Author Affiliations: Department of General and Liver Transplant Surgery, Montpellier University Hospital, College of Medicine, 80 Avenue Augustin Fliche 34295, Montpellier-Cedex 5, France (Panaro F, Hacina L, Bouyabrine H, Al-Hashmi A, Herrero A and Navarro F)

 

Corresponding Author: Fabrizio Panaro, MD, PhD, Department of Surgery, Division of Transplantation, Montpellier University Hospital, College of Medicine, 80 Avenue Augustin Fliche 34295, Montpellier-Cedex 5, France (Tel: +33-0467336733; Fax: +33-0467337623; Email: f-panaro@chu-montpellier.fr)

 

© 2016, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(15)60424-6

Published online September 17, 2015.

 

 

Contributors: PF and HL proposed the study. PF, HL, AA and HA wrote the first draft. PF, HL and BH collected the data. PF, HL, AA and NF contributed to the design and interpretation of the study and to further drafts. PF and HL contributed equally to this article. NF is the guarantor.

Funding: None.

Ethical approval: This study was approved by the Ethics Committee of the Montpellier University Hospital School of Medicine (2014-0041).

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: The primary focus of the study was to analyze the risk factors for bile leakage after hepatectomy for benign or malignant tumors.

 

METHODS: A total of 411 patients who had undergone hepatectomy between December 2006 and December 2011 were retrospectively analyzed. The severity of bile leakage was graded according to the ISGLS classification. Twenty-eight pre- and postoperative parameters were analyzed.

 

RESULTS: The overall bile leakage incidence was 10.2% (42/411). The severity of the leakage was classified according to the ISGLS classification. Bile leakage was detected early in case of abdominal drainage (11.4% vs 1.9%, P=0.034). It prolonged the time of hospitalization (16 vs 9 days, P=0.001). In all patients, wedge resection was associated with a higher incidence of bile leakage in contrast to anatomical resections (25.6% vs 4.1%, P<0.0001) regardless of the underlying liver disease. Furthermore, total vascular exclusion increased risk of bile leakage (P=0.008).

 

CONCLUSIONS: Bile leakage as a major issue after hepatic resection is related to the postoperative morbidity and the hospitalization time. It is associated with non-anatomical resection and a total vascular exclusion.

 

KEY WORDS: liver resection; bile leakage; wedge; total vascular exclusion

Bile leakage is a common complication of liver resection.^[1-3] Despite recent technological advances in hepatobiliary surgery, the constant incidence of bile leakage ranges from 2.6% to 15%.^[1-5] There are many factors relating to the increased risk of bile leakage such as preoperative bile leakage, type of resection (anatomical/non-anatomical), segmentectomy of the posterior liver segments (VII-VIII) or segment I, duration of hepatic pedicle clamping, blood loss, types of surgical instruments, parenchyma texture, and chemotherapy toxicity.^[5-10] Moreover, with an increased survival rate of patients undergoing hepatic resection for cancer because of the use of new chemotherapy agents, the patients often undergo a repeat hepatectomy, that increases the risk of bile leakage. The aim of the present study was to identify the risk factors relating to the occurrence of bile leakage in patients undergoing hepatectomy.

 

 

Bile leakage was defined as the bilirubin concentration in the drain fluid being at least 3 times higher than the serum bilirubin concentration on or after postoperative day 3 or as the need for radiologic or operative intervention resulting from biliary collections or bile peritonitis. Using this criterion, we classified the severity of bile leakage according to its impact on patients’ clinical management. Grade A bile leakage causes no change in patients’ clinical management. Grade B bile leakage requires active therapeutic intervention but is manageable without re-laparotomy, whereas in grade C, bile leakage re-laparotomy is required.^[1]

 

Anatomic hepatectomy: if the line of resection follows the limits of one or more functional segments of the liver as defined by the Couinaud classification.^{[4, 8]} Non-anatomic (wedge) hepatectomy: if the line of resection does not follow the limits of one or more functional segments of the liver as defined by the Couinaud classification.^{[4, 8]} Major hepatectomy is defined as the resection of at least three segments of the liver.^{[4, 8-10]}

 

After approval from the Institutional Review Board of Montpellier University Hospital, retrospectively collected clinico-pathological data of 411 liver resections performed in our institution between December 2006 and December 2011 were reviewed.

 

All the consecutive patients who had undergone hepatectomy were included, except for those who had undergone liver biopsy, biliary surgery, fenestration or resection of benign cyst, hepatic resection associated with hepatico-jejunostomy and liver transplantation.

 

The demographic characteristics of the patients were identified. The operative indications were collected and classified as benign tumor, hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma, colorectal and non-colorectal liver metastasis, and other primary malignant tumors. The surgical technique, the type of hepatectomy (minor, major, anatomical, non-anatomical), the surgical devices utilized for liver transection, the type and duration of vascular clamping, the hemostatic agent used, and the type and length of drainage were also recorded. The medical records of these patients were retrospectively analyzed for bile leakage-related factors [presentation, length, quantity, quality, management (medical, surgical, endoscopic and/or radiological), complications (fever, pain, abscess, sepsis, pleural effusion) and recurrence]. The length of hospitalization and the mortality rate were collected.

 

Routinely, we did not perform magnetic resonance imaging (MRI) preoperatively for the biliary tree. However, in case of cholestasis (increase of gamma glutamyl transpeptidase, alkaline phosphatase, and total bilirubin serum level) or biliary abnormalities (dilated biliary tree at ultrasound or computed tomography), an MRI was performed.

 

Intraoperative ultrasound was routinely performed in order to detect the lesions described in the preoperative imaging and analyze their contiguity with the vascular structures. During the resection, the hepatic pedicle control was routinely performed. The pedicle clamping was complete in 27.3% of the patients, and selective (right/left) in 4.9%. In only 2.7% of the patients, we performed a complete vascular exclusion of the liver (segment I hypertrophy, giant lesions). The pedicle clamping was intermittent in all patients. The clamping time ranged from 10 to 60 minutes according to the type of resection, the state of underlying liver parenchyma and the instrument utilized for the resection.

 

During the study period, four senior surgeons performed 411 liver resections (excluding resection of Klatskin tumors and hepatectomy associated with biliary or pancreatic resection). The devices used for liver resection were different according to the practice of surgeons. Hemostasis and bile control were performed by ligation with no absorbable suture (polypropylene 4/0 and 5/0), and/or metal clips. The trans-cystic methylene blue test and/or a trans-cystic cholangiography after surgery were not systematically performed except in case of doubt about a bile duct injury or anatomic abnormalities. A withe lap test was applied for a few minutes on the cut surface of liver resection, to detect biliary leakage in all patients. The hemostatic agents were not applied routinely on the liver transection surface after surgery. A passive drainage is placed close to the cut surface of the liver at the end of the operation. This drain was left in place, on average, 3 to 5 days except in case of complication.

 

Parametric and nonparametric data were expressed as mean±standard deviation and median (range), respectively. Primary endpoints included patient survival. Statistical analysis was performed according to the Kaplan-Meier method and resulting curves were compared using the log-rank test. Univariate analysis was performed to identify factors associated with the incidence of bile leakage. A multivariate logistic regression analysis was performed, including variables associated with the occurrence of bile leakage with a P value less than 0.20. A difference was considered statistically significant when a P value less than 0.05. All statistical analyses were performed using the SPSS® statistical package (SAS Institute, Cary, NC, USA).

 

 

The cohort consisted of 411 patients including 240 (58.4%) males and 171 (41.6%) females. The median age was 60 years (range 18-84 years). Hepatectomy was indicated for benign liver tumor (adenoma, focal nodular hyperplasia, hemangioma, hydatid cyst, cystadenoma) in 98 (23.8%) patients, for HCC in 136 (33.1%) patients, for intrahepatic cholangiocarcinoma in 20 (4.9%) patients, for colorectal and non-colorectal liver metastasis in 154 (37.5%) patients and for other rare primary malignant tumor (sarcoma) in 3 (0.7%) patients. The underlying liver parenchyma was histologically normal in 115 patients ��28.0%) who received neoadjuvant chemotherapy, normal in 156 patients (38.0%) without chemotherapy, steato-hepatitis or sinusoidal obstructive syndrome in 9.2% (n=38) of the patients and cirrhotic in 24.8% (n=102) of the patients. Of the 153 patients that received neoadjuvant chemotherapy, 99 (64.7%) also received bevacizumab as anti-cancer drug. These data are summarized in Table 1.

 

Hepatectomies were performed by a laparotomy (subcostal, median) in 86.9% (n=357) of the patients and by a laparoscopic approach in 13.1% (n=54) of the patients. Liver resections were minor (one or two segments) in 63.3% (n=260) of the patients and major (beyond three segments) in 36.7% (n=151) of the patients. The surgical devices utilized for hepatic transection included an ultrasonic surgical aspirator Cavitron® CUSA (Dissectron®, Integra NeuroSciences Limited Newbury Road Andover - Hampshire SP10 DR, UK) in 39.4% (n=162) of the patients, the bipolar sealer (TissueLink® or Aquamantys®, Medtronic, Minneapolis, MN, 55432-5604, USA) in 24.1% (n=99) of the patients, and vessels sealing instruments (LigaSure®, Covidien, Medtronic, MN, Minnesota, 55432-5604, USA; or Ultracsion® Harmonic scalpel, Ethicon US, LLC) in 32.1% (n=132) of the patients, and crush clamping in the remnants 4.4% (n=18). Parenchymal resection and hemostasis were performed according to the surgeons’ preference and technique. Approximately 42.3% (n=174) of the patients received ligatures and titanium clips or polypropylene 5/0 and 4/0 ligature only, 38.2% (n=157) received, in addition to ligatures, hemostatic collagen sponge soaked with thrombin and human fibrinogen, 16.1% (n=66) of the patients received other hemostatic agents and 3.4% (n=14) received biological glue (Table 2).

 

In total, 268 (65.2%) patients did not require vascular clamping during hepatectomy, but 112 (27.3%) had a complete pedicle clamping, 20 (4.9%) had a selective clamping and 11 (2.7 %) had a total vascular exclusion (TVE). The length of clamping was less than 20 minutes in 84 (58.7%) of the 143 clamped patients. Passive drainage in contact with the liver surface was utilized in 359 (87.3%) of the patients and the duration of drainage was less than 5 days in 287 (80.0%) of the patients. The median length of hospitalization was 10 days (range 1-66 days).

 

Bile leakage was seen in 42 (10.2%) of the 411 patients within 30 days postoperatively. Nine (21.4%) patients were classified as grade A, 27 (64.3%) as grade B and 6 (14.3%) as grade C. Bile leakage was diagnosed by the presence of bile into the abdominal drain in 19 (45.2%) patients, and the presence of intra-abdominal collection containing bile in 22 (52.4%) of the patients (Table 3). The median time to onset of bile leakage was 5 days after surgery (range 2-21 days). In the group of atypical hepatic resections (n=117), bile leakage occurred in 30 (25.6%) of the patients vs 12 (4.1%) of the 294 in patients undergoing anatomic resection (P<0.0001). Among the various intra-operative types of vascular controls (selective, hepatic pedicle, TVE), univariate analysis revealed a predominance of bile leakage in case of TVE clamping (P=0.008) (Tables 4, 5).

 

The postoperative mortality (within 30 days) of the patients was 3.6% (n=15), including only 1 patient with bile leakage. The patient died of liver failure secondary to a cirrhosis decompensation. The length of hospitalization was longer in patients with bile leakage (median 16 days) than that in patients without bile leakage (median 9 days) (P<0.001). The management of bile leakage was purely medical in 9 (21.4%, grade A) of the 42 patients. Three patients (7.1%, grade B) required endoscopic treatment(two sphincterotomies and one biliary stent placement associated with sphincterotomy), 24 (57.1%, grade B) required treatment by radiological means (22 underwent single percutaneous drainage and two internal-external biliary drainage), and 6 (14.3%, grade C) required surgical intervention to optimize drainage of the bile.

 

The factors relating to bile leakage are summarized in Table 5. In the 117 patients with non-anatomical hepatectomies, 30 experienced bile leakage but in 294 patients who underwent anatomical resection, 12 had bile leakage (P<0.0001). Univariate analysis showed a predominance of bile leakage after use of TVE (P=0.008). Other factors such as the quality of the underlying liver (normal, steatosis, chemotherapy toxicity and cirrhosis), pathology (benign or malignant tumor), devices utilized for parenchymotomy, and minor or major hepatectomy showed no significant difference in occurrence of bile leakage after hepatic resection. Surgical re-intervention was required in 14.3% of the patients with bile leakage (6/42).

 

In case of bile leakage refractory to conservative medical treatment (9 patients, 21.4%) sphincterotomy/endoprothesis was performed in 3 (7.1%) patients, alternatively a radiologic procedure (internal/external drainage) was performed in 24 (57.1%) patients. In our series, radiological treatment was often prescribed because of the high volume of fluid collection (biloma). Laparotomy was done in 6 (14.3%) patients because of the radiological inefficacity.

 

 

The results of this study suggest that non-anatomical hepatic resections and TVE are associated with the increased rate of bile leakage after hepatectomy and therefore a longer hospitalization time.

 

In our patients, the incidence of bile leakage after hepatic resection was 10.2%, and it is comparable to that reported previously.^{[5, 11]} Therefore, bile leakage after hepatectomy remains a serious complication lengthening the hospitalization time and a causal factor for decompensation of liver function especially in cirrhotic patients.^[8-18]

 

In our patients, the quality of the remnant liver parenchyma was not associated with the occurrence of postoperative bile leakage contrary to what was found in the study by Guillaud et al.^[19] In fact, the patients with colorectal liver metastases who benefited from bevacizumab based chemotherapy showed a higher rate of bile leakage after hepatectomy. We found that atypical liver resection was associated with a significantly higher rate of postoperative bile leakage compared to anatomical resection. This can be explained by the injury of biliary and the vascular structures during the surgery as well reported in different studies.^[19-25] Concerning the devices used for the transection of the liver parenchyma, we did not find a causal link between the device utilized and the incidence of bile leakage. This is probably due to the miscellaneous methods used in our center. TVE of the liver during hepatectomy was associated (despite the small number of cases) with the occurrence of bile leakage after surgery, in contrast to the recently published study^[19] where the selective vascular clamping is more associated with the occurrence of bile leakage. Moreover, unlike what has been reported in some studies^{[6, 13]} (advocate the protective effect of biological agents on the bile leak appearance), we did not find any benefit of their use (thrombin human and fibrinogen patch agents, glue, etc.) compared to the standard ligature and clips. Two randomized trials^{[9, 19]} reported the benefit of “leakage tests” (methylene blue and/or cholangiography) in detecting bile leakage; in our study no any benefit was found. In our study, the presence of an abdominal drain allowed to perform an early diagnosis of bile leakage and therefore to perform a prompt medical treatment. Despite the limitations such as retrospective analysis, selection bias criteria, miscellaneous indications and procedures, and different surgeons, we report a large single center “real life” experience.

 

In conclusion, bile leakage is a common complication after liver resection and it has a significant effect on postoperative morbidity and cost of care (lengthening of the hospitalization). In our study, the occurrence of bile leakage is associated with non-anatomical (wedge) resection and TVE.

 

 

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