To our knowledge, this is the first prospective trial that aimed to identify suitable ERCP timing and the distribution of CBD stone sizes, as observed during single-stage, retrograde, endoscopic stone removal in patients with acute cholangitis and to compare differences between the mild and moderate stages of acute cholangitis that may affect treatment strategy. The most worrying issue under review in this investigation was whether direct stone extraction in mild to moderate acute cholangitis would increase complications, such as bleeding and pancreatitis. The institutional review board and ethics committee recommended that we adopt standard prevention strategies to reduce injuries, such as guidewire-based selective cannulation, long-term dilatation during EPBD, pancreas duct stenting, indomethacin use, aggressive hydration, and PPI administration.
Endoscopists skilled in ERCP can clear CBD stones successfully after EST in the early stages of mild cholangitis. However, adding EST may introduce a higher risk of unforeseen complications, such as bleeding (4–14.5%) (19, 20). Acute cholangitis seems to be an independent risk factor for post-EST bleeding (14, 21). Therefore, biliary drainage without sphincterotomy is recommended in patients with severe acute cholangitis (19). In a national, population-based study by Hung et al. (22), EPBD was the preferred method to decrease the risk of post-ERCP hemorrhage, especially in patients with liver cirrhosis or impaired renal function. Thus, we typically opt for EPBD (~ 90%) for stone removal in cases of acute cholangitis to reduce bleeding events. In this study, there was no case of post-EST bleeding (0/27; 0%), not even among the seven cases with transbiliary EST, eleven cases with fistulotomy, seven cases with limited precut EST, or the patient who received transpancreatic EST. One patient did experience mild bleeding after EPBD. The bleeding risk of EST in mild and moderate cholangitis may, therefore, be minimal and acceptable. Similarly, Ito et al. (7) associated no complications, such as pancreatitis, bleeding, or perforation, with procedures performed by experienced specialists concerning immediate EST for acute suppurative cholangitis. In our study cohort, there was an acceptable PEP complication rate (5/138; 3.6%) with the use of standard prevention strategies.
In clinical practice, the optimal timing for stone removal in moderate cholangitis varies. For example, Hui et al. (23) performed a second ERCP procedure on all patients four to eight weeks after the first operation for bile duct stone removal. In the study by Ito et al. (7), all patients underwent a second elective EST procedure one week after the first intervention for bile duct stone removal. Eto et al. (8) reported a 90% success rate for stone removal after single-stage treatment in patients with mild to moderate acute cholangitis, with an acceptable bleeding rate of 4% (2/50). However, these authors did not comment in detail on the differences in ERCP timing. In our study, among patients with acute cholangitis who were treated with early single-stage ERCP, hospitalization length declined significantly in the moderate cholangitis group (10.6 ± 6.1 vs. 18.7 ± 12.5 days; p = 0.001) and somewhat in the mild cholangitis group (10.0 ± 5.0 vs. 15.7 ± 6.8 days; p = 0.056) compared with those treated with delayed ERCP (Fig. 2). In the multivariate analysis, early ERCP was an independent factor predicting shorter hospitalization (OR, 7.689; p = 0.030).
Meanwhile, initial PTBD for acute cholangitis did not reduce the length of hospitalization. We suspect that patients with moderate cholangitis who receive early or delayed ERCP have different inflammation severity levels. In the sub-analysis of baseline characteristics of patients with moderate acute cholangitis who underwent early and delayed ERCP, respectively, there was no difference between the two groups in terms of age, renal function, albumin, WBC count, liver function, or bilirubin. However, patients with moderate cholangitis, who underwent early ERCP relative to delayed ERCP (125.5 ± 70.3 vs. 117.6 ± 93.9; p = 0.029), experienced a higher level of CRP. Therefore, it appears reasonable to suggest that the optimal timing of single-stage stone removal in both mild and moderate cholangitis is within 72 h.
On the other hand, there was a negative association between biliary drainage only (ERBD) for acute cholangitis and successful infection control as well as reduced hospital stay (OR: 0.358, p = 0.030) (Table 5). As shown in other studies addressing acute cholecystitis management, an early approach to emergency cholecystectomy within 72 h of symptom onset reduces operative time, decreases hospitalization length, is associated with fewer adverse postoperative outcomes, and reduces mortality (24–26). The circumstance might be related to the management of foreign-body infection (27): Removing debris from the site of injury reduces the bacterial load and thereby facilitates control infection. Bactibilia (the presence of bacteria in the biliary tract) increases in the presence of biliary obstruction, mainly partial obstruction, and in the presence of foreign bodies like stones (28). The most common bacteria linked to ascending cholangitis are Escherichia coli (29), Klebsiella (30), Enterobacter (31), and Enterococcus (32), which form a biofilm covering the surfaces of stones. This biofilm protects the bacteria from antibacterial agents and phagocytic leucocytes (33). Therefore, prompt removal of infected stones in cases of acute cholangitis is preferable.
The evaluation of stone size during single-stage removal in acute cholangitis is important. We determined that stones that it was not challenging to remove stones up to 1.5 cm (34), and successful stone removal (98.6–100%) was higher than when the stones were larger than 1.5 cm (success rate, 70.0–81.8%), as long as biliary cannulation was successful (Fig. 3). Thus, we recommend direct removal of stones in patients with mild and moderate cholangitis only if the stone size is 1.5 cm or smaller.
The limitations of the current study need to be acknowledged. First, this study was initially designed as a randomized controlled trial to compare single-stage and two-stage ERCP-based stone removal (biliary drainage first and bile stone removal one week later) in patients with moderate acute cholangitis. However, most patients refused to undergo two-stage ERCP because of the need for more than one session. Therefore, we altered the trial design to a prospective trial of single-stage ERCP in patients with mild and moderate cholangitis. The results indicated that treatment by biliary drainage only (ERBD) in acute cholangitis (OR: 0.358, p = 0.030) was negatively associated with a shorter hospital stay. Second, although limited EST plus endoscopic papillary large-balloon dilation to remove large bile duct stones (> 1.5 cm) was associated with a high success rate (98.3%) in our previous study (35), a single-stage treatment for larger stones (> 1.5 cm) in patients with moderate cholangitis might be more complicated. More research is required to assess the benefits and risks. Definitive treatment with removal of large stones is still recommended, but only after the patient's general condition becomes stable per the established guidelines.