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Early prediction of anastomotic leakage after colorectal surgery by measuring peritoneal cytokines: Prospective study
international journal of surgery 6 (2008) 28–35
www.theijs.com
Early prediction of anastomotic leakage after colorectal surgery by measuring peritoneal cytokines: Prospective study Burak Ug˘rasx a, Murat Girisx b, Yes x im Erbila,*, Murat Go¨kpı narb, Gamze C¸ı tlaka, _x severc, Alp Bozboraa, Serdar O¨ztezcanb Halim Is a
Department of General Surgery, Istanbul Medical Faculty, Istanbul University, 34093 Capa, Istanbul, Turkey Department of Biochemistry, Istanbul Medical Faculty, Istanbul University, 34093 Capa, Istanbul, Turkey c Department of Public Health, Istanbul Medical Faculty, Istanbul University, 34093 Capa, Istanbul, Turkey b
article info
abstract
Article history:
Background: Anastomotic leakage (AL) is a major cause of postoperative mortality and mor-
Received 15 July 2007
bidity in colorectal surgery. We investigated the early prediction of peritoneal cytokine
Received in revised form
levels in developing AL after colorectal surgery.
24 September 2007
Methods: Thirty-four patients with colorectal carcinoma, who underwent elective surgery,
Accepted 3 October 2007
were included prospectively. Peritoneal samples were collected on the fifth postoperative
Published online 11 October 2007
day and interleukin (IL)-6, IL-10 and tumor necrosis factor-a were measured. Patients were divided into two groups: those with clinical evidence of AL (group 1) and those with-
Keywords:
out any evidence of AL (group 2).
Colorectal surgery
Results: Of the 34 patients undergoing anastomoses, clinically evident AL occurred in 4 pa-
Anastomotic leaking
tients (11.7%). There was a positive correlation between AL and peritoneal cytokine levels
Cytokine
and blood loss and operation time and hospital stay. Peritoneal cytokine levels were significantly higher in group 1 as compared to group 2. The significant increase in patients with AL was observed between peritoneal cytokine levels and the postoperative days. However, a significant decrease in patients without AL was observed. Conclusion: The peritoneal cytokine levels can be an additional diagnostic tool that can support the early prediction of AL in colorectal surgery. ª 2007 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
Despite improvements in surgical technique and perioperative preparation, colorectal surgery is associated with a 5% mortality rate and a morbidity rate of 20–40%.1–7 Blood supply of the anastomotic edges, the level of the anastomosis, use of staples, adverse effect during operation, lack of bowel preparation and prophylactic antibiotic therapy, blood loss and blood transfusions during operation, and patient-related risk factors have been associated with a higher risk of anastomotic leaking.8–14
Early relaparotomy and draining are the most important salvage therapies in the secondary peritonitis due to anastomotic complications15; however, the exact laboratory biomarkers of early prediction complications are unclear. Several studies have demonstrated a significant systemic inflammatory host response in surgical patients with secondary peritonitis identified by the systemic release of proinflammatory cytokines16,19; however, the local cytokine response in the colorectal surgery is unclear. Recent reports investigated the local release of peritoneal cytokines in patients after colorectal surgery during the
* Corresponding author. Tel.: þ90 212 414 2000; fax: þ90 212 534 1605. E-mail address: [email protected] (Y. Erbil). 1743-9191/$ – see front matter ª 2007 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijsu.2007.10.001
29
international journal of surgery 6 (2008) 28–35
A
IL-6 (pg/ml) 300000
0.001
250000 0.001 200000 0.001
0.001
0.001
150000 100000 50000 0
B
day 1
day 2
day 3
day 4
day 5
IL-10 (pg/ml)
350000
0.001
300000
0.001
250000 200000
0.001
0.001 0.001
150000 100000 50000 0
C
day 1
day 2
day 3
day 4
day 5
TNFα (pg/ml) 400000
0.001
350000
0.001
300000
0.001
250000 200000
0.001 0.001
150000 100000 50000 0
day 1
day 2
day 3
day 4
day 5
Patients with anastomotic leakage Patients without anastomotic leakage Fig. 1 – Comparison of peritoneal cytokines between groups 1 and 2.
early postoperative period to evaluate whether it may serve as an indicator of evolving anastomotic complications. The increase in peritoneal cytokines can predict anastomotic complications.20–26 The purpose of this study was to prospectively investigate the correlation between levels of peritoneal cytokines and anastomotic leakage and early prediction of complications in patients undergoing colorectal surgery.
2.
Materials and methods
2.1.
Patients
In the Department of Surgery, Istanbul Faculty of Medicine, 34 patients with colorectal carcinoma, who underwent elective surgery from January 2005 to December 2005, were
30
international journal of surgery 6 (2008) 28–35
Table 1 – Comparison of study parameters between groups 1 and 2 Group 1 (n ¼ 4) Group 2 (n ¼ 30) (with leakage) (without leakage) Age (years) Gender (F/M) Tumor localization Rectum/colon Stapled usage Blood loss (ml) Blood transfusion Adverse effect Tumor perforation Positive leaking test Operation time (min) Hospital stay (days)
p
47 7 1/3
53 15 8/22
0.39 0.94
4/4 4/4 600 177 4/4
16/30 10/20 228 80 9/30
0.07 0.01 0.001 0.07
1/4 2/4 230 45 17.7 4
0/30 0/30 84 28 6.5 1
0.005 0.001 0.001 0.001
included prospectively in the present study. The indication for surgery was rectal carcinoma and colon carcinoma. A suction–irrigation drain was placed in the pelvis or abdomen. The abdominal drain was generally removed when drain production was less than 100 ml in a 24-h period. None of the patients had clinical evidence of a risk of cardiac or pulmonary function. The blood cell and serum protein levels remained within normal limits. All patients underwent mechanical bowel preparation the day prior to surgery. All patients were given cefuroxim and metronidazole for antibiotic prophylaxis. Deep vein thrombosis prophylaxis was performed with low-molecular-weight heparin. Red packed cell mass was transfused postoperatively in patients with hemoglobin levels below 9 g/dl. All patients received general anesthesia during surgery and a standardized analgesic regimen. All surgery procedures were performed by the same surgical team. Postoperative analgesia was achieved by patient-controlled analgesia via a pump containing morphine solution. The study protocol was approved by The Ethics Committee at Istanbul University. All patients received written information about the study and provided informed consent.
2.2.
Surgery
Surgical procedures included right hemicolectomies, transverse colectomies, sigmoid resection, anterior rectal resections, and low anterior rectal resections. Anastomoses were handsewn for colectomies and performed with an EEA stapler for anterior resections.
2.3.
compared to postoperative white blood cell count (WBC) and peritoneal tumor necrosis factor (TNF)-a, interleukin (IL)-6, and IL-10 response. The variables included in this analysis were gender, age, tumor stage, preoperative radiation, operative time, surgical procedure, blood loss during the operation, blood transfusion, type of anastomosis (stapled or handsewn), and presence of intraoperative adverse events. Adverse events were a positive anastomosis leakage test, loose anastomotic rings, iatrogenic tear in the distal rectum, iatrogenic perforation of the tumor, iatrogenic perforation of the colon or small bowel, or perforation of urogenital organs.
2.4.
Collection of peritoneal and blood samples
Blood and intra-abdominal fluid was obtained through abdominal silicone drains on days 1, 2, 3, 4, and 5 after the operation. However, the patients with anastomosis leakage, abdominal drains samples were collected some time after the fifth postoperative day (at the appropriate time). Samples were centrifuged at 3000 g for 10 min at 4 C and stored at 80 C until analysis.
2.5.
Cytokine measurement
IL-6, IL-10 and TNF-a were quantified using enzyme-linked immunosorbent assay (ELISA) kits specific for the previously mentioned human cytokines according to the manufacturer’s instructions and guidelines (Biosource Europe S.A., Nivelles, Belgium).
2.6.
Statistical analysis
Analysis was performed using SPSS for Windows version 11 (SPSS, Chicago, IL). Results were expressed as median (range), first through third quartile and mean values SD. For comparisons between the levels of cytokines and clinical parameters in the two groups the Mann–Whitney U and c2 tests were performed. These parameters were gender, age, tumor stage, preoperative radiation, operative time, type of anastomosis (stapled or hand-sewn) and surgical procedure, blood loss during the operation, blood transfusion, presence of intraoperative adverse events, and hospital stay. Spearman’s correlation coefficient was used to determine whether a correlation existed between cytokine levels on each postoperative day. Values of p < 0.05 were considered significant.
3.
Results
3.1.
Patients
Evaluation of complication
Postoperative complications were prospectively recorded. The definition of AL in the present study was made by clinical, laboratory tests, biological findings and abdominal CT-scans. Clinical AL was defined as gas, pus or fecal discharge from the drain, pelvic abscess, peritonitis, or discharge of pus per rectum or rectovaginal fistula. Patients were divided into two groups: those with clinical evidence of AL (group 1), and those without any evidence of AL (group 2). Patients with and without complications were
There were 25 men and 9 women with a median age of 52.5 years (range, 22–84 years). The indication for surgery was rectal carcinoma in 59% (20/34) and colon carcinoma in 41% (14/34). Preoperative adjuvant radio or chemotherapy was not necessary in any of the patients. Surgical procedures included 9 right hemicolectomies, 2 transverse colectomies, 3 sigmoid resection, 5 anterior resections of the rectum, and 15 low anterior rectal resections. A temporary loop ileostomy
31
international journal of surgery 6 (2008) 28–35
275000
350000
IL-6 (pg/ml)
p<0.05
IL-10 (pg/ml)
p<0.05
p<0.05
250000
300000 p<0.05
225000
p<0.05
250000 200000
p<0.05
200000 175000
150000
150000
125000
A day 1
100000 day 2
day 3
day 4
day 5
B day 1
day 2
day 3
day 4
day 5
TNF (pg/ml) P<0.05
400000
p<0.05
300000
200000
100000
C day 1
day 2
day 3
day 4
day 5
Fig. 2 – The correlations between IL-6 (A), IL-10 (B), TNF-a levels (C) and postoperative days in the patients with anastomotic leakage.
was constructed in two patients, who underwent low anterior resections, because of the presence of risk factors thought to increase the risk of AL. In the 11 patients, anastomoses were performed with a circular stapler.
3.2. Cytokine profiles and clinical parameters according to anastomotic leakage AL occurred in 4 (11.7%) patients. Although peritoneal cytokine levels were significantly higher beginning on day 1, clinically evident anastomotic leakage occurred on day 6. All patients developed temperature above 38 C and absence of bowel movement. All patients with proven AL were re-operated.
Two had a loop ileostomy and the remaining two anastomoses were taken down and a stoma was fashioned. No patients died of sepsis secondary to AL. Peritoneal cytokines levels were significantly higher in group 1, as compared to group 2 (Fig. 1). Hospital stay, operative time, blood loss during operation, usage of stapler, and intraoperative adverse events were significantly higher in patients with AL compared to patients without AL (Table 1). A significant increase in the patients with AL was observed between peritoneal IL-6, IL-10, TNF-a levels and postoperative days (Fig. 2). However, significant decreases between peritoneal IL-6, IL-10, and TNF-a levels and postoperative days were observed in patients without AL (Fig. 3).
32
international journal of surgery 6 (2008) 28–35
IL-10 (pg/ml)
100000
IL-6 (pg/ml)
60000 P<0.05 P<0.05
50000
P<0.05
80000 P<0.05
40000
P<0.05
60000 P<0.05
30000
P<0.05
40000 20000
20000 10000
0
A
0
P<0.05
day 1
day 2
day 3
day 4
day 5
B day 1
140000
day 2
day 3
day 4
day 5
TNF (pg/ml)
120000
100000 P<0.05
80000 P<0.05
2.00 P<0.05
60000
40000
20000
0
C day 1
day 2
day 3
day 4
day 5
Fig. 3 – The correlations between IL-6 (A), IL-10 (B), TNF-a levels (C) and postoperative days in the patients without anastomotic leakage.
3.3.
Correlations
There was a positive correlation between AL and IL-6 (rs ¼ 0.905, p ¼ 0.0001), IL-10 (rs ¼ 0.922, p ¼ 0.0001) and TNF-a (rs ¼ 0.870, p ¼ 0.0001). Moreover, there was also a positive correlation between AL and blood loss (rs ¼ 0.796, p ¼ 0.0001) and operation time (rs ¼ 0.781, p ¼ 0.0001) and hospital stay (rs ¼ 0.924, p ¼ 0.0001) (Fig. 4). Hospital stay was significantly and positively correlated with blood loss during operation (r ¼ 0.462, p ¼ 0.006) and operative time (r ¼ 0.492, p ¼ 0.003). There was a positive correlation between blood loss during operation and operative time (r ¼ 0.791, p ¼ 0.0001).
4.
Discussion
We investigated the early prediction of peritoneal IL-6, IL-10, and TNF-a levels in developing AL after colorectal surgery and found that peritoneal cytokine response was suitable for the early identification of AL. Peritoneal cytokine levels in the patients with AL were significantly higher than the patients without AL. According to correlation analysis, there was a positive correlation between AL and peritoneal cytokine levels and blood loss, operation time and hospital stay. Postoperatively, peritoneal cytokine levels in patients without AL
33
international journal of surgery 6 (2008) 28–35
150000
150000
rs = 0.905 p = 0.0001
120000
IL-10 (pg/ml)
IL-6 (pg/ml)
120000
90000
60000
90000
60000
30000
30000
0
rs = 0.922 p = 0.0001
A AL (–)
140000
0
AL (+)
B AL (–)
rs = 0.870 p = 0.0001
AL (+)
rs = 0.796 p = 0.0001
120000 800
Blood loss (ml)
TNF- (pg/ml)
100000 80000 60000 40000 20000 0
600
400
200
C AL (–)
350
D AL (+)
AL (–)
rs = 0.781 p = 0.0001
25
AL (+)
rs = 0.924 p = 0.0001
Hospital stay (day)
Operation time (min)
300
250
200
150
20
15
10
100
50
E AL (–)
5
AL (+)
F AL (–)
AL (+)
Fig. 4 – Relationship between anastomotic leakage and: IL-6 level (A), IL-10 level (B), TNF-a (C), blood loss (D), operation time (E), and hospital stay (F).
34
international journal of surgery 6 (2008) 28–35
were decreased; however, peritoneal cytokines levels in patients with AL were increased. Although modern surgical techniques and perioperative care have improved, AL remains one of the most serious and important complications in patients after colorectal surgery. The leakage rate varies from 3% to 21% and the mortality rate associated with symptomatic leaks is 6–22%.1–5 In several studies, the adequate blood supply of the anastomotic edges, the level of anastomosis, use of staples, adverse effect during the operation, lack of bowel preparation and prophylactic antibiotic therapy, blood loss and blood transfusions during operation, and patient-related risk factors including hypertension, tobacco and alcohol use, chronic obstructive pulmonary disease, obesity, and malnutrition have been associated with a higher risk of anastomotic leaking.6–13 The role of mechanical bowel preparation and prophylactic antibiotic therapy in preventing AL is unclear, despite some studies that describe a low incidence of AL.12–14 It is suggested that anastomoses close to the anal verge has a greater risk of anastomotic leak because of poor oxygenation and tension at the anastomotic level.5,6,10–12 In our study, a low anterior resection was performed in all patients with AL. The use of staples may contribute to AL due to poor blood flow at the anastomosis site, whereas results of AL regarding the association of the use of staplers are conflicting.8,9 In our study, the ratio of stapler usage, blood loss and intraoperative adverse effects on the patients with AL were significantly higher than patients without AL. Early relaparotomy and draining are the most important salvage therapies in patients who develop secondary peritonitis due to anastomotic complications.15 The early detection of these complications within the first postoperative day by clinical examination is difficult and the exact laboratory biomarkers of early prediction of these complications are unknown. Several authors have suggested that the use of intramucosal pH, tissue oxygen saturation, and peritoneal cytokine levels in patients with colorectal anastomosis may predict anastomotic complications.22–28 Proinflammatory cytokines such as TNF-a and IL-6, which are mostly released from macrophages, generate an inflammatory reaction. This reaction is inhibited by other cytokines such as IL-10.17,19 It has been shown that during the first postoperative days, the peritoneal concentrations of cytokines including TNF-a, IL-1, IL-6, and IL-10 reflect the severity of stress caused by abdominal operations.20–25 It is suggested that decreasing peritoneal cytokine levels characterize a normal postoperative course, whereas increasing levels indicate an abnormal postoperative course.22,24,25 The overexpression of peritoneal cytokines, as a local inflammatory response, in response to microbial invasion might be a very early event in the development of AL. In our study, peritoneal IL-6, IL-10 and TNF-a levels were significantly higher in patients with AL compared to patients without AL. On the first postoperative day, cytokines indicated severe local inflammation, which occurred days before the clinical signs of AL. In conclusion, peritoneal cytokine levels could serve as an additional diagnostic tool that can support the early prediction of AL in colorectal surgery.
Conflict of interest None declared.
Funding No external funding.
Ethical approval The study protocol was approved by the Ethics Committee of Istanbul University. All patients received written information about the study and gave their approval to participate.
references
1. Alves A, Panis Y, Trancart D, Regimbeau JM, Pocard M, Valleur P. Factors associated with clinically significant anastomotic leakage after large bowel resection: multivariate analysis of 707 patients. World J Surg 2002;26:499–502. 2. Golub R, Golub RW, Cantu R, Stein HD. A multivariate analysis of factors contributing to leakage of intestinal anastomoses. J Am Coll Surg 1997;184:364–72. 3. Rullier E, Laurent C, Garrelon JL, Michel P, Saric J, Parneix M. Risk factors for anastomotic leakage after resection of rectal cancer. Br J Surg 1998;85:355–8. 4. Moran BJ, Heald RJ. Risk factors for, and management of anastomotic leakage in rectal surgery. Colorectal Dis 2001;3:135–7. 5. Makela JT, Kiviniemi H, Laitinen K. Risk factors for anastomotic leakage after left-sided colorectal resection with rectal anastomosis. Dis Colon Rectum 2003;46:653–60. 6. Branagan G, Finnis F. Prognosis after anastomotic leakage in colorectal surgery. Dis Colon Rectum 2005;48:1021–6. 7. Alves A, Panis Y, Mathieu P, Mantion G, Kwiatkowski F, Slim K. Postoperative mortality and morbidity in French patients undergoing colorectal surgery: results of a prospective multicenter study. Arch Surg 2005;140:278–83. 8. Karanjia ND, Corder AP, Bearn P, Heald RJ. Leakage from stapled low anastomosis after total mesorectal excision for carcinoma of the rectum. Br J Surg 1994;81:1224–6. 9. Vignali A, Fazio VW, Lavery IC, Milsom JW, Church JM, Hull TL, et al. Factors associated with the occurrence of leaks in stapled rectal anastomoses: a review of 1014 patients. J Am Coll Surg 1997;185:105–13. 10. Marusch F, Koch A, Schmidt U, et al. Value of a protective stoma in low anterior resections for rectal cancer. Dis Colon Rectum 2002;45:1164–71. 11. Pakkastie TE, Ovaska JT, Pekkala ES, Geibetaler S, Dralle H, Saeger HD, et al. A randomized study of colostomies in low colorectal anastomoses. Eur J Surg 1997;163:929–33. 12. Biondo S, Pares D, Kreisler E, Rague JM, Fraccalvieri D, Ruiz AG, et al. Anastomotic dehiscence after resection and primary anastomosis in left-sided colonic emergencies. Dis Colon Rectum 2005;48:2272–80. 13. Bucher P, Gervaz P, Soravia C. Randomized clinical trial of mechanical bowel preparation versus no preparation before elective left-sided colorectal surgery. Br J Surg 2005;92:409–14. 14. Ram E, Sherman Y, Weil R, Vishne T, Kravarusic D, Dreznik Z. Is mechanical bowel preparation mandatory for elective colon surgery? A prospective randomized study. Arch Surg 2005;140:285–8. 15. Parc Y, Frileux P, Schmitt G, Dehni N, Ollivier JM, Parc R. Management of postoperative peritonitis after anterior resection: experience from a referral intensive care unit. Dis Colon Rectum 2000;43:579–87. 16. Sarbinowski R, Arvidsson S, Tylman M, Oresland T, Bengtsson A. Plasma concentration of procalcitonin and
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17.
19.
20.
21.
22.
systemic inflammatory response syndrome after colorectal surgery. Acta Anaesthesiol Scand 2005;49:191–6. Sherwood ER, Toliver-Kinsky T. Mechanisms of the inflammatory response. Best Pract Res Clin Anaesthesiol 2004; 18:385–405. Sido B, Teklote JR, Hartel M, Friess H, Buchler MW. Inflammatory response after abdominal surgery. Best Pract Res Clin Anaesthesiol 2004;18:439–54. Scheingraber S, Bauerfeind F, Bohme J, Dralle H. Limits of peritoneal cytokine measurements during abdominal lavage treatment for intraabdominal sepsis. Am J Surg 2001;181: 301–8. Jansson K, Redler B, Truedsson L, Magnuson A, Matthiessen P, Andersson M, et al. Intraperitoneal cytokine response after major surgery: higher postoperative intraperitoneal versus systemic cytokine levels suggest the gastrointestinal tract as the major source of the postoperative inflammatory reaction. Am J Surg 2004;187:372–7. Herwig R, Glodny B, Kuhle C, Schluter B, Brinkmann OA, Strasser H, et al. Early identification of peritonitis by peritoneal cytokine measurement. Dis Colon Rectum 2002;45: 514–21.
35
23. Chuang D, Paddison JS, Booth RJ, Hill AG. Differential production of cytokines following colorectal surgery. Aust NZ J Surg 2006;76:821–4. 24. van Berge Henegouwen MI, van der Poll T, van Deventer SJ, Gouma DJ. Peritoneal cytokine release after elective gastrointestinal surgery and postoperative complications. Am J Surg 1998;175:311–6. 25. Slotwinski R, Olszewski WL, Chaber A, Slodkowski M, Zaleska M, Krasnodebski IW. The soluble tumor necrosis factor receptor I is an early predictor of local infective complications after colorectal surgery. J Clin Immunol 2002;22:289–96. 26. Cheong YC, Laird SM, Shelton JB, Ledger WL, Li TC, Cooke ID. The correlation of adhesions and peritoneal fluid cytokine concentrations: a pilot study. Hum Reprod 2002;17:1039–45. 27. Millan M, Garcia-Granero E, Flor B, Garcia-Botello S, Lledo S. Early prediction of anastomotic leak in colorectal cancer surgery by intramucosal pH. Dis Colon Rectum 2006;49:595–601. 28. Hirano Y, Omura K, Tatsuzawa Y, Shimizu J, Kawaura Y, Watanabe G. Tissue oxygen saturation during colorectal surgery measured by near-infrared spectroscopy: pilot study to predict anastomotic complications. World J Surg 2006;30: 457–61.
www.theijs.com
Early prediction of anastomotic leakage after colorectal surgery by measuring peritoneal cytokines: Prospective study Burak Ug˘rasx a, Murat Girisx b, Yes x im Erbila,*, Murat Go¨kpı narb, Gamze C¸ı tlaka, _x severc, Alp Bozboraa, Serdar O¨ztezcanb Halim Is a
Department of General Surgery, Istanbul Medical Faculty, Istanbul University, 34093 Capa, Istanbul, Turkey Department of Biochemistry, Istanbul Medical Faculty, Istanbul University, 34093 Capa, Istanbul, Turkey c Department of Public Health, Istanbul Medical Faculty, Istanbul University, 34093 Capa, Istanbul, Turkey b
article info
abstract
Article history:
Background: Anastomotic leakage (AL) is a major cause of postoperative mortality and mor-
Received 15 July 2007
bidity in colorectal surgery. We investigated the early prediction of peritoneal cytokine
Received in revised form
levels in developing AL after colorectal surgery.
24 September 2007
Methods: Thirty-four patients with colorectal carcinoma, who underwent elective surgery,
Accepted 3 October 2007
were included prospectively. Peritoneal samples were collected on the fifth postoperative
Published online 11 October 2007
day and interleukin (IL)-6, IL-10 and tumor necrosis factor-a were measured. Patients were divided into two groups: those with clinical evidence of AL (group 1) and those with-
Keywords:
out any evidence of AL (group 2).
Colorectal surgery
Results: Of the 34 patients undergoing anastomoses, clinically evident AL occurred in 4 pa-
Anastomotic leaking
tients (11.7%). There was a positive correlation between AL and peritoneal cytokine levels
Cytokine
and blood loss and operation time and hospital stay. Peritoneal cytokine levels were significantly higher in group 1 as compared to group 2. The significant increase in patients with AL was observed between peritoneal cytokine levels and the postoperative days. However, a significant decrease in patients without AL was observed. Conclusion: The peritoneal cytokine levels can be an additional diagnostic tool that can support the early prediction of AL in colorectal surgery. ª 2007 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
Despite improvements in surgical technique and perioperative preparation, colorectal surgery is associated with a 5% mortality rate and a morbidity rate of 20–40%.1–7 Blood supply of the anastomotic edges, the level of the anastomosis, use of staples, adverse effect during operation, lack of bowel preparation and prophylactic antibiotic therapy, blood loss and blood transfusions during operation, and patient-related risk factors have been associated with a higher risk of anastomotic leaking.8–14
Early relaparotomy and draining are the most important salvage therapies in the secondary peritonitis due to anastomotic complications15; however, the exact laboratory biomarkers of early prediction complications are unclear. Several studies have demonstrated a significant systemic inflammatory host response in surgical patients with secondary peritonitis identified by the systemic release of proinflammatory cytokines16,19; however, the local cytokine response in the colorectal surgery is unclear. Recent reports investigated the local release of peritoneal cytokines in patients after colorectal surgery during the
* Corresponding author. Tel.: þ90 212 414 2000; fax: þ90 212 534 1605. E-mail address: [email protected] (Y. Erbil). 1743-9191/$ – see front matter ª 2007 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijsu.2007.10.001
29
international journal of surgery 6 (2008) 28–35
A
IL-6 (pg/ml) 300000
0.001
250000 0.001 200000 0.001
0.001
0.001
150000 100000 50000 0
B
day 1
day 2
day 3
day 4
day 5
IL-10 (pg/ml)
350000
0.001
300000
0.001
250000 200000
0.001
0.001 0.001
150000 100000 50000 0
C
day 1
day 2
day 3
day 4
day 5
TNFα (pg/ml) 400000
0.001
350000
0.001
300000
0.001
250000 200000
0.001 0.001
150000 100000 50000 0
day 1
day 2
day 3
day 4
day 5
Patients with anastomotic leakage Patients without anastomotic leakage Fig. 1 – Comparison of peritoneal cytokines between groups 1 and 2.
early postoperative period to evaluate whether it may serve as an indicator of evolving anastomotic complications. The increase in peritoneal cytokines can predict anastomotic complications.20–26 The purpose of this study was to prospectively investigate the correlation between levels of peritoneal cytokines and anastomotic leakage and early prediction of complications in patients undergoing colorectal surgery.
2.
Materials and methods
2.1.
Patients
In the Department of Surgery, Istanbul Faculty of Medicine, 34 patients with colorectal carcinoma, who underwent elective surgery from January 2005 to December 2005, were
30
international journal of surgery 6 (2008) 28–35
Table 1 – Comparison of study parameters between groups 1 and 2 Group 1 (n ¼ 4) Group 2 (n ¼ 30) (with leakage) (without leakage) Age (years) Gender (F/M) Tumor localization Rectum/colon Stapled usage Blood loss (ml) Blood transfusion Adverse effect Tumor perforation Positive leaking test Operation time (min) Hospital stay (days)
p
47 7 1/3
53 15 8/22
0.39 0.94
4/4 4/4 600 177 4/4
16/30 10/20 228 80 9/30
0.07 0.01 0.001 0.07
1/4 2/4 230 45 17.7 4
0/30 0/30 84 28 6.5 1
0.005 0.001 0.001 0.001
included prospectively in the present study. The indication for surgery was rectal carcinoma and colon carcinoma. A suction–irrigation drain was placed in the pelvis or abdomen. The abdominal drain was generally removed when drain production was less than 100 ml in a 24-h period. None of the patients had clinical evidence of a risk of cardiac or pulmonary function. The blood cell and serum protein levels remained within normal limits. All patients underwent mechanical bowel preparation the day prior to surgery. All patients were given cefuroxim and metronidazole for antibiotic prophylaxis. Deep vein thrombosis prophylaxis was performed with low-molecular-weight heparin. Red packed cell mass was transfused postoperatively in patients with hemoglobin levels below 9 g/dl. All patients received general anesthesia during surgery and a standardized analgesic regimen. All surgery procedures were performed by the same surgical team. Postoperative analgesia was achieved by patient-controlled analgesia via a pump containing morphine solution. The study protocol was approved by The Ethics Committee at Istanbul University. All patients received written information about the study and provided informed consent.
2.2.
Surgery
Surgical procedures included right hemicolectomies, transverse colectomies, sigmoid resection, anterior rectal resections, and low anterior rectal resections. Anastomoses were handsewn for colectomies and performed with an EEA stapler for anterior resections.
2.3.
compared to postoperative white blood cell count (WBC) and peritoneal tumor necrosis factor (TNF)-a, interleukin (IL)-6, and IL-10 response. The variables included in this analysis were gender, age, tumor stage, preoperative radiation, operative time, surgical procedure, blood loss during the operation, blood transfusion, type of anastomosis (stapled or handsewn), and presence of intraoperative adverse events. Adverse events were a positive anastomosis leakage test, loose anastomotic rings, iatrogenic tear in the distal rectum, iatrogenic perforation of the tumor, iatrogenic perforation of the colon or small bowel, or perforation of urogenital organs.
2.4.
Collection of peritoneal and blood samples
Blood and intra-abdominal fluid was obtained through abdominal silicone drains on days 1, 2, 3, 4, and 5 after the operation. However, the patients with anastomosis leakage, abdominal drains samples were collected some time after the fifth postoperative day (at the appropriate time). Samples were centrifuged at 3000 g for 10 min at 4 C and stored at 80 C until analysis.
2.5.
Cytokine measurement
IL-6, IL-10 and TNF-a were quantified using enzyme-linked immunosorbent assay (ELISA) kits specific for the previously mentioned human cytokines according to the manufacturer’s instructions and guidelines (Biosource Europe S.A., Nivelles, Belgium).
2.6.
Statistical analysis
Analysis was performed using SPSS for Windows version 11 (SPSS, Chicago, IL). Results were expressed as median (range), first through third quartile and mean values SD. For comparisons between the levels of cytokines and clinical parameters in the two groups the Mann–Whitney U and c2 tests were performed. These parameters were gender, age, tumor stage, preoperative radiation, operative time, type of anastomosis (stapled or hand-sewn) and surgical procedure, blood loss during the operation, blood transfusion, presence of intraoperative adverse events, and hospital stay. Spearman’s correlation coefficient was used to determine whether a correlation existed between cytokine levels on each postoperative day. Values of p < 0.05 were considered significant.
3.
Results
3.1.
Patients
Evaluation of complication
Postoperative complications were prospectively recorded. The definition of AL in the present study was made by clinical, laboratory tests, biological findings and abdominal CT-scans. Clinical AL was defined as gas, pus or fecal discharge from the drain, pelvic abscess, peritonitis, or discharge of pus per rectum or rectovaginal fistula. Patients were divided into two groups: those with clinical evidence of AL (group 1), and those without any evidence of AL (group 2). Patients with and without complications were
There were 25 men and 9 women with a median age of 52.5 years (range, 22–84 years). The indication for surgery was rectal carcinoma in 59% (20/34) and colon carcinoma in 41% (14/34). Preoperative adjuvant radio or chemotherapy was not necessary in any of the patients. Surgical procedures included 9 right hemicolectomies, 2 transverse colectomies, 3 sigmoid resection, 5 anterior resections of the rectum, and 15 low anterior rectal resections. A temporary loop ileostomy
31
international journal of surgery 6 (2008) 28–35
275000
350000
IL-6 (pg/ml)
p<0.05
IL-10 (pg/ml)
p<0.05
p<0.05
250000
300000 p<0.05
225000
p<0.05
250000 200000
p<0.05
200000 175000
150000
150000
125000
A day 1
100000 day 2
day 3
day 4
day 5
B day 1
day 2
day 3
day 4
day 5
TNF (pg/ml) P<0.05
400000
p<0.05
300000
200000
100000
C day 1
day 2
day 3
day 4
day 5
Fig. 2 – The correlations between IL-6 (A), IL-10 (B), TNF-a levels (C) and postoperative days in the patients with anastomotic leakage.
was constructed in two patients, who underwent low anterior resections, because of the presence of risk factors thought to increase the risk of AL. In the 11 patients, anastomoses were performed with a circular stapler.
3.2. Cytokine profiles and clinical parameters according to anastomotic leakage AL occurred in 4 (11.7%) patients. Although peritoneal cytokine levels were significantly higher beginning on day 1, clinically evident anastomotic leakage occurred on day 6. All patients developed temperature above 38 C and absence of bowel movement. All patients with proven AL were re-operated.
Two had a loop ileostomy and the remaining two anastomoses were taken down and a stoma was fashioned. No patients died of sepsis secondary to AL. Peritoneal cytokines levels were significantly higher in group 1, as compared to group 2 (Fig. 1). Hospital stay, operative time, blood loss during operation, usage of stapler, and intraoperative adverse events were significantly higher in patients with AL compared to patients without AL (Table 1). A significant increase in the patients with AL was observed between peritoneal IL-6, IL-10, TNF-a levels and postoperative days (Fig. 2). However, significant decreases between peritoneal IL-6, IL-10, and TNF-a levels and postoperative days were observed in patients without AL (Fig. 3).
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international journal of surgery 6 (2008) 28–35
IL-10 (pg/ml)
100000
IL-6 (pg/ml)
60000 P<0.05 P<0.05
50000
P<0.05
80000 P<0.05
40000
P<0.05
60000 P<0.05
30000
P<0.05
40000 20000
20000 10000
0
A
0
P<0.05
day 1
day 2
day 3
day 4
day 5
B day 1
140000
day 2
day 3
day 4
day 5
TNF (pg/ml)
120000
100000 P<0.05
80000 P<0.05
2.00 P<0.05
60000
40000
20000
0
C day 1
day 2
day 3
day 4
day 5
Fig. 3 – The correlations between IL-6 (A), IL-10 (B), TNF-a levels (C) and postoperative days in the patients without anastomotic leakage.
3.3.
Correlations
There was a positive correlation between AL and IL-6 (rs ¼ 0.905, p ¼ 0.0001), IL-10 (rs ¼ 0.922, p ¼ 0.0001) and TNF-a (rs ¼ 0.870, p ¼ 0.0001). Moreover, there was also a positive correlation between AL and blood loss (rs ¼ 0.796, p ¼ 0.0001) and operation time (rs ¼ 0.781, p ¼ 0.0001) and hospital stay (rs ¼ 0.924, p ¼ 0.0001) (Fig. 4). Hospital stay was significantly and positively correlated with blood loss during operation (r ¼ 0.462, p ¼ 0.006) and operative time (r ¼ 0.492, p ¼ 0.003). There was a positive correlation between blood loss during operation and operative time (r ¼ 0.791, p ¼ 0.0001).
4.
Discussion
We investigated the early prediction of peritoneal IL-6, IL-10, and TNF-a levels in developing AL after colorectal surgery and found that peritoneal cytokine response was suitable for the early identification of AL. Peritoneal cytokine levels in the patients with AL were significantly higher than the patients without AL. According to correlation analysis, there was a positive correlation between AL and peritoneal cytokine levels and blood loss, operation time and hospital stay. Postoperatively, peritoneal cytokine levels in patients without AL
33
international journal of surgery 6 (2008) 28–35
150000
150000
rs = 0.905 p = 0.0001
120000
IL-10 (pg/ml)
IL-6 (pg/ml)
120000
90000
60000
90000
60000
30000
30000
0
rs = 0.922 p = 0.0001
A AL (–)
140000
0
AL (+)
B AL (–)
rs = 0.870 p = 0.0001
AL (+)
rs = 0.796 p = 0.0001
120000 800
Blood loss (ml)
TNF- (pg/ml)
100000 80000 60000 40000 20000 0
600
400
200
C AL (–)
350
D AL (+)
AL (–)
rs = 0.781 p = 0.0001
25
AL (+)
rs = 0.924 p = 0.0001
Hospital stay (day)
Operation time (min)
300
250
200
150
20
15
10
100
50
E AL (–)
5
AL (+)
F AL (–)
AL (+)
Fig. 4 – Relationship between anastomotic leakage and: IL-6 level (A), IL-10 level (B), TNF-a (C), blood loss (D), operation time (E), and hospital stay (F).
34
international journal of surgery 6 (2008) 28–35
were decreased; however, peritoneal cytokines levels in patients with AL were increased. Although modern surgical techniques and perioperative care have improved, AL remains one of the most serious and important complications in patients after colorectal surgery. The leakage rate varies from 3% to 21% and the mortality rate associated with symptomatic leaks is 6–22%.1–5 In several studies, the adequate blood supply of the anastomotic edges, the level of anastomosis, use of staples, adverse effect during the operation, lack of bowel preparation and prophylactic antibiotic therapy, blood loss and blood transfusions during operation, and patient-related risk factors including hypertension, tobacco and alcohol use, chronic obstructive pulmonary disease, obesity, and malnutrition have been associated with a higher risk of anastomotic leaking.6–13 The role of mechanical bowel preparation and prophylactic antibiotic therapy in preventing AL is unclear, despite some studies that describe a low incidence of AL.12–14 It is suggested that anastomoses close to the anal verge has a greater risk of anastomotic leak because of poor oxygenation and tension at the anastomotic level.5,6,10–12 In our study, a low anterior resection was performed in all patients with AL. The use of staples may contribute to AL due to poor blood flow at the anastomosis site, whereas results of AL regarding the association of the use of staplers are conflicting.8,9 In our study, the ratio of stapler usage, blood loss and intraoperative adverse effects on the patients with AL were significantly higher than patients without AL. Early relaparotomy and draining are the most important salvage therapies in patients who develop secondary peritonitis due to anastomotic complications.15 The early detection of these complications within the first postoperative day by clinical examination is difficult and the exact laboratory biomarkers of early prediction of these complications are unknown. Several authors have suggested that the use of intramucosal pH, tissue oxygen saturation, and peritoneal cytokine levels in patients with colorectal anastomosis may predict anastomotic complications.22–28 Proinflammatory cytokines such as TNF-a and IL-6, which are mostly released from macrophages, generate an inflammatory reaction. This reaction is inhibited by other cytokines such as IL-10.17,19 It has been shown that during the first postoperative days, the peritoneal concentrations of cytokines including TNF-a, IL-1, IL-6, and IL-10 reflect the severity of stress caused by abdominal operations.20–25 It is suggested that decreasing peritoneal cytokine levels characterize a normal postoperative course, whereas increasing levels indicate an abnormal postoperative course.22,24,25 The overexpression of peritoneal cytokines, as a local inflammatory response, in response to microbial invasion might be a very early event in the development of AL. In our study, peritoneal IL-6, IL-10 and TNF-a levels were significantly higher in patients with AL compared to patients without AL. On the first postoperative day, cytokines indicated severe local inflammation, which occurred days before the clinical signs of AL. In conclusion, peritoneal cytokine levels could serve as an additional diagnostic tool that can support the early prediction of AL in colorectal surgery.
Conflict of interest None declared.
Funding No external funding.
Ethical approval The study protocol was approved by the Ethics Committee of Istanbul University. All patients received written information about the study and gave their approval to participate.
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