J Hepatobiliary Pancreat Sci (2015) 22:446–453 DOI: 10.1002/jhbp.222
ORIGINAL ARTICLE
Randomized clinical trial of peritoneal lavage for preventing surgical site infection in elective liver surgery Kuniya Tanaka · Kenichi Matsuo · Daisuke Kawaguchi · Takashi Murakami · Yukihiko Hiroshima · Atsushi Hirano · Sho Sato · Itaru Endo · Masataka Taguri · Keiji Koda Published online: 22 January 2015 © 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery
Abstract Background Although intraoperative peritoneal lavage is often performed routinely with the aim of reducing peritoneal contamination, little evidence of lavage benefits in elective liver resection without bile duct resection is available. We addressed the issue with a randomized clinical trial. Methods We prospectively and randomly assigned consecutive patients undergoing liver resection to a lavage group or a non-lavage group. Peritoneal lavage was performed at the end of operation for patients in the lavage group. The primary endpoint was the rate of surgical site infection. Results Ninety-six patients were assigned to the lavage group and 97 to the non-lavage group. When superficial/ deep incisional infection and organ/space infection were considered together, no significant difference in surgical site infection rate was evident between lavage (21.9%) and nonlavage groups (13.4%, P = 0.135). However, organ/space infection was significantly more frequent in the lavage group (16.7%) than the non-lavage group (7.2%, P = 0.048). Peritoneal lavage was identified as a risk factor for organ/space infection by multivariate analysis (relative risk, 2.977; confidence interval, 1.094 to 8.100; P = 0.033).
K. Tanaka (✉) · K. Matsuo · D. Kawaguchi · T. Murakami · Y. Hiroshima · A. Hirano · K. Koda Department of Surgery, Teikyo University Chiba Medical Center, 3426-3 Anesaki, Ichihara, Chiba 299-0111, Japan e-mail: [email protected] S. Sato · I. Endo Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan M. Taguri Department of Biostatistics and Epidemiology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
Conclusion Intraoperative peritoneal lavage does not reduce overall incidence of surgical site infection and may increase risk of organ/space infection. Keywords infection
Liver surgery · Peritoneal lavage · Surgical site
Introduction Despite technical advances and ongoing accrual of experience, liver resection still carries a relatively high risk of posthepatectomy morbidity and mortality. Although rates vary according to the disease requiring resection, overall morbidity has ranged from 13.54% to 47.7%, while mortality has ranged from 0.24% to 7.4% [1–8]. Common complications after liver resection include liver failure, infectious disease, bile leakage, and hemorrhage. Among these, liver insufficiency or failure is particularly dreaded by surgeons. Measures taken to prevent liver failure include careful assessment of hepatic functional reserve, prevention of intraoperative bleeding, avoidance of blood transfusion, and minimizing duration of hepatic inflow occlusion. As severe surgical site infection (SSI) and remote infection sometimes compromise systemic status and induce liver failure, reducing incidence of SSI can contribute importantly to maintenance of hepatic function after liver resection. Recently reported incidence figures for SSI following liver resection without resection or reconstruction of bile duct have varied between hepatectomy procedures, ranging from 9.7% to 18.3% [9]. Overall incidence of SSI after elective liver resection presently is 11.5% [9] to 14.5% [10]. Intraoperative peritoneal lavage is performed routinely with the aim of reducing peritoneal contamination. Many studies have maintained that intraoperative peritoneal lavage improved postoperative infectious morbidity and mortality, while sometimes also characterizing differences between
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specific irrigation fluids [11]. However, since this treatment may owe more to historic practice than to rigorous scientific evaluation, debate continues as to whether or not lavage should be undertaken. Intraoperative peritoneal lavage may have several actions. Sterile saline and water can accomplish mechanical cleansing, washing away bacteria, debris, and body fluids such as blood or bile. Lavage with such fluids also has a dilutional effect when fluids are repeatedly instilled and then aspirated from the abdomen. Further, intraoperative peritoneal lavage may result in lysis of tumor cells and bacterial cells. According to Whiteside et al. [11], 97% of surgeons who responded to mailed questionnaires practiced intraoperative peritoneal lavage; 34% of respondents included lavage even in clean cases, while about 70% performed lavage during intra-abdominal cancer surgery. While such studies confirm that intraoperative peritoneal lavage is common practice, little conclusive evidence documents its benefits. In the present study, we hypothesized that SSI after elective liver resection for several kinds of liver disease not requiring resection or reconstruction of bile duct or intestine could be reduced by peritoneal lavage at the end of the operation. We prospectively analyzed randomly assigned patients treated at our institution to assess benefit of peritoneal lavage during elective liver resection. Methods This was a single-center randomized controlled study. Patients were recruited in the Department of Gastroenterological Surgery at the Yokohama City University Graduate School of Medicine between October 2011 and December 2013 before they underwent liver resection without resection/ reconstruction of the bile duct or intestine. By its nature this study was non-blinded. However, decisions regarding abdominal drain removal and hospital discharge were made strictly according to our institutional criteria. The study protocol was approved by the Institutional Ethical Committee at Yokohama City University, Japan (notice of approval of IRB protocol number, B110901024). Written informed consent was obtained from all patients participating. The study was registered and assigned UMIN reference number 000007058.
Randomization Eligible patients were randomized to either undergo or not undergo intraoperative peritoneal lavage at the end of the operation. Just before concluding surgery, simple randomization was carried out by comparing a number within a sealed envelope with numbers in a computer-generated random number table created using Microsoft Office Excel (Microsoft, Redmond, WA, USA). Exclusion criteria were
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hepatectomy with resection/reconstruction of the bile duct and/or intestine, an operation designated Class III or higher according to Centers for Disease Control and Prevention (CDC) guidelines [12], and detection of peritoneal dissemination of cancer. Study intervention Regardless of group assignment, all patients routinely received a prophylactic antibiotic (flomoxef sodium; Shionogi, Osaka, Japan). On the day of operation, 1 g was administered intravenously 30 min before surgery, 1 g every 3 h during surgery, and 1 g 2 h after completion of surgery. Then 2 g was given daily following the day of operation (1 g every 12 h). This prophylactic administration was terminated on postoperative day (POD) 4 [13]. During hepatectomy, parenchymal dissection was performed using the CUSA system (Valley Lab, Boulder, CO, USA). Additionally, SALIENT monopolar apparatus (Medtronic Advanced Energy, Portsmouth, NH, USA) was used for hemostasis at the transection plane. Intraoperative ultrasonography (US; SSD-2000 or ProSound SSD-4000, Aloka, Tokyo, Japan) was used to detect any tumors not identified preoperatively, and to confirm relationships between tumors and vasculobiliary structures. When necessary, the liver pedicle was clamped intermittently using Pringle’s maneuver or selective clamping in cycles of 15 min of clamping and 5 min of reperfusion. The Brisbane 2000 terminology of the International Hepato-Pancreato-Biliary Association was used for operative procedures [14]. In this study, en bloc removal at least a hemiliver (hemihepatectomy, extended hemihepatectomy, or trisectionectomy) or two sections with or without additional partial resections was defined as major hepatectomy, while performance of multiple minor resections (i.e. less than two sections) was defined as minor hepatectomy. After removal of resected liver and confirmation of hemostasis, the lavage group underwent irrigation with sterile saline at approximately 37 °C directed particularly at the dissected area. Saline volume was 3000 mL in open surgery and 1000 mL in laparoscopic surgery. Lavage volume was decided according to previous reports in which lavage generally was performed using 2000 to 5000 mL of saline [11]. In laparoscopic surgery, however, lavage with 3 L of saline would require excessive time, in part because the skin incision is smaller than that used for open resection. We therefore reduced lavage volume to 1000 mL for laparoscopic procedures. A closed suction drain (J-Vac drain, Johnson & Johnson, Somerville, NJ, USA) was placed near the transection plane of the liver parenchyma for both lavage and nonlavage groups. The drain was brought out through a separate stab wound in the anterior abdominal wall and connected to
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a closed system. Patient warming devices were used during the operation. In both groups, wound washout was performed using warm sterile saline after fascial closure but before skin closure.
hemorrhage, bile leakage, and liver failure were defined and graded according to standards of the International Study Group of Liver Surgery (ISGLS) [17–19]. Hepatic insufficiency of grade B or C was considered liver failure.
Postoperative management
Other recorded data
All patients followed the same postoperative regimen. Early mobilization was encouraged and implemented on the day after surgery, as was fluid intake. Patients began a light diet on day 2 and could progress to full meals as tolerated. The abdominal drainage tube usually was removed within 2 to 4 postoperative days as soon as the bilirubin concentration ratio (ratio of bilirubin concentrations in drainage fluids to those in serum) times volume of drainage fluid in milliliters was less than 200. Exceptions were made when intra-abdominal infection or bile leakage developed [15]. Patients were discharged when all of the following predefined criteria were met: no signs of systemic infection such as fever; toleration of meals without nausea or vomiting; normalized liver function test values; and adequate pain control with oral analgesia.
Operations were timed from skin incision to application of dressing. Investigators took a complete medical history, performed a physical examination, and obtained baseline information regarding preoperative risk factors for postoperative infection. Vital signs and laboratory test results were recorded. Physical status (PS) was rated according to the classification of the American Society of Anesthesiologists (ASA). Nutritional status was evaluated using a prognostic nutritional index (PNI) derived from the peripheral blood lymphocyte count and the serum albumin concentration according to the formula: lymphocyte count (/mm2) × 0.05 + serum albumin (g/dL) × 10 [21]. Systemic inflammatory response syndrome (SIRS) was diagnosed according to consensus criteria established by the American Thoracic Society and the Society of Critical Care Medicine [20]. Vital signs were measured daily while the patient was hospitalized and at the 4-week follow-up assessment. Hematologic and biochemical tests were performed before surgery, immediately after surgery, and 1 week after surgery. Drainage fluid specimens were obtained from all patients early in the morning on postoperative day 1 for bacteriologic culture. Investigators performed detailed wound assessments at least every other day for up to 7 days during hospitalization, at discharge, and at the 4-week follow-up visit.
Study endpoints The primary endpoint of this study was the rate of surgical site infection according to a follow-up assessment 4 weeks after surgery. Success was defined as absence of signs or symptoms of infection at the surgical site and lack of need for further antimicrobial therapy or surgery. Failure in preventing infection was determined by the site investigator on the basis of criteria for SSI developed by the CDC. SSI was defined as incisional infection (either superficial or deep) or organ/space infection. Superficial incisional infection involved skin and subcutaneous tissue, while deep incisional infection involved deeper soft tissue related to the incision. Organ/space infection involved any organ or space other than the incised layers of body wall that were opened or manipulated during the initial surgical procedure. An incisional infection was defined by clinically apparent cellulitis, induration, or purulent discharge from the closure site. Organ/space infection was defined by radiologic evidence of a fluid collection necessitating drainage, or antibiotic therapy when drainage was difficult. All inpatient morbidity was recorded prospectively. Assessment of complications followed a recently published standardized complication assessment system (Dindo-Clavien classification) [16]. Complications were defined as any deviation from an uneventful postoperative course. Remote infection was defined as a condition where bacteria were detected in sputum, blood, or urine, in association with signs of inflammation such as leukocytosis and fever. Postoperative
Sample size This was a randomized phase II study. We sought to determine whether the incidence of SSI was less than the null proportion in each arm. As noted in the Introduction, reported incidence of SSI following liver resection without resection or reconstruction of the bile duct is about 15% [9, 10]. We predicted a likely incidence of 7% in the peritoneal lavage group. When the null proportion was set at 15% and the alternative proportion was set at 7%, a minimum of 97 patients were required in each group to achieve 78% power for a single-arm test at a one-sided significance level of 5%. We therefore aimed for 100 patients per group.
Statistical analysis Continuous data are expressed as mean (s.d.) or median (range), and were analyzed using the parametric Student’s t-
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Results
Enrolment
Assessed for eligibility n = 200 Excluded Gastrointestinal injury Massive bile leakage Biliary reconstruction
Randomized n = 193
Analysis
n=7 2 3 2
No peritoneal lavage n = 97
Peritoneal lavage n = 96
Follow-up
Allocation
449
No patients lost to follow up
Analyzed n = 96
Analyzed n = 97
Fig. 1 Flow diagram accounting for patients through the steps of our protocol, according to the CONSORT statement
test or the non-parametric Mann–Whitney U-test respectively. The χ 2 test or Fisher’s exact test was used for analysis of categorical variables. Cut-off values for multivariate analysis of continuous variables were determined using the median values. Multivariate regression analysis was carried out by a proportional hazard method using a Cox model. A difference was considered significant when the two-sided P-value was below 0.05.
Number of entries Two hundred consecutive patients who underwent liver resection during the study period were assessed intraoperatively for eligibility and then randomized into two groups. During liver resection, two patients had gastrointestinal injury and three had substantial bile spillage into the operative field during liver resection; another two had procedures including bile duct resection. These seven patients were excluded (Fig. 1). The remaining 193 patients consisted of 127 men (66%) and 66 women (34%); their median age was 68.5 years (range, 21 to 87). Ninety-six patients were assigned to the lavage group and 97 to the non-lavage group. After group assignment, no patients were excluded from the study.
Background characteristics The two groups were comparable with regard to age, gender, ASA grade, nutritional status determined according to the PNI, baseline liver function, and specific diagnoses of liver disease. Prevalence of diabetes mellitus (DM) as a comorbidity with surgery and body mass index (BMI) values were comparable between groups (Table 1).
Table 1 Patient profiles
Age, years Gender ASA-PS
Male Female 1 2 3
BMI PNI ICGR15, min Co-morbid Diagnosis
DM HCC CCC Lmets Others
Lavage group (n = 96)
Non-lavage group (n = 97)
P-value
66.4 ± 11.2 (68.5, 33–87) 64 32 20 71 5 21.6 ± 3.2 (21.3, 15.8–35.6) 47.22 ± 6.15 (47.65, 29.55–63.33) 14.7 ± 6.5 (14.3, 1.3–31.3) 23 (24.0%) 35 3 45 13
66.8 ± 11.3 (68.5, 21–86) 63 34 15 77 5 21.4 ± 3.1 (21.0, 14.9–30.6) 47.25 ± 4.70 (47.45, 34.79–57.54) 15.5 ± 7.6 (15.0, 2.2–42.4) 19 (19.6%) 37 2 52 6
0.819 0.880 0.621
0.726 0.860 0.670 0.490 0.343
ASA American Society of Anesthesiologists, BMI body mass index, CCC cholangiocellular carcinoma, DM diabetes mellitus, HCC hepatocellular carcinoma, ICGR15 indocyanine green retention rate at 15 min, Lmets liver metastases, PNI prognostic nutritional index, PS physical status
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Table 2 Operative variables Lavage group (n = 96)
Table 4 Surgical site infection Non-lavage group (n = 97)
Hepatectomy procedure Major 33 32 Minor 63 65 Initial vs. repeat Initial 83 88 Repeat 13 9 Approach Open 83 87 Laparoscopic 13 10 Operation time, min 403.3 ± 131.2 380.3 ± 120.1 (371, 194–878) (370, 148–909) Blood loss, mL 662.9 ± 789.9 784.3 ± 2002.9 (483, 30–6890) (505, 15–19 723) Transfused patients 12 (12.5%) 8 (8.2%)
P-value
0.880
Non-lavage group (n = 97)
P-value
21 (21.9%) 7 (7.3%) 16 (16.7%)
13 (13.4%) 6 (6.2%) 7 (7.2%)
0.135 0.783 0.048
0.375
0.514 0.391 0.950 0.356
Surgical procedures and intraoperative results
the non-lavage group. The 41 complications among the 37 lavage patients with complications, included 13 liver-related complications, 24 infectious complications, and four other complications. The 43 complications in the 36 non-lavage patients with complications included 15 liver-related complications, 18 infectious complications, and 10 other
Table 5 Multivariate analysis of risk factors for organ/space infections after hepatectomy Variables
Extent of liver resection (major vs. minor) was similar between groups. Repeat resection for remaining liver recurrences was equally frequent in the two groups, as was resection using a laparoscopic approach. Duration of operation, intraoperative blood loss, and administration of blood transfusions also were similar between groups (Table 2).
Postoperative course Two patients in the lavage group and one patient in the nonlavage group died of liver failure within 90 days of liver resection. In the lavage group, 37 patients (38.5%) experienced postoperative complications, as did 36 patients (37.1%) in Table 3 Postoperative outcome
Mortality (≤90 days) Morbidity Dindo-Clavien class I II IIIa IIIb IVa V Hospital stay, days
Total Superficial/deep Organ/space
Lavage group (n = 96)
Lavage group (n = 96)
Non-lavage group (n = 97)
P-value
2 (2.1%) 37 (38.5%)
1 (1.0%) 36 (37.1%)
0.621 0.883
10 15 9 – 1 2 15.2 ± 13.4 (10.5, 4–87)
10 17 7 – 1 1 15.2 ± 13.1 (11, 4–82)
0.952
0.879
95% CI
Odds ratio
Age ≤68 0.998 Gender Male 2.555 Diagnosis HCC/CCC 0.517 ASA-PS 2/3 0.926 BMI >21 0.915 PNI >47.5 0.357 ICGR15 >14.7% 0.544 DM Present 1.862 Hepatectomy procedure Minor 0.688 Operative time ≤370 min 1.247 Intraoperative bleeding ≤500 mL 0.726 Blood transfusion Performed 0.789 Lavage Performed 2.977
Lower limit
Upper limit
P-value
0.367
2.713
0.997
0.715
9.120
0.149
0.177
1.511
0.228
0.261
3.278
0.905
0.347
2.414
0.857
0.122
1.045
0.060
0.198
1.495
0.238
0.660
5.254
0.240
0.261
1.814
0.449
0.436
3.563
0.681
0.257
2.048
0.545
0.187
3.328
0.747
1.094
8.100
0.033
ASA American Society of Anesthesiologists, BMI body mass index, DM diabetes mellitus, ICGR15 indocyanine green retention rate at 15 min, Lmets liver metastases, PNI prognostic nutritional index, PS physical status
J Hepatobiliary Pancreat Sci (2015) 22:446–453 Fig. 2 Serial changes in postoperative white blood cell count (a) and C-reactive protein concentration (b) in all patients undergoing hepatectomy. Each value is the mean. ■, lavage group, n = 96; □, non-lavage group, n = 97; Pre, preoperative.
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(a)
(b)
(/mm3)
(mg/dL) 6
14 000 12 000
5 Lavage
No lavage 10 000
4 Lavage
No lavage
8000 3 6000 2 4000 1
2000
0
0
Pre
0
1
2
complications. No postoperative bleeding occurred in either group. In order of severity, incidence of postoperative complications was grade I in 10 lavage patients (10.4%); grade II in 15 (15.6%); grade IIIa in nine (9.4%); grade IVa in one (1.0%); and grade V in two (2.1%). In the non-lavage group, respective incidences were 10 (10.3%); 17 (17.5%); seven (7.2%); one (1.0%); and one (1.0%). Length of hospital stay did not differ between groups (Table 3).
Surgical site infection Incidence of incisional infection (either superficial or deep) did not differ significantly between groups. However, contrary to our expectations, incidence of organ/space infection was significantly higher in the lavage group than in the nonlavage group (P = 0.048, Table 4). Among risk factors for organ/space infection, abdominal lavage was selected by multivariate analysis (relative risk or RR, 2.977; 95% confidence intervals or CI, 1.094 to 8.100; P = 0.033; Table 5).
3
4
5
6
Pre
0
1
2
3
4
5
6
lavage group and 5.2% (5/97) in the non-lavage group (P = 0.282). Bacteria in drainage fluids included Staphylococcus in three patients, Enterococcus in three, Pseudomonas in two, and Bacteroides in one for the lavage group and Staphylococcus in two, Corynebacterium in two, and Enterococcus in one for the non-lavage group. White blood cell (WBC) counts (Fig. 2a) and concentrations of C-reactive protein (CRP; Fig. 2b) were compared between groups over time. No significant differences were evident between groups in WBC either or CRP at any time. Peak CRP concentrations occurred on POD3; subsequently, CRP gradually decreased to baseline values. However, concentrations on POD3 were slightly greater in the lavage group than the non-lavage group. On POD3, the mean (±s.d.) for CRP was 5.2 ± 3.8 (median, 4.4) in the lavage group and 4.8 ± 3.8 (median, 3.7) in the non-lavage group (P = 0.273); on POD4, 4.8 ± 4.1 (3.6) vs. 4.1 ± 3.2 (3.4) (P = 0.333); on POD5, 4.4 ± 3.7 (3.3) vs. 3.4 ± 2.8 (2.4) (P = 0.094); and on POD6, 3.6 ± 3.5 (1.5) vs. 2.9 ± 2.6 (1.0) (P = 0.292).
Discussion SIRS occurrences, bacteriologic findings, hematologic values, and biochemical results Occurrences of SIRS after surgery were 49% (47/96) in the lavage group and 35% (34/97) in the non-lavage group (P = 0.059). Duration of SIRS in days was 1.80 ± 1.92 (median, 1; range, 1 to 13) in the lavage group and 1.79 ± 1.52 (median, 1; range, 1 to 7) in the non-lavage group (P = 0.742). Frequency of positive bacteriologic cultures of drainage fluid obtained on postoperative day 1 was 9.4% (9/96) in the
As for the primary study endpoint, no difference was detected between groups concerning total incidence of SSI. However, incidence of organ/space infection was significantly higher in the lavage group than the non-lavage group, an unexpected result. Not only did this randomized clinical trial fail to show a benefit from peritoneal lavage in elective liver surgery, but peritoneal lavage actually was associated with increased incidence of organ/space infection. Indeed, abdominal lavage was selected by multivariate analysis as an independent risk factor for organ/space infection.
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In the peritoneal cavity, bacteria and fluid rapidly pass through mesothelial stomata on the underside of the diaphragm to enter the lymphatics and ultimately the circulation [22, 23]. Lavage has been claimed to remove not only bacteria but also material that may promote bacterial proliferation (e.g. blood) and proinflammatory cytokines that may enhance local inflammation [22, 24]. However, lavage also has been reported to impair peritoneal defense mechanisms in multiple ways [25]. Increased volumes of peritoneal fluid can interfere with containment of contaminated material and accelerate entry of bacteria and endotoxin into the systemic circulation through the diaphragmatic stomata [26]; lavage may have such an effect [25]. Peritoneal mesothelium tends to slough after even brief exposure to either air or saline, glucose, or other solutions [27–29]. Further, lavage has been found to retard mesothelial healing [30]. Lavage also might remove important anti-infectious mediators such as opsonic proteins, complement, proteases, and immunoglobulins [31, 32]. Considering these previous observations together with our present results, we conclude that peritoneal lavage upon completion of elective liver resection without resection or reconstruction of bile duct or intestine does not reduce SSI incidence, and could actually increase incidence of organ/space infection. According to a previous non-randomized study of patients undergoing elective colorectal surgery who underwent intraoperative peritoneal lavage, bacterial counts from swab specimens obtained from various sites within the abdomen decreased greatly; nonetheless, the lavage group had higher rates of postoperative wound infection, intra-abdominal abscess, and septicemia than did the control group [33]. While our present study found no significant difference in frequency of positive bacteriologic cultures of drainage fluid obtained on POD1, the frequency in the non-lavage group was slightly lower than in the lavage group. We obtained this drainage fluid early in the morning of POD1, decreasing the likelihood that the bacterial isolates represented an infection ascending through the inserted drain [15]. Even though removal of bacteria by lavage could not affect subsequent ascending infections involving drains, the greater frequency of postoperative SSI in our lavage group resembled findings of the previous report [33]. Microbes can be difficult to remove completely from the peritoneal cavity because they adhere to mesothelial cells [34] and then invade submesothelial tissues [25]. Such adherent bacteria therefore would appear likely to resist peritoneal lavage [35]. Removal of infectious agents from the peritoneal cavity probably requires more than simple mechanical cleansing. We found no significant difference between groups concerning changes in results of serial postoperative laboratory tests. However, CRP on or after POD3 was slightly greater in the lavage group than in the non-lavage group. Further, SIRS occurred somewhat more often after surgery in the
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lavage group than in the non-lavage group. The potential for conversion of a localized area of contamination to a more extensive one by lavage has been demonstrated experimentally using radiolabelled markers [36], representing another likely disadvantage of peritoneal lavage. The somewhat higher CRP and somewhat greater occurrence of SIRS in the lavage group thus may reflect spread of local infection. Most surgeons use intraoperative peritoneal lavage to remove clotted blood, devitalized tissue, and foreign bodies, as well as to facilitate assessment of hemostasis. Postoperative bleeding increases risk of liver failure after hepatectomy, but in fact no postoperative bleeding occurred in either of our groups. While our study did not determine whether removal of clot or other material by lavage affected postoperative bleeding, no increased risk of postoperative bleeding from omitting lavage was demonstrated. In conclusion, no significant difference in morbidity or overall infectious complications was noted between our lavage and non-lavage groups. Further, frequency of organ/space infection was significantly higher in the lavage group. These results suggest that routine intraoperative lavage for elective liver resection does not prevent intra-abdominal infection and should be avoided. Conflict of interest
None declared.
Author contribution Study design: Tanaka. Acquisition of data: Matsuo, Kawaguchi, Murakami, Hirano and Sato. Analysis and interpretation: Taguri and Hiroshima. Manuscript drafted by: Tanaka. Revision: Endo and Koda. Statistical advice: Taguri.
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and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864–74. Onodera T, Goseki N, Kosaki G. Prognostic nutritional index in gastrointestinal surgery of malnourished cancer patients. Nippon Geka Gakkai Zasshi 1984;85:1001–5 (In Japanese with English abstract). Hall JC, Heel KA, Papadamitriou J, Platell C. The pathobiology of peritonitis. Gastroenterology. 1998;114:185–96. Dumont A, Maas W, Iliescu H, Shin R. Increased survival from peritonitis after blockade of transdiaphragmatic absorption of bacteria. Surg Gynecol Obstet. 1986;162:248–52. Adam U, Ledwon D, Hopt UT. Programmed lavage as a basic principle in therapy of diffuse peritonitis. Langenbecks Arch Chir. 1997;382:S18–S21. Platell C, Papadimitriou JM, Hall JC. The influence of lavage on peritonitis. J Am Coll Surg. 2000;191:672–80. Dunn DL, Barke RA, Ahrenholz DH, Humphrey EW, Simmons RL. The adjuvant effect of peritoneal fluid in experimental peritonitis. Mechanism and clinical implications. Ann Surg. 1984;199:37–43. Whitaker D, Papadimitriou JM, Walters MN. The mesothelium and its reactions: a review. Crit Rev Toxicol. 1982;10:81–144. Yaacobi Y1, Goldberg EP, Habal MB. Effect of Ringer’s lactate irrigation on the formation of postoperative abdominal adhesions. J Invest Surg. 1991;4:31–6. Breborowicz A, Rodela H, Oreopoulos DG. Toxicity of osmotic solutes on human mesothelial cells in vitro. Kidney Int. 1992;41:1280–5. Tolhurst Cleaver CL, Hopkins AD, Kee Kwong KC, Raftery AT. The effect of postoperative peritoneal lavage on survival, peritoneal wound healing and adhesion formation following fecal peritonitis: an experimental study in the rat. Br J Surg. 1974;61:601–4. Maddaus MA, Ahrenholz D, Simmons RL. The biology of peritonitis and implications for treatment. Surg Clin North Am. 1988;68:431–43. Lamperi S, Carozzi S. Immunologic patterns in CAPD patients with peritonitis. Clin Nephrol. 1988;30:S41–4. Minervini S, Bentley S, Youngs D, Alexander-Williams J, Burdon DW, Keighley MR. Prophylactic saline peritoneal lavage in elective colorectal operations. Dis Colon Rectum. 1980;23:392–4. Haagen IA, Heezius HC, Verkooyen RP, Verhoef J, Verbrugh HA. Adherence of peritonitis-causing staphylococci to human peritoneal mesothelial cell monolayers. J Infect Dis. 1990;161:266–73. Edmiston CE Jr, Goheen MP, Kornhall S, Jones FE, Condon RE. Fecal peritonitis: microbial adherence to serosal mesothelium and resistance to peritoneal lavage. World J Surg. 1990;14:176–83. Rosenshein N, Blake D, McIntyre PA, Parmley T, Natarajan TK, Dvornicky J, et al. The effect of volume on the distribution of substances instilled into the peritoneal cavity. Gynecol Oncol. 1978;6:106–10.
ORIGINAL ARTICLE
Randomized clinical trial of peritoneal lavage for preventing surgical site infection in elective liver surgery Kuniya Tanaka · Kenichi Matsuo · Daisuke Kawaguchi · Takashi Murakami · Yukihiko Hiroshima · Atsushi Hirano · Sho Sato · Itaru Endo · Masataka Taguri · Keiji Koda Published online: 22 January 2015 © 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery
Abstract Background Although intraoperative peritoneal lavage is often performed routinely with the aim of reducing peritoneal contamination, little evidence of lavage benefits in elective liver resection without bile duct resection is available. We addressed the issue with a randomized clinical trial. Methods We prospectively and randomly assigned consecutive patients undergoing liver resection to a lavage group or a non-lavage group. Peritoneal lavage was performed at the end of operation for patients in the lavage group. The primary endpoint was the rate of surgical site infection. Results Ninety-six patients were assigned to the lavage group and 97 to the non-lavage group. When superficial/ deep incisional infection and organ/space infection were considered together, no significant difference in surgical site infection rate was evident between lavage (21.9%) and nonlavage groups (13.4%, P = 0.135). However, organ/space infection was significantly more frequent in the lavage group (16.7%) than the non-lavage group (7.2%, P = 0.048). Peritoneal lavage was identified as a risk factor for organ/space infection by multivariate analysis (relative risk, 2.977; confidence interval, 1.094 to 8.100; P = 0.033).
K. Tanaka (✉) · K. Matsuo · D. Kawaguchi · T. Murakami · Y. Hiroshima · A. Hirano · K. Koda Department of Surgery, Teikyo University Chiba Medical Center, 3426-3 Anesaki, Ichihara, Chiba 299-0111, Japan e-mail: [email protected] S. Sato · I. Endo Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan M. Taguri Department of Biostatistics and Epidemiology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
Conclusion Intraoperative peritoneal lavage does not reduce overall incidence of surgical site infection and may increase risk of organ/space infection. Keywords infection
Liver surgery · Peritoneal lavage · Surgical site
Introduction Despite technical advances and ongoing accrual of experience, liver resection still carries a relatively high risk of posthepatectomy morbidity and mortality. Although rates vary according to the disease requiring resection, overall morbidity has ranged from 13.54% to 47.7%, while mortality has ranged from 0.24% to 7.4% [1–8]. Common complications after liver resection include liver failure, infectious disease, bile leakage, and hemorrhage. Among these, liver insufficiency or failure is particularly dreaded by surgeons. Measures taken to prevent liver failure include careful assessment of hepatic functional reserve, prevention of intraoperative bleeding, avoidance of blood transfusion, and minimizing duration of hepatic inflow occlusion. As severe surgical site infection (SSI) and remote infection sometimes compromise systemic status and induce liver failure, reducing incidence of SSI can contribute importantly to maintenance of hepatic function after liver resection. Recently reported incidence figures for SSI following liver resection without resection or reconstruction of bile duct have varied between hepatectomy procedures, ranging from 9.7% to 18.3% [9]. Overall incidence of SSI after elective liver resection presently is 11.5% [9] to 14.5% [10]. Intraoperative peritoneal lavage is performed routinely with the aim of reducing peritoneal contamination. Many studies have maintained that intraoperative peritoneal lavage improved postoperative infectious morbidity and mortality, while sometimes also characterizing differences between
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specific irrigation fluids [11]. However, since this treatment may owe more to historic practice than to rigorous scientific evaluation, debate continues as to whether or not lavage should be undertaken. Intraoperative peritoneal lavage may have several actions. Sterile saline and water can accomplish mechanical cleansing, washing away bacteria, debris, and body fluids such as blood or bile. Lavage with such fluids also has a dilutional effect when fluids are repeatedly instilled and then aspirated from the abdomen. Further, intraoperative peritoneal lavage may result in lysis of tumor cells and bacterial cells. According to Whiteside et al. [11], 97% of surgeons who responded to mailed questionnaires practiced intraoperative peritoneal lavage; 34% of respondents included lavage even in clean cases, while about 70% performed lavage during intra-abdominal cancer surgery. While such studies confirm that intraoperative peritoneal lavage is common practice, little conclusive evidence documents its benefits. In the present study, we hypothesized that SSI after elective liver resection for several kinds of liver disease not requiring resection or reconstruction of bile duct or intestine could be reduced by peritoneal lavage at the end of the operation. We prospectively analyzed randomly assigned patients treated at our institution to assess benefit of peritoneal lavage during elective liver resection. Methods This was a single-center randomized controlled study. Patients were recruited in the Department of Gastroenterological Surgery at the Yokohama City University Graduate School of Medicine between October 2011 and December 2013 before they underwent liver resection without resection/ reconstruction of the bile duct or intestine. By its nature this study was non-blinded. However, decisions regarding abdominal drain removal and hospital discharge were made strictly according to our institutional criteria. The study protocol was approved by the Institutional Ethical Committee at Yokohama City University, Japan (notice of approval of IRB protocol number, B110901024). Written informed consent was obtained from all patients participating. The study was registered and assigned UMIN reference number 000007058.
Randomization Eligible patients were randomized to either undergo or not undergo intraoperative peritoneal lavage at the end of the operation. Just before concluding surgery, simple randomization was carried out by comparing a number within a sealed envelope with numbers in a computer-generated random number table created using Microsoft Office Excel (Microsoft, Redmond, WA, USA). Exclusion criteria were
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hepatectomy with resection/reconstruction of the bile duct and/or intestine, an operation designated Class III or higher according to Centers for Disease Control and Prevention (CDC) guidelines [12], and detection of peritoneal dissemination of cancer. Study intervention Regardless of group assignment, all patients routinely received a prophylactic antibiotic (flomoxef sodium; Shionogi, Osaka, Japan). On the day of operation, 1 g was administered intravenously 30 min before surgery, 1 g every 3 h during surgery, and 1 g 2 h after completion of surgery. Then 2 g was given daily following the day of operation (1 g every 12 h). This prophylactic administration was terminated on postoperative day (POD) 4 [13]. During hepatectomy, parenchymal dissection was performed using the CUSA system (Valley Lab, Boulder, CO, USA). Additionally, SALIENT monopolar apparatus (Medtronic Advanced Energy, Portsmouth, NH, USA) was used for hemostasis at the transection plane. Intraoperative ultrasonography (US; SSD-2000 or ProSound SSD-4000, Aloka, Tokyo, Japan) was used to detect any tumors not identified preoperatively, and to confirm relationships between tumors and vasculobiliary structures. When necessary, the liver pedicle was clamped intermittently using Pringle’s maneuver or selective clamping in cycles of 15 min of clamping and 5 min of reperfusion. The Brisbane 2000 terminology of the International Hepato-Pancreato-Biliary Association was used for operative procedures [14]. In this study, en bloc removal at least a hemiliver (hemihepatectomy, extended hemihepatectomy, or trisectionectomy) or two sections with or without additional partial resections was defined as major hepatectomy, while performance of multiple minor resections (i.e. less than two sections) was defined as minor hepatectomy. After removal of resected liver and confirmation of hemostasis, the lavage group underwent irrigation with sterile saline at approximately 37 °C directed particularly at the dissected area. Saline volume was 3000 mL in open surgery and 1000 mL in laparoscopic surgery. Lavage volume was decided according to previous reports in which lavage generally was performed using 2000 to 5000 mL of saline [11]. In laparoscopic surgery, however, lavage with 3 L of saline would require excessive time, in part because the skin incision is smaller than that used for open resection. We therefore reduced lavage volume to 1000 mL for laparoscopic procedures. A closed suction drain (J-Vac drain, Johnson & Johnson, Somerville, NJ, USA) was placed near the transection plane of the liver parenchyma for both lavage and nonlavage groups. The drain was brought out through a separate stab wound in the anterior abdominal wall and connected to
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a closed system. Patient warming devices were used during the operation. In both groups, wound washout was performed using warm sterile saline after fascial closure but before skin closure.
hemorrhage, bile leakage, and liver failure were defined and graded according to standards of the International Study Group of Liver Surgery (ISGLS) [17–19]. Hepatic insufficiency of grade B or C was considered liver failure.
Postoperative management
Other recorded data
All patients followed the same postoperative regimen. Early mobilization was encouraged and implemented on the day after surgery, as was fluid intake. Patients began a light diet on day 2 and could progress to full meals as tolerated. The abdominal drainage tube usually was removed within 2 to 4 postoperative days as soon as the bilirubin concentration ratio (ratio of bilirubin concentrations in drainage fluids to those in serum) times volume of drainage fluid in milliliters was less than 200. Exceptions were made when intra-abdominal infection or bile leakage developed [15]. Patients were discharged when all of the following predefined criteria were met: no signs of systemic infection such as fever; toleration of meals without nausea or vomiting; normalized liver function test values; and adequate pain control with oral analgesia.
Operations were timed from skin incision to application of dressing. Investigators took a complete medical history, performed a physical examination, and obtained baseline information regarding preoperative risk factors for postoperative infection. Vital signs and laboratory test results were recorded. Physical status (PS) was rated according to the classification of the American Society of Anesthesiologists (ASA). Nutritional status was evaluated using a prognostic nutritional index (PNI) derived from the peripheral blood lymphocyte count and the serum albumin concentration according to the formula: lymphocyte count (/mm2) × 0.05 + serum albumin (g/dL) × 10 [21]. Systemic inflammatory response syndrome (SIRS) was diagnosed according to consensus criteria established by the American Thoracic Society and the Society of Critical Care Medicine [20]. Vital signs were measured daily while the patient was hospitalized and at the 4-week follow-up assessment. Hematologic and biochemical tests were performed before surgery, immediately after surgery, and 1 week after surgery. Drainage fluid specimens were obtained from all patients early in the morning on postoperative day 1 for bacteriologic culture. Investigators performed detailed wound assessments at least every other day for up to 7 days during hospitalization, at discharge, and at the 4-week follow-up visit.
Study endpoints The primary endpoint of this study was the rate of surgical site infection according to a follow-up assessment 4 weeks after surgery. Success was defined as absence of signs or symptoms of infection at the surgical site and lack of need for further antimicrobial therapy or surgery. Failure in preventing infection was determined by the site investigator on the basis of criteria for SSI developed by the CDC. SSI was defined as incisional infection (either superficial or deep) or organ/space infection. Superficial incisional infection involved skin and subcutaneous tissue, while deep incisional infection involved deeper soft tissue related to the incision. Organ/space infection involved any organ or space other than the incised layers of body wall that were opened or manipulated during the initial surgical procedure. An incisional infection was defined by clinically apparent cellulitis, induration, or purulent discharge from the closure site. Organ/space infection was defined by radiologic evidence of a fluid collection necessitating drainage, or antibiotic therapy when drainage was difficult. All inpatient morbidity was recorded prospectively. Assessment of complications followed a recently published standardized complication assessment system (Dindo-Clavien classification) [16]. Complications were defined as any deviation from an uneventful postoperative course. Remote infection was defined as a condition where bacteria were detected in sputum, blood, or urine, in association with signs of inflammation such as leukocytosis and fever. Postoperative
Sample size This was a randomized phase II study. We sought to determine whether the incidence of SSI was less than the null proportion in each arm. As noted in the Introduction, reported incidence of SSI following liver resection without resection or reconstruction of the bile duct is about 15% [9, 10]. We predicted a likely incidence of 7% in the peritoneal lavage group. When the null proportion was set at 15% and the alternative proportion was set at 7%, a minimum of 97 patients were required in each group to achieve 78% power for a single-arm test at a one-sided significance level of 5%. We therefore aimed for 100 patients per group.
Statistical analysis Continuous data are expressed as mean (s.d.) or median (range), and were analyzed using the parametric Student’s t-
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Results
Enrolment
Assessed for eligibility n = 200 Excluded Gastrointestinal injury Massive bile leakage Biliary reconstruction
Randomized n = 193
Analysis
n=7 2 3 2
No peritoneal lavage n = 97
Peritoneal lavage n = 96
Follow-up
Allocation
449
No patients lost to follow up
Analyzed n = 96
Analyzed n = 97
Fig. 1 Flow diagram accounting for patients through the steps of our protocol, according to the CONSORT statement
test or the non-parametric Mann–Whitney U-test respectively. The χ 2 test or Fisher’s exact test was used for analysis of categorical variables. Cut-off values for multivariate analysis of continuous variables were determined using the median values. Multivariate regression analysis was carried out by a proportional hazard method using a Cox model. A difference was considered significant when the two-sided P-value was below 0.05.
Number of entries Two hundred consecutive patients who underwent liver resection during the study period were assessed intraoperatively for eligibility and then randomized into two groups. During liver resection, two patients had gastrointestinal injury and three had substantial bile spillage into the operative field during liver resection; another two had procedures including bile duct resection. These seven patients were excluded (Fig. 1). The remaining 193 patients consisted of 127 men (66%) and 66 women (34%); their median age was 68.5 years (range, 21 to 87). Ninety-six patients were assigned to the lavage group and 97 to the non-lavage group. After group assignment, no patients were excluded from the study.
Background characteristics The two groups were comparable with regard to age, gender, ASA grade, nutritional status determined according to the PNI, baseline liver function, and specific diagnoses of liver disease. Prevalence of diabetes mellitus (DM) as a comorbidity with surgery and body mass index (BMI) values were comparable between groups (Table 1).
Table 1 Patient profiles
Age, years Gender ASA-PS
Male Female 1 2 3
BMI PNI ICGR15, min Co-morbid Diagnosis
DM HCC CCC Lmets Others
Lavage group (n = 96)
Non-lavage group (n = 97)
P-value
66.4 ± 11.2 (68.5, 33–87) 64 32 20 71 5 21.6 ± 3.2 (21.3, 15.8–35.6) 47.22 ± 6.15 (47.65, 29.55–63.33) 14.7 ± 6.5 (14.3, 1.3–31.3) 23 (24.0%) 35 3 45 13
66.8 ± 11.3 (68.5, 21–86) 63 34 15 77 5 21.4 ± 3.1 (21.0, 14.9–30.6) 47.25 ± 4.70 (47.45, 34.79–57.54) 15.5 ± 7.6 (15.0, 2.2–42.4) 19 (19.6%) 37 2 52 6
0.819 0.880 0.621
0.726 0.860 0.670 0.490 0.343
ASA American Society of Anesthesiologists, BMI body mass index, CCC cholangiocellular carcinoma, DM diabetes mellitus, HCC hepatocellular carcinoma, ICGR15 indocyanine green retention rate at 15 min, Lmets liver metastases, PNI prognostic nutritional index, PS physical status
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Table 2 Operative variables Lavage group (n = 96)
Table 4 Surgical site infection Non-lavage group (n = 97)
Hepatectomy procedure Major 33 32 Minor 63 65 Initial vs. repeat Initial 83 88 Repeat 13 9 Approach Open 83 87 Laparoscopic 13 10 Operation time, min 403.3 ± 131.2 380.3 ± 120.1 (371, 194–878) (370, 148–909) Blood loss, mL 662.9 ± 789.9 784.3 ± 2002.9 (483, 30–6890) (505, 15–19 723) Transfused patients 12 (12.5%) 8 (8.2%)
P-value
0.880
Non-lavage group (n = 97)
P-value
21 (21.9%) 7 (7.3%) 16 (16.7%)
13 (13.4%) 6 (6.2%) 7 (7.2%)
0.135 0.783 0.048
0.375
0.514 0.391 0.950 0.356
Surgical procedures and intraoperative results
the non-lavage group. The 41 complications among the 37 lavage patients with complications, included 13 liver-related complications, 24 infectious complications, and four other complications. The 43 complications in the 36 non-lavage patients with complications included 15 liver-related complications, 18 infectious complications, and 10 other
Table 5 Multivariate analysis of risk factors for organ/space infections after hepatectomy Variables
Extent of liver resection (major vs. minor) was similar between groups. Repeat resection for remaining liver recurrences was equally frequent in the two groups, as was resection using a laparoscopic approach. Duration of operation, intraoperative blood loss, and administration of blood transfusions also were similar between groups (Table 2).
Postoperative course Two patients in the lavage group and one patient in the nonlavage group died of liver failure within 90 days of liver resection. In the lavage group, 37 patients (38.5%) experienced postoperative complications, as did 36 patients (37.1%) in Table 3 Postoperative outcome
Mortality (≤90 days) Morbidity Dindo-Clavien class I II IIIa IIIb IVa V Hospital stay, days
Total Superficial/deep Organ/space
Lavage group (n = 96)
Lavage group (n = 96)
Non-lavage group (n = 97)
P-value
2 (2.1%) 37 (38.5%)
1 (1.0%) 36 (37.1%)
0.621 0.883
10 15 9 – 1 2 15.2 ± 13.4 (10.5, 4–87)
10 17 7 – 1 1 15.2 ± 13.1 (11, 4–82)
0.952
0.879
95% CI
Odds ratio
Age ≤68 0.998 Gender Male 2.555 Diagnosis HCC/CCC 0.517 ASA-PS 2/3 0.926 BMI >21 0.915 PNI >47.5 0.357 ICGR15 >14.7% 0.544 DM Present 1.862 Hepatectomy procedure Minor 0.688 Operative time ≤370 min 1.247 Intraoperative bleeding ≤500 mL 0.726 Blood transfusion Performed 0.789 Lavage Performed 2.977
Lower limit
Upper limit
P-value
0.367
2.713
0.997
0.715
9.120
0.149
0.177
1.511
0.228
0.261
3.278
0.905
0.347
2.414
0.857
0.122
1.045
0.060
0.198
1.495
0.238
0.660
5.254
0.240
0.261
1.814
0.449
0.436
3.563
0.681
0.257
2.048
0.545
0.187
3.328
0.747
1.094
8.100
0.033
ASA American Society of Anesthesiologists, BMI body mass index, DM diabetes mellitus, ICGR15 indocyanine green retention rate at 15 min, Lmets liver metastases, PNI prognostic nutritional index, PS physical status
J Hepatobiliary Pancreat Sci (2015) 22:446–453 Fig. 2 Serial changes in postoperative white blood cell count (a) and C-reactive protein concentration (b) in all patients undergoing hepatectomy. Each value is the mean. ■, lavage group, n = 96; □, non-lavage group, n = 97; Pre, preoperative.
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(a)
(b)
(/mm3)
(mg/dL) 6
14 000 12 000
5 Lavage
No lavage 10 000
4 Lavage
No lavage
8000 3 6000 2 4000 1
2000
0
0
Pre
0
1
2
complications. No postoperative bleeding occurred in either group. In order of severity, incidence of postoperative complications was grade I in 10 lavage patients (10.4%); grade II in 15 (15.6%); grade IIIa in nine (9.4%); grade IVa in one (1.0%); and grade V in two (2.1%). In the non-lavage group, respective incidences were 10 (10.3%); 17 (17.5%); seven (7.2%); one (1.0%); and one (1.0%). Length of hospital stay did not differ between groups (Table 3).
Surgical site infection Incidence of incisional infection (either superficial or deep) did not differ significantly between groups. However, contrary to our expectations, incidence of organ/space infection was significantly higher in the lavage group than in the nonlavage group (P = 0.048, Table 4). Among risk factors for organ/space infection, abdominal lavage was selected by multivariate analysis (relative risk or RR, 2.977; 95% confidence intervals or CI, 1.094 to 8.100; P = 0.033; Table 5).
3
4
5
6
Pre
0
1
2
3
4
5
6
lavage group and 5.2% (5/97) in the non-lavage group (P = 0.282). Bacteria in drainage fluids included Staphylococcus in three patients, Enterococcus in three, Pseudomonas in two, and Bacteroides in one for the lavage group and Staphylococcus in two, Corynebacterium in two, and Enterococcus in one for the non-lavage group. White blood cell (WBC) counts (Fig. 2a) and concentrations of C-reactive protein (CRP; Fig. 2b) were compared between groups over time. No significant differences were evident between groups in WBC either or CRP at any time. Peak CRP concentrations occurred on POD3; subsequently, CRP gradually decreased to baseline values. However, concentrations on POD3 were slightly greater in the lavage group than the non-lavage group. On POD3, the mean (±s.d.) for CRP was 5.2 ± 3.8 (median, 4.4) in the lavage group and 4.8 ± 3.8 (median, 3.7) in the non-lavage group (P = 0.273); on POD4, 4.8 ± 4.1 (3.6) vs. 4.1 ± 3.2 (3.4) (P = 0.333); on POD5, 4.4 ± 3.7 (3.3) vs. 3.4 ± 2.8 (2.4) (P = 0.094); and on POD6, 3.6 ± 3.5 (1.5) vs. 2.9 ± 2.6 (1.0) (P = 0.292).
Discussion SIRS occurrences, bacteriologic findings, hematologic values, and biochemical results Occurrences of SIRS after surgery were 49% (47/96) in the lavage group and 35% (34/97) in the non-lavage group (P = 0.059). Duration of SIRS in days was 1.80 ± 1.92 (median, 1; range, 1 to 13) in the lavage group and 1.79 ± 1.52 (median, 1; range, 1 to 7) in the non-lavage group (P = 0.742). Frequency of positive bacteriologic cultures of drainage fluid obtained on postoperative day 1 was 9.4% (9/96) in the
As for the primary study endpoint, no difference was detected between groups concerning total incidence of SSI. However, incidence of organ/space infection was significantly higher in the lavage group than the non-lavage group, an unexpected result. Not only did this randomized clinical trial fail to show a benefit from peritoneal lavage in elective liver surgery, but peritoneal lavage actually was associated with increased incidence of organ/space infection. Indeed, abdominal lavage was selected by multivariate analysis as an independent risk factor for organ/space infection.
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In the peritoneal cavity, bacteria and fluid rapidly pass through mesothelial stomata on the underside of the diaphragm to enter the lymphatics and ultimately the circulation [22, 23]. Lavage has been claimed to remove not only bacteria but also material that may promote bacterial proliferation (e.g. blood) and proinflammatory cytokines that may enhance local inflammation [22, 24]. However, lavage also has been reported to impair peritoneal defense mechanisms in multiple ways [25]. Increased volumes of peritoneal fluid can interfere with containment of contaminated material and accelerate entry of bacteria and endotoxin into the systemic circulation through the diaphragmatic stomata [26]; lavage may have such an effect [25]. Peritoneal mesothelium tends to slough after even brief exposure to either air or saline, glucose, or other solutions [27–29]. Further, lavage has been found to retard mesothelial healing [30]. Lavage also might remove important anti-infectious mediators such as opsonic proteins, complement, proteases, and immunoglobulins [31, 32]. Considering these previous observations together with our present results, we conclude that peritoneal lavage upon completion of elective liver resection without resection or reconstruction of bile duct or intestine does not reduce SSI incidence, and could actually increase incidence of organ/space infection. According to a previous non-randomized study of patients undergoing elective colorectal surgery who underwent intraoperative peritoneal lavage, bacterial counts from swab specimens obtained from various sites within the abdomen decreased greatly; nonetheless, the lavage group had higher rates of postoperative wound infection, intra-abdominal abscess, and septicemia than did the control group [33]. While our present study found no significant difference in frequency of positive bacteriologic cultures of drainage fluid obtained on POD1, the frequency in the non-lavage group was slightly lower than in the lavage group. We obtained this drainage fluid early in the morning of POD1, decreasing the likelihood that the bacterial isolates represented an infection ascending through the inserted drain [15]. Even though removal of bacteria by lavage could not affect subsequent ascending infections involving drains, the greater frequency of postoperative SSI in our lavage group resembled findings of the previous report [33]. Microbes can be difficult to remove completely from the peritoneal cavity because they adhere to mesothelial cells [34] and then invade submesothelial tissues [25]. Such adherent bacteria therefore would appear likely to resist peritoneal lavage [35]. Removal of infectious agents from the peritoneal cavity probably requires more than simple mechanical cleansing. We found no significant difference between groups concerning changes in results of serial postoperative laboratory tests. However, CRP on or after POD3 was slightly greater in the lavage group than in the non-lavage group. Further, SIRS occurred somewhat more often after surgery in the
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lavage group than in the non-lavage group. The potential for conversion of a localized area of contamination to a more extensive one by lavage has been demonstrated experimentally using radiolabelled markers [36], representing another likely disadvantage of peritoneal lavage. The somewhat higher CRP and somewhat greater occurrence of SIRS in the lavage group thus may reflect spread of local infection. Most surgeons use intraoperative peritoneal lavage to remove clotted blood, devitalized tissue, and foreign bodies, as well as to facilitate assessment of hemostasis. Postoperative bleeding increases risk of liver failure after hepatectomy, but in fact no postoperative bleeding occurred in either of our groups. While our study did not determine whether removal of clot or other material by lavage affected postoperative bleeding, no increased risk of postoperative bleeding from omitting lavage was demonstrated. In conclusion, no significant difference in morbidity or overall infectious complications was noted between our lavage and non-lavage groups. Further, frequency of organ/space infection was significantly higher in the lavage group. These results suggest that routine intraoperative lavage for elective liver resection does not prevent intra-abdominal infection and should be avoided. Conflict of interest
None declared.
Author contribution Study design: Tanaka. Acquisition of data: Matsuo, Kawaguchi, Murakami, Hirano and Sato. Analysis and interpretation: Taguri and Hiroshima. Manuscript drafted by: Tanaka. Revision: Endo and Koda. Statistical advice: Taguri.
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