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Incidence and management of bile leakage after hepatic resection for malignant hepatic tumors
Incidence and Management of Bile Leakage after Hepatic Resection for Malignant Hepatic Tumors Shogo Tanaka, MD, Kazuhiro Hirohashi, MD, Hiromu Tanaka, MD, Taichi Shuto, MD, Sang Hun Lee, MD, Shoji Kubo, MD, Shigekazu Takemura, MD, Takatsugu Yamamoto, MD, Takahiro Uenishi, MD, Hiroaki Kinoshita, MD BACKGROUND: Bile leakage is one of the frequent and disturbing complications of hepatic resection. STUDY DESIGN: Clinical records of the 363 patients who underwent hepatic resections without biliary recon-
struction for hepatic cancers between January 1994 and June 2001 were reviewed. Postoperative bile leakage was defined as continuous drainage with a bilirubin concentration of 20 mg/dL or 1,500 mg/d lasting 2 days. Leakage that continued longer than 2 weeks or that required surgical intervention was defined as uncontrollable. Differences in incidence and frequency of uncontrollable leakage for the different types of hepatic resection, tumors, and underlying liver disease were investigated. Outcomes after treatment for uncontrollable bile leakage were also reviewed. RESULTS: Postoperative bile leakage occurred in 26 of 363 patients (7.2%). Although the incidence in patients with cholangiocellular carcinoma (3/9 [33%]) was higher (p ⫽ 0.03) than in patients with hepatocellular carcinoma, rates of occurrence were similar among the different types of hepatic resection and underlying liver disease. Eight of the 26 patients (31%) had uncontrollable leakage. Two patients required reoperation to control leakage; one of these developed hepatic failure and died 2 months after surgery. Four patients underwent endoscopic nasobiliary drainage 21 to 34 days after hepatectomy, and the leakage resolved within 3 to 21 days. Fibrin glue sealing was effective in two patients whose leaking bile ducts were not connected to the common bile duct. CONCLUSIONS: Although meticulous surgical technique can minimize the risk of postoperative bile leakage, some instances of leakage are unavoidable. Nonsurgical treatments, such as nasobiliary drainage or fibrin glue sealing, are preferable to reoperation. ( J Am Coll Surg 2002;195:484–489. © 2002 by the American College of Surgeons)
Bile leakage after hepatic resection is a common and disturbing complication. Recent advances in liver surgery have markedly decreased the overall complication rate, but the incidence of bile leakage has not changed,1-4 and it still occurs in 3.1% to 15.6% of patients.1-10 In most patients, bile leakage resolves spontaneously, but sometimes it is unremitting.11,12 The presence of bile, blood, and necrotic tissue in a dead space after hepatic resection provides the ideal environment for bacterial growth; this environment impairs the normal host defense mechanism13,14 and predisposes the patient to the development of sepsis, liver failure, and death.15,16 The
incidence of postoperative bile leakage has been reported to be similar among patients with and without hepatitis or liver cirrhosis,5 but some surgeons have found an association between uncontrollable postoperative ascites11 and type of resection.11,12 Although adequate preventive measures are essential, it is also important to know which patients are at high risk for leakage and should receive preventive management. This study was designed to answer these questions. METHODS The clinical records of patients who underwent hepatic resection without biliary reconstruction in our department between January 1994 and June 2001 were reviewed. The cohort consisted of 295 men and 68 women, with a mean age of 62 years (range 3 to 82 years). The indication for hepatectomy was hepatocellular carcinoma (HCC) in 316 patients, cholangiocellular carcinoma (CCC) in 9, metastatic carcinoma in 33, and other pathology in 5. Before
No competing interests declared.
Received February 27, 2002; Revised May 10, 2002; Accepted May 22, 2002. From the Department of Gastroenterological and Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Osaka City University, Osaka, Japan. Correspondence address: Shogo Tanaka, MD, Gastroenterological and Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
© 2002 by the American College of Surgeons Published by Elsevier Science Inc.
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ISSN 1072-7515/02/$21.00 PII S1072-7515(02)01288-7
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Vol. 195, No. 4, October 2002
Abbreviations:
CCC ⫽ cholangiocellular carcinoma HCC ⫽ hepatocellular carcinoma NBD ⫽ nasobiliary drainage POD ⫽ postoperative day PTPE ⫽ percutaneous transhepatic portal vein embolization TAE ⫽ transcatheter arterial embolization
surgery, transcatheter arterial embolization (TAE), percutaneous transhepatic portal vein embolization (PTPE), or both17-19 were performed in 35, 9, and 26 patients, respectively. The hepatectomies analyzed in this study were the first hepatic procedure in 304 patients, the second in 57, and the third in 2. In most patients who underwent subsegmentectomy or more extensive resection, an ultrasonic dissector was used for hepatic dissection (from 1994 to 1999, the SONOP SUS-202 dissector [Aloka, Tokyo, Japan] was used, and from 2000 to the present, we have used the CUSA EXcel [Valleylab, Boulder, CO]) during total20 or unilateral clamping of hepatic vascular inflow.21 In most of the patients who underwent limited hepatic resection, division of hepatic parenchyma was performed with scissors after coagulation with a microwave tissue coagulator (Microtaze; Heiwa Electronics Industry Inc., Tokyo, Japan). The major branches of the Glissonean sheath and the hepatic vein on the raw cut surface were ligated using 3-0 silk sutures. A unipolar or bipolar electrocoagulator was used to achieve hemostasis on the cut surface. Hepatic anatomy and the type of hepatic resection were classified according to Healey’s segments.22 Hepatic resection that was less than a subsegmentectomy was defined as a limited resection. Of 363 patients, 192 patients underwent cholecystectomy, intraoperative cholangiography, and the biliary sealing test with 20 mL indocyanine green solution through a balloon catheter made by ourselves.23
Management of Bile Leakage
485
Z-shaped sutures of 4-0 Vicryl (Ethicon, Somerville, NJ) were used to close the bile leaks. Fibrin glue (Beriplast; Aventis, Tokyo, Japan) or a fibrin sheet (TachoComb; Nycomed Pharma, Roskilde, Denmark) was applied to the raw cut surface of the liver to promote hemostasis11 in 205 patients. One or two drainage tubes were placed, and these were removed once the fluid became serous and was no longer bile stained, usually around the third to fifth postoperative day (POD). Prophylactic antibacterial drugs were routinely given until the third or fifth POD. Postoperative bile leakage was defined as continuous drainage with a bilirubin concentration above 20 mg/dL or 1,500 mg/d for more than 2 days. Fluid collection detected on ultrasonography or CT that healed without any treatment was not defined as bile leakage, even if the leakage was highly suspect clinically. Leakage that continued for above 2 weeks or that needed surgical treatment was defined as uncontrollable. We analyzed differences in the incidence of bile leakage among patients with different types of hepatic tumor and different methods of hepatic resection, and we studied the clinical course in patients with uncontrollable bile leakage. Significance of differences of the incidence of leakage was determined by Fisher’s exact test. A p value less than 0.05 (two-tailed) was considered significant. This study was conducted in accordance with the Helsinki Declaration and the guidelines of the Ethics Committee of our institution. Written informed consent was obtained from each patient or the patient’s parents. RESULTS Postoperative bile leakage occurred in 26 of 338 patients (7.2%) (Table 1). Seven of the 26 cases of bile leakage were discovered after percutaneous drainage of the intraabdominal abscess was detected on ultrasonography or CT, and none of these led to sepsis by continuous drainage. The incidence of leakage in patients with CCC was higher than in those with HCC (p ⫽ 0.03). Of the 316
Table 1. Indications for Hepatic Resection and Incidence of Postoperative Bile Leakage in 363 Patients Who Underwent Hepatic Resection Patients with bile leakage Diagnosis
Hepatocellular carcinoma Cholangiocellular carcinoma Metastatic liver tumors Other pathology Total
n
n
%
316 9 33 5 363
23 3 0 0 26
7.3 33.3 0 0 7.2
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Table 2. Types of Hepatic Resection and Incidence of Postoperative Bile Leakage in 363 Patients Who Underwent Hepatic Resection Patients with bile leakage Total Type of hepatic resection
Hepatectomy of more than two segments Right two or more Left two or more Central bisegmentectomy Segmentectomy Anterior segmentectomy Posterior segmentectomy Lateral segmentectomy Medial segmentectomy Other types—two subsegmentectomies Subsegmentectomy Limited resections Right lobe Left lobe Bilobular Caudate lobectomy
patients with HCC, 132 (42%) had histologic evidence of liver cirrhosis. The difference in the incidence of bile leakage in patients with or without liver cirrhosis (6/132 [4.5%] versus 20/231 [8.7%], respectively) was not significant (p ⫽ 0.20). Preoperative treatments such as TAE or PTPE did not affect the incidence of bile leakage (TAE alone, p ⫽ 0.29; performed 4/35 [11.4%] and not performed, 22/328 [6.7%]; PTPE alone, p ⫽ 0.49; performed, 1/9 [11.1%] and not performed, 25/354 [7.1%]; both TAE and PTPE, p ⫽ 0.10; performed 4/26 [15.4%] and not performed, 22/337 [6.5%], respectively). There was no difference in the incidence of bile leakage between patients who underwent first hepatectomy and those undergoing repeated hepatectomies (p ⫽ 0.28, 24/304 [7.9%] and 2/59 [3.4%], respectively). There were no differences in the incidence of bile leakage for the different types of hepatectomy, but the incidence in patients who underwent resection of two or more hepatic segments—left or central bisegmentectomy—tended to be higher than right hepatectomy (p ⫽ 0.097) (Table 2). Lymph node dissection in the hepatoduodenal ligament was performed in 3 of 316 (0.9%) patients with HCC, 5 of 9 (56%) patients with CCC, 4 of 33 (12%) patients with metastatic tumor, and 2 of 4 (50%) patients with other histology. The incidence of bile leakage was similar with or without
Uncontrollable
n
n
%
n
%
78 51 18 9 62 18 13 14 11 6 33 179 111 42 26 11
11 4 4 3 6 3 1 0 2 0 4 5 3 1 1 0
14.1 7.8 22.2 33.3 9.7 16.7 7.7 0 18.2 0 12.1 2.8 2.7 2.4 3.8 0
5 3 1 1 0 0 0 0 0 0 1 2 2 0 0 0
46 75 25 33 0 0 0 0 0 0 25 40 67 0 0 0
lymph node dissection (p ⫽ 0.29, 2/14 [14%] and 24/ 324 [7.4%], respectively). Intraoperative biliary sealing test did not affect the incidence of postoperative bile leakage (p ⫽ 0.22, performed 17/192 [8.9%] and not performed 9/171 [5.3%]). Fibrin glue or fibrin sheet on raw cut surface did not reduce the incidence of postoperative bile leakage (p ⫽ 0.22, 18/205 [8.8%] and 8/158 [5.1%], respectively). Bile leakage healed spontaneously within 2 weeks in 18 of 26 (69%) patients, but the other 8 patients (31%) required additional treatments, such as reoperation, endoscopic nasobiliary drainage (NBD), or fibrin glue sealing. All of these eight patients had cirrhosis or chronic hepatitis. In patients with bile leakage after a resection more extensive than a bisegmentectomy, the incidence of uncontrollable leakage tended to be higher after right-sided hepatectomy than other resections, but not significantly higher (p ⫽ 0.166). Leakage was from the cut surface of the right hepatic lobe in the three patients with uncontrollable bile leakage after resections of one segment or less. Characteristics, treatment, and outcomes in patients with uncontrollable bile leakage are summarized in Table 3. Reoperation was performed in two patients (patients 1 and 2). One patient (patient 1) developed bile leakage 3 days after right hepatectomy, with 200 mL/d of drainage. Reoperation on POD 11 failed to identify
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Table 3. Clinical Characteristics of Eight Patients with Uncontrollable Bile Leakage
Pt. Age Underlying No. (y) Gender Diagnosis hepatic diseases
58
F
HCC
2
35
M
HCC
3
69
F
HCC
4
69
M
HCC
5
66
M
HCC
6
55
M
HCC
7
72
F
CCC
8
59
F
HCC
Liver cirrhosis
Right lobectomy
Sites of bile leakage
⫹
Treatments
Outcomes
11
0
14
29
⫹
Reoperation, RTBD Reoperation, repair, RTBD NBD
34
3
⫹
NBD
31
18
⫹
NBD
21
21
Died of cancer recurrence at 15 mo Alive at 15 mo
⫹
NBD
21
16
Alive at 13 mo
⫺
Fibrin glue sealing
78
0
Alive at 17 mo
⫺
Fibrin glue sealing
50
0
Died of cancer recurrence at 50 mo
⫹
*Duration from treatment for leakage to closure. CCC, cholangiocellular carcinoma; HCC, hepatocellular carcinoma; NBD, nasobiliary drainage; POD, postoperative day; RTBD, retrograde transhepatic biliary drainage.
Died of hepatic failure 80 days later Alive at 69 mo Alive at 60 mo
Management of Bile Leakage
Raw surface of the liver Chronic hepatitis Right lobectomy Hepatic duct (posterior branch) Lupoid hepatitis Right lobectomy Hepatic duct (caudate branch) Liver cirrhosis Limited resection Raw surface of the (anterior segment) liver Chronic hepatitis Central Hepatic duct bisegmentectomy (median branch) Chronic hepatitis Subsegmentectomy Raw surface of the (anterior segment) liver Chronic hepatitis Left hepatectomy Hepatic duct (caudate branch) Chronic hepatitis Limited resection Raw surface of the (anterior segment) liver
Duration of Time of alternate treatments treatment (POD) (d)*
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Type of resection
Communication with the common bile duct
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488
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Management of Bile Leakage
the source of the leak, and retrograde transhepatic biliary drainage was performed. Bile discharge from the drainage tube resolved 7 days after reoperation, but the patient developed hepatic failure and died 80 days after hepatectomy. Another patient (patient 2), who underwent reoperation on POD 14, had begun experiencing bile leakage on POD 1 after right hepatectomy, with approximately 200 mL/d of drainage. Ligation of the site of the leak, the posterior branch, and retrograde transhepatic biliary drainage were performed, but the bile leakage continued for 29 more days. Four patients (patients 3 to 6) underwent endoscopic retrograde cholangiopancreatograms on PODs 21 to 34. In these patients, the leak resolved 3 to 21 days later without major complications. In the two other patients whose leaking bile duct was separated from the common bile duct, biliary drainage continued for 50 and 78 days after surgery. After confirmation that the fistula was aseptic and that the volume was less than 50 mL/d, the fistula was completely sealed with a mixture of fibrin glue and iodized oil (Lipiodol; Kodama Pharmaceutical, Tokyo, Japan) by means of the method for portal vein embolization.19 The fistula was immediately closed without any major complications except for a transient elevation in the serum transaminase concentrations. DISCUSSION Incidence of bile leakage after hepatic resection in our study (7.2%) was consistent with data in previous reports.1-10 Left-sided hemihepatectomy and central bisegmentectomy had a high incidence of postoperative bile leakage, which coincides with the experience of other investigators who found a high incidence of bile leakage after left hepatectomy.11 Lo and colleagues12 reported that left-sided major hepatectomy was an independent risk factor for the development of postoperative bile leakage because of the risk of damaging bile ducts from the caudate lobe, because the right posterior segment bile duct frequently drains into the left duct.24 Nakai and colleagues10 also reported that bile leakage occurs more frequently in patients who undergo left than right lobectomy after selective Glissonean pedicle transection. The reason for the high incidence of bile leakage in patients with CCC is uncertain, but it might be because surgeons attempt to resect the hepatic duct extensively to obtain tumor-free margins of resection.25 Underlying hepatic diseases, such as hepatitis and cirrhosis, did not increase the risk of bile leakage, but wound healing
J Am Coll Surg
is likely to be impaired in patients with these diseases, and bile discharge tended to be persistent. The relatively high incidence of uncontrollable leakage in patients after rightsided hepatectomy might be related to the pumping action of the right hemidiaphragm.9,26 When leakage continues to be uncontrollable, immediate drainage or biliary decompression is required to prevent IP collections and sepsis.11,15,16 Reoperation for identification and repair of the site of the leak, peritoneal drainage, and biliary decompression have been performed traditionally, but reoperation is often complicated by dense adhesions that render dissection and identification of the leakage site difficult.27 It also sometimes induces a second attack of systemic inflammatory response.28 For these reasons, nonsurgical treatment, including endoscopic or percutaneous procedures, is preferred.11,29-31 Endoscopic retrograde cholangiopancreatography is now the diagnostic procedure of choice to identify the exact site of bile leakage after cholecystectomy.29,32-36 Some reports have stated that most bile leaks were from the cystic duct, common bile duct, or right hepatic duct after cholecystectomy closed within 1 week by NBD.33-36 The presence of underlying parenchymal disease might also affect the efficacy of NBD. Biliary decompression will not be effective when the leaking ducts do not communicate with the common bile duct. In such cases, some surgeons11,37 recommended repeated ethanol injection into the bile duct to destroy the biliary epithelium. The fibrin glue sealing described here might also be useful when the fistula is aseptic and the leakage is little. Although we have no data on how large an amount of leakage could be sealed with the fibrin glue, we believe that leakages of less than 50 mL/d could be blocked by the procedure. Once the glue sealed the fistula completely, the effect was immediate and safe. Although good surgical technique should minimize the incidence of bile leakage, bile leakage is an inevitable consequence of hepatobiliary surgery. In such cases, noninvasive treatment, such as NBD or fibrin glue, is preferred to reoperation. Author Contributions: Study conception and design: Tanaka S, Hirohashi, Tanaka H, Kubo, Uenishi Acquisition of data: Tanaka S, Hirohashi, Tanaka H, Shuto, Lee, Takemura, Yamamoto
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Analysis and interpretation of data: Tanaka S, Tanaka H, Uenishi, Kinoshita Drafting of manuscript: Tanaka S, Tanaka H, Kinoshita Critical revision: Tanaka S, Tanaka H, Kubo, Kinoshita REFERENCES 1. Tsao JI, Loftus JP, Nagorney DM, et al. Trends in morbidity and mortality of hepatic resection for malignancy: a matched comparative analysis. Ann Surg 1995;220:199–205. 2. Miyagawa S, Makuuchi M, Kawasaki S, Kakazu T. Criteria for safe hepatic resection. Am J Surg 1995;169:199–205. 3. Fan ST, Lai ECS, Lo CM, et al. Hepatectomy with an ultrasonic dissector for hepatocellular carcinoma. Br J Surg 1996;83:117– 120. 4. Shimada M, Matsumata T, Akazawa K, et al. Estimation of risk of major complications after hepatic resection. Am J Surg 1994; 167:399–403. 5. Midorikawa Y, Kubota K, Takayama T, et al. A comparative study of postoperative complications after hepatectomy in patients with and without chronic liver disease. Surgery 1999;126: 484–491. 6. Thompson HH, Tompkins RK, Longmire WP. Major hepatic resection: a 25-year experience. Ann Surg 1983;197:375–388. 7. Iwatsuki S, Starzl TE. Personal experience with 411 hepatic resections. Ann Surg 1988;208:421–434. 8. Cosenza CA, Hoffman AL, Podesta LG, et al. Hepatic resection for malignancy in the elderly. Am Surg 1995;61:889–895. 9. Paquet JC, Dziri C, Hay JM, et al. Prevention of deep abdominal complications with omentoplasty on the raw surface after hepatic resection. Am J Surg 2000;179:103–109. 10. Nakai T, Koh K, Funai S, et al. Comparison of controlled and Glisson’s pedicle transactions of hepatic hilum occlusion for hepatic resection. J Am Coll Surg 1999;189:300–304. 11. Yamashita Y, Hamatsu T, Rikimaru T, et al. Bile leakage after hepatic resection. Ann Surg 2001;233:45–50. 12. Lo CM, Fan ST, Liu CL, et al. Biliary complications after hepatic resection. Arch Surg 1998;133:156–161. 13. Hau T, Simmons RL. Mechanism of the adjuvant effect of hemoglobin in experimental peritonitis: III. The influence of hemoglobin on phagocytosis and intracellular killing by human granulocytes. Surgery 1980;87:588. 14. Anderson R, Tranberg KG, Bengmark S. Role of bile and bacteria in biliary peritonitis. Br J Surg 1990;77:36–39. 15. Norton L, Moore G, Eiseman B. Liver failure in the postoperative patient: the role of sepsis and immunologic deficiency. Surgery 1975;78:6–13. 16. Yanaga K, Kanematsu T, Takenaka K, Sugimachi K. Intraperitoneal septic complications after hepatectomy. Ann Surg 1986; 203:148–152. 17. Yamada R, Nakamura K, Nishida N, et al. New therapy complementary to transcatheter arterial embolization for hepatocellular carcinoma. World J Surg 2001;25:381–385. 18. Kinoshita H, Sakai K, Hirohashi K, et al. Preoperative portal vein embolization for hepatocellular carcinoma. World J Surg 1986;10:803–808.
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19. Tanaka H, Hirohashi K, Kubo S, et al. Preoperative portal vein embolization improves prognosis after right hepatectomy for hepatocellular carcinoma in patients with impaired hepatic function. Br J Surg 2000;87:879–882. 20. Pringle JH. Notes on the arrest of hepatic hemorrhage due to trauma. Ann Surg 1908;48:541–549. 21. Makuuchi M, Mori T, Gunven P, et al. Safety of hemihepatic vascular occlusion during resection of the liver. Surg Gynecol Obstet 1987;164:155–158. 22. Healey JE Jr, Schroy PC. Anatomy of the biliary ducts within the human liver: analysis of the prevailing pattern of branching and the major variations of the biliary ducts. Arch Surg 1953; 66:599–616. 23. Kubo S, Sakai K, Kinoshita H, Hirohashi K. Intraoperative cholangiography using a balloon catheter in liver surgery. World J Surg 1986;10:844–850. 24. Mizumoto R, Suzuki H. Surgical anatomy of the hepatic hilum with special reference to the caudate lobe. World J Surg 1988; 12:2–10. 25. Uenishi T, Hirohashi K, Kubo S, et al. Clinicopathological factors predicting outcome after resection of mass-forming intrahepatic cholangiocarcinoma. Br J Surg 2001;88:969–974. 26. Brummelkamp WH. Subphrenic and intraperitoneal abscess. In: Schwartz S, Ellis H. 9th ed. Maingot’s abdominal operations, Vol 1. Norwalk, CT: Appleton and Lange; 1989:361–385. 27. Pace RF, Blenkharn JI, Edwars WJ, et al. Intraabdominal sepsis after hepatic resection. Ann Surg 1989;209:302–306. 28. Namekata K, Takamori S, Kojima K, et al. Significant changes in the serum levels of IL-6, h-HGF, and type IV collagen 7S during the perioperative period of a hepatectomy: relevance to SIRS. Surg Today 2000;30:403–409. 29. Davids PHP, Rauws EAJ, Tytgat GNJ, Huibregtse K. Postoperative bile leakage: endoscopic management. Gut 1992;33: 1118–1122. 30. Sherman S, Shaked A, Cryer HM, et al. Endoscopic management of biliary fistulas complicating liver transplantation and other hepatobiliary operations. Ann Surg 1993;218:167–175. 31. Binmoeller KF, Katon RM, Shneidman R. Endoscopic management of postoperative biliary leaks: review of 77 cases and report of two cases with biloma formation. Am J Gastroenterol 1991; 86:227–231. 32. Mortensen J, Kruse A. Endoscopic management of postoperative bile leaks. Br J Surg 1992;79:1339–1341. 33. Barthel J, Scheider D. Advantages of sphincterotomy and nasobiliary tube drainage in the treatment of cystic duct stump leak complicating laparoscopic cholecystectomy. Am J Gastroenterol 1995;90:1322–1324. 34. Pencev D, Brady PG, Pinkas H, Boulay J. The role of ERCP in patients after laparoscopic cholecystectomy. Am J Gastroenterol 1994;89:1523–1527. 35. Kozarek RA, Traverso LW. Endoscopic stent placement for cystic duct leak after laparoscopic cholecystectomy. Gastrointest Endosc 1995;90:1322–1324. 36. Born P, Bruhl K, Rosch T, et al. Long-term follow-up of endoscopic therapy in patients with post-surgical biliary leakage. Hepatogastroenterology 1996;43:477–482. 37. Kyokane T, Nagino M, Sano T, Nimura Y. Ethanol ablation for segmental bile duct leakage after hepatobiliary resection. Surgery 2002;131:111–113.
struction for hepatic cancers between January 1994 and June 2001 were reviewed. Postoperative bile leakage was defined as continuous drainage with a bilirubin concentration of 20 mg/dL or 1,500 mg/d lasting 2 days. Leakage that continued longer than 2 weeks or that required surgical intervention was defined as uncontrollable. Differences in incidence and frequency of uncontrollable leakage for the different types of hepatic resection, tumors, and underlying liver disease were investigated. Outcomes after treatment for uncontrollable bile leakage were also reviewed. RESULTS: Postoperative bile leakage occurred in 26 of 363 patients (7.2%). Although the incidence in patients with cholangiocellular carcinoma (3/9 [33%]) was higher (p ⫽ 0.03) than in patients with hepatocellular carcinoma, rates of occurrence were similar among the different types of hepatic resection and underlying liver disease. Eight of the 26 patients (31%) had uncontrollable leakage. Two patients required reoperation to control leakage; one of these developed hepatic failure and died 2 months after surgery. Four patients underwent endoscopic nasobiliary drainage 21 to 34 days after hepatectomy, and the leakage resolved within 3 to 21 days. Fibrin glue sealing was effective in two patients whose leaking bile ducts were not connected to the common bile duct. CONCLUSIONS: Although meticulous surgical technique can minimize the risk of postoperative bile leakage, some instances of leakage are unavoidable. Nonsurgical treatments, such as nasobiliary drainage or fibrin glue sealing, are preferable to reoperation. ( J Am Coll Surg 2002;195:484–489. © 2002 by the American College of Surgeons)
Bile leakage after hepatic resection is a common and disturbing complication. Recent advances in liver surgery have markedly decreased the overall complication rate, but the incidence of bile leakage has not changed,1-4 and it still occurs in 3.1% to 15.6% of patients.1-10 In most patients, bile leakage resolves spontaneously, but sometimes it is unremitting.11,12 The presence of bile, blood, and necrotic tissue in a dead space after hepatic resection provides the ideal environment for bacterial growth; this environment impairs the normal host defense mechanism13,14 and predisposes the patient to the development of sepsis, liver failure, and death.15,16 The
incidence of postoperative bile leakage has been reported to be similar among patients with and without hepatitis or liver cirrhosis,5 but some surgeons have found an association between uncontrollable postoperative ascites11 and type of resection.11,12 Although adequate preventive measures are essential, it is also important to know which patients are at high risk for leakage and should receive preventive management. This study was designed to answer these questions. METHODS The clinical records of patients who underwent hepatic resection without biliary reconstruction in our department between January 1994 and June 2001 were reviewed. The cohort consisted of 295 men and 68 women, with a mean age of 62 years (range 3 to 82 years). The indication for hepatectomy was hepatocellular carcinoma (HCC) in 316 patients, cholangiocellular carcinoma (CCC) in 9, metastatic carcinoma in 33, and other pathology in 5. Before
No competing interests declared.
Received February 27, 2002; Revised May 10, 2002; Accepted May 22, 2002. From the Department of Gastroenterological and Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Osaka City University, Osaka, Japan. Correspondence address: Shogo Tanaka, MD, Gastroenterological and Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
© 2002 by the American College of Surgeons Published by Elsevier Science Inc.
484
ISSN 1072-7515/02/$21.00 PII S1072-7515(02)01288-7
Tanaka et al
Vol. 195, No. 4, October 2002
Abbreviations:
CCC ⫽ cholangiocellular carcinoma HCC ⫽ hepatocellular carcinoma NBD ⫽ nasobiliary drainage POD ⫽ postoperative day PTPE ⫽ percutaneous transhepatic portal vein embolization TAE ⫽ transcatheter arterial embolization
surgery, transcatheter arterial embolization (TAE), percutaneous transhepatic portal vein embolization (PTPE), or both17-19 were performed in 35, 9, and 26 patients, respectively. The hepatectomies analyzed in this study were the first hepatic procedure in 304 patients, the second in 57, and the third in 2. In most patients who underwent subsegmentectomy or more extensive resection, an ultrasonic dissector was used for hepatic dissection (from 1994 to 1999, the SONOP SUS-202 dissector [Aloka, Tokyo, Japan] was used, and from 2000 to the present, we have used the CUSA EXcel [Valleylab, Boulder, CO]) during total20 or unilateral clamping of hepatic vascular inflow.21 In most of the patients who underwent limited hepatic resection, division of hepatic parenchyma was performed with scissors after coagulation with a microwave tissue coagulator (Microtaze; Heiwa Electronics Industry Inc., Tokyo, Japan). The major branches of the Glissonean sheath and the hepatic vein on the raw cut surface were ligated using 3-0 silk sutures. A unipolar or bipolar electrocoagulator was used to achieve hemostasis on the cut surface. Hepatic anatomy and the type of hepatic resection were classified according to Healey’s segments.22 Hepatic resection that was less than a subsegmentectomy was defined as a limited resection. Of 363 patients, 192 patients underwent cholecystectomy, intraoperative cholangiography, and the biliary sealing test with 20 mL indocyanine green solution through a balloon catheter made by ourselves.23
Management of Bile Leakage
485
Z-shaped sutures of 4-0 Vicryl (Ethicon, Somerville, NJ) were used to close the bile leaks. Fibrin glue (Beriplast; Aventis, Tokyo, Japan) or a fibrin sheet (TachoComb; Nycomed Pharma, Roskilde, Denmark) was applied to the raw cut surface of the liver to promote hemostasis11 in 205 patients. One or two drainage tubes were placed, and these were removed once the fluid became serous and was no longer bile stained, usually around the third to fifth postoperative day (POD). Prophylactic antibacterial drugs were routinely given until the third or fifth POD. Postoperative bile leakage was defined as continuous drainage with a bilirubin concentration above 20 mg/dL or 1,500 mg/d for more than 2 days. Fluid collection detected on ultrasonography or CT that healed without any treatment was not defined as bile leakage, even if the leakage was highly suspect clinically. Leakage that continued for above 2 weeks or that needed surgical treatment was defined as uncontrollable. We analyzed differences in the incidence of bile leakage among patients with different types of hepatic tumor and different methods of hepatic resection, and we studied the clinical course in patients with uncontrollable bile leakage. Significance of differences of the incidence of leakage was determined by Fisher’s exact test. A p value less than 0.05 (two-tailed) was considered significant. This study was conducted in accordance with the Helsinki Declaration and the guidelines of the Ethics Committee of our institution. Written informed consent was obtained from each patient or the patient’s parents. RESULTS Postoperative bile leakage occurred in 26 of 338 patients (7.2%) (Table 1). Seven of the 26 cases of bile leakage were discovered after percutaneous drainage of the intraabdominal abscess was detected on ultrasonography or CT, and none of these led to sepsis by continuous drainage. The incidence of leakage in patients with CCC was higher than in those with HCC (p ⫽ 0.03). Of the 316
Table 1. Indications for Hepatic Resection and Incidence of Postoperative Bile Leakage in 363 Patients Who Underwent Hepatic Resection Patients with bile leakage Diagnosis
Hepatocellular carcinoma Cholangiocellular carcinoma Metastatic liver tumors Other pathology Total
n
n
%
316 9 33 5 363
23 3 0 0 26
7.3 33.3 0 0 7.2
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Table 2. Types of Hepatic Resection and Incidence of Postoperative Bile Leakage in 363 Patients Who Underwent Hepatic Resection Patients with bile leakage Total Type of hepatic resection
Hepatectomy of more than two segments Right two or more Left two or more Central bisegmentectomy Segmentectomy Anterior segmentectomy Posterior segmentectomy Lateral segmentectomy Medial segmentectomy Other types—two subsegmentectomies Subsegmentectomy Limited resections Right lobe Left lobe Bilobular Caudate lobectomy
patients with HCC, 132 (42%) had histologic evidence of liver cirrhosis. The difference in the incidence of bile leakage in patients with or without liver cirrhosis (6/132 [4.5%] versus 20/231 [8.7%], respectively) was not significant (p ⫽ 0.20). Preoperative treatments such as TAE or PTPE did not affect the incidence of bile leakage (TAE alone, p ⫽ 0.29; performed 4/35 [11.4%] and not performed, 22/328 [6.7%]; PTPE alone, p ⫽ 0.49; performed, 1/9 [11.1%] and not performed, 25/354 [7.1%]; both TAE and PTPE, p ⫽ 0.10; performed 4/26 [15.4%] and not performed, 22/337 [6.5%], respectively). There was no difference in the incidence of bile leakage between patients who underwent first hepatectomy and those undergoing repeated hepatectomies (p ⫽ 0.28, 24/304 [7.9%] and 2/59 [3.4%], respectively). There were no differences in the incidence of bile leakage for the different types of hepatectomy, but the incidence in patients who underwent resection of two or more hepatic segments—left or central bisegmentectomy—tended to be higher than right hepatectomy (p ⫽ 0.097) (Table 2). Lymph node dissection in the hepatoduodenal ligament was performed in 3 of 316 (0.9%) patients with HCC, 5 of 9 (56%) patients with CCC, 4 of 33 (12%) patients with metastatic tumor, and 2 of 4 (50%) patients with other histology. The incidence of bile leakage was similar with or without
Uncontrollable
n
n
%
n
%
78 51 18 9 62 18 13 14 11 6 33 179 111 42 26 11
11 4 4 3 6 3 1 0 2 0 4 5 3 1 1 0
14.1 7.8 22.2 33.3 9.7 16.7 7.7 0 18.2 0 12.1 2.8 2.7 2.4 3.8 0
5 3 1 1 0 0 0 0 0 0 1 2 2 0 0 0
46 75 25 33 0 0 0 0 0 0 25 40 67 0 0 0
lymph node dissection (p ⫽ 0.29, 2/14 [14%] and 24/ 324 [7.4%], respectively). Intraoperative biliary sealing test did not affect the incidence of postoperative bile leakage (p ⫽ 0.22, performed 17/192 [8.9%] and not performed 9/171 [5.3%]). Fibrin glue or fibrin sheet on raw cut surface did not reduce the incidence of postoperative bile leakage (p ⫽ 0.22, 18/205 [8.8%] and 8/158 [5.1%], respectively). Bile leakage healed spontaneously within 2 weeks in 18 of 26 (69%) patients, but the other 8 patients (31%) required additional treatments, such as reoperation, endoscopic nasobiliary drainage (NBD), or fibrin glue sealing. All of these eight patients had cirrhosis or chronic hepatitis. In patients with bile leakage after a resection more extensive than a bisegmentectomy, the incidence of uncontrollable leakage tended to be higher after right-sided hepatectomy than other resections, but not significantly higher (p ⫽ 0.166). Leakage was from the cut surface of the right hepatic lobe in the three patients with uncontrollable bile leakage after resections of one segment or less. Characteristics, treatment, and outcomes in patients with uncontrollable bile leakage are summarized in Table 3. Reoperation was performed in two patients (patients 1 and 2). One patient (patient 1) developed bile leakage 3 days after right hepatectomy, with 200 mL/d of drainage. Reoperation on POD 11 failed to identify
Vol. 195, No. 4, October 2002
Table 3. Clinical Characteristics of Eight Patients with Uncontrollable Bile Leakage
Pt. Age Underlying No. (y) Gender Diagnosis hepatic diseases
58
F
HCC
2
35
M
HCC
3
69
F
HCC
4
69
M
HCC
5
66
M
HCC
6
55
M
HCC
7
72
F
CCC
8
59
F
HCC
Liver cirrhosis
Right lobectomy
Sites of bile leakage
⫹
Treatments
Outcomes
11
0
14
29
⫹
Reoperation, RTBD Reoperation, repair, RTBD NBD
34
3
⫹
NBD
31
18
⫹
NBD
21
21
Died of cancer recurrence at 15 mo Alive at 15 mo
⫹
NBD
21
16
Alive at 13 mo
⫺
Fibrin glue sealing
78
0
Alive at 17 mo
⫺
Fibrin glue sealing
50
0
Died of cancer recurrence at 50 mo
⫹
*Duration from treatment for leakage to closure. CCC, cholangiocellular carcinoma; HCC, hepatocellular carcinoma; NBD, nasobiliary drainage; POD, postoperative day; RTBD, retrograde transhepatic biliary drainage.
Died of hepatic failure 80 days later Alive at 69 mo Alive at 60 mo
Management of Bile Leakage
Raw surface of the liver Chronic hepatitis Right lobectomy Hepatic duct (posterior branch) Lupoid hepatitis Right lobectomy Hepatic duct (caudate branch) Liver cirrhosis Limited resection Raw surface of the (anterior segment) liver Chronic hepatitis Central Hepatic duct bisegmentectomy (median branch) Chronic hepatitis Subsegmentectomy Raw surface of the (anterior segment) liver Chronic hepatitis Left hepatectomy Hepatic duct (caudate branch) Chronic hepatitis Limited resection Raw surface of the (anterior segment) liver
Duration of Time of alternate treatments treatment (POD) (d)*
Tanaka et al
1
Type of resection
Communication with the common bile duct
487
488
Tanaka et al
Management of Bile Leakage
the source of the leak, and retrograde transhepatic biliary drainage was performed. Bile discharge from the drainage tube resolved 7 days after reoperation, but the patient developed hepatic failure and died 80 days after hepatectomy. Another patient (patient 2), who underwent reoperation on POD 14, had begun experiencing bile leakage on POD 1 after right hepatectomy, with approximately 200 mL/d of drainage. Ligation of the site of the leak, the posterior branch, and retrograde transhepatic biliary drainage were performed, but the bile leakage continued for 29 more days. Four patients (patients 3 to 6) underwent endoscopic retrograde cholangiopancreatograms on PODs 21 to 34. In these patients, the leak resolved 3 to 21 days later without major complications. In the two other patients whose leaking bile duct was separated from the common bile duct, biliary drainage continued for 50 and 78 days after surgery. After confirmation that the fistula was aseptic and that the volume was less than 50 mL/d, the fistula was completely sealed with a mixture of fibrin glue and iodized oil (Lipiodol; Kodama Pharmaceutical, Tokyo, Japan) by means of the method for portal vein embolization.19 The fistula was immediately closed without any major complications except for a transient elevation in the serum transaminase concentrations. DISCUSSION Incidence of bile leakage after hepatic resection in our study (7.2%) was consistent with data in previous reports.1-10 Left-sided hemihepatectomy and central bisegmentectomy had a high incidence of postoperative bile leakage, which coincides with the experience of other investigators who found a high incidence of bile leakage after left hepatectomy.11 Lo and colleagues12 reported that left-sided major hepatectomy was an independent risk factor for the development of postoperative bile leakage because of the risk of damaging bile ducts from the caudate lobe, because the right posterior segment bile duct frequently drains into the left duct.24 Nakai and colleagues10 also reported that bile leakage occurs more frequently in patients who undergo left than right lobectomy after selective Glissonean pedicle transection. The reason for the high incidence of bile leakage in patients with CCC is uncertain, but it might be because surgeons attempt to resect the hepatic duct extensively to obtain tumor-free margins of resection.25 Underlying hepatic diseases, such as hepatitis and cirrhosis, did not increase the risk of bile leakage, but wound healing
J Am Coll Surg
is likely to be impaired in patients with these diseases, and bile discharge tended to be persistent. The relatively high incidence of uncontrollable leakage in patients after rightsided hepatectomy might be related to the pumping action of the right hemidiaphragm.9,26 When leakage continues to be uncontrollable, immediate drainage or biliary decompression is required to prevent IP collections and sepsis.11,15,16 Reoperation for identification and repair of the site of the leak, peritoneal drainage, and biliary decompression have been performed traditionally, but reoperation is often complicated by dense adhesions that render dissection and identification of the leakage site difficult.27 It also sometimes induces a second attack of systemic inflammatory response.28 For these reasons, nonsurgical treatment, including endoscopic or percutaneous procedures, is preferred.11,29-31 Endoscopic retrograde cholangiopancreatography is now the diagnostic procedure of choice to identify the exact site of bile leakage after cholecystectomy.29,32-36 Some reports have stated that most bile leaks were from the cystic duct, common bile duct, or right hepatic duct after cholecystectomy closed within 1 week by NBD.33-36 The presence of underlying parenchymal disease might also affect the efficacy of NBD. Biliary decompression will not be effective when the leaking ducts do not communicate with the common bile duct. In such cases, some surgeons11,37 recommended repeated ethanol injection into the bile duct to destroy the biliary epithelium. The fibrin glue sealing described here might also be useful when the fistula is aseptic and the leakage is little. Although we have no data on how large an amount of leakage could be sealed with the fibrin glue, we believe that leakages of less than 50 mL/d could be blocked by the procedure. Once the glue sealed the fistula completely, the effect was immediate and safe. Although good surgical technique should minimize the incidence of bile leakage, bile leakage is an inevitable consequence of hepatobiliary surgery. In such cases, noninvasive treatment, such as NBD or fibrin glue, is preferred to reoperation. Author Contributions: Study conception and design: Tanaka S, Hirohashi, Tanaka H, Kubo, Uenishi Acquisition of data: Tanaka S, Hirohashi, Tanaka H, Shuto, Lee, Takemura, Yamamoto
Vol. 195, No. 4, October 2002
Analysis and interpretation of data: Tanaka S, Tanaka H, Uenishi, Kinoshita Drafting of manuscript: Tanaka S, Tanaka H, Kinoshita Critical revision: Tanaka S, Tanaka H, Kubo, Kinoshita REFERENCES 1. Tsao JI, Loftus JP, Nagorney DM, et al. Trends in morbidity and mortality of hepatic resection for malignancy: a matched comparative analysis. Ann Surg 1995;220:199–205. 2. Miyagawa S, Makuuchi M, Kawasaki S, Kakazu T. Criteria for safe hepatic resection. Am J Surg 1995;169:199–205. 3. Fan ST, Lai ECS, Lo CM, et al. Hepatectomy with an ultrasonic dissector for hepatocellular carcinoma. Br J Surg 1996;83:117– 120. 4. Shimada M, Matsumata T, Akazawa K, et al. Estimation of risk of major complications after hepatic resection. Am J Surg 1994; 167:399–403. 5. Midorikawa Y, Kubota K, Takayama T, et al. A comparative study of postoperative complications after hepatectomy in patients with and without chronic liver disease. Surgery 1999;126: 484–491. 6. Thompson HH, Tompkins RK, Longmire WP. Major hepatic resection: a 25-year experience. Ann Surg 1983;197:375–388. 7. Iwatsuki S, Starzl TE. Personal experience with 411 hepatic resections. Ann Surg 1988;208:421–434. 8. Cosenza CA, Hoffman AL, Podesta LG, et al. Hepatic resection for malignancy in the elderly. Am Surg 1995;61:889–895. 9. Paquet JC, Dziri C, Hay JM, et al. Prevention of deep abdominal complications with omentoplasty on the raw surface after hepatic resection. Am J Surg 2000;179:103–109. 10. Nakai T, Koh K, Funai S, et al. Comparison of controlled and Glisson’s pedicle transactions of hepatic hilum occlusion for hepatic resection. J Am Coll Surg 1999;189:300–304. 11. Yamashita Y, Hamatsu T, Rikimaru T, et al. Bile leakage after hepatic resection. Ann Surg 2001;233:45–50. 12. Lo CM, Fan ST, Liu CL, et al. Biliary complications after hepatic resection. Arch Surg 1998;133:156–161. 13. Hau T, Simmons RL. Mechanism of the adjuvant effect of hemoglobin in experimental peritonitis: III. The influence of hemoglobin on phagocytosis and intracellular killing by human granulocytes. Surgery 1980;87:588. 14. Anderson R, Tranberg KG, Bengmark S. Role of bile and bacteria in biliary peritonitis. Br J Surg 1990;77:36–39. 15. Norton L, Moore G, Eiseman B. Liver failure in the postoperative patient: the role of sepsis and immunologic deficiency. Surgery 1975;78:6–13. 16. Yanaga K, Kanematsu T, Takenaka K, Sugimachi K. Intraperitoneal septic complications after hepatectomy. Ann Surg 1986; 203:148–152. 17. Yamada R, Nakamura K, Nishida N, et al. New therapy complementary to transcatheter arterial embolization for hepatocellular carcinoma. World J Surg 2001;25:381–385. 18. Kinoshita H, Sakai K, Hirohashi K, et al. Preoperative portal vein embolization for hepatocellular carcinoma. World J Surg 1986;10:803–808.
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