Prospective randomized trial of systemic antibiotics in patients undergoing liver resection. Perioperative synbiotic treatment to prevent postoperative infectious complications in biliary cancer surgery: a randomized controlled trial. Effects of major liver resection, with or without recombinant bactericidal/permeability-increasing protein (rBPI21), on the angiogenic profile of patients with metastatic colorectal carcinoma. Bactericidal/permeability-increasing protein preserves leukocyte functions after major liver resection. Duration of antimicrobial prophylaxis in patients undergoing hepatectomy: a prospective randomized controlled trial using flomoxef. Synbiotics reduce postoperative infectious complications: a randomized controlled trial in biliary cancer patients undergoing hepatectomy. A new method to prevent wound infection: a controlled clinical trial in patients with combined liver and bile duct resection.
Systemic antibiotics are administered frequently after hepatectomy to prevent infective complications, but their effectiveness is uncertain.
                A total of 127 patients with liver tumours were prospectively randomized into two groups after hepatectomy: in group 1 (62 patients) no antibiotics were given until the appearance of infective complications; in group 2 (65 patients) intravenous cephazolin 1 g every 6 h and gentamicin 80 mg every 8 h were given for 7 days. On the day before surgery all patients received bowel preparation by clear liquid diet and oral antibiotics (neomycin 1 g and erythromycin 1 g, given together in three doses).
                The infective complication rate was 23 per cent in both groups (P = 0.95). The hospital costs were higher in group 2 (P < 0.001). Of the group 1 patients, 51 (82 per cent) did not require antibiotic treatment. No patient in either group died after hepatectomy.
                Postoperative systemic antibiotics cannot prevent infective complications, and their routine use after hepatectomy is unnecessary and costly. The use of antibiotics should be delayed until infective complications and persistent septic symptoms occur. Use of synbiotics has been reported to benefit human health, but clinical value in surgical patients remains unclear.
                To investigate the effect of perioperative oral administration of synbiotics upon intestinal barrier function, immune responses, systemic inflammatory responses, microflora, and surgical outcome in patients undergoing high-risk hepatobiliary resection.
                Patients with biliary cancer involving the hepatic hilus (n = 101) were randomized before hepatectomy, into a group receiving postoperative enteral feeding with synbiotics (group A); or another receiving preoperative plus postoperative synbiotics (group B). Lactulose-mannitol (L/M) ratio, serum diamine oxidase (DAO) activity, natural killer (NK) cell activity, interleukin-6 (IL-6), fecal microflora, and fecal organic acid concentrations were determined before and after hepatectomy. Postoperative infectious complications were recorded.
                Of 101 patients, 81 completed the trial. Preoperative and postoperative changes in L/M ratio and DAO activity were similar between groups. Preoperatively in group B, NK activity, and lymphocyte counts increased, while IL-6 decreased significantly (P < 0.05). Postoperative serum IL-6, white blood cell counts, and C-reactive protein in group B were significantly lower than in group A (P < 0.05). During the preoperative period, numbers of Bifidobacterium colonies cultured from and total organic acid concentrations measured in feces increased significantly in group B (P < 0.05). Postoperative concentrations of total organic acids and acetic acid in feces were significantly higher in group B than in group A (P < 0.05). Incidence of postoperative infectious complications was 30.0% (12 of 40) in group A and 12.1% (5 of 41) in group B (P < 0.05).
                Preoperative oral administration of synbiotics can enhance immune responses, attenuate systemic postoperative inflammatory responses, and improve intestinal microbial environment. These beneficial effects likely reduce postoperative infectious complications after hepatobiliary resection for biliary tract cancer. Surgery induces a process of wound healing, which has immunological and angiogenic aspects. Bactericidal/permeability-increasing protein (BPI) is found in azurophilic granules of human neutrophils, which is bactericidal and neutralizes lipo-polysaccharide (LPS). This may reduce postoperative infectious complications. In addition, BPI has been shown to be an inhibitor of angiogenesis.
                A total of 18 patients with metastasized colorectal carcinoma to the liver were double blind randomized. The levels of the pro-angiogenic factors interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) and the angiogenesis inhibitor endostatin were investigated after liver surgery with perioperative administration of either rBPI(21) or placebo.
                The highest IL-6 levels were found during the first 24 hr and reached peak levels already at 2 hr postoperatively in both groups. In both groups VEGF levels decreased sharply in the postoperative hours, returning to baseline levels in the days afterwards. In both groups, an immediate decrease in endostatin levels was observed which remained significantly low. RBPI(21) transiently influenced IL-6 and VEGF.
                RBPI(21) only marginally affected IL-6 and VEGF levels. Surgery per se induced an immediate immune response (IL-6) and an immediate angiogenic response, reflected in an initial VEGF decrease and a longer lasting decrease of endostatin. These findings demonstrate the dynamics of tissue responses in the first phase of wound healing.
                Copyright 2003 Wiley-Liss, Inc. To analyze postoperative leukocyte functions in patients undergoing hemihepatectomy, and to assess the effect of treatment with the endotoxin-neutralizing agent bactericidal/permeability-increasing protein (rBPI21).
                Extensive liver resection is associated with a high incidence of infectious complications. Because elimination of pathogenic microorganisms occurs mainly by leukocytes, this increased rate of infections is most likely due to an impaired function of these cells. Endotoxin, translocated from the gut into the systemic circulation as a result of increased gut permeability and reduced hepatic clearance function after major liver resection, may play an important role in the impairment of posthepatectomy leukocyte function.
                To investigate whether hemihepatectomy results in impaired leukocyte functions and to determine the role of endotoxin in this process, leukocyte oxidative burst and leukocyte antigen expression were studied in three groups of patients: patients undergoing a hemihepatectomy and receiving rBPI21 treatment, patients undergoing hemihepatectomy and receiving placebo, and as an extra control group patients undergoing other major abdominal surgeries. Blood samples were collected before surgery, 2 hours after surgery, and at days 1, 2, 5, and 7. Phorbol myristate acetate-stimulated oxidative burst was measured using dihydrorhodamine, and leukocyte surface expression of the antigens CD11b, CD16, and CD14 was investigated by indirect immunofluorescence. Both oxidative burst and membrane surface expression were quantified by flow cytometry. An indication of the antiendotoxin effect of rBPI21 treatment was provided by assessment of plasma lipopolysaccharide binding protein (LBP) levels by enzyme-linked immunosorbent assay.
                The oxidative burst in the hemihepatectomized patients receiving placebo and the controls increased 2 hours after surgery, whereas it decreased in the rBPI21-treated patients, resulting in significant differences between the groups. On day 1, neutrophil CD11b expression and monocyte CD14 expression in the rBPI21-treated patients and controls were significantly lower than in the placebo group. At 2 hours, CD16 expression in the placebo-treated patients was significantly higher than in the rBPI21-treated patients and controls. On day 5 and day 7, plasma LBP levels were significantly higher in the placebo-treated patients compared with the rBPI21-treated patients.
                The results of this study show that patients undergoing major liver resection have an increased activation of leukocytes compared with those undergoing other major abdominal surgery. This enhanced activation may contribute to the increased risk of infection in these patients. Administration of the endotoxin-neutralizing agent rBPI21 to hemihepatectomy patients was shown to reduce plasma LBP levels, to preserve leukocyte functions partially, and to reduce leukocyte activation to the level of other, nonhepatic abdominal surgery. Although the usefulness of antimicrobial prophylaxis for clean-contaminated surgery has been recognized, only a few randomized controlled studies on the duration of administration after hepatectomy have been performed. We investigated the duration of antimicrobial prophylaxis after hepatectomy.
                The subjects were 180 patients who underwent hepatectomy without reconstruction of the biliary or intestinal tract between April 2003 and March 2006 at our department. The patients were randomly allocated to groups to be treated with flomoxef sodium as antimicrobial prophylaxis for 2 days (89 patients) or 5 days (91 patients), including the operation day. The presence or absence of systemic inflammatory response syndrome (SIRS) and infections was investigated.
                No significant differences were noted in patient background between the two groups. Infections occurred in seven and six patients in the 2 day and 5 day treatment groups (7.9% and 6.6%), respectively, showing no significant difference between the two groups. No significant difference was noted when the cases were divided into surgical site infections and remote infections. The positive rate of SIRS was significantly higher in the 2 day treatment group than in the 5 day treatment group on days 2 and 3 after surgery. The risk factors in patients who developed infections were blood loss, operation time and the complication of biliary fistula.
                Two day administration of flomoxef sodium may be sufficient for antimicrobial prophylaxis after hepatectomy. However, when SIRS is positive on post-operative day 2, and induction of liver failure is of concern, it may be safer to continue antimicrobial drug administration until SIRS is eliminated. The clinical value of synbiotics in surgical patients remains unclear. The aim of this study was to investigate the effect of synbiotics on intestinal integrity and microflora, as well as on surgical outcome, in patients undergoing high-risk hepatectomy.
                Fifty-four patients with biliary cancer were randomly allocated to two groups before hepatectomy. One group received postoperative enteral feeding that included synbiotics; the other received enteral feeding only. Lactulose/mannitol (L/M) ratio, serum diamine oxidase (DAO) activity, and fecal microflora and organic acid concentrations were determined. Postoperative infectious complications were recorded.
                Of the 54 patients, 44 completed the trial (21 receiving synbiotics and 23 others as controls). Postoperative changes in L/M ratios and serum DAO activities were identical between the two groups. Numbers of beneficial bacteria increased in the synbiotics group after surgery but decreased in controls. Numbers of harmful microorganisms decreased in the synbiotics group but increased in controls. Total organic acid concentrations increased in the synbiotics group but decreased in controls. Incidence of infectious complications was 19% (4/21) in the synbiotics group and 52% (12/23) in controls (P<0.05). All study patients tolerated surgery (mortality 0%).
                Synbiotics, combined with early enteral nutrition, can reduce postoperative infections. This beneficial effect presumably involves correction of an intestinal microbial imbalance induced by surgical stress. Despite advances in antibiotic prophylaxis, postoperative wound infection remains a major source of morbidity after digestive surgery. Its prevention is a challenging problem, especially in high-risk patients. The authors introduced a new method to prevent surgical wound infections and evaluated its efficacy in a prospective, randomized trial in markedly high-risk patients.
                Patients with biliary tract carcinoma who were scheduled to undergo combined liver and extrahepatic bile duct resection with biliary reconstruction were randomly assigned to one of two groups, well matched in terms of clinical characteristics at baseline. In one group the new treatment was employed (sealed group, n=31), and in the other the wound was treated in the usual fashion (open group, n=28). In the sealed group, povidone-iodine gel was administered to the subcutaneous tissue, and the skin and peritoneum were approximated with a continuous suture. Wound infection was registered up to 30 days after surgery.
                Wound infection occurred in 18 patients: 5 (16%) patients in the sealed group and 13 (46%) in the open group (P<0.05). All 18 underwent preoperative percutaneous transhepatic biliary drainage and had positive bile culture findings. In 13 of these 18 patients (72%) the microorganisms isolated from the infected wound were identical to those in the bile.
                Our results confirm the close association between infected bile and wound infection in hepatobiliary surgery. Our new method, "direct wound sealing," is simple, easy to perform, virtually cost-free, and has the potential to prevent wound infections even in markedly high-risk patients.
There is currently no evidence to support or refute the use of any treatment to reduce infectious complications after liver resections. Further well designed trials with low risk of systematic error and low risk of random errors are necessary.