Comparison of the safety profile, conversion rate and hospitalization duration between early and delayed laparoscopic cholecystectomy for acute cholecystitis: a systematic review and meta-analysis

Background Although the past decade has witnessed unprecedented medical progress, no consensus has been reached on the optimal approach for patients with acute cholecystitis. Herein, we conducted a systematic review and meta-analysis to assess the differences in patient outcomes between Early Laparoscopic Cholecystectomy (ELC) and Delayed Laparoscopic Cholecystectomy (DLC) in the treatment of acute cholecystitis. Our protocol was registered in the PROSPERO database (registration number: CRD42023389238). Objectives We sought to investigate the differences in efficacy, safety, and potential benefits between ELC and DLC in acute cholecystitis patients by conducting a systematic review and meta-analysis. Methods The online databases PubMed, Springer, and the Cochrane Library were searched for randomized controlled trials (RCTs) and retrospective studies published between Jan 1, 1999 and Jan 1, 2022. Results 21 RCTs and 13 retrospective studies with a total of 7,601 cases were included in this research. After a fixed-effects model was applied, the pooled analysis showed that DLC was associated with a significantly high conversion rate (OR: 0.6247; 95%CI: 0.5115–0.7630; z = −4.61, p < 0.0001) and incidence of postoperative complications (OR: 0.7548; 95%CI: 0.6197–0.9192; z = −2.80, p = 0.0051). However, after applying a random-effects model, ELC was associated with significantly shorter total hospitalization duration than DLC (MD: −4.0657; 95%CI: −5.0747 to −3.0566; z = −7.90, p < 0.0001). Conclusion ELC represents a safe and feasible approach for acute cholecystitis patients since it shortens hospitalization duration and decreases the incidence of postoperative complications of laparoscopic cholecystectomy. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=389238, identifier (CRD42023389238).


Introduction
Laparoscopic Cholecystectomy (LC) represents the standard of care treatment for patients requiring a cholecystectomy (1,2).Acute cholecystitis has long been considered unsuitable for immediate surgical treatment.However, with the significant progress achieved in minimally invasive technology, the number of patients undergoing early laparoscopic surgery has significantly escalated (3,4).Nevertheless, no consensus has been reached on the optimal timing for surgery.It has long been thought that the risk of intraoperative conversion to laparotomy and intraoperative or postoperative complications was increased with early laparoscopic cholecystectomy (ELC) due to gallbladder congestion and edema, severe peripheral inflammatory reaction, and undefined anatomy of the Calot triangle (5)(6)(7)(8).However, in recent years, with an improved knowledge of the etiology of the abovementioned complications and surgical method improvements, the incidence of intraoperative and postoperative complications has markedly decreased (9, 10).Compared to delayed laparoscopic cholecystectomy (DLC), ELC for acute cholecystitis reportedly decreases the operative complications and conversion rate and shortens the hospitalization duration (11-13).Nonetheless, the optimal timing for surgery remains subject to debate, emphasizing the need for further research.
Even though the superiority of ELC over DLC has been increasingly documented in the literature, most studies were based on relatively small populations (14-17).Accordingly, we comprehensively studied the current literature to determine the efficiency, safety profile, and potential benefits of ELC in contrast to DLC.

Data extraction
Literature was included in strict compliance with the PICOS principle.The target population consisted of "patients with acute cholecystitis, " the intervention was "LC, " the comparison was conducted between "ELC" and "DLC, " the outcomes consisted of "primary (conversion rate, intraoperative and postoperative complications) and secondary outcomes (Operation time, postoperative hospitalization duration and total hospitalization duration)" and the study design included "RCTs and retrospective studies." The reporting principle of this meta-analysis complied with the Preferred Reporting Items for Systematic Review and metaanalysis (PRISMA) 2020 protocol and Meta-analysis of Observational Studies in Epidemiology (MOOSE) declaration (18,19).

Method of literature-search
Our literature search was carried out in July of 2022 with no restriction to countries, type of publication or language utilized in the following electronic databases: PubMed and the Cochrane Library.The following MeSH terms and combinations were utilized to search the title, abstract and keyword sections: Early Laparoscopic Cholecystectomy OR Delay Laparoscopic Cholecystectomy AND acute cholecystitis AND complication AND timing.

Inclusion and exclusion criteria
All reports included in our study were randomized controlled trials (RCTs) or retrospective comparative studies (cohort or casecontrol studies) contrasted ELC to DLC irrespective of age, and analyzed at least one of our primary outcomes.During literature screening, the following were excluded: Animal experimental studies, case reports, letters to the editor and review articles.

Data extraction and outcomes of interest
The primary outcomes included intraoperative complication rate, postoperative complication rate and conversion rate.Intraoperative complications were common complications encountered during surgery, such as intraoperative bleeding, bile duct injury, and gallbladder perforation.In contrast, postoperative complications were defined as bleeding, wound infection, bile leakage, and so on (20,21).Conversion was defined as open cholecystectomy performed when the anatomical structure around the gallbladder was unclear, pericholecystic inflammation was severe or intraoperative bleeding could not be controlled.The secondary outcomes were operative time (min), postoperative hospitalization duration (d) and total hospitalization duration (d).Comparative indicators included at least one primary outcome and one secondary outcome.

Quality assessment and statistical methods
The Cochrane Collaboration's tool was used for assessing the risk of bias of RCTs graded as "low, " "unclear" or "high risk" (22).The Newcastle-Ottawa Scale (NOS) was employed for the quality assessment of retrospective research based on criteria categorized into three dimensions: selection, comparability, and outcomes.A total score > 5 was associated with a low risk of bias (23).
R software Version 4.1.3was used to perform the meta-analysis of included studies.For continuous data, "metacont" from "meta" package was used to pool the data, and "metabin" was used for binary data.The pooled results of continuous and binary data were compared using weighted mean difference (WMD) and Odds Ratio (OR), respectively.When I 2 < 50%, we used a fixed-effects model for pooling WMD or OR and its 95% confidence interval.Otherwise, a randomeffects model was selected.Heterogeneity among the studies was explored by using subgroup analysis and meta-regression.To assess the pooled results' stability, the "metainf " function was utilized for sensitivity analysis.Finally, Egger's test and funnel plots were used to indicate the publication bias.When Egger's value of p<0.05, the trimand-fill approach was used for funnel plot asymmetry adjustment.

Literature selection
861 studies were retrieved for a preliminary search in online databases PubMed, Springer, and Cochrane Library, according to the

Quality assessment of the included studies
The risk of bias in the included retrospective studies was evaluated using the Newcastle-Ottawa Scale based on the following domains subject selection, comparability and outcomes.The total scoring of each retrospective study was more than 5 points (Table 1).The Cochrane bias risk assessment system was employed to assess the included RCTs (Figure 2).Overall, the literature quality assessment found a low risk of bias for all included studies.

Meta-regression for investigating sources of heterogeneity
Furthermore, we analyzed the heterogeneity source using a Metaregression analysis, revealing that the operation time and location accounted for the heterogeneity among studies (z = 2.5294, 95%CI: 4.9790-39.2566,p = 0.0114), consistent with the results of subgroup analysis (Figure 7).

Discussion
Since the first laparoscopic cholecystectomy was successfully performed in the late 1980s, minimally invasive surgery has been increasingly used to treat biliary tract diseases.Nowadays, LC has become the most common surgical approach for cholecystectomy.Due to the limitations of this new technology in the early days, laparoscopic cholecystectomy was not recommended for patients who suffered from acute cholecystitis due to the severe edema, the unclear anatomic structure of the Calot triangle, the uncontrollable bleeding around the gallbladder and the degree of surgeon's experience (53)(54)(55).However, with the rapid development of laparoscopic technology and the refined understanding of intraoperative and postoperative complications of laparoscopic cholecystectomy, performing laparoscopic cholecystectomy for acute cholecystitis in the early period is no longer regarded as a contraindication (56,57).Nevertheless, little is currently known about the optimal timing.Indeed, during the initial stages of acute cholecystitis, acute inflammatory reaction and edematous connective tissues impede the dissection of Calot's triangle, contributing to reactive hyperemia and increase bleeding and bile duct injury during ELC.Accordingly, this may increase the operative time due to the severe inflammatory response in the early period of acute cholecystitis patients.Indeed, a longer operative time may increase the open surgery conversion rate and risk of biliary damage.On the other hand, patients that undergo Current strategies to solve bile leakage include (1).Evaluation of the anatomical structure of the biliary tract; (2).For relatively small leaks, an indwelling abdominal tube should be placed for adequate drainage; (3).For relatively large leaks, a biliary stent may be inserted by ERCP (62,63).Indeed, during the early stages of acute cholecystitis, gallbladder congestion, edema, brittle tissue bleeding and other factors may make laparoscopic dissection more challenging and constitute the main reason for conversion to laparotomy.Our meta-analysis found that compared with ELC, DLC was associated with a high conversion rate and high postoperative complications with a fixed-effects model.However, the total hospitalization time in ELC was significantly shorter than in DLC when a random-effects model was utilized.In order to assess the heterogeneity in this meta-analysis, subgroup analysis and metaregression were also employed, and both approaches indicated that regional factors accounted for the heterogeneity of this study.Subgroup analysis according to the operation time indicated that compared with Europe and America, a significantly longer operation time was observed for ELC patients in Asia, which suggested that acute inflammation and other factors during the early stage of acute cholecystitis were inclined to prolong the operation time in Asia (35,36).During the subgroup analysis of hospitalization duration, we found that patients that underwent DLC in America correlated with shorter hospitalization than in Asia or Europe.The longest hospitalization duration was 7.10 ± 0.50 days (14) in America, which was shorter than in Asia (15.1 ± 11.1 days) (34) and Europe (20.5 ± 11.0 days) (26).This finding may account for the heterogeneity in our meta-analysis.
To investigate the stability and reliability of our findings, a sensitivity analysis was performed by removing one study each time.No study interfered with the results of this meta-analysis, substantiating the stability and reliability of our pooled estimates (Appendix 7).To analyze the possible presence of publication bias in this meta-analysis, we conducted an Egger's test and generated funnel plots.Egger's test showed that the funnel plots of intraoperative complications and postoperative hospital stay time were asymmetric.Next, we evaluated the impact of publication bias on the results by using the trim-and-fill method.It was found that with 4 added studies on intraoperative complications and 10 on postoperative hospitalization duration, there was no significant change in OR, WMD and their corresponding p values.Our funnel plot with filled-in data which was based on the trim-and-fill approach exhibited a symmetrical distribution (Figure 8).
Several limitations found in this meta-analysis should be acknowledged.First, about one-third of the studies were retrospective studies, and the blinding method was not mentioned, which impacted the quality of included studies.Besides, studies from different locations accounted for the heterogeneity in this metaanalysis.Selecting uniform RCTs might reduce the heterogeneity, but it would increase the risk of bias.Moreover, for publication bias on intraoperative complications and postoperative hospital stay time, although the funnel plot with filled-in data based on the trim-and-fill approach exhibited a symmetrical distribution, other factors such as study design, exceeding positive results and greater weight mean difference may account for publication bias.Accordingly, more largescale, high-quality RCTs are required in the future.

Conclusion
This meta-analysis revealed that compared with DLC, ELC was associated with a lower conversion rate and incidence of postoperative complications and shorter hospitalization duration for acute cholecystitis.ELC brings significant advantages in terms of safety profile and cost-effectiveness.Nevertheless, despite our rigorous methodology, some limitations were still unavoidable.Large-scale and high-quality RCTs with long follow-ups are warranted to validate the findings of this meta-analysis.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.Funnel plots illustrated meta-analysis of primary and secondary outcomes.(A-C) represented the funnel plots of primary outcomes (A: Conversion rate; B: Intraoperative complications; C:Postoperative complications), the x-axis stood for odds ratio, while y-axis stood for standard error.(D-F) represented the funnel plots of secondary outcomes (D: Operation time; E: Postoperative hospital stay time; F: Total hospital stay time), the x-axis stood for mean difference while y-axis stood for standard error.Both funnel plots of B,D,E using trim-and-fill method, after filling studies indicated as hollow circle dots in the funnel plots, the funnel plot is basically symmetrical.

FIGURE 1 PRISMA
FIGURE 1PRISMA flowchart of literatures screening.

FIGURE 3 Forest
FIGURE 3Forest plot of primary outcomes between ELC and DLC.(A).Conversion rate; (B).Intraoperative complications; (C).Postoperative complications.Green squares represent the point estimates of the treatment effect OR, with 95% CI indicated by horizontal bars.Blue diamonds represent the summary estimate from the pooled studies with 95% CI using common fixed models.

FIGURE 4 Forest
FIGURE 4 Forest plots of secondary outcomes between ELC and DLC.(A) Operation time; (B) Postoperative hospital stay duration; (C) Total hospital stay duration.Green squares represent the point estimates of the treatment effect OR, with 95% CI indicated by horizontal bars.Blue diamonds represent the summary estimate from the pooled studies with 95% CI using random effected models.

FIGURE 5
FIGURE 5 Subgroup analysis of location factors for operation time between ELC and DLC.(A) Subgroup for American population; (B) Subgroup for Asian population; (C) Subgroup for European population.

FIGURE 6
FIGURE 6 Subgroup analysis of location factors for total hospital stay duration between ELC and DLC.(A) Subgroup for Asian population; (B) Subgroup for American population; (C) Subgroup for European population.

FIGURE 7
FIGURE 7Meta regression of operation time and total hospital stay time between ELC and DLC.The results indicated that location factor was responsible for the source of heterogeneity with statistical significance (OR = 22.1178, 95%CI: 4.979-39.2566).

TABLE 1
Quality assessment of retrospective research base on Newcastle-Ottawa Scale.

TABLE 2
The characteristics of including studies.