AIM: To assess systematically the safety and efficacy of bile leakage test in liver resection.

METHODS: Randomized controlled trials and controlled clinical trials involving the bile leakage test were included in a systematic literature search. Two authors independently assessed the studies for inclusion and extracted the data. A meta-analysis was conducted to estimate postoperative bile leakage, intraoperative positive bile leakage, and complications. We used either the fixed-effects or random-effects model.

RESULTS: Eight studies involving a total of 1253 patients were included and they all involved the bile leakage test in liver resection. The bile leakage test group was associated with a significant reduction in bile leakage compared with the non-bile leakage test group (RR = 0.39, 95%CI: 0.23-0.67; I² = 3%). The white test had superiority for detection of intraoperative bile leakage compared with the saline solution test (RR = 2.38, 95%CI: 1.24-4.56, P = 0.009). No significant intergroup differences were observed in total number of complications, ileus, liver failure, intraperitoneal hemorrhage, pulmonary disorder, abdominal infection, and wound infection.

CONCLUSION: The bile leakage test reduced postoperative bile leakage and did not increase incidence of complications. Fat emulsion is the best choice of solution for the test.

With the refinement of surgical techniques and perioperative care in liver surgery, the postoperative morbidity and mortality have markedly decreased. However, the incidence of bile leakage has not changed over the past few decades, ranging from 4.0% to 9.8% in recent studies[1-7]. Biliary complications remain a common cause of major morbidity after hepatic resection[1]. The presence of bile in the peritoneal cavity may impair the normal host defense mechanisms and predispose to the development of sepsis, liver failure and mortality[2,3]. Therefore, many methods have been introduced to prevent bile leakage after liver transection, including intraoperative cholangiography[8], spreading fibrin glue on the transected liver surface[9], assessing bile duct patency by injecting air under ultrasonographic monitoring[10], and the bile leakage test. The latter is a common approach to reduce postoperative bile leakage[11]. With this technique, after cholecystectomy and liver parenchymatous division, a catheter is inserted through the cystic duct into the common bile duct and the distal common bile duct is occluded. A solution, such as isotonic sodium, fat emulsion, indocyanine green or methylene blue, is slowly injected into the biliary tree and a clinical judgment is then made as to whether a bile leak is present on the transected surface of the liver. If so, the bile leakage site will be closed steadily beforehand[11]. Using this technique, some studies[2,11-14] have identified intraoperatively additional potential bile leakage points in 19.7%-80.8% of the patients. The bile leakage test proved to be useful for preventing postoperative bile leakage in several studies, however, other studies suggested no advantage in using the bile leakage test. Moreover, the additional operation associated with the test may also result in a risk of postoperative complications. Some studies have suggested excessive bile duct pressure from the bile leakage test could cause cholangiovenous reflux and cholangitis[15,16].

Many randomized controlled trials (RCTs) and controlled clinical trials have evaluated the feasibility, safety and efficacy of the bile leakage test, however, the clinical significance of this technique remains inconsistent. To date, we have been unable to identify any meta-analysis that assessed the role of the bile leakage test. We conducted a systematic review and meta-analysis to evaluate the safety and efficacy of the test in liver resection.

We conducted the meta-analysis and systematic review according to the Cochrane Handbook for Systematic Reviews of Interventions[17] and preferred reporting items for systematic reviews and meta-analysis[18].

Bile leakage is a common complication after hepatic resection and seriously affects postoperative quality of life, and also causes intra-abdominal infection and liver failure[13]. During the operation, it is difficult for surgeons to identify bile leakage by traditional methods such as the gauze test. Technical diligence in liver resection is required intraoperatively to minimize bile leakage. The bile leakage test is considered to be an effective method to prevent intraoperative bile leakage. The aim of the bile leakage test is to detect insufficiently closed stumps of bile ducts on the transected liver surface by elevating biliary pressure[24] and then the leakage site is sutured.

We conducted a systematic review and meta-analysis and eight trials including three aspects of the bile leakage test were included. In the bile leakage test group vs non-bile leakage test group, studies involving the bile leakage test drew different conclusions. Three studies[2,12,13] showed that the bile leakage test decreased postoperative bile leakage, whereas two studies[11,24] showed no significant difference. Our meta-analysis showed that the bile leakage test group had a lower incidence of bile leakage than the non-bile leakage test group. Moreover, there was no significant difference in complications between the two groups. This suggests an effective and safe method for prevention of postoperative bile leakage. In the ICGF test group, ICG was injected into the biliary duct and then bound with proteins in bile[28]. The ICG-bile mixture can evoke fluorescent images that are obtained using an infrared camera system. Bile leakage can be easily detected by the extra-biliary fluorescent signal[25,27]. Meta-analysis found no difference in bile leakage rate and postoperative complications. Only one self-controlled study[26] compared the white test with the saline solution test and only positive rate of the intraoperative bile leakage test could be used for analysis. Meta-analysis found that the white test was superior for the detection of bile leakage compared with the saline solution test. However, the limitations of the number of trials (only one) may have affected our results and interpretation. Therefore, our results showed that the bile leakage test reduced postoperative biliary leakage, and considering the solution used in the test, fat emulsion may be more effective than saline solution.

To perform the bile leakage test, incidental cholecystectomy and cystic duct exploration are always necessary. One meta-analysis[29] reported increased morbidity in patients undergoing incidental cholecystectomy. However, in our meta-analysis, total complications, wound infection, ileus, liver insufficiency, intraperitoneal hemorrhage, pulmonary disorder, and hepatic failure showed no significant difference. The detection of bile leakage depends on elevated pressure by injecting solution into the biliary tract, however, excessive bile duct pressure could lead to regurgitation of bacteria and induce cholangitis and abdominal infection[15,16]. Although abdominal infection did occur in some trials, our meta-analysis showed that the bile leakage test did not increase the risk of abdominal infection. Therefore, the bile leakage test is a safe technique and does not cause additional complications.

In all the included studies, the bile leakage test detected leakage in an average of 39.3% patients (range, 19.7%-80.8%). After prophylactic closure of the leaking bile duct stump, bile leakage occurred in only an average of 3.42% of patients, which was significantly lower than before. This suggests that the bile leakage test can reduce bile leakage in liver resection, but it does not completely eliminate it. Several reasons could explain this. First, we need to consider the lack of refinement of surgical techniques. For example, the pressure on the bile duct was not high enough so that bile leakage was not observed during the operation. Inadequate suturing of the defect[2] also could lead to bile leakage. Second, minor bile ducts in the wound surface of the liver were obstructed by microliths, and the bile leakage was formed when the microliths dropped off after the operation[13]. Third, there were defects in the technique of the bile leakage test. Parts of the leaky bile ducts were not in communication with the biliary tree, therefore, the leakage sites could not be identified through the use of an intraoperative bile leakage test[13]. Moreover, solutions such as ICG and methylene blue have the drawback of staining surrounding tissues, and saline solution has poor sensitivity. These drawbacks make precise localization or identification of multiple sites of leakage difficult[12]. However, the white fat emulsion can be easily washed out from the bile ducts[26] and it does not contaminate the surface of the wound, and it can be used repeatedly in tests. This may be the reason why the white test can decrease bile leakage more than the saline solution test can.

However, some patients without the bile leakage test did not develop bile leakage, for the following reasons. First, partial minor leakage points can be closed spontaneously. Second, bile leakage from small biliary stumps with some communication to the main biliary tree would usually close spontaneously, with the restoration of peristalsis and papillary function[11]. Thus, the bile leakage test could not completely eliminate bile leakage, but just decrease it.

This review had some limitations. The first concerns the small number of RCTs included, and we also included non-randomized trials. Second, incomplete reporting of important methodological issues, such as randomization process and blinding assessment of trial quality, raises doubts about the adequate power of these studies. Third, the heterogeneity of the patients in the included trials may have influenced the conclusions because some trials included liver tumor patients and only one study included living donors. To overcome these limitations, more RCTs should be conducted with large numbers of patients to achieve a sufficient level of statistical power for accurate evaluation of the bile leakage test.

In conclusion, this review provides the best available evidence for the safety and efficacy of the bile leakage test. On the basis of this evidence, the bile leakage test appears to reduce the incidence of postoperative bile leakage and does not increase the incidence of other complications. In addition, fat emulsion may be the best choice of solution for use in the bile leakage test. Further trials are required to assess the role of the bile leakage test in liver resection patients.