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The effect of preoperative biliary drainage on infectious complications after hepatobiliary resection with cholangiojejunostomy
The effect of preoperative biliary drainage on infectious complications after hepatobiliary resection with cholangiojejunostomy Gen Sugawara, MD, Tomoki Ebata, MD, Yukihiro Yokoyama, MD, Tsuyoshi Igami, MD, Yu Takahashi, MD, Daisuke Takara, MD, and Masato Nagino, MD, PhD, Nagoya, Japan
Background. Arguments against biliary drainage before pancreatoduodenectomy have been gaining momentum recently. The benefits of biliary drainage before hepatobiliary resection, ie, combined liver and extrahepatic bile duct resection, however, are still debatable. Objective. To review the outcomes of patients who underwent hepatobiliary resection, with special attention to preoperative biliary drainage, to investigate whether biliary drainage increases the risk of postoperative infectious complications. Methods. This study involved 587 patients who underwent hepatobiliary resection with cholangiojejunostomy, including 475 patients who underwent preoperative biliary drainage and 112 patients who did not. Before each operation, surveillance bile cultures were performed at least once a week. Postoperatively, the bile and drainage fluid were cultured on days 1, 4, and 7. The hospital records of consecutive patients who underwent hepatobiliary resection were reviewed retrospectively. Results. Of the 475 patients with biliary drainage, 356 (74.9%) had a positive bile culture during the preoperative period. The incidence of postoperative infectious complications, including surgical-site infection and bacteremia, was similar between patients with biliary drainage and those without (28.2% vs 28.6%, P = .939). A positive bile culture during the perioperative period was highly associated with infectious complications and was one of the independent predictive factors related to infectious complications in a multivariate analysis. Conclusion. Preoperative biliary drainage is unlikely to increase the incidence of infectious complications after hepatobiliary resection. Perioperative surveillance bile culture is useful for the perioperative selection of appropriate antibiotics because of the high likelihood that micro-organisms isolated from infected sites are identical to those isolated from bile. (Surgery 2013;153:200-10.) From the Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
SEVERAL AUTHORS1-5 recently have analyzed the outcomes of pancreatoduodenectomy and have concluded that preoperative biliary drainage is not necessary, in principle. Furthermore, in some studies5-8 authors have shown that the presence of bacterobilia caused by preoperative biliary drainage is associated with surgical-site infection (SSI) and mortality after pancreatoduodenectomy. These findings support arguments against biliary drainage before pancreatoduodenectomy. Accepted for publication July 30, 2012. Reprint requests: Masato Nagino, MD, PhD, Professor and Chairman, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 4668550, Japan. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2012.07.032
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In contrast, the debate over the benefits of biliary drainage before hepatobiliary resection, ie, combined liver and extrahepatic bile duct resection, remains unsettled. Mortality after extended hepatobiliary resection remains high, with levels near 10%,9-11 and the cause of death is mainly hepatic failure. Biliary drainage can ameliorate liver damage caused by obstructive jaundice; therefore, biliary drainage seems to be a pivotal element of presurgical management in patients with obstructive jaundice who are to undergo hepatobiliary resection.12-14 In contrast, Ferrero et al15 and Hochward et al16 showed that prehepatectomy biliary drainage increases the incidence of postoperative infectious complications and that it does not lead to improved surgical outcomes in jaundiced patients. Cherqui et al17 and El-Hanafy18 reported that major hepatobiliary resections without biliary
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drainage can be performed safely in most patients with obstructive jaundice. In 1 previous study,15 the criteria for biliary drainage were not described clearly, and other studies16,17 did not include data on preoperative hepatic function or the extent of liver resection. Therefore, their conclusions must be interpreted cautiously. In the present study, we reviewed the outcomes of patients who underwent hepatobiliary resection, with special attention to preoperative biliary drainage, to investigate whether biliary drainage increases postoperative infectious complications in this difficult setting. MATERIALS AND METHODS Patients. This study involved 587 consecutive patients who underwent combined liver and extrahepatic bile duct resection with intrahepatic cholangiojejunostomy19 between January 2001 and September 2011 at the First Department of Surgery, Nagoya University Hospital. Patients who underwent hepatopancreatoduodenectomy were included in this study.20,21 There were 363 (61.8%) men and 224 (38.2%) women with a mean age of 65 ± 10 years (range, 22–83). Of these patients, 477 (81.3%) patients had cholangiocarcinoma, 64 (10.9%) gallbladder cancer, 23 (3.9%) other malignancies, and the remaining 23 (3.9%) benign disease (Table I). Of the 587 study patients, 350 patients (59.6%) overlapped with the cohort of our previous study on biliary methicillin-resistant Staphylococcus aureus (MRSA) infection.22 Preoperative biliary drainage and portal vein embolization. Preoperative management was performed according to the flow chart described in Figure. In case of jaundice (serum total bilirubin level S2.0 mg/dL) and/or dilated bile ducts in the future remnant lobe, preoperative biliary drainage was performed. Before 2005, percutaneous transhepatic biliary drainage (PTBD) routinely was selected as a method of preoperative biliary drainage.23-25 After 2005, our strategy for drainage changed gradually as we considered seeding metastasis associated with PTBD.26 Endoscopic nasobiliary drainage (ENBD) was used when possible,27,28 and PTBD was used only when ENBD was not feasible. Overall, 374 (63.7%) patients were jaundiced at the time of admission (serum total bilirubin level S2.0 mg/dL), with a mean serum total bilirubin concentration of 9.7 ± 6.5 mg/dL (2.0– 40.4 mg/dL). A total of 475 (80.9%) patients, including all of the jaundiced patients and 101 (17.2%) nonjaundiced patients who had
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intrahepatic biliary dilatation, underwent preoperative biliary drainage to relieve biliary obstruction, treat segmental cholangitis24 and/or to define the anatomy of the biliary tree. The method of biliary drainage was PTBD in 290 patients, ENBD in 156 patients, endoscopic biliary stenting (EBS) in 15 patients, or both PTBD and ENBD in 14 patients (Table I). Hemobilia (n = 6) or catheter dislodgement (n = 24) occurred after PTBD, and these patients were treated by catheter exchange or additional PTBD. Post-ENBD pancreatitis (grade 2 or 3)29 occurred in 6 patients and was treated with conservative therapy. These procedure-related complications of PTBD or ENBD never precluded the planned operation. The remaining 112 (19.1%) patients did not undergo preoperative biliary drainage. In general, when a future liver remnant ICGK value (ICGK-F = ICGK 3 proportion of the future liver remnant) was less than 0.05,30 portal vein embolization (PVE) was indicated to avoid the risk of postoperative hepatic failure. Embolization of the right portal vein was performed in 189 patients who were to undergo right hepatectomy. Embolization of the right and left medial portal veins was carried out in 34 patients who were to undergo right hepatic trisectionectomy. Embolization of the left and right anterior portal veins was performed in 105 patients who were to undergo left hepatic trisectionectomy. Embolization of the right anterior and left medial portal veins was performed in 1 patient who was to undergo central bisegmentectomy. Preoperative bile culture. Bile drained externally from the PTBD or ENBD catheter was sampled for aerobic and anaerobic bacterial culture at least once a week during the preoperative period.22 The bile specimens were cultured for at least 3 days using 3 aerobic media (5% sheep blood agar, SS agar, and Macconkey agar), anaerobic media (Brucella HK agar RS), and CHROM agar for MRSA surveillance. The cost of bile culture was approximately 30 US $/sample. Blood and bile were obtained for cultures if a patient developed a fever exceeding 38.58C at any time after biliary drainage, irrespective of the presence or absence of other infectious sources. A diagnosis of cholangitis was made when a patient had a fever (>38.58C), a positive bile culture, and abnormalities in liver function test results, provided that other septic complications were ruled out.24 Perioperative nutritional management. Preoperatively, all patients received a regular diet, and no
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Table I. Characteristics of patients according to the presence or absence of preoperative biliary drainage Age Sex (male/female) ICGK value Disease, n (%) Cholangiocarcinoma Gallbladder cancer Other malignancies Benign Method of biliary drainage PTBD/ENBD/EBS/PTBD+ENBD Preoperative cholangitis, n (%) Preoperative bacteremia, n (%) Serum total bilirubin, mg/dL On admission One day before operation
With PBD (n = 475)
Without PBD (n = 112)
65 ± 10 287/188 0.160 ± 0.029
65 ± 11 76/36 0.160 ± 0.031
399 45 15 16
(84.0) (9.5) (3.2) (3.3)
78 19 8 7
P .957 .145 .887 .017
(69.6) (17.0) (7.1) (6.3)
290/156/15/14 76 (16.0) 33 (6.9)
— 0 0
<.001 .008
7.7 ± 6.7 0.8 ± 0.4
0.9 ± 0.5 0.9 ± 0.5
<.001 .589
ENBD, Endoscopic nasobiliary drainage; EBS, endoscopic biliary stenting; ICGK, indocyanine green clearance rate; PBD, preoperative biliary drainage; PTBD, percutaneous transhepatic biliary drainage.
Figure. Flow chart for preoperative treatment T.Bil, serum total bilirubin concentration; PVE, Portal vein embolization.
patients received parenteral or enteral nutritional supplementation. As previously reported,31 all bile drained externally from the biliary drainage catheter was replaced orally or via a nasoduodenal tube to maintain intestinal integrity regardless of the
presence of bacteria in the bile. Preoperative synbiotic treatment was used routinely for at least 2 weeks before operation since 2005, after its validation in a randomized controlled trial.32-34 The following agents were administered orally: one 80-mL bottle of Yakult 400 (Yakult Honsha, Tokyo, Japan) containing at least 4 3 1010 living Lactobacillus casei strain Shirota, one 100 -mL bottle of Bifiene (Yakult Honsha) containing at least 1 3 1010 living Bifidobacterium breve strain Yakult, and galacto-oligosaccharides (Oligomate 55, Yakult Honsha; 15 g/day). During the procedure, an 8-Fr catheter was placed through a jejunal limb for postoperative enteral feeding. After the operation, enteral feeding (Racol, 1 Kcal/mL; EN Otsuka Pharmaceutical, Japan) was initiated on postoperative day 1 at 200 Kcal/ day and was gradually increased to 400 Kcal/day by day 4. Oral intake began on day 5, with enteral feeding decreasing gradually as oral intake increased. Total parenteral nutrition was not implemented, and the central venous catheter inserted in the operating room was removed 1 to 3 days postoperatively. Postoperative synbiotic treatment was performed routinely starting in 2003 and was administered through the feeding catheter from postoperative days 1 to 14.32 The synbiotics used after hepatectomy were Yakult BL granule (Yakult Honsha) containing 1 3 108 living Lactobacillus casei strain Shirota and 1 3 108 living Bifidobacterium breve strain Yakult per gram as well as galactooligosaccharides (Oligomate 55; Yakult Honsha). Perioperative antibiotic treatment. During the preoperative period, antibiotic treatment was
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performed only when a patient developed probable cholangitis and bacteremia with a high fever and leukocytosis. On the day of the operation, all patients received antibiotic prophylaxis as a single intravenous drip infusion 30 minutes before the procedure. Postoperative antibiotic prophylaxis was used for at least 3 days after operation, with a mean duration of 3.8 ± 2.4 days. Prophylactic antibiotics were selected according to the surveillance bile culture; when the bile culture was negative, first- or second-generation cephalosporins were used, and when the bile culture was positive, antibiotics were selected according to the susceptibility of the specific microorganisms detected. When MRSA or Enterococcus species susceptible to vancomycin alone was positive, vancomycin plus other antibiotics effective against gramnegative rods were selected as prophylactic antibiotics.22 Surgery. All hepatectomies were carried out after the serum total bilirubin concentration decreased to less than 2 mg/dL. Liver transection was carried out using CUSA or P ean forceps according to the surgeon preference during both hepatic artery and portal vein clamping for 15 minutes at 5-minute intervals. Bilioenteric continuity was reestablished by Roux-en-Y cholangiojejunostomy in all patients as reported previously.19 In cases of hepatopancreatoduodenectomy, reconstruction was performed according to Child’s method with an end-to-side pancreaticojejunostomy. All anastomosed bile ducts were drained externally and, in effect, stented at the anastomosis with a 6-Fr polyvinyl chloride tube (PTBD tube; Hakko, Chikuma, Japan). Transanastomotic stents were introduced via a transjejunal route. Initially, we fixed the drainage tube(s) in position with 5-0 PDS, and the tubes were not removed until at least 3 weeks after the hepatectomy. For the past 6 years, we have fixed tube(s) in position with 5-0 polyglactin (VICRYL Rapide; Ethicon, Somerville, NJ) and removed the tubes within 2 weeks of the hepatobiliary resection. The abdominal cavity was drained routinely using a closed multichannel silicone drain. Postoperative management of biliary drainage and abdominal drainage. Postoperatively, bile drained externally from the transjejunal stent tube(s), and fluid from the abdominal drain(s) was cultured routinely on days 1, 4, and 7 for surveillance. Blood was cultured when a patient developed a fever exceeding 38.58C at any time after the operation, irrespective of the presence or absence of other infectious sources.35 The abdominal drains were removed on postoperative day 7 when the drainage fluid was clear.
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Recording of postoperative complications. Detailed daily records of patients’ postoperative courses were kept, and infectious complications were recorded for up to 30 days after the procedure. All infections were proven to be bacteriologic, as determined by a positive culture. SSI, including superficial/deep incisional SSI and organ/space SSI, was defined as a condition in which purulent discharge was observed from any incision or space that was manipulated intraoperatively within 30 days after the operation, according to the guideline by The Centers for Disease Control and Prevention.36 Bacteremia was diagnosed when a single blood culture grew an isolate of organisms, unless the isolate was Staphylococcus epidermidis or a coagulasenegative Staphylococcus species. Pneumonia was defined as a characteristic pulmonary infiltrate on a chest radiograph accompanied by leukocytosis. The types of microorganisms isolated from superficial/deep incisional SSIs, organ/space SSIs, and the blood were compared with those from perioperative bile culture. Pancreatic fistula was defined according to the International Study Group of Pancreatic Fistula.37 Hepatic failure was defined as an increased serum total bilirubin concentration >10 mg/dL. Statistics. The statistical analysis was performed using Dr SPSS II for Windows Version 11.01 J (SPSS Inc, Chicago, IL). Quantitative data are expressed as means with SD. The Student t test was used to compare parametric data. Qualitative data were compared using the chi-square test or the Fisher exact test, where appropriate. The multivariate analysis was performed using logistic regression models. RESULTS Patient demographics. The patients’ characteristics are summarized in Table I according to the absence or presence of preoperative biliary drainage. Of the 475 patients with preoperative biliary drainage, 76 (16.0%) had preoperative cholangitis, and 33 (6.9%) had preoperative bacteremia. Of the 112 patients without preoperative biliary drainage, none had cholangitis and bacteremia. Serum bilirubin levels on admission were greater in patients with preoperative biliary drainage (7.7 ± 6.7) than in those without (0.9 ± 0.5; P < .001). The time between admission and the operation was 49 days (range, 5–254) in patients with biliary drainage, and it was 27 days (range, 6–124) in patients without biliary drainage (P < .001). Most of the patients were discharged from the hospital after completion of a preoperative workup including biliary drainage
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or PVE and were readmitted 2 to 3 days before the operation. The surgical procedures performed are summarized in Table II. A left-sided hepatectomy was performed in 287 (48.9%) patients, a right-sided hepatectomy in 268 (45.7%) patients, and a central hepatectomy in 32 (5.4%) patients. Resection of the extrahepatic bile duct was performed in all patients. Combined caudate lobectomy was performed in 563 (95.9%) patients. Combined pancreatoduodenectomy20,21 was performed in 109 (18.6%) patients. Portal vein and/or hepatic artery resection and reconstruction38,39 were performed in 228 (38.8%) patients. There were differences between the 2 groups regarding both the incidence of combined pancreatoduodenectomy (P = .017) and combined resection of the portal vein and/or hepatic artery (P < .001). Operative time was greater in patients with preoperative biliary drainage (P < .001), as was blood loss (P = .024). As a result, the incidence of perioperative blood transfusion was greater in the former group of patients (P < .001). Preoperative bile and blood culture. Of the 475 patients with preoperative biliary drainage, 356 (74.9%) had a positive bile culture, and the remaining 119 (25.1%) had negative bile culture during the preoperative period. Of the 356 patients with positive bile culture, 184 (51.7%) had a mixed infection with 2 or more microorganisms. A total of 671 microorganisms were isolated from the bile of the 356 patients (Table III). The most commonly isolated bacteria were Enterococcus species (23.0%), followed by Klebsiella species (14.3%), Staphylococcus species (14.2%), and Enterobacter species (9.4%) in decreasing order. Preoperative cholangitis occurred in 76 (16.0%) of the 475 patients with preoperative biliary drainage. Preoperative bacteremia occurred in 33 (6.9%) of the 475 patients, and in 27 (81.8%) patients of these 33 patients, the microorganism(s) isolated from blood was the same as that isolated from the bile. The most commonly isolated bacteria from the blood in patients with bacteremia were Enterococcus species (31.4%), followed by Staphylococcus species (20.0%) and Klebsiella species (20.0%). All patients who suffered from preoperative bacteremia had preoperative cholangitis. As the result of appropriate biliary drainage and administration of antibiotics, all patients with preoperative bacteremia were in good condition at the time of operation. No preoperative cholangitis or preoperative bacteremia occurred in the 112 patients without biliary drainage. Postoperative complications. The postoperative complications are listed in Table IV. Of the 475 patients with preoperative biliary drainage, 134
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(28.2%) patients had postoperative infectious complications, including SSI, bacteremia, and pneumoniae. The incidence of postoperative infectious complications was not different between patients with PTBD and those with ENBD (30.0% vs 23.1%, P = .118). Of the 112 patients without preoperative biliary drainage, 32 (28.6%) patients had postoperative infectious complications. There was no difference in the incidence of postoperative infectious complications between the 2 groups (P = .939). Similarly, there was no difference in the incidence of other complications such as leakage of cholangiojejunostomy, pancreatic fistula (Grade B or C of International Study Group of Pancreatic Fistula classification), and hepatic failure. Of the 587 study patients, 19 (3.2%) patients died of hepatic failure (n = 16), intra-abdominal bleeding (n = 2), or septic shock (n = 1), and the remaining 568 (96.8%) patients were discharged from the hospital in good condition. The mortality rate was similar between the 2 groups (P = .941). Of the 166 patients with postoperative infectious complications, 150 (90.4%) patients were discharged in good condition, and the remaining 16 (9.6%) patients (13 patients with preoperative biliary drainage and 3 patients without preoperative biliary drainage) died. Of the 421 patients without postoperative infectious complications, only 3 (0.7%) patients (all patients with preoperative biliary drainage) died of hepatic failure after portal vein thrombus. The postoperative hospital stay was similar between the 2 groups (40 vs 38 days; P = .482). Postoperative cultures from bile and the sites of infectious complications. Of the 587 study patients, 404 (68.8%) had a positive bile culture during the postoperative period. Of these patients, 203 (50.2%) had a mixed infection with 2 or more microorganisms. A total of 777 microorganisms were isolated from the bile of the 404 patients (Table V). The most commonly isolated bacteria were Enterococcus species (27.9%), followed by Klebsiella species (15.4%) and Enterobacter species (14.0%). Through the perioperative (pre - and postoperative) period, 493 (83.9%) of the 587 study patients had a positive bile culture. Of the 475 patients with preoperative biliary drainage, 428 (90.1%) had a positive bile culture through the perioperative period. In contrast, of the 112 patients without biliary drainage, 65 (58.0%) had a positive bile culture through the perioperative period. The presence of preoperative biliary drainage did affect the incidence of perioperative bile contamination (P < .001). In the 72 patients with superficial/deep incisional SSIs, a total of 117 microorganisms were
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Table II. Operative procedures performed Operative procedure, n (%) Type of hepatectomy Left-sided hepatectomy Right-sided hepatectomy Central hepatectomy Combined pancreatoduodenectomy Combined PV and/or HA resection Operative time, min, mean ± SD Blood loss, mL, mean ± SD Perioperative blood transfusion, n (%)
With PBD (n = 475)
Without PBD (n = 112)
234 (49.3) 226 (47.6) 15 (3.1) 97 (20.4) 207 (43.6) 642 ± 152 2,097 ± 2,662 183 (38.5)
53 (47.3) 42 (37.5) 17 (15.2) 12 (10.7) 21 (18.8) 583 ± 142 1,700 ± 1,094 22 (19.6)
P <.001
.017 <.001 <.001 .024 <.001
HA, Hepatic artery; PBD, preoperative biliary drainage; PV, portal vein.
Table III. Microorganisms isolated from bile and blood culture before the procedure in patients with preoperative biliary drainage Bile (n = 356) Gram-positive bacteria, n (%) Enterococcus species 154 (23.0) Staphylococcus species 95 (14.2) MRSA 16 (2.4) Streptococcus species 17 (2.5) Bacillus species 7 (1.0) Gram-negative bacteria Klebsiella species 96 (14.3) Enterobacter species 63 (9.4) Citrobacter species 35 (5.2) Acinetobacter species 34 (5.1) Pseudomonas species 33 (4.9) Escherichia species 28 (4.2) Stenotrophomonas species 22 (3.3) Serratia species 17 (2.5) Aeromonas species 13 (1.9) Others 18 (2.7) Candida species 39 (5.8)
Blood (n = 33) 11 7 2 1 1
(31.4) (20.0) (5.7) (2.9) (2.9)
7 (20.0) 1 (2.9) 0 2 (5.7) 1 (2.9) 1 (2.9) 1 (2.9) 0 0 1 (2.9) 1 (2.9)
MRSA, Methicillin-resistant Staphylococcus aureus.
isolated from the site of the incisional SSI: the most commonly isolated bacteria were Enterococcus species (28.2%), followed by Staphylococcus species (24.8%; Table V). Of these 72 patients, 71 (98.6%) had positive bile culture during the perioperative period, and in 64 (88.9%) patients, the microorganism(s) isolated from the site of the incisional SSI was the same as that isolated from the bile. In the 114 patients with organ/space SSIs, a total of 278 microorganisms were isolated from the organ/space SSI. The most commonly isolated bacteria were Enterococcus species (24.1%), followed by Enterobacter species (14.4%; Table V). Of these
114 patients, 109 (95.6%) had a positive bile culture during the perioperative period, and in 97 (85.1%) patients, the microorganism(s) isolated from the abscess was the same as that isolated from the bile. In the 42 patients with bacteremia, a total of 65 microorganisms were isolated from the blood: the most commonly isolated bacteria were Enterococcus species (24.6%), followed by Staphylococcus species (20.0%; Table V). All 42 patients had a positive bile culture during the perioperative period, and in 31 (73.8%) patients, the microorganism(s) isolated from blood was the same as that isolated from the bile. Overall, the majority of patients with postoperative infectious complications had a positive bile culture, irrespective of preoperative biliary drainage, and the microorganism(s) from the site of postoperative infectious complications was associated closely with that isolated from the bile. Postoperative infectious complications according to the results of bile culture. Of the 587 study patients, 493 (84.0%) had a positive bile culture during the perioperative period, and the remaining 94 (16.0%) patients had a negative bile culture. Postoperative infectious complications according to the bile culture results are listed in Table VI. A positive bile culture affected the incidence of all infectious complications (161 vs 5; P < .001), SSI (147 vs 5; P < .001), incisional SSI (71 vs 1; P < .001), organ/space SSI (109 vs 5; P < .001), bacteremia (42 vs 0; P = .007), and hepatic failure (41 vs 0; P = .007). As a result, the postoperative hospital stay was greater for patients with a positive bile culture than for those with a negative culture (42 vs 30 days; P < .001). Factors associated with postoperative infectious complications. Eleven possible risk factors for the postoperative infectious complications were analyzed by a univariate analysis; age (S65), sex
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Table IV. Postoperative complications Patients with any infectious complications, n (%) Surgical site infections (SSI) Superficial/deep incisional SSI Organ/space SSI Bacteremia Pneumoniae Leakage of CJ anastomosis Pancreatic fistula* (n = 109) Hepatic failurey Hospital death Postoperative hospital stay, days
With PBD (n = 475)
Without PBD (n = 112)
P
134 (28.2) 125 (26.3) 61 (12.8) 93 (19.6) 34 (7.2) 6 (1.3) 19 (4.) 65 (n = 97; 67.0%) 37 (7.8) 16 (3.4) 40 ± 27
32 (28.6) 27 (24.1) 11 (9.8) 21 (18.8) 8 (7.1) 5 (4.5) 3 (2.7) 11 (n = 12; 91.7%) 4 (3.6) 3 (2.7) 38 ± 26
.939 .631 .381 .842 .843 .073 .699 .155 .171 .941 .482
*Grade B or C of International Study Group of Pancreatic Fistula classification. yDefined as an increased serum total bilirubin concentration >10 mg/dL. CJ, Cholangiojejunostomy; PBD, preoperative biliary drainage.
Table V. Micro-organisms isolated from bile and sources of infectious complications after the operation Bile (n = 404) Gram-positive bacteria, n (%) Enterococcus species Staphylococcus species MRSA Streptococcus species Bacillus species Gram-negative bacteria Klebsiella species Enterobacter species Citrobacter species Acinetobacter species Pseudomonas species Escherichia species Stenotrophomonas species Serratia species Aeromonas species Others Candida species
I.SSI (n = 72)
O.SSI (n = 114)
Blood (n = 42) 16 (24.6) 13 (20.0) 7 (10.8) 0 0
217 52 30 3 1
(27.9) (6.7) (3.9) (0.4) (0.1)
33 (28.2) 29 (24.8) 19 (16.2) 0 0
67 (24.1) 34 (12.2) 22 (7.9) 0 3 (1.1)
120 109 25 39 38 30 26 32 5 8 72
(15.4) (14.0) (3.2) (5.0) (4.9) (3.9) (3.3) (4.1) (0.7) (1.1) (9.3)
14 16 4 1 4 3
32 40 13 6 13 15 10 14 2 3 26
4 1 4 4
(12.0) (13.6) (3.4) (0.9) (3.4) (2.6) 0 (3.4) (0.9) (3.4) (3.4)
(11.5) (14.4) (4.7) (2.1) (4.7) (5.4) (3.6) (5.0) (0.8) (1.1) (9.3)
9 7 1 3 2 3 1 3 1 2 4
(13.8) (10.8) (1.5) (4.6) (3.1) (4.6) (1.5) (4.6) (1.5) (3.1) (6.3)
I.SSI, Superficial/deep incisional SSI; MRSA, methicillin-resistant Staphylococcus aureus; O.SSI, organ/space SSI.
(male), body mass index (S22), K-ICG (< 0.160), positive bile culture, operative time (S600 minutes), blood loss (S2,000 mL), and the presence of combined pancreatoduodenectomy were significant (Table VII). On multivariate analysis, age, body mass index, positive bile culture, operative time, blood loss, and the presence of combined pancreatoduodenectomy were independent risk factors for postoperative infectious complications (Table VII). DISCUSSION Hepatobiliary resection, that is, combined hepatectomy and extrahepatic bile duct resection
followed by cholangiojejunostomy, is a complicated and technically demanding procedure. This procedure creates a high risk of postoperative infectious complications because of bilio-enteric anastomosis during the bile duct resection.40,41 Possible bile contamination of the operative field is likely to increase postoperative infectious complications, especially when the bile is colonized/infected with bacteria.9 In this context, we analyzed the relationship between bile colonization and infectious complications in complicated hepatectomy. This study is the first large-series report with detailed bacteriologic analysis using prospective data collection of perioperative cultures.
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Table VI. Infectious complications according to bile culture Bile culture Positive (n = 493) Patients with any infectious complications, n (%) Surgical-site infections (SSI) Superficial/deep incisional SSI Organ/space SSI Bacteremia Pneumoniae Hepatic failure* Hospital death Postoperative hospital stay (days)
161 (32.7) 147 (29.8) 71 (14.4) 109 (22.1) 42 (8.5) 11 (2.2) 41 (8.3) 19 (3.9) 42 ± 29
Negative (n = 94) 5 5 1 5
(5.3) (5.3) (1.1) (5.3) 0 0 0 0 30 ± 14
P <.001 <.001 <.001 <.001 .007 .295 .007 .105 <.001
*Defined as an increased serum total bilirubin concentration >10 mg/dL.
Many authors 6,8,16,42-44 have reported that bile is contaminated in 47–94% of patients with biliary obstruction after biliary drainage whereas contaminated bile is observed in less than 20% of patients without drainage. According to previous studies, the most commonly isolated microorganisms in the bile after biliary drainage were Enterococcus species 8,16,42,43 or Escherichia coli.6,45 In our series, bile culture was positive in approximately three-fourths of the patients with biliary drainage before operation; approximately one-half of the patients with positive bile cultures had mixed biliary infections, and the most common bacteria isolated from the bile were Enterococcus species (23.0%). These observations were comparable with previous studies.6,8,16,42-44 After the procedure, the most common bacteria isolated from both the bile and infectious sources also was Enterococcus species. An important finding is that the bile was contaminated after the operation in more than half (58%, 65/112) of the patients without preoperative biliary drainage. Once the bile duct is divided and anastomosed to the jejunum, bacterobilia is likely to occur, leading to infectious complications regardless of the absence or presence of preoperative biliary drainage. In addition, transanastomotic biliary stents routinely were used postoperatively in our series. Although speculative, the placement of the stents may have caused bile contamination after the operation, and, in turn, may have affected the surgical outcome. In our study, the microorganisms isolated from the infectious sites after the procedure were identical to those isolated from the bile during the perioperative period in most, although not all, patients. This finding strongly supports the use of perioperative-specific antibiotic prophylaxis on the basis of preoperative surveillance bile cultures to prevent and/or attenuate postoperative infectious complications. Furthermore, postoperative surveillance bile culture appears to be helpful for
selecting the antibiotics to treat infectious complications, especially in the case of organ/space SSI or bacteremia. We can use the surveillance bile culture to choose appropriate antibiotics more promptly. The incidence of postoperative MRSA infection in this study was similar to the results of previous studies on hepatobiliary-pancreatic surgery,46 and vancomycin-resistant species were never isolated. Our strategy for antibiotic selection, therefore, seems unlikely to accelerate the antibiotic resistance of causative micro-organisms. Collectively, routine perioperative surveillance bile culture is useful and recommended for patients undergoing hepatobiliary resection with cholangiojejunostomy. Cherqui et al17 reported that a major hepatectomy could be performed safely without preoperative biliary drainage in most patients with jaundice. This study was performed more than 10 years ago but only attracted attention for a brief time, and Cherqui himself noted that the study lead to incorrect conclusions (personal communication, May, 2012). As mentioned previously, a consensus has been established that preoperative biliary drainage usually is unnecessary in patients who are to undergo pancreatoduodenectomy. In contrast, hepatobiliary resection for biliary cancer is still challenging and associated with high rates of morbidity and mortality.9-11 Preoperative biliary drainage, therefore, is necessary for the safe performance of such a demanding hepatectomy. To our knowledge, biliary drainage is still used as a routine method of preoperative management for patients with jaundice who are to undergo a major hepatobiliary resection in both most Eastern and Western centers. In contrast, some authors15,16 have shown that preoperative biliary drainage is associated with postoperative infectious complications and that it does not lead to improved surgical outcomes in patients with hilar cholangiocarcinoma. The criticism
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Table VII. Univariate and multivariate analyses for postoperative infectious complications after the operation
Variables Age, yr <65 S65 Gender Male Female Body mass index <22 S22 K-ICG* <0.160 S0.160 Preoperative biliary drainage Without With Perioperative bile culture Negative Positive Operative time, min <600 S600 Operative blood loss <2000m L S2000mL Type of hepatectomyy Minor Major Combined pancreatoduodenectomy Absent Present Combined PV and/or HA resection Absent Present
No.
Postoperative infectious complications (n = 166)
Univariate P
Multivariate RR (95% CI)
.029 261 326
62 104
(23.7) (31.9)
363 224
114 52
(31.4) (23.2)
330 257
81 85
(24.5) (33.1)
288 290
94 69
(32.6) (23.8)
112 475
32 134
(28.6) (28.2)
94 493
5 161
(5.3) (32.7)
264 323
39 127
(14.4) (39.3)
395 192
78 88
(19.7) (45.8)
193 394
49 117
(25.4) (29.7)
478 109
116 50
(24.3) (45.8)
359 228
96 70
(26.4) (30.7)
P .035
1.00 1.57 (1.03–2.39) .032
.023
.003 1.00 1.87 (1.25–2.82)
.018
.939 <.001
<.001 1.00 6.52 (2.50–16.96)
<.001
.004 1.00 2.04 (1.25–3.32)
<.001
.001 1.00 2.12 (1.36–3.31)
.276 <.001
.033 1.00 1.70 (1.04–2.78)
.299
*A total of 9 patients did not receive an indocyanine green clearance (ICG) examination before operation. yRight hepatectomy, right trisectionectomy, and left trisectionectomy are categorized as ‘‘major’’ hepatectomy. Other hepatectomies (left hepatectomy and central hepatectomy) are included in ‘‘minor’’ hepatectomy. Values are n (%) unless otherwise noted. HA, Hepatic artery; PV, portal vein.
of these studies is their retrospective nature, a limited number of patients enrolled, and no definite criteria for biliary drainage or the inclusion of palliative surgery. Compared with those without drainage, the patients with preoperative biliary drainage clearly were more complicated and challenging, and they therefore underwent more extended operations, with greater operative times and blood loss; nevertheless, there were no differences in morbidity and mortality between the 2 groups. These observations may support a ‘‘positive’’ effect of preoperative biliary
drainage. In contrast, even if preoperative biliary drainage would have a ‘‘negative’’ effect, it may have been attenuated and unevaluable because of the highly invasive nature of the operations performed in this series. To formulate a convincing conclusion, a randomized controlled trial is necessary but such a study cannot be recommended because it would be unethical to deny the benefit of a safer hepatectomy to patients with jaundice. Regarding the method of biliary drainage, Kawakami et al28 compared PTBD, ENBD, and EBS in patients with perihilar cholangiocarcinoma. They
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found that serious complications occurred in more than 10% of patients with PTBD, and tube occlusions with cholangitis developed in as many as 60% of patients with EBS. In contrast, the complications associated with ENBD were less frequent; therefore, the authors concluded that ENBD is the most suitable preoperative drainage method. More recently, we evaluated the efficacy of ENBD in 164 patients with suspected perihilar cholangiocarcinoma (nearly 80% of the patients had Bismuth type III - IV tumors) who underwent ENBD, and we demonstrated that a unilateral ENBD for future remnant lobe(s) can be performed safely with a high rate of success.29 Considering the increased incidence of troublesome complications associated with PTBD or EBS27,28 and the satisfactory efficacy of ENBD,29 ENBD is better to be used for preoperative biliary drainage in patients who are to undergo difficult hepatobiliary resection. Several authors6,7,42,43 have reported that positive bile cultures during operation are associated with postoperative morbidity. Similarly, in our study, the incidence of infectious complications and hepatic failure was greater in patients with a positive bile culture during the perioperative period, and the postoperative hospital stay was greater for the same group of patients. On the basis of multivariate analysis, bacterobilia during the perioperative period was one of the independent factors related to infectious complications. Therefore, in the case of bacterobilia, bile spillage in the operative field should be avoided whenever possible, and careful postoperative management is essential, with special attention paid to the occurrence of infectious complications.47 Preoperative biliary drainage is unlikely to increase the incidence of infectious complications after hepatobiliary resection with cholangiojejunostomy. Perioperative surveillance bile culture is useful for the selection of appropriate antibiotics because of the high likelihood that micro-organisms isolated from the infectious sites are identical to those isolated from bile. Because the current report is a large but retrospective study, further studies are essential to validate our conclusion. REFERENCES 1. Povoski SP, Karpeh MS Jr, Conlon KC, Blumgart LH, Brennan MF. Association of preoperative biliary drainage with postoperative outcome following pancreaticoduodenectomy. Ann Surg 1999;230:131-42. 2. Sewnath ME, Birjmohun RS, Rauws EA, Huibregtse K, Obertop H, Gouma DJ. The effect of preoperative biliary drainage on postoperative complications after pancreaticoduodenectomy. J Am Coll Surg 2001;192:726-34.
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3. Martignoni ME, Wagner M, Krahenbuhl L, Redaelli CA, Friess H, Buchler MW. Effect of preoperative biliary drainage on surgical outcome after pancreatoduodenectomy. Am J Surg 2001;181:52-9; discussion 87. 4. Pisters PW, Hudec WA, Hess KR, Lee JE, Vauthey JN, Lahoti S, et al. Effect of preoperative biliary decompression on pancreaticoduodenectomy-associated morbidity in 300 consecutive patients. Ann Surg 2001;234:47-55. 5. van der Gaag NA, Rauws EA, van Eijck CH, Bruno MJ, van der Harst E, Kubben FJ, et al. Preoperative biliary drainage for cancer of the head of the pancreas. N Engl J Med 2010; 362:129-37. 6. Jagannath P, Dhir V, Shrikhande S, Shah RC, Mullerpatan P, Mohandas KM. Effect of preoperative biliary stenting on immediate outcome after pancreaticoduodenectomy. Br J Surg 2005;92:356-61. 7. Sivaraj SM, Vimalraj V, Saravanaboopathy P, Rajendran S, Jeswanth S, Ravichandran P, et al. Is bactibilia a predictor of poor outcome of pancreaticoduodenectomy? Hepatobiliary Pancreat Dis Int 2010;9:65-8. 8. Povoski SP, Karpeh MS Jr, Conlon KC, Blumgart LH, Brennan MF. Preoperative biliary drainage: impact on intraoperative bile cultures and infectious morbidity and mortality after pancreaticoduodenectomy. J Gastrointest Surg 1999;3:496-505. 9. Sakata J, Shirai Y, Tsuchiya Y, Wakai T, Nomura T, Hatakeyama K. Preoperative cholangitis independently increases in-hospital mortality after combined major hepatic and bile duct resection for hilar cholangiocarcinoma. Langenbecks Arch Surg 2009;394:1065-72. 10. Hemming AW, Reed AI, Fujita S, Foley DP, Howard RJ. Surgical management of hilar cholangiocarcinoma. Ann Surg 2005;241:693-9; discussion 699–702. 11. Regimbeau JM, Fuks D, Le Treut YP, Bachellier P, Belghiti J, Boudjema K, et al. Surgery for hilar cholangiocarcinoma: a multi-institutional update on practice and outcome by the AFC-HC study group. J Gastrointest Surg 2011;15:480-8. 12. Nagino M, Takada T, Miyazaki M, Miyakawa S, Tsukada K, Kondo S, et al. Preoperative biliary drainage for biliary tract and ampullary carcinomas. J Hepatobiliary Pancreat Surg 2008;15:25-30. 13. Seyama Y, Kubota K, Sano K, Noie T, Takayama T, Kosuge T, et al. Long-term outcome of extended hemihepatectomy for hilar bile duct cancer with no mortality and high survival rate. Ann Surg 2003;238:73-83. 14. Kawasaki S, Imamura H, Kobayashi A, Noike T, Miwa S, Miyagawa S. Results of surgical resection for patients with hilar bile duct cancer: application of extended hepatectomy after biliary drainage and hemihepatic portal vein embolization. Ann Surg 2003;238:84-92. 15. Ferrero A, Lo Tesoriere R, Vigano L, Caggiano L, Sgotto E, Capussotti L. Preoperative biliary drainage increases infectious complications after hepatectomy for proximal bile duct tumor obstruction. World J Surg 2009;33:318-25. 16. Hochwald SN, Burke EC, Jarnagin WR, Fong Y, Blumgart LH. Association of preoperative biliary stenting with increased postoperative infectious complications in proximal cholangiocarcinoma. Arch Surg 1999;134:261-6. 17. Cherqui D, Benoist S, Malassagne B, Humeres R, Rodriguez V, Fagniez PL. Major liver resection for carcinoma in jaundiced patients without preoperative biliary drainage. Arch Surg 2000;135:302-8. 18. El-Hanafy E. Pre-operative biliary drainage in hilar cholangiocarcinoma, benefits and risks, single center experience. Hepatogastroenterology 2010;57:414-9.
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19. Nagino M, Nishio H, Ebata T, Yokoyama Y, Igami T, Nimura Y. Intrahepatic cholangiojejunostomy following hepatobiliary resection. Br J Surg 2007;94:70-7. 20. Ebata T, Nagino M, Nishio H, Arai T, Nimura Y. Right hepatopancreatoduodenectomy: improvements over 23 years to attain acceptability. J Hepatobiliary Pancreat Surg 2007;14:131-5. 21. Ebata T, Yokoyma Y, Igami T, Sugawara G, Takahashi Y, Nimura Y, et al. Hepatopancreatoduodenectomy for cholangiocarcinoma: a single-center review of 85 consecutive patients. Ann Surg 2012;256:297-305. 22. Takara D, Sugawara G, Ebata T, Yokoyama Y, Igami T, Nagino M. Preoperative biliary MRSA infection in patients undergoing hepatobiliary resection with cholangiojejunostomy: incidence, antibiotic treatment, and surgical outcome. World J Surg 2011;35:850-7. 23. Nagino M, Hayakawa N, Nimura Y, Dohke M, Kitagawa S. Percutaneous transhepatic biliary drainage in patients with malignant biliary obstruction of the hepatic confluence. Hepatogastroenterology 1992;39:296-300. 24. Kanai M, Nimura Y, Kamiya J, Kondo S, Nagino M, Miyachi M, et al. Preoperative intrahepatic segmental cholangitis in patients with advanced carcinoma involving the hepatic hilus. Surgery 1996;119:498-504. 25. Nimura Y. Preoperative biliary drainage before resection for cholangiocarcinoma (Pro). HPB (Oxford) 2008;10:130-3. 26. Takahashi Y, Nagino M, Nishio H, Ebata T, Igami T, Nimura Y. Percutaneous transhepatic biliary drainage catheter tract recurrence in cholangiocarcinoma. Br J Surg 2010;97:1860-6. 27. Kawakami H, Kondo S, Kuwatani M, Yamato H, Ehira N, Kudo T, et al. Preoperative biliary drainage for hilar cholangiocarcinoma: which stent should be selected? J Hepatobiliary Pancreat Sci 2011;18:630-5. 28. Kawakami H, Kuwatani M, Onodera M, Haba S, Eto K, Ehira N, et al. Endoscopic nasobiliary drainage is the most suitable preoperative biliary drainage method in the management of patients with hilar cholangiocarcinoma. J Gastroenterol 2011;46:242-8. 29. Kawashima H, Itoh A, Ohno E, Itoh Y, Ebata T, Nagino M, et al. Preoperative endoscopic nasobiliary drainage in 164 consecutive patients with suspected perihilar cholangiocarcinoma: A retrospective study of efficacy and risk factors related to complications. Ann Surg 2012 [Epub ahead of print]. 30. Yokoyama Y, Nishio H, Ebata T, Igami T, Sugawara G, Nagino M. Value of indocyanine green clearance of the future liver remnant in predicting outcome after resection for biliary cancer. Br J Surg 2010;97:1260-8. 31. Kamiya S, Nagino M, Kanazawa H, Komatsu S, Mayumi T, Takagi K, et al. The value of bile replacement during external biliary drainage: an analysis of intestinal permeability, integrity, and microflora. Ann Surg 2004;239:510-7. 32. Kanazawa H, Nagino M, Kamiya S, Komatsu S, Mayumi T, Takagi K, et al. Synbiotics reduce postoperative infectious complications: a randomized controlled trial in biliary cancer patients undergoing hepatectomy. Langenbecks Arch Surg 2005;390:104-13. 33. Sugawara G, Nagino M, Nishio H, Ebata T, Takagi K, Asahara T, et al. Perioperative synbiotic treatment to prevent postoperative infectious complications in biliary cancer surgery: a randomized controlled trial. Ann Surg 2006;244:706-14.
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34. Mizuno T, Yokoyama Y, Nishio H, Ebata T, Sugawara G, Asahara T, et al. Intraoperative bacterial translocation detected by bacterium-specific ribosomal rna-targeted reverse-transcriptase polymerase chain reaction for the mesenteric lymph node strongly predicts postoperative infectious complications after major hepatectomy for biliary malignancies. Ann Surg 2010;252:1013-9. 35. Shigeta H, Nagino M, Kamiya J, Uesaka K, Sano T, Yamamoto H, et al. Bacteremia after hepatectomy: an analysis of a single-center, 10-year experience with 407 patients. Langenbecks Arch Surg 2002;387:117-24. 36. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for prevention of surgical site infection, 1999. Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol 1999;20:250-78; quiz 79– 80. 37. Bassi C, Dervenis C, Butturini G, Fingerhut A, Yeo C, Izbicki J, et al. Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery 2005;138:8-13. 38. Ebata T, Nagino M, Kamiya J, Uesaka K, Nagasaka T, Nimura Y. Hepatectomy with portal vein resection for hilar cholangiocarcinoma: audit of 52 consecutive cases. Ann Surg 2003;238:720-7. 39. Nagino M, Nimura Y, Nishio H, Ebata T, Igami T, Matsushita M, et al. Hepatectomy with simultaneous resection of the portal vein and hepatic artery for advanced perihilar cholangiocarcinoma: an audit of 50 consecutive cases. Ann Surg 2010;252:115-23. 40. Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, Bodniewicz BJ, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 2001;234:507-17; discussion 17–9. 41. Nagino M, Kamiya J, Uesaka K, Sano T, Yamamoto H, Hayakawa N, et al. Complications of hepatectomy for hilar cholangiocarcinoma. World J Surg 2001;25:1277-83. 42. Cortes A, Sauvanet A, Bert F, Janny S, Sockeel P, Kianmanesh R, et al. Effect of bile contamination on immediate outcomes after pancreaticoduodenectomy for tumor. J Am Coll Surg 2006;202:93-9. 43. Limongelli P, Pai M, Bansi D, Thiallinagram A, Tait P, Jackson J, et al. Correlation between preoperative biliary drainage, bile duct contamination, and postoperative outcomes for pancreatic surgery. Surgery 2007;142:313-8. 44. Sudo T, Murakami Y, Uemura K, Hayashidani Y, Hashimoto Y, Ohge H, et al. Specific antibiotic prophylaxis based on bile cultures is required to prevent postoperative infectious complications in pancreatoduodenectomy patients who have undergone preoperative biliary drainage. World J Surg 2007;31:2230-5. 45. Isla AM, Griniatsos J, Riaz A, Karvounis E, Williamson RC. Pancreaticoduodenectomy for periampullary malignancies: the effect of bile colonization on the postoperative outcome. Langenbecks Arch Surg 2007;392:67-73. 46. Sanjay P, Fawzi A, Kulli C, Polignano FM, Tait IS. Impact of methicillin-resistant Staphylococcus Aureus (MRSA) infection on patient outcome after pancreatoduodenectomy (PD)–a cause for concern? Pancreas 2010;39:1211-4. 47. Igami T, Nishio H, Ebata T, Yokoyama Y, Sugawara G, Nimura Y, et al. Surgical treatment of hilar cholangiocarcinoma in the ‘‘new era’’: the Nagoya University experience. J Hepatobiliary Pancreat Sci 2010;17:449-54.
Background. Arguments against biliary drainage before pancreatoduodenectomy have been gaining momentum recently. The benefits of biliary drainage before hepatobiliary resection, ie, combined liver and extrahepatic bile duct resection, however, are still debatable. Objective. To review the outcomes of patients who underwent hepatobiliary resection, with special attention to preoperative biliary drainage, to investigate whether biliary drainage increases the risk of postoperative infectious complications. Methods. This study involved 587 patients who underwent hepatobiliary resection with cholangiojejunostomy, including 475 patients who underwent preoperative biliary drainage and 112 patients who did not. Before each operation, surveillance bile cultures were performed at least once a week. Postoperatively, the bile and drainage fluid were cultured on days 1, 4, and 7. The hospital records of consecutive patients who underwent hepatobiliary resection were reviewed retrospectively. Results. Of the 475 patients with biliary drainage, 356 (74.9%) had a positive bile culture during the preoperative period. The incidence of postoperative infectious complications, including surgical-site infection and bacteremia, was similar between patients with biliary drainage and those without (28.2% vs 28.6%, P = .939). A positive bile culture during the perioperative period was highly associated with infectious complications and was one of the independent predictive factors related to infectious complications in a multivariate analysis. Conclusion. Preoperative biliary drainage is unlikely to increase the incidence of infectious complications after hepatobiliary resection. Perioperative surveillance bile culture is useful for the perioperative selection of appropriate antibiotics because of the high likelihood that micro-organisms isolated from infected sites are identical to those isolated from bile. (Surgery 2013;153:200-10.) From the Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
SEVERAL AUTHORS1-5 recently have analyzed the outcomes of pancreatoduodenectomy and have concluded that preoperative biliary drainage is not necessary, in principle. Furthermore, in some studies5-8 authors have shown that the presence of bacterobilia caused by preoperative biliary drainage is associated with surgical-site infection (SSI) and mortality after pancreatoduodenectomy. These findings support arguments against biliary drainage before pancreatoduodenectomy. Accepted for publication July 30, 2012. Reprint requests: Masato Nagino, MD, PhD, Professor and Chairman, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 4668550, Japan. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2012.07.032
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In contrast, the debate over the benefits of biliary drainage before hepatobiliary resection, ie, combined liver and extrahepatic bile duct resection, remains unsettled. Mortality after extended hepatobiliary resection remains high, with levels near 10%,9-11 and the cause of death is mainly hepatic failure. Biliary drainage can ameliorate liver damage caused by obstructive jaundice; therefore, biliary drainage seems to be a pivotal element of presurgical management in patients with obstructive jaundice who are to undergo hepatobiliary resection.12-14 In contrast, Ferrero et al15 and Hochward et al16 showed that prehepatectomy biliary drainage increases the incidence of postoperative infectious complications and that it does not lead to improved surgical outcomes in jaundiced patients. Cherqui et al17 and El-Hanafy18 reported that major hepatobiliary resections without biliary
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drainage can be performed safely in most patients with obstructive jaundice. In 1 previous study,15 the criteria for biliary drainage were not described clearly, and other studies16,17 did not include data on preoperative hepatic function or the extent of liver resection. Therefore, their conclusions must be interpreted cautiously. In the present study, we reviewed the outcomes of patients who underwent hepatobiliary resection, with special attention to preoperative biliary drainage, to investigate whether biliary drainage increases postoperative infectious complications in this difficult setting. MATERIALS AND METHODS Patients. This study involved 587 consecutive patients who underwent combined liver and extrahepatic bile duct resection with intrahepatic cholangiojejunostomy19 between January 2001 and September 2011 at the First Department of Surgery, Nagoya University Hospital. Patients who underwent hepatopancreatoduodenectomy were included in this study.20,21 There were 363 (61.8%) men and 224 (38.2%) women with a mean age of 65 ± 10 years (range, 22–83). Of these patients, 477 (81.3%) patients had cholangiocarcinoma, 64 (10.9%) gallbladder cancer, 23 (3.9%) other malignancies, and the remaining 23 (3.9%) benign disease (Table I). Of the 587 study patients, 350 patients (59.6%) overlapped with the cohort of our previous study on biliary methicillin-resistant Staphylococcus aureus (MRSA) infection.22 Preoperative biliary drainage and portal vein embolization. Preoperative management was performed according to the flow chart described in Figure. In case of jaundice (serum total bilirubin level S2.0 mg/dL) and/or dilated bile ducts in the future remnant lobe, preoperative biliary drainage was performed. Before 2005, percutaneous transhepatic biliary drainage (PTBD) routinely was selected as a method of preoperative biliary drainage.23-25 After 2005, our strategy for drainage changed gradually as we considered seeding metastasis associated with PTBD.26 Endoscopic nasobiliary drainage (ENBD) was used when possible,27,28 and PTBD was used only when ENBD was not feasible. Overall, 374 (63.7%) patients were jaundiced at the time of admission (serum total bilirubin level S2.0 mg/dL), with a mean serum total bilirubin concentration of 9.7 ± 6.5 mg/dL (2.0– 40.4 mg/dL). A total of 475 (80.9%) patients, including all of the jaundiced patients and 101 (17.2%) nonjaundiced patients who had
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intrahepatic biliary dilatation, underwent preoperative biliary drainage to relieve biliary obstruction, treat segmental cholangitis24 and/or to define the anatomy of the biliary tree. The method of biliary drainage was PTBD in 290 patients, ENBD in 156 patients, endoscopic biliary stenting (EBS) in 15 patients, or both PTBD and ENBD in 14 patients (Table I). Hemobilia (n = 6) or catheter dislodgement (n = 24) occurred after PTBD, and these patients were treated by catheter exchange or additional PTBD. Post-ENBD pancreatitis (grade 2 or 3)29 occurred in 6 patients and was treated with conservative therapy. These procedure-related complications of PTBD or ENBD never precluded the planned operation. The remaining 112 (19.1%) patients did not undergo preoperative biliary drainage. In general, when a future liver remnant ICGK value (ICGK-F = ICGK 3 proportion of the future liver remnant) was less than 0.05,30 portal vein embolization (PVE) was indicated to avoid the risk of postoperative hepatic failure. Embolization of the right portal vein was performed in 189 patients who were to undergo right hepatectomy. Embolization of the right and left medial portal veins was carried out in 34 patients who were to undergo right hepatic trisectionectomy. Embolization of the left and right anterior portal veins was performed in 105 patients who were to undergo left hepatic trisectionectomy. Embolization of the right anterior and left medial portal veins was performed in 1 patient who was to undergo central bisegmentectomy. Preoperative bile culture. Bile drained externally from the PTBD or ENBD catheter was sampled for aerobic and anaerobic bacterial culture at least once a week during the preoperative period.22 The bile specimens were cultured for at least 3 days using 3 aerobic media (5% sheep blood agar, SS agar, and Macconkey agar), anaerobic media (Brucella HK agar RS), and CHROM agar for MRSA surveillance. The cost of bile culture was approximately 30 US $/sample. Blood and bile were obtained for cultures if a patient developed a fever exceeding 38.58C at any time after biliary drainage, irrespective of the presence or absence of other infectious sources. A diagnosis of cholangitis was made when a patient had a fever (>38.58C), a positive bile culture, and abnormalities in liver function test results, provided that other septic complications were ruled out.24 Perioperative nutritional management. Preoperatively, all patients received a regular diet, and no
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Table I. Characteristics of patients according to the presence or absence of preoperative biliary drainage Age Sex (male/female) ICGK value Disease, n (%) Cholangiocarcinoma Gallbladder cancer Other malignancies Benign Method of biliary drainage PTBD/ENBD/EBS/PTBD+ENBD Preoperative cholangitis, n (%) Preoperative bacteremia, n (%) Serum total bilirubin, mg/dL On admission One day before operation
With PBD (n = 475)
Without PBD (n = 112)
65 ± 10 287/188 0.160 ± 0.029
65 ± 11 76/36 0.160 ± 0.031
399 45 15 16
(84.0) (9.5) (3.2) (3.3)
78 19 8 7
P .957 .145 .887 .017
(69.6) (17.0) (7.1) (6.3)
290/156/15/14 76 (16.0) 33 (6.9)
— 0 0
<.001 .008
7.7 ± 6.7 0.8 ± 0.4
0.9 ± 0.5 0.9 ± 0.5
<.001 .589
ENBD, Endoscopic nasobiliary drainage; EBS, endoscopic biliary stenting; ICGK, indocyanine green clearance rate; PBD, preoperative biliary drainage; PTBD, percutaneous transhepatic biliary drainage.
Figure. Flow chart for preoperative treatment T.Bil, serum total bilirubin concentration; PVE, Portal vein embolization.
patients received parenteral or enteral nutritional supplementation. As previously reported,31 all bile drained externally from the biliary drainage catheter was replaced orally or via a nasoduodenal tube to maintain intestinal integrity regardless of the
presence of bacteria in the bile. Preoperative synbiotic treatment was used routinely for at least 2 weeks before operation since 2005, after its validation in a randomized controlled trial.32-34 The following agents were administered orally: one 80-mL bottle of Yakult 400 (Yakult Honsha, Tokyo, Japan) containing at least 4 3 1010 living Lactobacillus casei strain Shirota, one 100 -mL bottle of Bifiene (Yakult Honsha) containing at least 1 3 1010 living Bifidobacterium breve strain Yakult, and galacto-oligosaccharides (Oligomate 55, Yakult Honsha; 15 g/day). During the procedure, an 8-Fr catheter was placed through a jejunal limb for postoperative enteral feeding. After the operation, enteral feeding (Racol, 1 Kcal/mL; EN Otsuka Pharmaceutical, Japan) was initiated on postoperative day 1 at 200 Kcal/ day and was gradually increased to 400 Kcal/day by day 4. Oral intake began on day 5, with enteral feeding decreasing gradually as oral intake increased. Total parenteral nutrition was not implemented, and the central venous catheter inserted in the operating room was removed 1 to 3 days postoperatively. Postoperative synbiotic treatment was performed routinely starting in 2003 and was administered through the feeding catheter from postoperative days 1 to 14.32 The synbiotics used after hepatectomy were Yakult BL granule (Yakult Honsha) containing 1 3 108 living Lactobacillus casei strain Shirota and 1 3 108 living Bifidobacterium breve strain Yakult per gram as well as galactooligosaccharides (Oligomate 55; Yakult Honsha). Perioperative antibiotic treatment. During the preoperative period, antibiotic treatment was
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performed only when a patient developed probable cholangitis and bacteremia with a high fever and leukocytosis. On the day of the operation, all patients received antibiotic prophylaxis as a single intravenous drip infusion 30 minutes before the procedure. Postoperative antibiotic prophylaxis was used for at least 3 days after operation, with a mean duration of 3.8 ± 2.4 days. Prophylactic antibiotics were selected according to the surveillance bile culture; when the bile culture was negative, first- or second-generation cephalosporins were used, and when the bile culture was positive, antibiotics were selected according to the susceptibility of the specific microorganisms detected. When MRSA or Enterococcus species susceptible to vancomycin alone was positive, vancomycin plus other antibiotics effective against gramnegative rods were selected as prophylactic antibiotics.22 Surgery. All hepatectomies were carried out after the serum total bilirubin concentration decreased to less than 2 mg/dL. Liver transection was carried out using CUSA or P ean forceps according to the surgeon preference during both hepatic artery and portal vein clamping for 15 minutes at 5-minute intervals. Bilioenteric continuity was reestablished by Roux-en-Y cholangiojejunostomy in all patients as reported previously.19 In cases of hepatopancreatoduodenectomy, reconstruction was performed according to Child’s method with an end-to-side pancreaticojejunostomy. All anastomosed bile ducts were drained externally and, in effect, stented at the anastomosis with a 6-Fr polyvinyl chloride tube (PTBD tube; Hakko, Chikuma, Japan). Transanastomotic stents were introduced via a transjejunal route. Initially, we fixed the drainage tube(s) in position with 5-0 PDS, and the tubes were not removed until at least 3 weeks after the hepatectomy. For the past 6 years, we have fixed tube(s) in position with 5-0 polyglactin (VICRYL Rapide; Ethicon, Somerville, NJ) and removed the tubes within 2 weeks of the hepatobiliary resection. The abdominal cavity was drained routinely using a closed multichannel silicone drain. Postoperative management of biliary drainage and abdominal drainage. Postoperatively, bile drained externally from the transjejunal stent tube(s), and fluid from the abdominal drain(s) was cultured routinely on days 1, 4, and 7 for surveillance. Blood was cultured when a patient developed a fever exceeding 38.58C at any time after the operation, irrespective of the presence or absence of other infectious sources.35 The abdominal drains were removed on postoperative day 7 when the drainage fluid was clear.
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Recording of postoperative complications. Detailed daily records of patients’ postoperative courses were kept, and infectious complications were recorded for up to 30 days after the procedure. All infections were proven to be bacteriologic, as determined by a positive culture. SSI, including superficial/deep incisional SSI and organ/space SSI, was defined as a condition in which purulent discharge was observed from any incision or space that was manipulated intraoperatively within 30 days after the operation, according to the guideline by The Centers for Disease Control and Prevention.36 Bacteremia was diagnosed when a single blood culture grew an isolate of organisms, unless the isolate was Staphylococcus epidermidis or a coagulasenegative Staphylococcus species. Pneumonia was defined as a characteristic pulmonary infiltrate on a chest radiograph accompanied by leukocytosis. The types of microorganisms isolated from superficial/deep incisional SSIs, organ/space SSIs, and the blood were compared with those from perioperative bile culture. Pancreatic fistula was defined according to the International Study Group of Pancreatic Fistula.37 Hepatic failure was defined as an increased serum total bilirubin concentration >10 mg/dL. Statistics. The statistical analysis was performed using Dr SPSS II for Windows Version 11.01 J (SPSS Inc, Chicago, IL). Quantitative data are expressed as means with SD. The Student t test was used to compare parametric data. Qualitative data were compared using the chi-square test or the Fisher exact test, where appropriate. The multivariate analysis was performed using logistic regression models. RESULTS Patient demographics. The patients’ characteristics are summarized in Table I according to the absence or presence of preoperative biliary drainage. Of the 475 patients with preoperative biliary drainage, 76 (16.0%) had preoperative cholangitis, and 33 (6.9%) had preoperative bacteremia. Of the 112 patients without preoperative biliary drainage, none had cholangitis and bacteremia. Serum bilirubin levels on admission were greater in patients with preoperative biliary drainage (7.7 ± 6.7) than in those without (0.9 ± 0.5; P < .001). The time between admission and the operation was 49 days (range, 5–254) in patients with biliary drainage, and it was 27 days (range, 6–124) in patients without biliary drainage (P < .001). Most of the patients were discharged from the hospital after completion of a preoperative workup including biliary drainage
204 Sugawara et al
or PVE and were readmitted 2 to 3 days before the operation. The surgical procedures performed are summarized in Table II. A left-sided hepatectomy was performed in 287 (48.9%) patients, a right-sided hepatectomy in 268 (45.7%) patients, and a central hepatectomy in 32 (5.4%) patients. Resection of the extrahepatic bile duct was performed in all patients. Combined caudate lobectomy was performed in 563 (95.9%) patients. Combined pancreatoduodenectomy20,21 was performed in 109 (18.6%) patients. Portal vein and/or hepatic artery resection and reconstruction38,39 were performed in 228 (38.8%) patients. There were differences between the 2 groups regarding both the incidence of combined pancreatoduodenectomy (P = .017) and combined resection of the portal vein and/or hepatic artery (P < .001). Operative time was greater in patients with preoperative biliary drainage (P < .001), as was blood loss (P = .024). As a result, the incidence of perioperative blood transfusion was greater in the former group of patients (P < .001). Preoperative bile and blood culture. Of the 475 patients with preoperative biliary drainage, 356 (74.9%) had a positive bile culture, and the remaining 119 (25.1%) had negative bile culture during the preoperative period. Of the 356 patients with positive bile culture, 184 (51.7%) had a mixed infection with 2 or more microorganisms. A total of 671 microorganisms were isolated from the bile of the 356 patients (Table III). The most commonly isolated bacteria were Enterococcus species (23.0%), followed by Klebsiella species (14.3%), Staphylococcus species (14.2%), and Enterobacter species (9.4%) in decreasing order. Preoperative cholangitis occurred in 76 (16.0%) of the 475 patients with preoperative biliary drainage. Preoperative bacteremia occurred in 33 (6.9%) of the 475 patients, and in 27 (81.8%) patients of these 33 patients, the microorganism(s) isolated from blood was the same as that isolated from the bile. The most commonly isolated bacteria from the blood in patients with bacteremia were Enterococcus species (31.4%), followed by Staphylococcus species (20.0%) and Klebsiella species (20.0%). All patients who suffered from preoperative bacteremia had preoperative cholangitis. As the result of appropriate biliary drainage and administration of antibiotics, all patients with preoperative bacteremia were in good condition at the time of operation. No preoperative cholangitis or preoperative bacteremia occurred in the 112 patients without biliary drainage. Postoperative complications. The postoperative complications are listed in Table IV. Of the 475 patients with preoperative biliary drainage, 134
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(28.2%) patients had postoperative infectious complications, including SSI, bacteremia, and pneumoniae. The incidence of postoperative infectious complications was not different between patients with PTBD and those with ENBD (30.0% vs 23.1%, P = .118). Of the 112 patients without preoperative biliary drainage, 32 (28.6%) patients had postoperative infectious complications. There was no difference in the incidence of postoperative infectious complications between the 2 groups (P = .939). Similarly, there was no difference in the incidence of other complications such as leakage of cholangiojejunostomy, pancreatic fistula (Grade B or C of International Study Group of Pancreatic Fistula classification), and hepatic failure. Of the 587 study patients, 19 (3.2%) patients died of hepatic failure (n = 16), intra-abdominal bleeding (n = 2), or septic shock (n = 1), and the remaining 568 (96.8%) patients were discharged from the hospital in good condition. The mortality rate was similar between the 2 groups (P = .941). Of the 166 patients with postoperative infectious complications, 150 (90.4%) patients were discharged in good condition, and the remaining 16 (9.6%) patients (13 patients with preoperative biliary drainage and 3 patients without preoperative biliary drainage) died. Of the 421 patients without postoperative infectious complications, only 3 (0.7%) patients (all patients with preoperative biliary drainage) died of hepatic failure after portal vein thrombus. The postoperative hospital stay was similar between the 2 groups (40 vs 38 days; P = .482). Postoperative cultures from bile and the sites of infectious complications. Of the 587 study patients, 404 (68.8%) had a positive bile culture during the postoperative period. Of these patients, 203 (50.2%) had a mixed infection with 2 or more microorganisms. A total of 777 microorganisms were isolated from the bile of the 404 patients (Table V). The most commonly isolated bacteria were Enterococcus species (27.9%), followed by Klebsiella species (15.4%) and Enterobacter species (14.0%). Through the perioperative (pre - and postoperative) period, 493 (83.9%) of the 587 study patients had a positive bile culture. Of the 475 patients with preoperative biliary drainage, 428 (90.1%) had a positive bile culture through the perioperative period. In contrast, of the 112 patients without biliary drainage, 65 (58.0%) had a positive bile culture through the perioperative period. The presence of preoperative biliary drainage did affect the incidence of perioperative bile contamination (P < .001). In the 72 patients with superficial/deep incisional SSIs, a total of 117 microorganisms were
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Table II. Operative procedures performed Operative procedure, n (%) Type of hepatectomy Left-sided hepatectomy Right-sided hepatectomy Central hepatectomy Combined pancreatoduodenectomy Combined PV and/or HA resection Operative time, min, mean ± SD Blood loss, mL, mean ± SD Perioperative blood transfusion, n (%)
With PBD (n = 475)
Without PBD (n = 112)
234 (49.3) 226 (47.6) 15 (3.1) 97 (20.4) 207 (43.6) 642 ± 152 2,097 ± 2,662 183 (38.5)
53 (47.3) 42 (37.5) 17 (15.2) 12 (10.7) 21 (18.8) 583 ± 142 1,700 ± 1,094 22 (19.6)
P <.001
.017 <.001 <.001 .024 <.001
HA, Hepatic artery; PBD, preoperative biliary drainage; PV, portal vein.
Table III. Microorganisms isolated from bile and blood culture before the procedure in patients with preoperative biliary drainage Bile (n = 356) Gram-positive bacteria, n (%) Enterococcus species 154 (23.0) Staphylococcus species 95 (14.2) MRSA 16 (2.4) Streptococcus species 17 (2.5) Bacillus species 7 (1.0) Gram-negative bacteria Klebsiella species 96 (14.3) Enterobacter species 63 (9.4) Citrobacter species 35 (5.2) Acinetobacter species 34 (5.1) Pseudomonas species 33 (4.9) Escherichia species 28 (4.2) Stenotrophomonas species 22 (3.3) Serratia species 17 (2.5) Aeromonas species 13 (1.9) Others 18 (2.7) Candida species 39 (5.8)
Blood (n = 33) 11 7 2 1 1
(31.4) (20.0) (5.7) (2.9) (2.9)
7 (20.0) 1 (2.9) 0 2 (5.7) 1 (2.9) 1 (2.9) 1 (2.9) 0 0 1 (2.9) 1 (2.9)
MRSA, Methicillin-resistant Staphylococcus aureus.
isolated from the site of the incisional SSI: the most commonly isolated bacteria were Enterococcus species (28.2%), followed by Staphylococcus species (24.8%; Table V). Of these 72 patients, 71 (98.6%) had positive bile culture during the perioperative period, and in 64 (88.9%) patients, the microorganism(s) isolated from the site of the incisional SSI was the same as that isolated from the bile. In the 114 patients with organ/space SSIs, a total of 278 microorganisms were isolated from the organ/space SSI. The most commonly isolated bacteria were Enterococcus species (24.1%), followed by Enterobacter species (14.4%; Table V). Of these
114 patients, 109 (95.6%) had a positive bile culture during the perioperative period, and in 97 (85.1%) patients, the microorganism(s) isolated from the abscess was the same as that isolated from the bile. In the 42 patients with bacteremia, a total of 65 microorganisms were isolated from the blood: the most commonly isolated bacteria were Enterococcus species (24.6%), followed by Staphylococcus species (20.0%; Table V). All 42 patients had a positive bile culture during the perioperative period, and in 31 (73.8%) patients, the microorganism(s) isolated from blood was the same as that isolated from the bile. Overall, the majority of patients with postoperative infectious complications had a positive bile culture, irrespective of preoperative biliary drainage, and the microorganism(s) from the site of postoperative infectious complications was associated closely with that isolated from the bile. Postoperative infectious complications according to the results of bile culture. Of the 587 study patients, 493 (84.0%) had a positive bile culture during the perioperative period, and the remaining 94 (16.0%) patients had a negative bile culture. Postoperative infectious complications according to the bile culture results are listed in Table VI. A positive bile culture affected the incidence of all infectious complications (161 vs 5; P < .001), SSI (147 vs 5; P < .001), incisional SSI (71 vs 1; P < .001), organ/space SSI (109 vs 5; P < .001), bacteremia (42 vs 0; P = .007), and hepatic failure (41 vs 0; P = .007). As a result, the postoperative hospital stay was greater for patients with a positive bile culture than for those with a negative culture (42 vs 30 days; P < .001). Factors associated with postoperative infectious complications. Eleven possible risk factors for the postoperative infectious complications were analyzed by a univariate analysis; age (S65), sex
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Table IV. Postoperative complications Patients with any infectious complications, n (%) Surgical site infections (SSI) Superficial/deep incisional SSI Organ/space SSI Bacteremia Pneumoniae Leakage of CJ anastomosis Pancreatic fistula* (n = 109) Hepatic failurey Hospital death Postoperative hospital stay, days
With PBD (n = 475)
Without PBD (n = 112)
P
134 (28.2) 125 (26.3) 61 (12.8) 93 (19.6) 34 (7.2) 6 (1.3) 19 (4.) 65 (n = 97; 67.0%) 37 (7.8) 16 (3.4) 40 ± 27
32 (28.6) 27 (24.1) 11 (9.8) 21 (18.8) 8 (7.1) 5 (4.5) 3 (2.7) 11 (n = 12; 91.7%) 4 (3.6) 3 (2.7) 38 ± 26
.939 .631 .381 .842 .843 .073 .699 .155 .171 .941 .482
*Grade B or C of International Study Group of Pancreatic Fistula classification. yDefined as an increased serum total bilirubin concentration >10 mg/dL. CJ, Cholangiojejunostomy; PBD, preoperative biliary drainage.
Table V. Micro-organisms isolated from bile and sources of infectious complications after the operation Bile (n = 404) Gram-positive bacteria, n (%) Enterococcus species Staphylococcus species MRSA Streptococcus species Bacillus species Gram-negative bacteria Klebsiella species Enterobacter species Citrobacter species Acinetobacter species Pseudomonas species Escherichia species Stenotrophomonas species Serratia species Aeromonas species Others Candida species
I.SSI (n = 72)
O.SSI (n = 114)
Blood (n = 42) 16 (24.6) 13 (20.0) 7 (10.8) 0 0
217 52 30 3 1
(27.9) (6.7) (3.9) (0.4) (0.1)
33 (28.2) 29 (24.8) 19 (16.2) 0 0
67 (24.1) 34 (12.2) 22 (7.9) 0 3 (1.1)
120 109 25 39 38 30 26 32 5 8 72
(15.4) (14.0) (3.2) (5.0) (4.9) (3.9) (3.3) (4.1) (0.7) (1.1) (9.3)
14 16 4 1 4 3
32 40 13 6 13 15 10 14 2 3 26
4 1 4 4
(12.0) (13.6) (3.4) (0.9) (3.4) (2.6) 0 (3.4) (0.9) (3.4) (3.4)
(11.5) (14.4) (4.7) (2.1) (4.7) (5.4) (3.6) (5.0) (0.8) (1.1) (9.3)
9 7 1 3 2 3 1 3 1 2 4
(13.8) (10.8) (1.5) (4.6) (3.1) (4.6) (1.5) (4.6) (1.5) (3.1) (6.3)
I.SSI, Superficial/deep incisional SSI; MRSA, methicillin-resistant Staphylococcus aureus; O.SSI, organ/space SSI.
(male), body mass index (S22), K-ICG (< 0.160), positive bile culture, operative time (S600 minutes), blood loss (S2,000 mL), and the presence of combined pancreatoduodenectomy were significant (Table VII). On multivariate analysis, age, body mass index, positive bile culture, operative time, blood loss, and the presence of combined pancreatoduodenectomy were independent risk factors for postoperative infectious complications (Table VII). DISCUSSION Hepatobiliary resection, that is, combined hepatectomy and extrahepatic bile duct resection
followed by cholangiojejunostomy, is a complicated and technically demanding procedure. This procedure creates a high risk of postoperative infectious complications because of bilio-enteric anastomosis during the bile duct resection.40,41 Possible bile contamination of the operative field is likely to increase postoperative infectious complications, especially when the bile is colonized/infected with bacteria.9 In this context, we analyzed the relationship between bile colonization and infectious complications in complicated hepatectomy. This study is the first large-series report with detailed bacteriologic analysis using prospective data collection of perioperative cultures.
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Table VI. Infectious complications according to bile culture Bile culture Positive (n = 493) Patients with any infectious complications, n (%) Surgical-site infections (SSI) Superficial/deep incisional SSI Organ/space SSI Bacteremia Pneumoniae Hepatic failure* Hospital death Postoperative hospital stay (days)
161 (32.7) 147 (29.8) 71 (14.4) 109 (22.1) 42 (8.5) 11 (2.2) 41 (8.3) 19 (3.9) 42 ± 29
Negative (n = 94) 5 5 1 5
(5.3) (5.3) (1.1) (5.3) 0 0 0 0 30 ± 14
P <.001 <.001 <.001 <.001 .007 .295 .007 .105 <.001
*Defined as an increased serum total bilirubin concentration >10 mg/dL.
Many authors 6,8,16,42-44 have reported that bile is contaminated in 47–94% of patients with biliary obstruction after biliary drainage whereas contaminated bile is observed in less than 20% of patients without drainage. According to previous studies, the most commonly isolated microorganisms in the bile after biliary drainage were Enterococcus species 8,16,42,43 or Escherichia coli.6,45 In our series, bile culture was positive in approximately three-fourths of the patients with biliary drainage before operation; approximately one-half of the patients with positive bile cultures had mixed biliary infections, and the most common bacteria isolated from the bile were Enterococcus species (23.0%). These observations were comparable with previous studies.6,8,16,42-44 After the procedure, the most common bacteria isolated from both the bile and infectious sources also was Enterococcus species. An important finding is that the bile was contaminated after the operation in more than half (58%, 65/112) of the patients without preoperative biliary drainage. Once the bile duct is divided and anastomosed to the jejunum, bacterobilia is likely to occur, leading to infectious complications regardless of the absence or presence of preoperative biliary drainage. In addition, transanastomotic biliary stents routinely were used postoperatively in our series. Although speculative, the placement of the stents may have caused bile contamination after the operation, and, in turn, may have affected the surgical outcome. In our study, the microorganisms isolated from the infectious sites after the procedure were identical to those isolated from the bile during the perioperative period in most, although not all, patients. This finding strongly supports the use of perioperative-specific antibiotic prophylaxis on the basis of preoperative surveillance bile cultures to prevent and/or attenuate postoperative infectious complications. Furthermore, postoperative surveillance bile culture appears to be helpful for
selecting the antibiotics to treat infectious complications, especially in the case of organ/space SSI or bacteremia. We can use the surveillance bile culture to choose appropriate antibiotics more promptly. The incidence of postoperative MRSA infection in this study was similar to the results of previous studies on hepatobiliary-pancreatic surgery,46 and vancomycin-resistant species were never isolated. Our strategy for antibiotic selection, therefore, seems unlikely to accelerate the antibiotic resistance of causative micro-organisms. Collectively, routine perioperative surveillance bile culture is useful and recommended for patients undergoing hepatobiliary resection with cholangiojejunostomy. Cherqui et al17 reported that a major hepatectomy could be performed safely without preoperative biliary drainage in most patients with jaundice. This study was performed more than 10 years ago but only attracted attention for a brief time, and Cherqui himself noted that the study lead to incorrect conclusions (personal communication, May, 2012). As mentioned previously, a consensus has been established that preoperative biliary drainage usually is unnecessary in patients who are to undergo pancreatoduodenectomy. In contrast, hepatobiliary resection for biliary cancer is still challenging and associated with high rates of morbidity and mortality.9-11 Preoperative biliary drainage, therefore, is necessary for the safe performance of such a demanding hepatectomy. To our knowledge, biliary drainage is still used as a routine method of preoperative management for patients with jaundice who are to undergo a major hepatobiliary resection in both most Eastern and Western centers. In contrast, some authors15,16 have shown that preoperative biliary drainage is associated with postoperative infectious complications and that it does not lead to improved surgical outcomes in patients with hilar cholangiocarcinoma. The criticism
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Table VII. Univariate and multivariate analyses for postoperative infectious complications after the operation
Variables Age, yr <65 S65 Gender Male Female Body mass index <22 S22 K-ICG* <0.160 S0.160 Preoperative biliary drainage Without With Perioperative bile culture Negative Positive Operative time, min <600 S600 Operative blood loss <2000m L S2000mL Type of hepatectomyy Minor Major Combined pancreatoduodenectomy Absent Present Combined PV and/or HA resection Absent Present
No.
Postoperative infectious complications (n = 166)
Univariate P
Multivariate RR (95% CI)
.029 261 326
62 104
(23.7) (31.9)
363 224
114 52
(31.4) (23.2)
330 257
81 85
(24.5) (33.1)
288 290
94 69
(32.6) (23.8)
112 475
32 134
(28.6) (28.2)
94 493
5 161
(5.3) (32.7)
264 323
39 127
(14.4) (39.3)
395 192
78 88
(19.7) (45.8)
193 394
49 117
(25.4) (29.7)
478 109
116 50
(24.3) (45.8)
359 228
96 70
(26.4) (30.7)
P .035
1.00 1.57 (1.03–2.39) .032
.023
.003 1.00 1.87 (1.25–2.82)
.018
.939 <.001
<.001 1.00 6.52 (2.50–16.96)
<.001
.004 1.00 2.04 (1.25–3.32)
<.001
.001 1.00 2.12 (1.36–3.31)
.276 <.001
.033 1.00 1.70 (1.04–2.78)
.299
*A total of 9 patients did not receive an indocyanine green clearance (ICG) examination before operation. yRight hepatectomy, right trisectionectomy, and left trisectionectomy are categorized as ‘‘major’’ hepatectomy. Other hepatectomies (left hepatectomy and central hepatectomy) are included in ‘‘minor’’ hepatectomy. Values are n (%) unless otherwise noted. HA, Hepatic artery; PV, portal vein.
of these studies is their retrospective nature, a limited number of patients enrolled, and no definite criteria for biliary drainage or the inclusion of palliative surgery. Compared with those without drainage, the patients with preoperative biliary drainage clearly were more complicated and challenging, and they therefore underwent more extended operations, with greater operative times and blood loss; nevertheless, there were no differences in morbidity and mortality between the 2 groups. These observations may support a ‘‘positive’’ effect of preoperative biliary
drainage. In contrast, even if preoperative biliary drainage would have a ‘‘negative’’ effect, it may have been attenuated and unevaluable because of the highly invasive nature of the operations performed in this series. To formulate a convincing conclusion, a randomized controlled trial is necessary but such a study cannot be recommended because it would be unethical to deny the benefit of a safer hepatectomy to patients with jaundice. Regarding the method of biliary drainage, Kawakami et al28 compared PTBD, ENBD, and EBS in patients with perihilar cholangiocarcinoma. They
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found that serious complications occurred in more than 10% of patients with PTBD, and tube occlusions with cholangitis developed in as many as 60% of patients with EBS. In contrast, the complications associated with ENBD were less frequent; therefore, the authors concluded that ENBD is the most suitable preoperative drainage method. More recently, we evaluated the efficacy of ENBD in 164 patients with suspected perihilar cholangiocarcinoma (nearly 80% of the patients had Bismuth type III - IV tumors) who underwent ENBD, and we demonstrated that a unilateral ENBD for future remnant lobe(s) can be performed safely with a high rate of success.29 Considering the increased incidence of troublesome complications associated with PTBD or EBS27,28 and the satisfactory efficacy of ENBD,29 ENBD is better to be used for preoperative biliary drainage in patients who are to undergo difficult hepatobiliary resection. Several authors6,7,42,43 have reported that positive bile cultures during operation are associated with postoperative morbidity. Similarly, in our study, the incidence of infectious complications and hepatic failure was greater in patients with a positive bile culture during the perioperative period, and the postoperative hospital stay was greater for the same group of patients. On the basis of multivariate analysis, bacterobilia during the perioperative period was one of the independent factors related to infectious complications. Therefore, in the case of bacterobilia, bile spillage in the operative field should be avoided whenever possible, and careful postoperative management is essential, with special attention paid to the occurrence of infectious complications.47 Preoperative biliary drainage is unlikely to increase the incidence of infectious complications after hepatobiliary resection with cholangiojejunostomy. Perioperative surveillance bile culture is useful for the selection of appropriate antibiotics because of the high likelihood that micro-organisms isolated from the infectious sites are identical to those isolated from bile. Because the current report is a large but retrospective study, further studies are essential to validate our conclusion. REFERENCES 1. Povoski SP, Karpeh MS Jr, Conlon KC, Blumgart LH, Brennan MF. Association of preoperative biliary drainage with postoperative outcome following pancreaticoduodenectomy. Ann Surg 1999;230:131-42. 2. Sewnath ME, Birjmohun RS, Rauws EA, Huibregtse K, Obertop H, Gouma DJ. The effect of preoperative biliary drainage on postoperative complications after pancreaticoduodenectomy. J Am Coll Surg 2001;192:726-34.
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