Early versus delayed laparoscopic cholecystectomy after endoscopic retrograde cholangiopancreatography: A meta-analysis

Abstract

Purposes:

Patients with cholecysto- and choledocholithiasis usually undergo endoscopic retrograde cholangiopancreatography (ERCP)/-endoscopic sphincterotomy followed by laparoscopic cholecystectomy (LC). However, differences in the timing of LC after the ERCP may alter the post-operative outcomes. The aim of this study was to compare the effect of early (≤3 days) or delayed LC (>3 days) following ERCP on the post-operative outcomes.

Methods:

A comprehensive search of the 3 databases PubMed, EMBASE and the Cochrane Library was performed. Articles related to LC at different time-points after ERCP were retrieved. Dichotomous and continuous outcomes were analyzed by risk ratio (RR) and mean difference, and RevMan was used to analyze each group.

Results:

A total of 7 studies, including 5 randomized controlled studies and 2 retrospective studies, involved a total of 711 patients. There were 332 patients in early LC group and 379 in delayed LC group. The conversion rate was lower in the early LC group compared to the delayed LC group (RR 0.38, 95% confident interval 0.19 to 0.74, P = .005, I² = 0%). Early LC resulted in a shorter operation time (RR −6.2, 95% CI −27.2 to −5.2, P = .004, I² = 97%) and fewer complications (RR 0.48, 95% CI 0.29 to 0.79, P = .004, I² = 17%). Subgroup analysis found that there were no significant differences in the conversion rate (RR 0.61, 95% CI 0.25 to 1.45, P = .26, I² = 0%) or complications between the early LC group and the delayed group who underwent LC after 1 month.

Conclusion:

Early LC after ERCP is the preferred treatment for patients with concurrent cholecysto- and choledocholithiasis due to improved clinical outcomes as compared to those who undergo delayed LC.

1. Introduction

Gallbladder stones are a common problem worldwide, and 10%–20% of patients also have common bile duct stones.^[1–4] In otherwise, patients-treatment of gallstones with common bile duct stones requires removal of both common bile duct stones and gallstones.^[5]

If endoscopic retrograde cholangiopancreatography (ERCP) is feasible, ERCP combined with laparoscopic cholecystectomy (LC) has been recommended for patients with gallbladder stones combined with common bile duct stones.^[6,7] Studies have confirmed that LC after ERCP is necessary to effectively reduce biliary complications and improve quality of life.^[8–12] ERCP + LC can be performed either synchronously (one step approach) or by preoperative ERCP and stone extraction followed by LC (two-stage approach). The 1-step approach has been shown to reduce surgical complications and hospital stay compared to the 2-step approach.^[13–16] However, most hospitals still adopt the 2-stage approach, because the 1-step approach often requires coordination of a multidisciplinary team with significant hardware that is not practical for many health systems.^[17–21] The timing of LC after ERCP remains controversial. Some studies have pointed out that the bile duct cannulation, contrast agent infusion and sphincterotomy involved in ERCP cause inflammatory adhesions around the bile duct and increase the difficulty of operation and the probability of transfer to laparotomy.^[22–24]

The aim of this study was to assess the post-operative outcomes in patients who underwent ERCP followed by LC.

2. Methods

This meta-analysis followed the PRISMA guidelines. The PRISMA Statement checklist for reporting systematic review.^[25]

2.1. Literature search

PubMed, Embase, and Cochrane Library databases were searched to identify all relevant literature on endoscopic treatment of common bile duct stones and gallstones between January 2000 and February 2022.The following MeSH, Emtree, and keyword search terms were used in various combinations: “cholelithiasis” OR “bile duct stone” OR “common bile duct stone” OR “gallstone” OR “biliary calculi” OR “biliary lithiasis” OR “biliary tract calculus” OR “cholecystolithiasis” OR “gallbladder stone” OR “choledochal calculus” OR “choledocholithiasis” OR “choledochus calculus” OR “choledochus stone” OR “common biliary duct stone” AND “endoscopic retrograde cholangio pancreatography” OR “sphincterotomy” OR “endoscopic sphincterotomy” OR “sphincterotomy” AND “cholecystectomy” OR “gallbladder resection.” References of the included trials were checked manually for further studies.

2.2. Study selection and inclusion criteria

Three researchers (SQ, CY, and JX) independently screened relevant literature, and through step-by-step screening, identified the research that met the inclusion criteria. By screening the title, abstract and full text, every study of LC after endoscopic treatment of common bile duct stones was selected. We focused on the selection of the interval time between the 2 operations to ensure it was in accord with the literature of this study.

Those who met the following requirements were included in the study: successful endoscopic removal of common bile duct stones; removal of the gallbladder after ERCP/endoscopic sphincterotomy; age 18 years and older; and patients had to be able to be divided into either an early LC group (≤3 day from ERCP) or late LC group (>3 days from ERCP). Exclusion criteria: laparoscopic-endoscopic rendezvous, case reports, duplicate reports. Researchers carefully checked the titles and abstracts of all identified articles, first excluding unrelated studies, and then reading the full text to further exclude non-conforming studies. In cases of disagreement, other authors would intervene to resolve the difference of opinion to reach a consensus.

2.3. Data extraction and outcome measures

The 3 authors independently extracted data. The main contents were: author, year of publication, patient age and gender, stone size, type of endoscopy technique, intervention measures: the time interval between the 2 operations, the conversion rate of LC, the time of cholecystectomy, the method of cholecystectomy, the design and follow-up of the experiment, bile duct injury, hospital stay, complications including wound infection and bile leak.

The subgroup analysis was based on the time of the start of LC after ERCP in the delayed LC group. In 1 group, LC started 3 days after ERCP (A group), while in the other group LC started 1 month after ERCP (B group). One study that did not meet grouping requirements of the subgroup analysis was excluded. In order to show the advantages of the early group, the study is not set up 3 groups.

2.4. Quality assessment

The quality of non-randomized studies was evaluated according to the Newcastle–Ottawa Scale. The scale consists of 3 elements: patient selection, comparability of the study groups, and assessment of outcomes. Each study has a score ranging from 0 to 9 and a score of 5 or higher is considered high quality.

The quality of randomized studies was assessed using the Cochrane risk of bias tool, which consists of 7 factors: performance and detection of bias by checking for blinding of personnel, and outcome assessment and attrition as well as reporting bias by evaluating for incomplete and selective data reporting and other bias. If at least 2 plates were judged to be high or unclear risk, the trial was assessed as having a high risk of bias. For primary outcome measures, any disagreement between the 2 researchers was resolved by the third reviewer. For primary outcome measures, evidence of publication bias and other biases were assessed based on a regression analysis of the funnel plot asymmetry.

2.5. Statistical analysis

Data analysis was performed in RevManAnalysis5.3 (RevMan). Dichotomous and continuous outcomes were analyzed as risk ratio (RR) and mean difference). The relative risk (RR) and 95% confidence intervals (95% CIs) were calculated using RevManAnalysis5.3. We used the I² statistic to estimate statistical heterogeneity, where an I² > 50% indicated significant heterogeneity. The fixed effects model was used when the heterogeneity was < 50%, and when the I² > 50% was used in the random effects model in the meta-analysis.^[26] The one-by-one exclusion method was used as a method of sensitivity analysis, but only reported when there was a difference. For the main outcome measures, publication bias and other biases were evaluated based on regression analysis of the funnel plot asymmetry.^[27] This systematic review and meta-analysis were carried out strictly in accordance with the guidelines of the preferred reporting items for systematic reviews and meta-analyses.^[25] Sensitivity and subgroup analysis were used to evaluate the source of heterogeneity. Some studies did not directly provide the values of mean and standard deviation. If the author was contacted and there was no reply, the relevant data of the study was calculated by applying statistical methods.^[28]

3. Results

3.1. Study identification

The screening process is described in detail in Figure 1. A total of 711 patients were included in 7 studies, comprising 5 randomized trials and 2 retrospective studies. Of the 711 patients 379 (53%) were in the delayed LC group. The time range of published data was 2005 to 2016.^[29–35] The baseline characteristics of the included studies are presented in Table 1. Funnel plot of conversion is shown in Figure 2.

Figure 1.

Flow diagram of studies included in the meta-analysis.

Table 1.

Included studies.

Study	Yr	Design	Time of Lc	Number of patients	Conversion (open)	Time of operation (min)	Operative complications	NOS quality score/cochrane bias
Aziret	2018	NOT Rct	Early	30	1	60 ± 30	1	8
			After 3 day	55	9	85 ± 10.3	13
Elnakeeb	2016	Rct	Early	55	5	50 ± 37.5	7	6
			After 3 day	55	6	60 ± 37.5	13
Ghnnam	2016	Rct	Early	41	0	53.6 ± 32.2	1	6
			After 3 day	45	2	79.8 ± 26.3	4
Gorla	2014	Rct	Early	28	0	81 ± 31	0	5
			After 3 day	22	2	101 ± 33	4
Reinders	2010	Rct	Early	47	2	59 ± 23.8	6	6
			After 3 day	47	4	60 ± 22	6
Salman	2009	Rct	Early	39	1	38.3 ± 7.8	1	5
			After 3 day	40	7	68.4 ± 6	4
Zang	2011	Not Rct	Early	92	1	51.4 ± 12.3	4	7
			After 3 day	115	2	52.5 ± 13.7	4

NOT RCT = retrospective study, RCT = randomized controlled trial.

Figure 2.

Funnel plot of conversion.

3.2. Conversion

Of 711 patients included, 379 were in the delayed group. A total of 10/332 (3.0%) peoples in the early group and 32/379 (8%) patients in the delayed LC group (RR 0.38, 95% CI 0.19 to 0.74, P = .005, I2 = 0%) were transferred for open surgery (Fig. 3A). In the subgroup analysis, there was no difference in the conversion rate between the early LC group and LC after 1 month group. But, the conversion rate in the early and LC after 3 days groups was compared (RR 0.22, 95% CI 0.06 to 0.84, P = .03, I² = 0%), and revealed that the conversion rate in the early cholecystectomy group was lower. There was no difference in the conversion rate between the early LC group and delayed group (Fig. 3B).

Figure 3.

Pooled estimates of conversion. (A) Forest plot of conversion in early and delayed groups. (B) Subgroup analysis of conversion in (A) and (B) groups.

3.3. Operation time

In 711 patients, the LC surgery time in the early and delayed groups was compared (RR −16.2, 95% CI −27.2 to −5.2, P = .004, I² = 97%), and revealed that the surgery time in the early cholecystectomy group was shorter (Fig. 4). In the subgroup analysis, there was no significant difference in the operation time of LC between the A group and the early group. In the subgroup analysis, there was no significant difference in the operation time of LC between randomized and non-randomized groups. Four of 7 studies showed a difference in operation time, while 3 of them showed no difference. There was no difference in 1 study but the surgeons in the delayed group had more experience.

Figure 4.

Forest plot of length of operative time in early and delayed groups.

3.4. Complications

The complications analyzed in the included studies were not all the same reported in a standardized way. The incidence of post-operative complications was low. Comparison of the rate of surgical complications between the early LC group and the delayed LC group in the 7 studies revealed that the early group had fewer surgical complications (RR 0.48, 95% CI 0.29 to 0.79, P = .004, I² = 17%).

3.5. Hospital stays

The time of the postoperative hospital stay was compared between the early LC group and the delayed LC group (RR 0.4, 95% CI −1.0 to 0.2, P = .14, I² = 83%).

4. Discussion

This study compared the outcome of LC ≤ 3 days and LC > 3 days later after ERCP in patients with gallbladder stones and bile duct stones. The results of the study confirmed that the conversion rate and the incidence of surgical complications in the early LC group were lower than in the delayed LC group. Because the data heterogeneity was high, the results of this study showed no difference in operation time were not reliable. Disadvantages of this study were as follows: the sample size of the study was small, the number of studies was also small and the results indicators were more related to the experience of the surgeons in the different hospitals.

Multiple studies have confirmed that there is no significant difference in the success rate or the stone removal rate of 1-step surgery compared with 2-step surgery.^[36–38] However, 1-step surgery can effectively reduce the incidence of postoperative pancreatitis and reduce the hospitalization time and cost.^[19] For patients with gallbladder stones as well as bile duct stones, if the experience of the surgical team at the medical center and the equipment in the hospital meet the requirements and ERCP can be used to remove the stones, it is recommended that 1-step treatment be performed to relieve the patients’ pain.^[20] However, most medical centers still adopt 2-step surgery due to the available conditions.^[20,39] At present, controversy remains concerning the optimal timing of LC. Some studies have concluded that early LC after ERCP is better, because it can reduce the difficulty of surgery and reduce the conversion rate.^[29,34]

One study found that inflammation is an independent risk factor for biliary tract injury during LC.^[40] Boerma, Gorlaa, and others proposed that repeated bile duct cannulation, contrast agent infusion, and preoperative cholangitis can cause local inflammatory reactions resulting in adhesions and fibrosis.^[23,32,41] Reinder found that the degree of adhesion in the delayed group was more serious than that in the early LC group, which significantly increased the difficulty of surgery and the conversion rate for surgeons with less surgical experience.^[22] With the development of fibrosis after inflammation, surgery becomes more difficult, so early LC is recommended.^[42]

After endoscopic sphincterotomy, bacteria will remain in the biliary tract, increasing the possibility of biliary tract infections and increasing the risk of postoperative biliary tract complications.^[43] Another study found that after endoscopic sphincterotomy, the bacterial infection rate increased with age and time, and that patients may develop more biliary complications while waiting for LC.^[44] Early LC after ERCP helps reduce the incidence of surgical complications.^[29–33] In terms of complications, it is also suggested that early LC has a better outcome after ERCP.

The surgical conversion rate (3.8%) in the early LC group was significantly lower than that in the delayed group (11.4%), which may be related to the fact that the severity of adhesion was different in the 2 groups. Subgroup analysis revealed that the conversion rate of patients starting LC after 1 month was not significantly different from those who received early LC, which may be related to the resolution of acute inflammatory edema after 1 month^.[45] The conversion rate of the B group was 8.2%, while the conversion rate of the A group was 6.2%. Because the surgeon experience was different, a direct comparison could not be performed. There was no significant difference in the conversion rate or the incidence of surgical complications between the early group and the delayed group, but the probability of biliary complications was increased.^[46–50] Although LC after 1 month did not cause an increase in the conversion rate, it resulted in increases in biliary complications. Therefore, early LC, within 3 days is recommended. At the same time, more research related to biliary complications of LC after 1 month is needed.

5. Conclusions

The preferred treatment for gallstones combined with bile duct stones is ERCP + LC. Early LC after ERCP (within 3 days) is the commonly-recommended surgical method, which can effectively reduce the difficulty of surgery, as well as reducing the conversion rate and the complications of surgery. Therefore, we recommend that LC be done within 3 days.

Acknowledgments

This study received no external financial support. We deeply appreciate your consideration of our manuscript, and we look forward to receiving comments from the reviewers. We thank International Science Editing (http://www.internationalscienceediting.com) for editing this manuscript.

Author contributions

Conceptualization: Sheng Qi.

Data curation: Sheng Qi, Jie Xu, Chao Yan, Yao Chen.

Formal analysis: Sheng Qi, Jie Xu, Yao Chen.

Methodology: Sheng Qi, Chao Yan.

Project administration: Yanan He.

Software: Chao Yan, Yanan He.

Writing – original draft: Sheng Qi, Jie Xu, Chao Yan.

Writing – review & editing: Sheng Qi, Chao Yan, Yanan He, Yao Chen.