Long-term prognosis and risk factors associated with 30-day unplanned repeated ERCP in patients with common bile duct stones

Abstract

Background:

The unplanned repeated endoscopic retrograde cholangiopancreatography (ERCP) in patients with common bile duct stone (CBDS) remains unclear.

Objectives:

To identify risk factors of unplanned repeated ERCP and its impact on clinical outcomes.

Design:

Retrospective cohort study.

Methods:

Patients who underwent ERCP for CBDSs from January 2013 to October 2023 were consecutively reviewed. Risk factors for unplanned repeated ERCP within 1 month were evaluated using logistic regression. The impact of unplanned repeated ERCP on adverse events, including ampullary bleeding, CBDSs recurrence, and biliary infection, was explored.

Results:

A total of 1241 patients were included, of which 50 patients underwent unplanned repeated ERCP in 1 month primarily because of unrelieved biliary obstruction or cholangitis. The repeated ERCP group had higher proportions of irregular papilla (42.0% vs 21.7%, p < 0.001), stones locating in superior common bile duct (CBD; 18.0% vs 8.8%, p = 0.05), larger CBD diameter (median 1.2 vs 1.0 cm, p = 0.002), or larger CBDS diameter (median 1.0 vs 0.8 cm, p = 0.004) than the unrepeated group. In the multivariate analysis, irregular papilla (odds ratio (OR) 3.494, p = 0.024), post-ERCP fever (OR 7.532, p < 0.001), post-ERCP abdominal pain (OR 2.810, p = 0.05), post-/pre-ERCP total bilirubin levels ⩾1.2 times (OR 6.973, p = 0.007), and post-/pre-ERCP transaminase levels ⩾1.2 times (OR 3.944, p = 0.026) were independent risk factors for unplanned repeated ERCP. The incidence of adverse events in the long term was higher in the repeated group than the unrepeated group (12.0% vs 5.0%, p = 0.068). Unplanned repeated ERCP, although not an independent factor, is partially relevant with increased likelihood of long-term adverse events (univariate OR 2.570, p = 0.038).

Conclusion:

Papillary morphology, post-ERCP symptoms, and serum biochemical parameters may help predict the occurrence of unplanned repeated ERCP in patients with CBDS. Unplanned repeated ERCP does not have a significant impact on the long-term prognosis.

Plain language summary

Unplanned repeated ERCP in patients with CBDS

What is already known about this subject?

- Unplanned reoperation or unplanned returns to the operating room, is an important metric for surgical quality, varying depending on multiple etiology.

- Endoscopic retrograde cholangiopancreatography (ERCP) is currently the first-line treatment option for many cases of cholelithiasis. Some patients still have abdominal complaints and biliary obstruction which requires repeated ERCP procedures in a short term.

- Unplanned reoperation increases risks of surgery-related complications and brings a great burden to the patients’ quality of life, length of hospital stay, and healthcare costs.

What are the new findings?

- The incidence of 30-day unplanned repeated ERCP in patients with common bile duct stone (CBDS) was about 2.95% in our center. Acute biliary infections or persistent biliary obstruction after complete stone removal are the main reasons for repeated ERCP.

- Irregular papilla, post-ERCP fever, postoperative serum total bilirubin (TBil) or transaminase increase were identified as independent risk factors for unplanned repeated ERCP.

- Patients with unplanned repeated ERCP exhibited higher propensity for CBDS recurrence and acute cholangitis in a short term but did not affect long-term outcomes.

How might it impact clinical practice in the foreseeable future?

- Unplanned repeated ERCP is a new concept in endoscopic field to reflect quality of ERCP procedures and help technique improvement and perioperative management.

- This study provides evidence for pre-ERCP risk stratification and post-ERCP surveillance to prevent or early recognize unplanned repeated ERCP.

Keywords

common bile duct stone endoscopic retrograde cholangiopancreatography prognosis risk factor unplanned repeated procedure

Introduction

Common bile duct stone (CBDS) is one of the most common digestive diseases. The prevalence of gallstones is approximately 10%–15% in the adult population.¹ Endoscopic retrograde cholangiopancreatography (ERCP) is currently the predominant and first-line treatment procedure for many cases of cholelithiasis, with advantages in flexibility and minimal invasiveness compared to conventional surgery. However, in clinical practice, we found that some patients still had recurrent abdominal symptoms or manifestations of biliary obstruction after complete CBDS clearance in the initial ERCP, which usually requires a second ERCP for examination and further treatment. In other words, this repeated ERCP was unplanned and brought a great burden to the patients’ recovery and quality of life, length of hospital stay, and healthcare costs.

Unplanned reoperation or unplanned returns to the operating room, particularly within 30 days, is a vital indicator of surgical quality and has been extensively studied in many surgical fields. For instance, the proportion of postoperative unplanned reoperation in patients with colorectal cancer ranges from 3% to 11%, mainly associated with severe complications.^2,3 Unplanned reoperations expose the patient to additional surgical risk, medical costs, and delay the recovery process. Thus, unplanned reoperation generally represents the quality and benchmark of surgical practice in healthcare services and institutions.⁴

Likewise, understanding of the incidence, risk factors, and impact of unplanned repeated ERCP is essential for improving ERCP quality, as well as an optimal approach to reduce its occurrence and burden. To our knowledge, the unplanned repeated ERCP is a novel indicator in the endoscopic field, which has not been elucidated in existing studies. The incidence, relevant factors, and prognosis of unplanned repeated ERCP in patients with CBDS remain unknown.

Therefore, we propose the concept “unplanned repeated ERCP” and conduct a 10-year retrospective cohort study of CBDS patients undergoing ERCP in our center. The purpose of this study is to investigate the risk factors of unplanned repeated ERCP in patients with CBDSs, as well as its impact on clinical prognosis, and to further provide insight into how pre-ERCP risk stratification and post-ERCP surveillance may decrease or early recognize the risk of unplanned repeated ERCP.

Methods

Patients

As shown in Figure 1, consecutive ERCP records were obtained from January 2013 to October 2023 in the endoscopic Medicare system of Peking Union Medical College Hospital. Patients with suspected CBDS were evaluated according to the 2019 European Society of Gastrointestinal Endoscopy guideline.⁵ ERCP was recommended for all patients with CBDS who presented cholangitis with a high likelihood of CBDS, or which was validated by abdominal ultrasound or computed tomography (CT) or magnetic resonance cholangiopancreatography (MRCP), or endoscopic ultrasound (EUS) with or without symptoms. We included patients who underwent ERCP for CBDSs and were also confirmed to have CBDSs through ERCP, and excluded those who underwent ERCP for other etiologies (e.g., biliary stricture, ampullary tumor) or had a previous history of biliary surgery. Through reviewing medical records and follow-up via telephone or outpatient visits, 1697 patients underwent ERCP for CBDSs, all of whom were aged over 16 years. Then, after excluding patients with incomplete stone removal, 1191 patients underwent ERCP procedure once, defined as “unrepeated ERCP group.” Among the 1697 patients with CBDSs, 402 patients performed ERCP procedures more than 2 times. We chose the patients who underwent ERCPs twice within 1 month and excluded the cases with planned repeated ERCP, such as incomplete stone removal in the initial ERCP, the usage of antiplatelet or anticoagulant drugs, and intolerability for non-anesthesia ERCP, etc. Finally, 50 patients who underwent ERCP twice within 1 month were included as “unplanned repeated ERCP group.”

Figure 1.

Flowchart study of participants. According to the inclusion and exclusion criteria, 1241 patients with CBDS who underwent ERCP between 2013 and 2023 were finally included.

Endoscopic procedures

After the wire-loaded sphincterotome, retrograde cholangiography was performed to confirm the existence of CBDS and measure the largest transverse diameter of stones and the common bile duct (CBD). Endoscopic sphincterotomy (EST) or endoscopic balloon dilation (EBD) was determined by the endoscopist based on multiple factors, including the CBD and CBDS diameter and the complexity of the procedure. The CBDSs were extracted using a basket and/or a balloon, and mechanical lithotripsy was performed if necessary. CBD stents or endoscopic nasobiliary drainage (ENBD) were optionally conducted based on the endoscopist’s decision. Finally, retrograde cholangiography was performed to confirm complete removal of CBDSs.

Data collection

The following data were collected from medical systems:

(1) Demographic data, comorbidities, previous history of cholecystectomy, status of smoking, and alcohol use.

(2) Pre-ERCP clinical data: symptoms of abdominal pain, jaundice, and fever and its duration; C-reactive protein (CRP) and serum biochemical parameters (the highest) within 3 days before the initial ERCP procedure, including total bilirubin (TBil) and direct bilirubin (DBil), transaminase (ALT), γ-glutamyl transpeptidase, total bile acid; serum lipid levels within 7 days before the initial ERCP procedure, including total cholesterol, triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol.

(3) ERCP procedures: periampullary diverticulum, papillary morphology (according to the endoscopic classification proposed by Haraldsson et al.⁶), location of CBDSs, the largest diameter of CBD and CBDS, size of EST, diameter of EBD, stone extraction tools (basket, balloon, etc.), CBD stents placement, ENBD placement, unintentional passage of guide wire into the pancreatic duct, and ampullary bleeding during ERCP.

(4) Post-ERCP clinical data: symptoms of abdominal pain and fever; CRP and serum biochemical parameters 1 day after the initial ERCP.

Follow-up and outcomes

The patients were followed up until December 2023 through outpatient visits or telephone interviews. The primary outcome was unplanned repeated ERCP within 1 month. The reasons for repeated ERCPs were evaluated by two sole physicians to verify its unintentional condition. The second outcomes were ampullary bleeding, recurrence of CBDSs, acute cholangitis, and acute cholecystitis in the follow-up period. Post-ERCP bleeding was determined based on clinical symptoms, decreased hemoglobin, and active bleeding in the ampullary region under duodenoscopy. Stone recurrence was defined as CBDS recurrence evidenced by retrograde cholangiography, CT, or MRCP under the premise of complete removal of CBDSs in the initial ERCP. Diagnosis of acute cholangitis and cholecystitis both followed the criteria in the Tokyo guidelines.^7,8 As the adverse events within 1 month after the first ERCP in the unplanned repeated group were mostly the reasons for their repeated ERCP, we retrospectively analyzed the adverse events that occurred within 1 month and over 1 month after the initial ERCP to more clearly elucidate the impact on the long-term outcomes. Furthermore, cholecystectomy in the follow-up period was also recorded through their hospital visits or telephone interviews. The gallbladder stones were ascertained based on any one measurement among the transabdominal ultrasound, CT, magnetic resonance imaging, MRCP, EUS, or ERCP.

Statistical analysis

Continuous variables were expressed as mean and standard deviation and analyzed using the bilateral t-test if they followed normal distribution according to the Kolmogorov–Smirnov test, otherwise nonnormally distributed continuous variables were presented as median and interquartile range and analyzed using the Wilcoxon rank sum test. Categorical data were presented as frequencies and percentages and were compared with the χ² test or the Fisher exact test. Diameters of CBD and CBDS were converted to categorical variables by the threshold level based on the maximum area under the curve in the receiver operating characteristic curve analysis.

Logistic regression analysis was performed to assess the risk factors associated with unplanned repeated ERCP and adverse outcomes. Variables with p < 0.10 at univariate analysis were included in multivariate analysis using a “backwards elimination procedure.” Post hoc subgroup analysis was performed to examine the impact of CBD diameter on the relationship between risk factors and unplanned repeated ERCP and the impact of gallbladder status on the relationship between risk factors and long-term adverse outcomes.

The p values <0.05 were considered statistically significant. All statistical analysis was performed using SPSS (version 29.0; IBM Corporation, Chicago, IL, USA).

The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement (Supplemental Material).

Results

Study participants and baseline characteristics

As shown in Figure 1, 1241 patients were consecutively enrolled in this study in total, of whom 50 patients underwent unplanned repeated ERCP within 1 month, and 1191 patients underwent ERCP once. As shown in Table 1, the unplanned repeated ERCP group and unrepeated ERCP group had no significant difference in pre-ERCP symptoms, disease duration, previous history of cholecystectomy, smoking and alcohol use, and body mass index. The repeated ERCP group had a higher percentage of fatty liver than the unrepeated ERCP group (8.0% vs 1.8%, p = 0.013), whereas their serum lipid levels were similar in the two groups.

Table 1.

Demographic and baseline characteristics of the enrolled patients.

Variables	Unplanned repeated ERCP ( n = 50)	Unrepeated ERCP ( n = 1191)	p Value
Male	29 (58.0)	629 (52.8)	0.472
Age (years)	64.5 (47.5–69.0)	63.0 (53.0–72.0)	0.508
Duration (months)	2.0 (0.7–12.0)	1.0 (0.3–6.0)	0.094
Comorbidities
Hypertension	22 (44.0)	454 (38.1)	0.402
Diabetes mellitus	8 (16.0)	223 (18.7)	0.628
Hyperlipidemia	3 (6.0)	122 (10.2)	0.329
Fatty liver	4 (8.0)	22 (1.8)	0.013
Cardiovascular or cerebrovascular diseases	12 (24.0)	191 (16.0)	0.136
Malignancy	4 (8.0)	114 (9.6)	0.711
History of smoking	14 (28.0)	276 (23.2)	0.430
Cigarettes per day	4.4 ± 7.6	4.2 ± 9.4	0.521
History of alcohol drinking	11 (22.0)	173 (14.5)	0.145
Alcohol intake per day (g)	11.8 ± 36.3	12.3 ± 40.3	0.540
BMI (kg/m²)	24.3 ± 3.8	23.9 ± 3.6	0.438
History of cholecystectomy^a	18 (36.0)	294 (24.7)	0.071
Abdominal pain	42 (84.0)	1088 (91.4)	0.126
Fever	18 (36.0)	476 (40.0)	0.575
CRP (mg/L)	2.4 (0.9–8.1)	7.9 (1.3–42.5)	0.010
TBil (μmol/L)	28.0 (12.9–84.6)	27.8 (13.6–75.6)	0.889
DBil (μmol/L)	15.8 (4.8–62.0)	14.0 (4.8–55.5)	0.719
GGT (U/L)	270.0 (23.0–433.0)	237.0 (74.0–492.3)	0.664
TBA (U/L)	5.3 (2.1–68.1)	5.8 (3.1–19.1)	0.625
ALT (U/L)	53.5 (25.8–116.0)	99.0 (28.0–250.0)	0.014
TC (mmol/L)	4.2 (3.5–4.8)	4.4 (3.7–5.2)	0.378
TG (mmol/L)	1.6 (1.0–2.1)	1.4 (1.0–1.9)	0.534
LDL-C (mmol/L)	2.4 (1.6–3.0)	2.7 (2.1–3.3)	0.163
HDL-C (mmol/L)	0.9 (0.5–1.2)	0.9 (0.7–1.2)	0.406

Continuous variables were expressed as mean ± standard deviation or median (interquartile range). Categorical variables were expressed as frequencies (percentages).

Patients who had a previous cholecystectomy before the initial ERCP procedure.

ALT, transaminase; BMI, body mass index; CRP, C-reactive protein; DBil, direct bilirubin; ERCP, endoscopic retrograde cholangiopancreatography; GGT, γ-glutamyl transpeptidase; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TBA, total bile acid; TBil, total bilirubin; TC, total cholesterol; TG, triglyceride.

As for the reasons of unplanned repeated ERCP within 1 month (Table 2), 49/50 patients performed the second ERCP due to postoperative unsatisfactory serum bilirubin reduction with or without fever, in which 37 patients were proved to have newly emerging CBDS in the second ERCP procedure, 3 patients appeared ENBD displacement, and 3 patients developed stent displacement or obstruction. The other 1/50 patient experienced hematemesis after the initial ERCP, which turned out to be active bleeding in the ampullary region.

Table 2.

ERCP-related technique parameters and post-ERCP variables in the repeated and unrepeated ERCP groups.

Variables	Unplanned repeated ERCP ( n = 50)	Unrepeated ERCP ( n = 1191)	p Value
Intra-operation
Periampullary diverticulum	17 (34.0)	449 (37.7)	0.597
Irregular papilla	21 (42.0)	259 (21.7)	<0.001
Superior CBD stones	9 (18.0)	105 (8.8)	0.051
CBD diameter (cm)	1.2 (1.0–1.5)	1.0 (0.6–1.2)	0.002
CBD diameter ⩾0.95 cm	40 (80.0)	624 (52.4)	<0.001
CBDS diameter (cm)	1.0 (0.7–1.3)	0.8 (0.5–1.0)	0.004
CBDS diameter ⩾0.65 cm	38 (76.0)	659 (55.3)	0.004
EST	45 (90.0)	1135 (95.3)	0.173
EBD	25 (50.0)	574 (48.2)	0.802
Stone extraction tools			0.003
Basket alone	14 (28.0)	224 (18.9)
Balloon alone	17 (34.0)	708 (59.5)
Basket plus balloon	18 (36.0)	220 (18.5)
CBD stent placement	7 (14.0)	251 (21.1)	0.227
ENBD	41 (82.0)	849 (71.3)	0.099
Unintended PD cannulation	7 (14.0)	363 (30.5)	0.013
Post-operation
Abdominal pain	21 (42.0)	144 (12.1)	<0.001
Fever	23 (46.0)	104 (8.7)	<0.001
TBil reduction value^a (μmol/L)	−14.5 (−67.6 to 1.9)	4.1 (−3.7 to 32.0)	<0.001
Post-/pre-ERCP TBil ratio^b			<0.001
<0.8	8 (16.0)	555 (46.6)
0.8-1.2	13 (26.0)	311 (26.1)
⩾1.2	29 (58.0)	324 (27.2)
DBil reduction value^a (μmol/L)	−6.3 (−50.8 to 1.5)	3.0 (−1.1 to 25.0)	<0.001
GGT reduction value^a (U/L)	59.0 (3.5–121.0)	8.5 (0–172.5)	0.304
ALT reduction value^a (U/L)	2.5 (−63.8 to 30.5)	30.0 (3.0–127.0)	<0.001
Post-/pre-ERCP ALT ratio^b			<0.001
<0.9	24 (48.0)	919 (77.2)
0.9-1.2	5 (10.0)	134 (11.3)
⩾1.2	21 (42.0)	138 (11.6)
CRP reduction value^a (mg/L)	−22.5 (−59.7 to −1.8)	0 (0–4.1)	<0.001
⩾0.75-fold preoperative CRP^b	21 (91.3)	241 (58.2)	0.002
Gallbladder status			0.035
Cholecystectomy^c	33 (66.0)	702 (58.9)
Gallbladder without stones	3 (6.0)	244 (20.5)
Gallbladder with stones	14 (28.0)	245 (20.6)
Adverse events
⩽1 month	42 (84.0)	16 (1.3)	<0.001
Bleeding	1	9	0.338
CBDS recurrence	37	1	<0.001
Biliary infection	18	6	<0.001
>1 month	6 (12.0)	60 (5.0)	0.068
Bleeding	0	1	1.0
CBDS recurrence	4	33	0.088
Biliary infection	3	37	0.468

Continuous variables were expressed as mean ± standard deviation or median (interquartile range). Categorical variables were expressed as frequencies (percentages).

Reduction value = pre-ERCP levels−post-ERCP levels.

Ratio = post-ERCP levels/pre-ERCP levels.

Patients who underwent cholecystectomy before the initial ERCP or in the follow-up period.

ALT, transaminase; CBDS, common bile duct stone; CRP, C-reactive protein; DBil, direct bilirubin; EBD, endoscopic balloon dilation; ENBD, endoscopic nasobiliary drainage; ERCP, endoscopic retrograde cholangiopancreatography; EST, endoscopic sphincterotomy; GGT, γ-glutamyl transpeptidase; PD, pancreatic duct; TBil, total bilirubin.

Comparison of clinical and procedural factors between the unplanned repeated and unrepeated ERCP groups

During the initial ERCP procedure (Table 2), the repeated ERCP group had more patients with irregular ampullary papilla (42.0% vs 21.7%, p < 0.001) and a wider CBD diameter (median 1.2 vs 1.0 cm, p = 0.002) than the unrepeated group. The CBDSs had a larger diameter (median 1.0 vs 0.8 cm, p = 0.004) and more proportion of locating in the superior CBD (18.0% vs 8.8%, p = 0.051) in the repeated ERCP group versus the unrepeated group. As for stone removal, the repeated ERCP group had a higher rate of basket usage (basket alone: 28.0% vs 18.9%, p = 0.003) and a lower rate of balloon usage than the unrepeated ERCP group (balloon alone: 34.0% vs 59.5%, p = 0.003). There were no significant differences in CBD stents or ENBD placement in the two groups.

As shown in Table 2, we compared pre- and post-ERCP clinical symptoms, liver function tests, and CRP changes. The complaint of abdominal pain (42.0% vs 12.1%, p < 0.001) and fever (46.0% vs 8.7%, p < 0.001) were more common in the repeated ERCP group than the unrepeated group. The post-ERCP next-day serum TBil levels decreased by a median of 4.1 μmol/L in the unrepeated group, whereas they increased by a median of 14.5 μmol/L in the repeated group (p < 0.001). Consistently, the reduction of serum DBil by a median of 3.0 μmol/L and an elevation by a median of 6.3 μmol/L were observed in the unrepeated group and repeated group, respectively (p < 0.001). Similarly, post-ERCP ALT reduction in the unrepeated ERCP group was more significant than repeated ERCP group (30.0 vs 2.5 U/L, p < 0.001). And, post-ERCP CRP levels were elevated with a median of 22.5 mg/L compared with pre-ERCP levels in the repeated ERCP group, while pre- and post-ERCP CRP levels presented no obvious changes in the unrepeated group. We listed the patients’ gallbladder conditions into three categories: cholecystectomy, gallbladder without stones, and gallbladder with stones. More than half in both groups (66.0% vs 58.9%) underwent cholecystectomy before the initial ERCP or in the follow-up period. Among the patients with preserved gallbladders, the proportion of patients with cholecystolithiasis was higher in the repeated group than the unrepeated group (28.0% vs 20.6%).

Analysis of risk factors for unplanned repeated ERCP

As shown in Table 3, in univariate analysis, irregular papillary morphology, superior CBDSs, CBD and CBDS diameter, post-ERCP abdominal pain and fever, post-ERCP TBil, ALT, and CRP levels, cholecystectomy, and comorbidity with fatty liver were all significantly associated with unplanned repeated ERCP. Multivariate analysis showed that irregular papilla (odds ratio (OR) 3.494, 95% confidence interval (CI) 1.175–10.386, p = 0.024), post-ERCP fever (OR 7.532, 95% CI 2.692–21.079, p < 0.001), post-ERCP abdominal pain (OR 2.810, 95% CI 0.999–7.903, p = 0.050), post/pre ERCP TBil levels ⩾1.2 times (OR 6.973, 95% CI 1.705–28.512, p = 0.007), and post/pre ERCP ALT levels ⩾1.2 times (OR 3.944, 95% CI 1.174–13.248, p = 0.026) were independent risk factors for unplanned repeated ERCP.

Table 3.

Analysis of risk factors for unplanned repeated ERCP in patients with CBDS.

Variables	Univariate analysis			Multivariate analysis
Variables	OR	95% CI	p Value	OR	95% CI	p Value
Irregular papilla	2.606	1.462–4.646	0.001	3.494	1.175–10.386	0.024
Superior CBDS	2.270	1.074–4.800	0.032	1.613	0.395–6.588	0.506
CBD diameter ⩾0.95 cm	3.635	1.801–7.335	<0.001	1.682	0.548–5.167	0.364
CBDS diameter ⩾0.65 cm	2.556	1.323–4.941	0.005	1.655	0.538–5.093	0.380
Fatty liver	4.621	1.530–13.955	0.007	2.780	0.318–24.268	0.355
Previous cholecystectomy	1.716	0.949–3.103	0.074	0.306	0.078–1.205	0.090
Post-ERCP abdominal pain	5.265	2.924–9.479	<0.001	2.810	0.999–7.903	0.050
Post-ERCP fever	8.903	4.928–16.084	<0.001	7.532	2.692–21.079	<0.001
Post-/pre-ERCP TBil ratio
<0.8	Ref	Ref	Ref	Ref	Ref	Ref
0.8–1.2	2.900	1.189–7.073	0.019	1.437	0.272–7.600	0.670
⩾1.2	6.209	2.805–13.745	<0.001	6.973	1.705–28.512	0.007
Post-/pre-ERCP ALT ratio
<0.9	Ref	Ref	Ref	Ref	Ref	Ref
0.9–1.2	1.429	0.536–3.809	0.476	1.826	0.422–7.907	0.421
⩾1.2	5.827	3.159–10.750	<0.001	3.944	1.174–13.248	0.026
Post-/pre-ERCP CRP ratio
<0.75	Ref	Ref	Ref	Ref	Ref	Ref
⩾0.75	7.537	1.744–32.569	0.007	1.740	0.322–9.396	0.520

ALT, transaminase; CBDS, common bile duct stone; CI, confidence interval; CRP, C-reactive protein; ERCP, endoscopic retrograde cholangiopancreatography; OR, odds ratio; Ref, reference; TBil, total bilirubin.

We performed a subgroup analysis of risk factors for unplanned repeated ERCP. As shown in Tables S1 and S2, for patients with a CBD diameter ⩾0.95 cm, univariate analysis revealed that irregular papilla, post-ERCP abdominal pain and fever, post-ERCP TBil, ALT, and CRP were associated with repeated ERCP demand. In multivariate analysis, post-ERCP abdominal pain (OR 4.769, 95% CI 1.425–15.957, p = 0.011), fever (OR 5.442, 95% CI 1.676–17.671, p = 0.005), and post/pre-ERCP TBil levels ⩾1.2 times (OR 5.348, 95% CI 1.325–21.581, p = 0.018) were independent risk factors for repeated ERCP. By contrast, for patients with a CBD diameter <0.95 cm, superior CBDSs (OR 9.059, 95% CI 1.572–52.218, p = 0.014), post-ERCP fever (OR 19.434, 95% CI 4.398–85.867, p < 0.001), and post-/pre-ERCP ALT levels ⩾1.2 times (OR 27.090, 95% CI 4.847–151.398, p < 0.001) remained independent risk factors for unplanned repeated ERCP.

The impact of unplanned repeated ERCP on the long-term outcome

The enrolled patients with CBDSs were followed up with a median of 43.7 months, with no significant difference between the two groups (repeated vs unrepeated: 38.0 (26.5–79.1) vs 43.9 (21.7–83.2) months, p = 0.929). There was no doubt about the higher percentage of adverse events within 1 month in the repeated group than in the unrepeated group. After 1 month of the initial ERCP procedure, the incidence of adverse events was slightly higher in the repeated group than in the unrepeated group (12.0% vs 5.0%, p = 0.068). Four (8.0%) and 33 (2.8%) patients had CBDS recurrence in the repeated and unrepeated groups, respectively (p = 0.088), which occurred at a similar time (since the initial ERCP: median 11.4 vs 6.2 months, p = 0.807). Three (6.0%) patients and 37 (3.1%) patients in the repeated and unrepeated group developed biliary infection with no statistical significance (p = 0.468).

In multivariate analysis, as shown in Table 4, CBD stent placement (OR 2.841, 95% CI 1.700–4.748, p < 0.001) and post-ERCP abdominal pain (OR 2.220, 95% CI 1.225–4.025, p = 0.009) were independently associated with adverse clinical events. There was no relevance between the gallbladder status and long-term outcomes. We performed subgroup analysis according to history of cholecystectomy or cholecystolithiasis, respectively. As shown in Tables S3 and S4, for patients who underwent cholecystectomy, unplanned repeated ERCP was related to increased long-term adverse outcomes (OR 2.747, 95% CI 0.924–8.167, p = 0.069). CBD stent placement and post-ERCP fever were other independent risk factors for adverse events. By contrast, for the patients who had not undergone cholecystectomy, CBDS diameter ⩾0.65 cm was the independent risk factor for adverse clinical outcomes instead of unplanned repeated ERCP or gallbladder with stones. Similarly, in Tables S5 and S6, unplanned repeated ERCP was non-independent relevant factor with adverse events in the patients without gallbladder stone or who had cholecystectomy (OR 2.107, 95% CI 0.709–6.256, p = 0.180), while for patients with cholecystolithiasis, irregular papilla (OR 2.954, 95% CI 0.942–9.266, p = 0.063) and CBDS diameter ⩾0.65 cm (OR 4.302, 95% CI 0.927–19.967, p = 0.062) may increase the risks of adverse events.

Table 4.

Analysis of risk factors for long-term adverse events in patients undergoing ERCP for CBDS.

Variables	Univariate analysis			Multivariate analysis
Variables	OR	95% CI	p Value	OR	95% CI	p Value
Unplanned repeated ERCP	2.570	1.054–6.269	0.038	1.918	0.716–5.138	0.195
Irregular papilla	0.974	0.559–1.825	0.974	–	–	–
Superior CBDS	1.391	0.647–2.991	0.398	–	–	–
CBD diameter ⩾0.95 cm	1.358	0.818–2.255	0.236	–	–	–
CBDS diameter ⩾0.65 cm	1.213	0.731–2.014	0.455	–	–	–
CBD stent placement	2.829	1.697–4.718	<0.001	2.841	1.700–4.748	<0.001
Unintended PD cannulation	1.025	0.597–1.758	0.929	–	–	–
Post-ERCP abdominal pain	2.203	1.223–3.969	0.009	2.220	1.225–4.025	0.009
Post-ERCP fever	2.283	1.208–4.315	0.011	1.593	0.777–3.265	0.203
Post-/pre-ERCP TBil ratio
<0.8	Ref	Ref	Ref	–	–	–
0.8–1.2	1.276	0.715–2.277	0.409	–	–	–
⩾1.2	0.874	0.468–1.634	0.674	–	–	–
Post-/pre-ERCP ALT ratio
<0.9	Ref	Ref	Ref	–	–	–
0.9–1.2	1.320	0.632–2.756	0.460	–	–	–
⩾1.2	1.279	0.633–2.587	0.493	–	–	–
Post-/pre-ERCP CRP ratio
<0.75	Ref	Ref	Ref	–	–	–
⩾0.75	1.086	0.529–2.230	0.823	–	–	–
Gallbladder status
Cholecystectomy	Ref	Ref	Ref
Gallbladder without stones	0.679	0.336–1.373	0.281	–	–	–
Gallbladder with stones	0.850	0.450–1.608	0.850	–	–	–

ALT, transaminase; CBDS, common bile duct stone; CI, confidence interval; CRP, C-reactive protein; ERCP, endoscopic retrograde cholangiopancreatography; OR, odds ratio; PD, pancreatic duct; Ref, reference; TBil, total bilirubin.

Discussion

To our knowledge, this is the first study to carry out the concept “unplanned repeated ERCP.” In this retrospective cohort, the majority of unplanned repeated ERCP for CBDS patients were postoperative unsatisfactory serum bilirubin reduction, with symptoms of cholangitis or not. Irregular papilla, post-ERCP fever and abdominal pain, post-/pre-ERCP serum TBil levels ⩾1.2 times, and post-/pre-ERCP serum ALT levels ⩾1.2 times were identified as independent risk factors for unplanned repeated ERCP. CBDS patients with unplanned repeated ERCP may exhibit a higher propensity for CBDS recurrence and biliary infection in the long term, without statistical significance.

In our study, the main reasons for unplanned repeated ERCP in patients with CBDS were unrelieved biliary obstruction or cholangitis. The threshold of interval time between the initial and unplanned repeated ERCP procedure was determined based on multiple factors, including the natural course of CBDS, the incidence of CBDS-related or procedure-related complications, the real experience of CBDS patients’ hospitalization in our center, and previous reports of unplanned reoperations. Recurrent biliary stone is one of the most common complications after stone removal, but there has not been an accurate definition for the recurrence time of CBDS. In recent clinical studies, 3 months was often selected as the criterion of the time interval between initial stone clearance and biliary stone recurrence.^9,10 So, to distinguish unplanned repeated ERCP demand from conventional complications, the time interval between the initial and repeated ERCP should be determined to be less than 3 months. In addition, sometimes temporary insertion of biliary plastic stents was performed in patients with CBDS for better biliary drainage. The usual replacement interval of biliary plastic stents is 3 months, varying depending on the etiology and expertise of endoscopists.¹¹ Kubesch et al.¹² previously reported that the median plastic stent patency was 41 days for scheduled stent exchange and was signiﬁcantly shorter (median 34 days) in cases with one plastic stent. Moreover, in surgery-related research, unplanned re-operation within 24 h, 48 h, or 30 days following the major surgery has been reported as the outcome of interest.^13–16 Therefore, it is reasonable and clinically valuable to analyze unplanned repeated ERCP within 1 month in our study.

In our cohort, the incidence of unplanned repeated ERCP within 1 month in CBDS patients was about 2.95%, which is comparable with those previously reported in low-risk surgical fields. Lim et al.¹⁷ found that the unplanned reoperation rate was 1.9% in 6749 cases of outpatient plastic surgery. And unplanned reoperation rate was about 4% in inpatient spinal surgery¹⁸ and up to 14.2% in major head and neck surgery.¹³ These suggest that ERCP procedures are relatively minimally invasive and safe therapeutic options with controllable risks.

In our analysis of risk factors for repeated ERCP, the irregular papilla, a dilated CBD, CBDS size, and location in the superior CBD were significantly associated with increased risks of unplanned repeated ERCP within 1 month. Papilla morphology can affect the difficulty of selective biliary cannulation, which is the milestone of the ERCP procedure. The irregular papilla, including small, protruding or pendulous, creased or ridged papilla, increased biliary cannulation difficulty, and post-ERCP infections or pancreatitis,^19,20 which may require repeated ERCP intervention. Then, CBD dilatation ⩾10 mm and intrahepatic CBDS were independent risk factors for CBDS recurrence, as previous studies reported.^21
–23 Common causes of CBD dilatation include cholelithiasis, tumor in the ampullary region, congenital factor, history of cholecystectomy, etc.²⁴ As benign or malignant biliary stricture was excluded in this study, CBD dilatation was mainly related to the stones and partially represented the severity of biliary obstruction. After ERCP, the dilated CBD appears to have increased enterobiliary reflux and infection.¹⁰ In addition, unintended guidewire passage into the pancreatic duct was always identified as a risk factor of post-ERCP pancreatitis,²⁵ but did not increase the risk of repeated ERCP within 1 month. Interestingly, the basket was used more for stone extraction in the repeated ERCP group versus the unrepeated group. However, several studies indicated that there was no significant difference in stone clearance and complications between the basket and balloon catheters.^26,27 We speculate this discrepancy may be affected by the size of CBDSs and endoscopists’ experience. In multivariate regression analysis, post-ERCP fever, abdominal pain, and elevated serum TBil or ALT over 1.2 times that of pre-ERCP were independent predictors for unplanned repeated ERCP. Tierney et al.²⁸ reported that patients developing post-ERCP cholangitis were more likely to have higher baseline TBil and ALT, which was not observed in our study. Compared with pre-ERCP serum liver function parameters, post-ERCP serum TBil and ALT levels were reduced less or even elevated in the repeated ERCP group than those in the unrepeated ERCP group. To better quantify the risk and improve utility, we categorized liver function indicators and found that if the post-ERCP TBil level decreased by less than 20% of the pre-ERCP TBil level, it is necessary to be cautious about repeated ERCP with a sensitivity of over 80%, while if the post-ERCP TBil level increased by more than 20% of the pre-ERCP TBil, this will be a strong indicator for repeated ERCP demand with the specificity of over 80%.

The total incidence of adverse events (bleeding: 0.9%, CBDS recurrence: 6.0%, biliary infection: 5.2%) in our study was comparable with previously reported, in which the general incidence rates of ERCP-related bleeding, CBDS recurrence, acute cholangitis, and cholecystitis were 0.3%–9.6%, 4%–25%, 0.5%–3.0%, and 0.5%–5.2%, respectively.^23,29 Generally, multiple ERCP sessions may increase the risks of procedure-related complications (bleeding, perforation, infection, pancreatitis). However, in our study, no significant increase in the risk of post-procedural bleeding or biliary infection was found in the repeated ERCP group, and no perforation or post-ERCP pancreatitis occurred. In terms of the impact of unplanned repeated ERCP on clinical outcomes, our data revealed that unplanned repeated ERCP, although not an independent factor, is partially relevant with increased likelihood of long-term adverse events (CBDS recurrence, acute cholangitis, or cholecystitis), especially in the patients who had gallbladder without stones or underwent cholecystectomy. We also investigated that cholecystectomy or cholecystolithiasis did not affect adverse outcomes (e.g., CBDS recurrence) in the long term. We predict the possible reason is: The common cause of CBDS is stone passage from the gallbladder. If this condition is excluded, other multiple factors may play a greater role in recurrent stone or biliary infection, including ERCP-related impairment of the biliary tract, anatomy, motility, or metabolic disorders.^{10,23,30
–32} Notably, besides unplanned repeated ERCP, biliary stent placement presented a significant association with poor prognosis in patients with a resected or stone-free gallbladder. A meta-analysis identified biliary stent placement as one of the strong risk factors of recurrent CBDS following ERCP,³⁰ which is partially consistent with our results. Long-term stent placement and CBD dilation may promote bacterial proliferation and stent-stone complex formation.^23,33 But for patients with cholecystolithiasis, it is the morphology of CBD or CBDS that plays the predominant role in long-term adverse events, specifically irregular papilla, CBD dilation, or CBDS diameter ⩾0.65 cm. These could provide the gastroenterologists with different surveillance strategies based on individual gallbladder status.

Our findings provide novel and valuable insights into perioperative management and quality control of ERCP procedures. Preoperative risk identification and intraoperative planning are key factors in preventing unplanned repeated ERCP. Postoperative surveillance, including abdominal symptoms or fever, unsatisfactory TBil reduction, will facilitate early recognition and interventions for repeated ERCP. In addition, like many surgical fields, the rate of unplanned repeated ERCP is also an outcome measure to determine a center’s ability to provide safe and effective care and cannot be understated. The relatively low reoperation rate makes this metric difficult to study on only one institution, urgently demanding a multi-center or national database establishment.

This study is the first to assess unplanned repeated operations in ERCP procedures. We found multiple factors associated with repeated ERCP risk based on clinical characteristics, ERCP technique parameters, and laboratory tests. These will help endoscopists to counsel patients on reoperation risk reduction and individualize surveillance in the perioperative period. Then, we performed follow-up over 3 years to evaluate the impact of unplanned repeated ERCP on clinical prognosis. There are also some limitations in our study. First, this is a single-center, retrospective, observational study. Despite the follow-up via telephone or hospital visits, CBDS recurrence may be underestimated to some degree, as cholelithiasis is sometimes asymptomatic, so that they usually do not perform radiographic examination routinely. The results may be more convincing if further multicenter, prospective studies are conducted. Second, the limited sample size in the repeated ERCP group may partially cause deviations in results or miss some potentially valuable risk factors. During subgroup analysis, the decrease in the sample size per subgroup may also reduce statistical power. Larger sample size studies are required to confirm these findings. Third, we cannot retrospectively identify the component of stones, which may affect the pattern of stone recurrence and disease progression.

Conclusion

Unplanned repeated ERCP is an important indicator of procedure quality in the healthcare system. Irregular papilla morphology, postoperative fever and abdominal pain, and postoperative serum TBil or ALT increase may be independently relevant with increased risk of unplanned repeated ERCP. The occurrence of unplanned repeated ERCP may not have a significant impact on the long-term prognosis, but the potential increased risk of postoperative CBDS recurrence and biliary infection still requires close attention for patients without cholecystolithiasis.

Supplemental Material

sj-docx-1-tag-10.1177_17562848251342342 – Supplemental material for Long-term prognosis and risk factors associated with 30-day unplanned repeated ERCP in patients with common bile duct stones

Supplemental material, sj-docx-1-tag-10.1177_17562848251342342 for Long-term prognosis and risk factors associated with 30-day unplanned repeated ERCP in patients with common bile duct stones by Mengmeng Zhang, Xi Wu, Dongsheng Wu, Qingwei Jiang, Yunlu Feng, Qiang Wang, Shengyu Zhang and Aiming Yang in Therapeutic Advances in Gastroenterology

Supplemental Material

sj-docx-2-tag-10.1177_17562848251342342 – Supplemental material for Long-term prognosis and risk factors associated with 30-day unplanned repeated ERCP in patients with common bile duct stones

Supplemental material, sj-docx-2-tag-10.1177_17562848251342342 for Long-term prognosis and risk factors associated with 30-day unplanned repeated ERCP in patients with common bile duct stones by Mengmeng Zhang, Xi Wu, Dongsheng Wu, Qingwei Jiang, Yunlu Feng, Qiang Wang, Shengyu Zhang and Aiming Yang in Therapeutic Advances in Gastroenterology

Footnotes

Appendix

Acknowledgements

The study has been read and approved by all the authors.

Declarations

ORCID iDs

Mengmeng Zhang

Aiming Yang

Supplemental material

Supplemental material for this article is available online.

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