Introduction
Common bile duct (CBD) stones are one of the most frequent indications for endoscopic retrograde cholangiopancreatography (ERCP). Endoscopic complete sphincterotomy (EST) followed by balloon or basket extraction is widely considered the gold standard technique for the treatment of CBD stones; being successful in more than 90% of cases with approximately 5% overall rate of adverse events [1].
Diverticula in the small intestine most often occur in the duodenum and are usually acquired during life. Specifically, periampullary diverticula (PAD) are rare in patients below 40 years [1] and according to the literature, they are more common in females than in males [2].
PAD not only causes mechanical compression of the lower part of the CBD by a retained food residue bezoar [2] but also induces dysfunction of the sphincter of Oddi and induces fibrosis of its lower part with subsequent biliary dilatation. They also lead to chronic bile stasis, allowing reflux of duodenal contents and ascending infection into the biliary system [1, 2]. These anatomical and physiological changes naturally accompanying PAD are considered the risk factors of how they lead to the formation of primary CBD stones, particularly post-cholecystectomy [3].
Primary stones formed in the setting of PAD tend to be large with a diameter greater than 10 mm, multiple, and non-barrel shaped with a relatively greater width-to-length ratio because multiple stones are formed in a chronically dilated CBD with a relatively narrow lower part [3]. These stones are difficult to extract and often require advanced techniques such as mechanical lithotripsy and extracorporeal or intracorporeal lithotripsy [4, 5].
PAD are well-known risk factors for difficult biliary cannulation, inability to complete the Oddi sphincterotomy, failed CBD stone extraction, and ERCP-related complications (bleeding and perforation) due to the deranged endoscopic anatomy of the periampullary region and the absence of the muscle layer in the diverticular wall. Hence, stone extraction in the setting of a PAD is a real challenge during ERCP with a relatively increased risk of failed extraction, resorting to mechanical lithotripsy, multiple attempts at stone extraction through multiple ERCP sessions, and consequently ERCP-related complications [6, 7].
In 2003, Ersoz et al. introduced endoscopic papillary large balloon dilatation (EPLBD) following a limited sphincterotomy as an innovative technique for the management of large CBD stones [8]. This approach has since then proved to be safe and effective for the extraction of large CBD stones. It reduces the need for mechanical lithotripsy, rates of repeated ERCP sessions, and ERCP-related complications as compared to endoscopic EST alone [9, 10]. The European Society of Gastrointestinal Endoscopy (ESGE) [11] and American Society for Gastrointestinal Endoscopy (ASGE) guidelines [12] based on these findings conditionally prefer sphincterotomy followed by a large balloon dilatation over EST alone for extracting large CBD stones, because combining dilatation with EST improves duct clearance and reduces the need for lithotripsy without adding risks.
Consequently, it can be inferred that EPLBD would be helpful when large stones do exist in the setting of PAD. The literature focusing on EPLBD efficacy in managing large CBD stones in the context of PAD is mainly retrospective, with scarce prospective data. Hence, this study aimed to compare the effectiveness and short-term safety of EPLBD after limited sphincterotomy with those of EST for extracting large CBD stones in the setting of PAD prospectively.
Patients and methods
This multi-center study was conducted in ERCP units of Hepatology, Gastroenterology, and Infectious Diseases Department, Zagazig University, Tropical Medicine Department, Suez University, and Hepatology, Gastroenterology, and Infectious Diseases Department, Kafrelsheikh University, Egypt during the period from October 2021 to October 2022.
Forty-eight patients with large CBD stones more than 1 cm in diameter (confirmed by one or more of the available imaging modalities) and a PAD found on facing the papilla during the ERCP were finally recruited (Fig. 1).
[See PDF for image]
Fig. 1
Study flow chart
Inclusion criteria
Patients with upper abdominal pain and imaging-confirmed large CBD stones, with or without signs of cholestasis, were eligible for ERCP and stone extraction. ERCP-naïve patients with confirmed large CBD (more than 1 cm) stone(s) were potential candidates for the study. Both male and female patients were included. In all patients, the endoscopic anatomy showed a PAD (Fig. 1).
Exclusion criteria
Patients with these criteria were excluded: asymptomatic large or < 1 cm CBD stone(s), no PAD, previous ERCP, evidence of preoperative and intraoperative biliary infection, cirrhotics, patients with major organ failure. Intra-operative exclusion criteria comprised failed biliary cannulation, unidentified intraductal stone(s), suspected malignant biliary obstruction, benign stenosis of the duodenum, or CBD stricture with a stone located above that stricture (Fig. 1).
Patient groups
Based on the intraoperative technique adopted for stone extraction; group I is patients treated with limited sphincterotomy followed by EPLBD, while group II is patients treated with EST.
All patients were subjected to full history taking, including operative history and previous ERCP, and thorough clinical examination. Pre-ERCP investigations comprised CBC, PT, PTT, INR, liver function tests, kidney function tests, HCV antibodies, HBs antigen, HIV antibodies, amylase, lipase, and CA 19–9. CBC, serum bilirubin, and pancreatic enzymes were performed for all patients in the post-ERCP follow-up. Imaging, including pelviabdominal ultrasound (US), contrast-enhanced computed tomography (CT), and/or magnetic resonance cholangiopancreatography (MRCP), were performed for all patients before ERCP. Plain erect X-ray abdomen and US were performed for all patients in the follow-up.
Endoscopy
Patients were operated on by the most experienced endoscopists with annual ERCP cases > 400. All patients received deep sedation with anesthesiologist support. The endoscope was introduced by the classic sunset technique with minimal air insufflation to enhance papillary facing and to avoid perforation of the diverticulum. PAD was classified in the current study following the Li-Tanaka classification based on the location of the major papilla in relation to the diverticulum [13]. Briefly, Type I: the papilla is located inside the diverticulum and not adjacent to the margin; Type II: the papilla is located in the margin of the diverticulum (type IIa: Inside of the margin; type IIb: outside of the margin, < 1 cm); Type III: the papilla is located outside the margin, ≥ 1 cm; Type IV: The papilla is located in the margin of the diverticulum, ≥ 2 diverticula (Type IVa: the papilla is located outside the margins of at least one diverticulum, < 1 cm; Type IVb: the papilla is located outside the margins of all the diverticula, ≥ 1 cm [13].
A standard biliary sphincterotome and guidewire were used for endoscopic biliary cannulation. In case biliary cannulation was difficult, a papillary precut needle knife was used for performing a proper incision at the standard eleven o’clock position to enhance the process of biliary cannulation. A 5 cm × 5 Fr pancreatic plastic stent was placed in the pancreatic duct following more than three pancreatic duct cannulations to prevent or minimize postoperative pancreatitis [11, 12, 14]. After successful biliary cannulation, patients were randomly assigned to either EPLBD group or EST group.
In EPLBD group, limited sphincterotomy was done using a standard biliary sphincterotome where the incision did not exceed half the length between the papillary orifice and the ampullary hooding fold. A standard large dilatation balloon was used for the dilatation of the resultant orifice and the lower CBD. The diameter of the dilatation balloon was determined according to the stone size and the CBD diameter above the stone (balloon diameter did not exceed maximum CBD diameter) and was controlled by the use of a biliary balloon insufflator under fluoroscopy. The duration of dilatation was controlled by the disappearance of the balloon waist or at maximum not exceeding 3 min.
In EST group, all patients were subjected to EST using a standard biliary sphincterotome with an incision at the classic eleven o’clock position from the papillary orifice to the ampullary hooding fold.
In both groups, stone extraction was done using a standard extraction balloon inflated above the stone, and withdrawal was done in the optimal extraction axis. After this step, stone extraction was documented to be either successful or failed. In both groups, a papillary balloon occlusion cholangiography was done to confirm complete clearance of the CBD and to exclude any leaks. Patients with failed stone extraction in both groups were not subjected to intraoperative lithotripsy to exclude lithotripsy as a factor of maneuver success or maneuver-related complications. In both groups, all patients were subjected to placement of a standard biliary plastic stent 10 cm × 10 Fr in the CBD across the resultant orifice and across the stone in case of failed stone extraction. In both groups, all patients received a single dose of rectal indomethacin immediately after ERCP [14].
Follow up
All patients were admitted for at least 24 h for clinical, laboratory, and radiologic follow-up. Definition of post-ERCP pancreatitis (PEP) in the current study followed the 2020 ESGE guidelines defining PEP as a condition that strictly combines any new or worsened abdominal pain with documented elevation (≥ 3 times upper limit of normal) pancreatic enzymes (amylase or lipase) level after exclusion of the common causes for new or worsened abdominal pain post-procedural. On the other hand, post-ERCP bleeding is defined as hematemesis and/or melena or hemoglobin drop > 2 g/dL [14].
Statistical analysis
Sample size calculation
There was no formal calculation of the sample size. However, all patients who were candidates for ERCP and met the inclusion and exclusion criteria during the study period were recruited.
Endpoints
Primary endpoint
This study evaluated the rate of CBD clearance from large stones following either EPLBD or EST, without the use of adjunctive techniques such as lithotripsy. Although this approach deviates from standard daily practice—where supportive methods are often employed—it was deliberately chosen to assess the efficacy profile of the primary balloon dilatation technique, while minimizing potential confounding factors that might affect the outcomes.
Secondary endpoint
This represents the short-term safety profile of the primary technique of large balloon dilatation in the presence of PAD.
Randomization
A simple randomization technique was applied. The first enrollment was randomly determined, and thereafter every other patient was enrolled in each group, with the odd numbers assigned to the EPLBD group while the even numbers were assigned to the EST group.
Blinding
Single-blind (patient side). However, outcome assessors were blinded to the treatment groups.
Analysis
Data were analyzed by SPSS version 26 (IBM Inc., Chicago, IL, USA). Quantitative variables were presented as mean and standard deviation (SD) and were compared between the two groups utilizing an unpaired Student’s t-test. Qualitative variables were presented as frequency and percentage and were compared between the two groups utilizing the Chi-square test or Fisher’s exact test when appropriate. A two-tailed p value < 0.05 was considered statistically significant.
Results
Patient characteristics
In the current study there was no significant difference between the two groups regarding the age, gender, patients’ complaint, CBC, AST, and ALT. All patients in both groups had elevated serum total and direct bilirubin (with no significant difference between groups) due to cholestasis from PAD. Serum indirect bilirubin and INR were normal in some patients and were high in the rest of the patients; however, there was no significant difference between the two groups. Furthermore, there was no significant difference between the two groups focusing on serum creatinine, CA19-9, amylase and lipase (Table 1).
Table 1. Preoperative demographic, clinical, imaging, and laboratory data in the two groups
EPLBD group (n = 24) | EST group (n = 24) | p value | ||
|---|---|---|---|---|
Age (years) | Mean ± SD | 57.58 ± 10.6 | 57 ± 14.56 | 0.875 |
Range | 38–75 | 20–79 | ||
< 45 years | 4 (16.67%) | 5 (20.83%) | 0.712 | |
≥ 45 years | 20 (83.33%) | 19 (79.17%) | ||
Sex | Male | 10 (41.67%) | 13 (54.17%) | 0.386 |
Female | 14 (58.33%) | 11 (45.83%) | ||
Complaint | Abdominal pain | 39 (56.52%) | 15 (34.88%) | 0.07 |
Vomiting | 6 (8.7%) | 4 (9.3%) | ||
Jaundice | 24 (34.78%) | 24 (55.81%) | ||
CBC | Normal | 21 (87.5%) | 21 (87.5%) | 1.000 |
Low | 3 (12.5%) | 3 (12.5%) | ||
Serum total bilirubin | Normal | 0 (0%) | 0 (0%) | – |
High | 24 (100%) | 24 (100%) | ||
Serum direct bilirubin | Normal | 0 (0%) | 0 (0%) | – |
High | 24 (100%) | 24 (100%) | ||
AST (IU/L) | Normal | 19 (79.17%) | 22 (91.67%) | 0.220 |
High | 5 (20.83%) | 2 (8.33%) | ||
ALT (IU/L) | Normal | 19 (79.17%) | 22 (91.67%) | 0.220 |
High | 5 (20.83%) | 2 (8.33%) | ||
INR | Normal | 7 (29.2%) | 6 (25%) | 0.034 |
High | 17 (70.8%) | 18 (75%) | ||
High | 0 (0%) | 0 (0%) | ||
CBD diameter (mm) by US, CT and/or MRCP | Mean ± SD | 14.17 ± 1.74 | 14.88 ± 1.26 | 0.113 |
Range | 12–17 | 13–18 | ||
Presence of IHBRD by US, CT and/or MRCP | Yes | 24 (100%) | 24 (100%) | – |
No | 0 (0%) | 0 (0%) | ||
CBC complete blood count, AST aspartate transaminase, ALT alanine transaminase, ALP alkaline phosphatase, GGT gamma-glutamyl transpeptidase, INR international normalized ratio, CA19-9 cancer antigen 19–9, CBD common bile duct, US ultrasonography, CT computed tomography, MRCP magnetic resonance cholangiopancreatography and IHBRD intrahepatic biliary radicle dilatation.
All patients (100%) had intrahepatic biliary radical dilatation (IHBRD) and abnormally high CBD diameter (14.17 ± 1.74 vs 14.88 ± 1.26 mm for EPLBD and EST groups respectively) because of the chronic intermittent bile outflow obstruction induced by the presence of the PAD. However, there was no significant difference between the two groups (p = 0.113).
Endoscopic management of both groups
The confounding endoscopic parameters that might impact the biliary cannulation or clearance rate were similar in both groups as shown in Table 2. There was no significant difference between the two groups regarding the site of the papillary orifice in relation to the PAD (type of the PAD per Li-Tanaka classification). Most of the cases had their papilla at the edge of the PAD (type IIa). Cannulation time, use of precut sphincterotomy, stone number, size, and shape on cholangiography were minimally different between the two groups; however, there was no significant difference between the two groups.
Table 2. Endoscopic parameters in both groups
EPLBD group (n = 24) | EST group (n = 24) | p value | ||
|---|---|---|---|---|
Site of the papillary orifice in relation to PAD | Inside (Type I) | 4 (16.67%) | 5 (20.85%) | 0.122 |
Edge (Type IIa) | 14 (58.33%) | 11 (45.83%) | ||
Outside (Type IIb) | 6 (25%) | 8 (33.33%) | ||
Cannulation time (min) | Mean ± SD | 15.38 ± 1.56 | 15.42 ± 1.56 | 0.927 |
Range | 13–20 | 12–18 | ||
Use of precut sphincterotomy | No | 20 (83.33%) | 23 (95.83%) | 0.156 |
Yes | 4 (16.67%) | 1 (4.17%) | ||
Stone number on cholangiography | Single | 14 (58.33%) | 13 (54.17%) | 0.771 |
Multiple | 10 (41.67%) | 11 (45.83%) | ||
Stone size on cholangiography | Mean ± SD | 13.25 ± 1.78 | 13.92 ± 1.32 | 0.146 |
Range | 11–18 mm | 12–18 mm | ||
10–15 mm | 18 (75%) | 19 (79.17%) | 0.731 | |
More than 15 mm | 6 (25%) | 5 (20.83%) | ||
Stone shape on cholangiography | Spherical | 16 (66.67%) | 14 (58.33%) | 0.671 |
Oblong | 7 (29.17%) | 8 (33.33%) | ||
Cubic | 1 (4.17%) | 2 (8.33%) | ||
PAD periampullary diverticulum
The primary endpoint of the current study is the single procedure, single session non-assisted large CBD stone extraction rate in the context of PAD. The overall stone extraction rate in the current study was only 77.3% (n = 34). The stone extraction rate in the EPLBD group was significantly higher (n = 21,87.5%) compared to the EST (n = 13, 54.17%) group (p value = 0.011) as shown in Table 3. The three patients with failed extraction in EPLBD had large stones with their transverse diameter larger than lower CBD.
Table 3. Stone(s) extraction rates in the two groups
EPLBD group (n = 24) | EST group (n = 24) | p value | ||
|---|---|---|---|---|
Successful stone(s) extraction | Yes | 21 (87.5%) | 13 (54.17%) | 0.011* |
No | 3 (12.5%) | 11 (45.83%) | ||
*Significantly different as p value < 0.05
The predictors of stone extraction were analyzed using univariate regression (Table 4), and it is noticeable that the used technique was the independent predictor of success in stone extraction (odds ratio: 5.92, 95% confidence interval: 1.38 to 25.30, p value = 0.009).
Table 4. Univariate regression of the parameters affecting stone extraction
Odds ratio | 95% CI | p value | |
|---|---|---|---|
The used technique | 5.92 | 1.38 to 25.30 | 0.009* |
Stone(s) number | 0.62 | 0.17 to 2.25 | 0.468 |
Stone(s) size (mm) | 2.59 | 0.63 to 10.56 | 0.187 |
Type of PAD | 1.32 | 0.65 to 2.67 | 0.437 |
*Significant as p value ≤ 0.05, PAD periampullary diverticulum
Short-term safety
This represents the second endpoint of the current study, as shown in Table 5. However, the reported complication rate should be interpreted in light of the limited sample size. Nevertheless, immediate intraoperative complications, such as bleeding and perforation, were mild. In both groups, intra-operative bleeding was minor and controllable, and there were no perforations. There was no significant difference between the two groups regarding postoperative bleeding and cholangitis. Pos-ERCP pancreatitis was reported among 7 patients (14.6%). Pos-ERCP pancreatitis was significantly higher in the EST (n = 6, 25%) group than in the EPLBD (n = 1, 4.1%) group (p value = 0.04). In all patients, pancreatitis was not severe, and all patients with pancreatitis were discharged from the hospital by the 3rd day after the procedure. There were no case fatalities in the current study.
Table 5. Adverse events in the two groups
EPLBD group (n = 24) | EST group (n = 24) | p value | ||
|---|---|---|---|---|
Intra-operative bleeding | Yes | 5 (20.83%) | 9 (37.5%) | 0.204 |
No | 19 (79.17%) | 15 (62.5%) | ||
Perforation | Yes | 0 (0%) | 0 (0%) | – |
No | 24 (100%) | 24 (100%) | ||
Post-operative bleeding | Yes | 7 (29.17%) | 6 (25%) | 0.745 |
No | 17 (70.83%) | 18 (75%) | ||
Pancreatitis | Yes | 1 (4.1%) | 6 (25%) | 0.04* |
No | 23 (95.9%) | 18 (74%) | ||
Cholangitis | Yes | 1 (4.17%) | 1 (4.17%) | 1.000 |
No | 23 (95.83%) | 23 (95.83%) | ||
*Significantly different as p value < 0.05
Discussion
Classically, ERCP associated EST followed by balloon or basket extraction is usually sufficient for removal of small stones < 1 cm in diameter. However, the presence of large and/or multiple stones necessitates the use of additional treatment modalities such as mechanical lithotripsy [15, 16].
Ersoz et al. [8] described for the first time EPLBD as an effective and safe technique in these challenging situations with the possibility to use a balloon diameter up to 20 mm following limited sphincterotomy. Since then, the cumulative data in the literature describe an effective technique; however, initial reports raised issues about procedure-related adverse events, especially bleeding and pancreatitis [17, 18–19]. EPLBD without EST has been reported to be useful for CBD clearance; however, it has a lower rate of stone extraction and a higher risk of pancreatitis but a lower risk of bleeding when compared to EST [20]. The introduction of limited sphincterotomy directs the force of dilatation toward the lower CBD and lessens the surrounding edema and hence lessens the frequency of post-ERCP pancreatitis after EPLBD. Consequently, EPLBD following limited sphincterotomy is an effective technique in the treatment of large CBD stones, and this is supported by the current practice guidelines [11, 12]. This was further reinforced in a large network meta-analysis comparing endoscopic techniques used for large CBD stone extraction by Aziz et al., who compared EST, EPLBD, and combined EST + EPLBD. Best outcome measures comprised a higher stone clearance rate, a lower need for mechanical lithotripsy, and fewer adverse events. Notably, the combined technique achieved the best balance of high efficacy and low complication probability [21].
PAD is not an uncommon endoscopic finding in patients with CBD stones [1, 10]. The presence of this anatomical abnormality and the resultant malfunction of the Oddi sphincter possibly play an important role in primary CBD stone formation [22]. PAD is a well-known risk factor for failed and difficult biliary cannulation, failed first-session stone extraction, intraoperative use of mechanical lithotripsy, and for increased intraoperative and postoperative risk of maneuver-related complications [2, 6, 10, 23]. Many studies evaluated the effectiveness and safety of EPLBD with or without limited sphincterotomy for extracting large CBD stones in the setting of PAD, and the cumulative data figured out higher rates of stone extraction without added adverse events. However, most of these studies were either large case series, retrospective in nature, or non-comparative [3, 9, 20, 24] and that is why this prospective randomized study was conducted.
The demographic (age and sex), clinical, imaging, and laboratory data at baseline were comparable in both groups, similar to earlier studies [25, 26, 27–28], comparing EPLBD to EST and hence ruling out these cofactors from affecting the final success rates of stone extraction.
The current study used the Li-Tanaka classification system to classify PAD [13] because it has clinical significance for ERCP cannulation in comparison to other classifications; it helps evaluate potentially difficult and successful cannulation cases among different types of PAD patients. In the current study, PAD falls into type 1, type 2a, and type 2b. Our results agree with Yue P et al. [13]; regarding the commonest type of PAD, they reported type 2 to be the most common, but we had higher rates of papillary cannulation (100%) for both type 1 and type 2 PAD compared to 90.8% and 99.4% reported by Yue et al., respectively, and this is directly related to the small number in our cohort (n = 48). In the current study, the distribution of PAD was not statistically significant in the two groups. Furthermore, in the univariate analysis, the PAD type did not affect the CBD stone clearance rate (p value = 0.437), similar to what was reported by Kim and Kim [24] who observed that the type of the PAD was not different between EPLBD and EST groups (p value = 0.334).
As regards cannulation time and the use of precut needle knife sphincterotomy, there was no significant difference between the two groups. These observations are similar to those of Kim and Kim [25], who stated that EPLBD with limited sphincterotomy and EST groups showed no statistically significant difference (p values = 0.571 and 0.668 respectively). These findings are directly related to the non-statistically significant difference in type of PAD among patients of the two groups.
There was no significant difference between the two groups as regards stone number, size, and shape on cholangiography. These results are in agreement with those of Kim and Kim [25] who found that stone number, size, and shape were non-statistically significantly different between EPLBD with limited sphincterotomy and EST groups (p values = 0.835, 0.252, and 0.144 respectively). Moreover, these results are in accordance with Li et al. [25], who concluded that stone number and size were statistically non-significantly different between EPLBD with limited sphincterotomy and EST groups (p values = 0.748 and 0.728 respectively).
Our results showed that EPLBD after limited sphincterotomy is superior to EST in extracting large CBD stones in the setting of PAD (87.5% vs 54.17%, p value = 0.011). These results are in agreement with Kim and Kim [25], Li et al. [26], Mohammed et al. [27], and Hwang et al. [28]. The superiority of stone extraction rates reflects the fact that large balloon dilatation is effective at removing strictures in the lower CBD either at the level of the papilla or at the level of the supra-papillary part of the CBD, making the whole CBD like a smooth regular tunnel through which the stone(s) can be easily extracted. On the other hand, complete sphincterotomy may be defective at incising through the internal part of the Oddi sphincter; a step which can be performed with intensified risk of bleeding and perforation, and the fact that complete sphincterotomy can never be used to get rid of a supra-papillary stricture made by the chronic fibrosis of the lower part of the CBD as an expected sequel in case of PAD.
The overall success rate of stone extraction in the current study (n = 34, 77.3%) is lower than the 99.4% reported by Xu et al. [29],96.4% by Ohm and Kim [23] and 94.9% by Zulli et al. [30], and this may be due to the small number of patients in the current study on one hand and non-use of assisted methods, e.g., lithotripsy, for stone extraction after failure of balloon clearance following the primary intervention on the other hand. This 77.3% one-session clearance rate should be interpreted as a single-session, single-technique success rate rather than total procedural success. In fact, this rate is lower than the figures achieved in routine clinical practice, i.e., the introduction of adjunct lithotripsy often achieves > 90% clearance, and what would be described as failure in the current study might ultimately succeed with the use of additional procedures, e.g., lithotripsy.
On regression analysis, the technique used for stone extraction was an independent predictor for the success of the CBD clearance rate (p value = 0.009). Earlier studies by Kuo et al. [31], Park et al. [32], and Aziz et al. [19] observed that the technique of intervention (either EPLBD or EST) was a predictor of success in CBD stone extraction.
Focusing on intraoperative complications, our results showed that there was minor controllable bleeding in the two groups with a non-significant statistical difference between the two groups (p value = 0.204). Furthermore, there were no perforations reported. These results are similar to those of Kim and Kim [25] and Hwang et al. [28]. Minor controllable intraoperative bleeding can be explained by the fact that large balloon dilatation may injure a vessel through traumatic stretch and the fact that sphincterotomy may injure a vessel through incision. In either condition, the injured vessel is small, and bleeding as a rule is controllable unless there is an underlying coagulation disorder. Sound endoscopic practices of the endoscopists following the practice guidelines in determining not only the diameter but also the direction and duration of the used balloons, the extension of the endoscopic sphincterotomy, and the fact that the most experienced endoscopist in each participating center carried out the intervention explain why perforations were not reported in the current study. The fact that no perforations occurred in either group is reassuring but not definitive given the incidence of ERCP-related perforation is around 0.1 to 0.55% [33], so dozens of patients are not enough to conclude the risk is zero.
Regarding postoperative complications, our results showed that there was no significant difference regarding bleeding, perforation, and cholangitis between the two groups. These findings agree with Kim and Kim [25], Hwang et al. [28], and Aziz et al. [21]. Generally speaking, postoperative cholangitis prevalence in the current study was 4.17% in both groups. This result is relatively higher compared to that of Du et al. [34], who revealed that the prevalence of post-ERCP cholangitis was 3.56% (62/1743) and documented that post-ERCP cholangitis is strongly associated not only with endoscopic interventions in the biliary system but also with any surgical intervention involving the biliary system before ERCP. This is attributed to the fact that following endoscopic or surgical interventions, minor or even major bile duct injury does occur, and this is followed by bacterial colonization in the gallbladder or the bile ducts. The infection is either blood-borne or more frequently ascending from the gut lumen after interruption of the Oddi sphincter function by either EST or EPLBD, although the sphincter function is partially preserved in EPLBD because of the limited and not generous sphincterotomy done. It is expected, in the current study, that both groups should have lower rates of cholangitis because incomplete biliary drainage is the most important predictor of this complication, and both groups should have secured drainage either through CBD clearance (77.3%) or through the insertion of stents in all cases with failed stone clearance. However, the small number of patients recruited may explain these findings.
The situation is rather different regarding post-ERCP pancreatitis; our results showed higher rates (14.6%) compared to the current literature, which cumulatively reports 3–5% rates [21, 27]. Furthermore, rates of post-ERCP pancreatitis were significantly higher in the EST (25%) group compared to the EPLBD (4.1%) group (p value = 0.04). This difference would be changed if EPLBD were performed without prior EST because EPLBD without prior sphincterotomy was linked to a higher risk of post-ERCP pancreatitis [20]. The explanation is related to the impairment of pancreatic duct flow through direct pancreatic duct injury caused by the physical stretch of the pancreatic duct orifice during balloon dilatation. The incidence of post-ERCP pancreatitis dropped among patients treated with EPLBD after the adoption of limited sphincterotomy as an initial step before dilatation; it is suggested that this limited sphincterotomy can decrease potential injury to the main pancreatic duct because it can steer the direction of balloon dilatation toward the CBD and minimize the pressure overload on the pancreatic orifice [17].
Our results are in agreement with earlier studies regarding the higher frequency of post-ERCP pancreatitis with EST compared to EPLBD. Mohammed et al. [24] found that procedure-related pancreatitis in the EPLBD group was lower compared to the EST group (3% versus 5%; p value > 0.05). Xu et al. [26] found that EST and EPLBD had 13.9% vs 8% for post-ERCP pancreatitis, p > 0.05, while Hwang et al. [28] did not report a significant difference between both groups regarding pancreatitis (p value = 0.593). Interpretation of the adverse events reported in the current study, especially the high post-ERCP pancreatitis rate, should be viewed in the setting of a small sample size and lack of formal sample size calculation based on statistical power.
We believe that our protocol’s strict standardization (no lithotripsy, liberal use of pancreatic duct stents when indicated, expert endoscopists > 400 ERCP annual rate performed the procedure) is a strength point because it maximizes safety and internal validity; however, some others can see it as a limitation because this may not reflect the real-world scenario and possibly the results would change if the procedure is performed with less experienced endoscopists without routine use of pancreatic duct stents, especially in low-volume centers. Some other points were not focused on in the analysis, and these are not limited to focusing on large CBD stones and PAD only on the occasion of benign CBD ruling out other pathologies, but also on other operator, procedure, and patient-related factors. Patient-related factors include CBD anatomy and stone composition. Operator and procedure-related factors include inter-operator variability, e.g., time to define failure; variability in the techniques of cannulation; diameters of the instruments used; how many trials of extraction balloon application before considering failure; and the diameter of the standard extraction balloon used; all these might have an impact on the results.
The results of the current study should be interpreted cautiously because of its numerous limitations. First, the small number of patients recruited. This small sample size potentially had an impact on the adverse events rate reported in the current study. Although the safety advantage of EPLBD in the context of PAD, while plausible (less cutting in friable tissue), the disparity in the occurrence of pancreatitis, lack of perforation, and slightly higher frequency of cholangitis should be cautiously reported. Also, the lack of statistical power calculation for the sample size raises the possibility that the results may differ when a larger sample size is studied. Second, the use of random allocation, although a simple method, is a potential source of selection bias. The process of randomization after successful cannulation is another potential source of selection bias. Third, deviation from the real clinical practice protocol, i.e., non-use of the assisted methods, including lithotripsy for cases of failure, can explain the low overall CBD clearance rate in the current study compared to the literature, but we aimed to investigate the safety profile of the primary technique of balloon dilatation and avoid any cofactor that might impact the results (primary endpoint). This means that the cases encountered as failures in our study would succeed with the introduction of other interventions, mainly lithotripsy, and hence higher rates of CBD stone clearance. Fourth, lack of long-term follow-up. Consequently, we cannot judge if EPLBD is superior to EST on stone recurrence, late complications like papillary stenosis, or the need for subsequent procedures. One proposed benefit of doing a large balloon dilatation is that it might achieve a more complete sphincter opening, potentially reducing the recurrence of bile duct stones. Conversely, one could speculate that preserving more sphincter (with limited cut) might increase recurrence. Furthermore, leaving a stent (in failures) could have its own implications, presumably returning for a second-stage clearance or adverse events related to the stent itself. Lastly, lack of cost-effectiveness calculation. Although cost-effectiveness is not addressed in the current study, it can be inferred that EPLBD requires a dilatation balloon and insufflator, which are additional equipment compared to EST alone, and it may prolong the procedure slightly; it might be cost-effective because it reduces the need for additional procedures like lithotripsy or the need for multiple ERCP sessions. These limitations could be solved with future studies recruiting a larger number of patients with longer follow-up and following the standard practice protocols; hence, the results of the current study should be viewed as exploratory for further confirmation with larger trials.
Conclusion
The current practice guidelines of the ESGE and ASGE suggest that for large CBD stones, an EST followed by a large balloon dilatation is preferable to EST alone because combining dilatation with EST improves duct clearance and reduces the need for lithotripsy without adding risk. These were further confirmed in many large studies and meta-analyses [16, 21, 25, 26–27, 35]. Our results among PAD patients seem to echo this: the EPLBD approach in comparison to EST yielded higher stone clearance on the first attempt even without using lithotripsy by the study design. Hence, based on the preliminary results figured out from the current study, these existing recommendations can be extrapolated to the PAD population based on our study, which is one of the first randomized trials in the specific PAD subgroup.
Acknowledgements
The authors would like to thank all colleagues who helped in running this study.
Authors’ contributions
G.A.M. supervised the study. Z.K. performed all sample collection, data analysis, figure generation, and bioinformatic analysis. Z.K. prepared the original draft of the manuscript, and G.A.M. revised the manuscript. All authors read and approved the final manuscript.
Funding
None
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
After the explanation of the procedure and its possible complications, written informed consent was obtained from all patients. The study adhered to the Declaration of Helsinki. The study was conducted according to sound clinical practice and was approved by the IRB for the Faculty of Medicine, Zagazig University, Egypt (IRB#:5694–6-11–2019).
Consent for publication
Taken from the patients, IRB committee, and all the authors
Competing interests
The authors declare no competing interests.
Abbreviations
Common bile duct
Endoscopic retrograde cholangiopancreatography
Endoscopic complete sphincterotomy
Periampullary diverticula
Endoscopic papillary large balloon dilatation
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Abstract
Background
Endoscopic papillary large balloon dilatation (EPLBD) is an effective technique in treating large common bile duct (CBD) stones. However, the efficacy and safety of EPLBD in the setting of periampullary diverticula (PAD) are prospectively lacking. This study aimed to compare the effectiveness and short-term safety of EPLBD after limited sphincterotomy with those of endoscopic sphincterotomy (EST) for extracting large CBD stones in the setting of PAD prospectively.
Methods
Forty-eight patients with large CBD stone(s) > 1 cm were recruited. All patients had a PAD. Before the procedure, patients were evaluated by history taking, clinical examination, full investigations including proper imaging studies. During the procedure, patients were randomized to either group I: patients treated with EPLBD after limited sphincterotomy, and group II: patients treated with EST. CBD clearance was defined as a single procedure (EPLBD vs EST), single session (no repeat ERCP), and non-assisted (no lithotripsy used) stone extraction. After the procedure, patients were hospitalized with clinical, laboratory, and imaging assessment.
Results
The overall stone extraction rate in the current study was only 77.3% (n = 34). The efficacy of stone extraction was significantly higher in the EPLBD (n = 21,87.5%) group compared to the EST (n = 13, 54.17%) group (p = 0.011). The procedure-related adverse events were lower in the EPLBD group compared to the EST group. Pancreatitis was significantly higher in the EST (n = 6, 25%) group than in the EPLBD (n = 1, 4.1%) group (p = 0.04). There was no significant difference between the two groups regarding postoperative bleeding and cholangitis. There were no perforations or case fatalities in either group.
Conclusion
Compared to EST, EPLBD is a more effective and safer method for extraction of large CBD stone(s) in the setting of PAD.
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Details
1 Zagazig University, Hepatology, Gastroenterology, and Infectious Diseases Department, Faculty of Medicine, Zagazig, Egypt (GRID:grid.31451.32) (ISNI:0000 0001 2158 2757)
2 Suez University, Tropical Medicine Department, Faculty of Medicine, Suez, Egypt (GRID:grid.430657.3) (ISNI:0000 0004 4699 3087)
3 Kafrelsheikh University, Hepatology, Gastroenterology, and Infectious Diseases Department, Faculty of Medicine, Kafr El-Sheikh, Egypt (GRID:grid.411978.2) (ISNI:0000 0004 0578 3577); Alyousif Hospital, Medicine Department, Alkhobar, Saudi Arabia (GRID:grid.411978.2)