Laparoscopic versus Conventional Surgery for Acute Cholangitis of Severe Type: A Systematic Review of Randomized Controlled Trials

Objective Currently, the choice between laparoscopic surgery and conventional laparotomy in the surgical treatment of acute cholangitis of severe type (ACST) is debatable. This study compared the clinical efficacy of these two surgical methods through a meta-analysis based on relevant clinical randomized controlled trials (RCT) on ACST. Methods We systematically searched several databases (PubMed, Web of Science, Embase, China National Knowledge Infrastructure, and WangFang) for RCT on the surgical treatment of ACST between 2010 and 2022. Relevant data were extracted, and a meta-analysis was performed using the statistical software Stata 16.0. Results From initial 1089 studies retrieved, 15 studies (n = 1247 patients) were eligible. The total number of patients was 1247, of whom 635 were classified in the treatment group (laparoscopic surgery) and 612 patients in the control group (conventional laparotomy). This meta-analysis showed that compared with conventional laparotomy, laparoscopic surgery was associated with higher effective rate (OR = 3.808, 95% CI [2.383, 6.085], P < 0.001), lower incidence rate of complications (OR = 0.192, 95% CI [0.139, 0.265], P < 0.001), shorter operation duration (SMD = −3.274, 95% CI [-4.503, -2.045], P < 0.001), and shorter postoperative hospital stay (SMD = −2.432, 95% CI [-2.988, -1.877], P < 0.001). Further, the indicators of symptomatic relief (anus exhaust time, jaundice relief time, gastrointestinal function recovery time, and abdominal pain relief time) and inflammatory levels (white blood cell count, alanine aminotransferase, total bilirubin level, and high-sensitivity C-reactive protein level) in the treatment group were better than those in the control group. Conclusion Laparoscopic surgery was associated with significant improvement in treatment efficiency, reduced risk of complications, and better treatment outcomes in patients with ACST.


Introduction
Acute cholangitis (AC) is defined as acute suppurative inflammation caused by ascending bacterial infections of the biliary tract. Specifically, biliary stones can induce sudden biliary obstruction, leading to cholestasis, elevated pressure, and infection in the biliary tract and ultimately reflux of bacteria into the blood [1]. AC is characterized by an acute onset, rapid progression, and high mortality rate [2]. According to the Tokyo Guidelines (TG13/18) for severity grading [3], AC combined with the presence of cardiovascular, neurological, respiratory, hematologic, renal, or hepatic dysfunction could be classified as AC of severe type (ACST).
Moderate AC is diagnosed when two of the following symptoms are present: abnormal white blood cell count (WBC), high fever, age ≥ 75 years old, hyperbilirubinemia, and hypoalbuminemia. ACST, also known as acute obstructive suppurative cholangitis (AOSC), is the most severe among different grades. It can progress rapidly and can have a high mortality rate unless timely treatment is provided [4]. Currently, the surgical maneuver for biliary surgery of ASCT remains challenging.
The 2018 Tokyo Guidelines (TG18) [5], interpreted by Hu et al., recommend that moderate to severe AC should be treated with urgent biliary drainage (BD), in addition to antibiotics, to relieve biliary hypertension caused by biliary obstruction and to avoid the entry of bacteria and toxins into the bloodstream, which could otherwise result in inflammatory cascades. Additionally, bile duct stones causing cholangitis must be removed after the improvement of the patient's condition. Clinically, safe biliary decompression can safely follow within 24 hours of antibiotic use, adequate resuscitation, and stabilization of organ function [6]. Early surgical treatment has been shown to reduce fatalities [7]. BD was previously performed surgically but has also been associated with a high mortality rate due to large trauma and high requirement for postoperative nursing. In recent years, with the advancement of endoscopic technology, endoscopic BD, including percutaneous transhepatic cholangial drainage (PTCD), endoscopic sphincterotomy (EST), and endoscopic nasobiliary drainage (ENBD), are currently the recommended types of surgery for treating ACST. ENBD and PTCD can be performed laparoscopically at the same time. The combination of duodenoscopy, laparoscopy, and choledochoscopy has been shown to reduce trauma and surgical procedures, thereby facilitating postoperative recovery and achieving better clinical results in elderly ACST patients [8,9]. However, some studies have revealed that EST combined with ENBD could also result in bleeding, acute pancreatitis, and even perforation, and the operation and proficiency of surgeons are highly demanded [10]. Thus, the choice of surgical methods for treating ACST remains debatable.
In this study, we systematically retrieved relevant randomized controlled trials (RCTs) comparing conventional surgery versus laparoscopic treatment for ACST and performed a meta-analysis to evaluate their therapeutic effects and associated posttreatment levels of inflammatory-related markers. We hope that these findings could provide evidence and guidance for the surgical management of ACST.

Materials and Methods
2.1. Search Strategy. PubMed, Web of Science, Embase, China National Knowledge Infrastructure, and WangFang databases were searched to identify randomized controlled trials (RCTs) comparing conventional surgery versus laparoscopic treatment for ACST from 2010 to 2022. The keywords used included "acute cholangitis of severe type" AND "laparoscopic surgery" OR "surgery".   Computational and Mathematical Methods in Medicine according to the guidelines for diagnosis and treatment of acute biliary tract infections (2021) [11]; (3) intervention measures: treatment group consisted of laparoscopic surgery, while the control group consisted of traditional laparotomy; and (4) outcome measures: at least with any one of the following parameters: effective rate, incidence rate of complications, duration of surgery, postoperative hospital stay, time to symptomatic recovery (i.e., anal exhaust, jaundice relief, gastrointestinal function recovery, abdominal pain relief), and inflammatory factor levels (WBC, alanine aminotransferase (ALT), total bilirubin (Tbil), and highsensitivity C-reactive protein (hs-CRP)).

Inclusion and Exclusion
The study exclusion criteria were as follows: (1) study design or intervention measures inconsistent with the topic of this meta-analysis; (2) original studies failed to provide relevant data required for this meta-analysis; (3) duplicate literature; and (4) literature with ambiguous diagnostic criteria or outcome measures.

Literature
Screening and Data Extraction. The literature titles retrieved were imported into the Endnote 7.0 software to eliminate repeated ones. Then, two investigators independently screened the literature to extract the data and evaluate the quality of the retrieved literature in strict accordance (2) incidence of complications after treatment; (3) operation duration; (4) hospital stay after treatment; (5) anal exhaust time after treatment; (6) jaundice relief time after treatment; (7) recovery time of gastrointestinal function after treatment; (8) duration of abdominal pain relief after treatment; (9) white blood cell count after treatment; (10) alanine aminotransferase level after treatment; (11) total bilirubin level after treatment; and (12) high-sensitive C-reactive protein level after treatment.

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with the inclusion and exclusion criteria. In case of any dispute, a third investigator was consulted for consensus. The data extracted mainly included the following: title, name of the first author, study design, intervention measures, patient baseline data, eradication rate of Hp, and incidence of adverse events. The risk of bias of the included articles was evaluated using the assessment tool recommended in Cochrane Handbook 5.1.0.

Statistical
Analysis. The Stata 16.0 statistical software was used for meta-analysis. Odds ratio (OR) and corresponding 95% confidence interval (CI) were used to express enumeration data, while continuous variables were expressed as standardized mean difference (SMD) and 95% confidence interval (CI). Heterogeneity among the results of each study was assessed using the chi-square test and I 2 statics. The fixed effects model was applied for comparisons without statistical heterogeneity among the studies (P > 0:05 and I 2 ≤ 50%); otherwise, the random effects model was used for analysis. P < 0:05 was considered statistically significant.

Meta-Analysis Results of Response Rate and Incidence of Complication after Treatment.
Twelve studies compared the treatment response rate after surgery in patients with ACST, and 15 studies reported the incidence of complications after treatment. There was no significant heterogeneity among the studies (treatment response rate: I 2 = 0:0%, P = 0:958; incidence rate of complications: I 2 = 0:0%, P = 0:869), and the fixed effects model was taken for analysis.
Further, sensitivity analysis was performed for the effective and incidence rates of complications (Figures 4(a) and 4(b)). The results were consistent with the P value, I 2 value, and OR of the original meta-analysis results, showing no significant difference and indicating good stability of the metaanalysis results. Subsequently, publication bias analysis was performed, and an asymmetric distribution was observed in the funnel plots (Figures 4(c) and 4(d)). Such distribution indicated that the included studies had a certain level of publication bias, which could be related to the small sample size of some studies or the low quality of the included literature.

Meta-Analysis Results of Duration of Surgery and
Postoperative Hospital Stay. Nine articles compared the duration of surgery, and 13 studies compared the postoperative hospital stay between the two groups. The random effects model was used to combine the effect sizes (operation duration: I 2 = 97:4%, P < 0:001; postoperative hospital stay: I 2 = 92:1%, P < 0:001). The results showed that compared with laparotomy, laparoscopic surgery was associated with shorter operation duration (SMD = −3:274,        Figure 5(b)). Sensitivity analysis was performed to identify the source of heterogeneity, and the random effects model was used for analysis. The results were consistent with the P value, I 2 value, and OR of the original meta-analysis results, showing no significant difference and indicating good stability of the meta-analysis results (Figures 5(c) and 5(d)). Further, sensitivity analysis was performed. The results were consistent with the P value, I 2 value, and OR of the original meta-analysis results, showing no significant difference and indicating good stability of the meta-analysis results (Figures 6(e)-6(h)).

Meta-Analysis Results of Inflammatory Factor
Indicators. Four RCTs reported on WBC and ALT levels, and Tbil and hs-CRP levels were mentioned in five studies. Compared with the control group, laparoscopic surgery was associated with lower postoperative levels of WBC (SMD = −0:943, 95% CI [-1.366, -0.521], P < 0:001; Figure 7

Discussion
Biliary obstruction caused by intrahepatic and extrahepatic bile duct stones, biliary stricture, or biliary ascariasis can result in hypertension and infection of the biliary tract infection, ultimately leading to bile reflux and bacteria into the blood and ACST [27]. Therefore, relieving obstruction via surgical biliary decompression and drainage is necessary to avoid further systemic organ injury and improve treatment outcomes [28]. Laparoscopic surgery was introduced in the treatment of biliary tract diseases because of its small incisions and good prognosis. Additionally, the surgical procedures are fewer, and the duration of surgery is shorter in laparoscopic surgery compared with laparotomy. A multicenter retrospective study by Sugiura et al. [29] observed that the probability of dysfunction in malignant hilar biliary obstruction using ENBD was 26.5%. Theoretically, laparoscopic surgery for ACST has shown good efficacy, but there is a lack of effective evidence, so exploring the actual effects of laparoscopic surgery for ACST could guide physicians to better plan surgical treatment.
This meta-analysis included 15 studies with a total of 1247 patients. According to the results, for patients with ASCT, laparoscopic surgery was associated with a higher effective rate, lower incidence of complications, and better performance of symptom relief and inflammation after treatment. These findings are consistent with the results of Hu, wherein endoscopic surgery was found to be significantly better than laparotomy in terms of abdominal pain disappearance time, off-bed activity time, incidence of complications, and hospital stay [30]. Traditional surgical treatment is invasive, needs more time to complete and longer recovery time, and could affect the recovery of patients, especially elderly and frail patients who have a poor tolerance to surgery due to diminished physiological function, and could thus lead to a higher risk of complications. With developments in endoscopic technology and minimally invasive surgeries, lesser invasive surgical strategies have the advantages of less trauma, quick recovery, and improved treatment outcomes [31,32].
Clinically, WBC, CRP, and Tbil levels and imaging findings are usually used as diagnostic and prognostic evaluations for AC [33]. The results of this study showed that WBC, Tbil, hs-CRP, and ALT levels in patients with ACST treated with laparoscopic surgery were markedly improved than those in those treated with traditional laparotomy. Our results concur with those of Li et al. [34], in which laparoscopic surgery was shown to be more conducive to postoperative inflammatory recovery in acute and severe cases than laparotomy, suggesting that the former could indeed reduce the risk of toxins entering the blood circulation and the spread of inflammation.

Conclusion
Compared with traditional laparotomy, laparoscopic surgery demonstrated good clinical efficacy in patients with ACST. Laparoscopy was associated with lesser trauma and faster recovery. Specifically, laparoscopic surgery had the advantages of shorter operation duration, lower incidence of complications, less postoperative inflammatory response, and shorter hospital stay. Thus, laparoscopy could be considered a safe and effective treatment method for patients with ACST, providing the theoretical basis to guide surgeons in making clinical decisions on the surgical management of these patients. 19 Computational and Mathematical Methods in Medicine