26). On the other hand, even though most of our patients were in fact operated on in a somewhat delayed fashion (median of a 56 days), in our analysis we did not find any statistical significance of such approach, positive or negative. This is not in

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

Ethics approval and consent to participate
Approval for the study was obtained from the Medical Ethics Committee of the Republic of Slovenia (MZ 0120-436/2018).

Consent for publication
Not applicable. The ROC curve and area under the curve (AUC) with 95% CI for two binary classifiers with different thresholds of time until operation.