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Antibiotic irrigation and the formation of intraabdominal adhesions
Antibiotic Irrigation and the Formation of Intraabdominal Adhesions William D. Rappaport, MD, Murray Holcomb, MD, John Valente, Milos Chvapil, MD, POD, DSC, TUCNMI,Arizona of a&biotic peritoneal lavage iu the prevention of postoperativeinfection is controversial. The role of intraperitoneallyadministeredcefaxolin aud tetracycliuein the formation of adhesions was studied in tbe rodent model. Thirty-two rats were divided iuto 3 epaps. Group 1 underwent midline laparotomy with iustillationof 10 ml of normal saline solution. Group 2 and Group 3 underwent the same procedure with instillationof 0.2 percent saline solutionsof c4Az&u or tetracycline, reqectively. Auimals were sacrificed after 2 weeks. Inadhesions were graded and samples ofpm+etalperitoneum were processedfor histologic data. Group 2 and Group 3 bad siguificantlyhigher adhesionscores6xunparedwitbCroupl (p
T
he efficacy of antibiotic peritoneal lavage in the prevention of postoperative infection is controversial. A number of authors cite reduction in infectious complications after intraabdominal surgery [1-I I]. others have noted no difference in infection rates when antibiotic irrigation was compared with the intravenous route [22171. In addition, toxicity from peritoneal irrigation has been reported [22,28-201. One area which has not been previously addressed is the role of antibiotic irrigation in the formation of intraabdominal adhesions. With adhesions being the most common cause of bowel obstruction, identification of contributing factors should prove helpful in prevention. MATERIAL AND METHODS Thirty-two Sprague-Dawley rats weighing between 240 to 300 g were divided into 3 groups. All operations were performed using Innovar@anesthesia. After preparFrom the Department of Surgery and the Section of Surgical Biology, University Arizona Health !3cienaa Center, Tucson, Arizona. Requests for reprints should be addrcsecd to Wii D. Rappaport, MD, Deportment of Surgery, University of Arizona Health Sciences Center, 1501 North Campbell Avenue, Tucson, Arizona 85724.
of
THE AMERICAN
MD,
ing the abdomen, a 3-cm midline laparotomy incision was made. After entering the abdomen, one of the three irrigation fluids was administered. Group 1(16 rats) underwent peritoneal cavity irrigation with 10 ml of normal saline solution (0.9 percent). Group 2 (8 rats) were irrigated with 10 ml of 0.2 percent cefaxolin in normal saline solution. Group 3 (8 rats) underwent irrigation with 0.2 percent tetracycline in normal saline solution. The abdomen was closed with a running 3-O prolene. The animals were sacrificed after 2 weeks when repeat laparotomy was performed. The system employed by Siegler et al was used for grading adhesions [Za]. This was performed in a blinded fashion. The grading system was as follows: 0, no adhesion; 1, thin, few, filmy; 2, thick, avascular; 3, thick, vascular, and extensive. A sample of the peritoneum away from the suture line was harvested for histologic evaluation. All data were subjected to analysis of variance. RJBULTS
There were no deaths, therefore all 32 rats were included in the study. When the incidence and score of adhesions in Group 1 was compared with Group 2, there was a statistically significant greater adhesion grade in the antibiotic-irrigated group (p
JOURNAL
OF SURGERY
VOLUME
158
NOVEMBER
1989
4%
of normal saline solution. Other investigators have demonstrated similar beneficial results with intraabdominal antibiotic irrigation [3,4,5,10]. A number of investigations have shown no benefit of antibiotic lavage in reducing infectious complications. Hau et al [9] showed no beneficial effect of peritoneal irrigation with cephalothin solution in the rat model with fecal peritonitis. Rambo [Z6] compared saline with cephalothin irrigation in patients with diffuse peritonitis and found no difference in patient survival. Other investigators have also demonstrated no benefit of intraabdominal antibiotic irrigation when compared with intravenous antibiotics [13,17]. Intraperitoneal antibiotic administration is not without complications. Rapid absorption occurs after instillation, with peak serum concentration at about 15 to 30 minutes [4,13,15,18]. Renal failure and ototoxicity have been reported after irrigation with aminoglycosides [4,22,28,20]. Majeski et al [21] have shown that certain commonly used antibiotics inhibit chemotactic response of leukocytes. The first report suggesting that antibiotics may cause adhesions was by Phillips and Dudley [22] who showed peritoneal damage as judged by electron microscopy. In the present study, we have shown that two commonly used antibiotic irrigants, tetracycline and cefazolin, produce parietal peritoneal damage and adhesion for-
mation in the rat model. As Ellis [23] points out, various chemicals and irritants produce varying effects on the serosal surfaces. Some initiate ischemia which leads to the formation of adhesions [24]. Others are cytotoxic by interfering with protein synthesis or other metabolic cell function. In this respect, some antibiotics (bacitracin) are less toxic than others (tetracycline). The nature of posttraumatic peritoneal adhesions is believed to be secondary to an outpouring of fibrin onto the traumatized surface. This causes a fibrin bond between intraabdominal organs. After 5 days, much of the fibrin has been absorbed, and collagen deposition by fibroblasts has begun [23]. In a final stage, the collagenous adhesion be comes crosslinkcd and a stable, rigid adhesion is formed. A number of both experimental and clinical measures have been tried to reduce adhesion formation [23-24. The majority of these attempts have met with limited success. Currently, the only accepted method of reducing adhesion formation is strict adherence to Halsted principles of meticulous handling of tissue and prevention of infection. In conclusion, we believe that until large prospective controlled studies are performed to investigate the role of antibiotic irrigation, these agents should be used cautiously. This is especially true in the low-risk elective surgery patient, since these agents may play a role in adhesion formation.
a6
158
THE AMERICAN
JOURNAL
OF SURGERY
VOLUME
NOVEMBER
1989
ANTIBIOTIC IRBIGATION AND INTBAABDOIWNALADHESIONS
The issues of peritonitis and peritoneal contamination continue to be in theforefront of both clinicalpracticeproblems and surgical research. The favorable and unfavorable effects of treatment directed to the site of injury, that is, the peritoneal cavity, have both clinical and further investigativerelevance. RElwwNcE!S 1. Silv~ SH, Ambrose NS, Youngs DJ, Shepherd AFI, Rob erts AP, Keighly MRB. The effect of peritoneal lavage with tetracycline solution on pcstoperative infection: a prospective, randomized, clinical trial. Dis Colon Rectum 1986; 29: 165-9. 2. Nomikos IN, Katsouyamri K, Papaioamtou AN. Washing with or without chloramphenicol in the treatment of peritonitis: a prospective clinical trial. Surgery 1986; 99: 20-5. 3. Bourgeois FJ, Pinkerton JA, Andersen W, Thiagrarjah S. Antibiotic irrigation prophylaxis in the high-risk ccsarean section patient. Am J Obstet Gynecol 1965; 153: 197-201. 4. Freissschlag JF, M&rattan M, Bussutil RW. Topical versus systemic cephalosporin administration in elective biliary operations. Surgery 1984; %: 686-93. 5. Grr JD. Antibiotic peritoneal lavage in childhood appendicitis. JR Coll Surg Edinb 1984; 29: 307-9. 6. Benjamin JB, Volx RG. Efficacy of a topical antibiotic irrigant in decreasing or eliminating bacterial contamination in surgical wounds. Clin Grthop 1984; 184: 114-7. 7. Lord JW. Intraoperative antibiotic wound irrigation. Surg Gyne co1 Obstet 1983; 157: 357-61. 8. Lord JW, LaRaja RD, Daliana M, Gordon MT. Prophylactic antibiotic wound irrigation in gastric, biliary, and colonic surgery. Am J Surg 1983; 145: 209-12. 9. Hau T, Niihikawa R, Phuangsab A. Irrigation of the peritoneal cavity and local antibiotics in the treatment of peritonitis. Surg Gynecol &&et 1983: 156: 25-30. 10. Saha SK. Peritoneal lavage with metronidaxole. Surg Gynecol Obstet 1985; 160: 335-8. 11. Anderson MG. Neomycin ototoxicity associated with wound irrigation in the local treatment of osteomyelitis. J Fla Med Assoc 1978; 65: 20-l. 12. Richardson H, Mueller CB. Topical neomycin. Can J Surg
1979; 22: 199-200. 13. Gonen R, Samberg I, Levi&i R, Levitan Z, Sharf M. Effect of irrigation or intravenous antibiotic prophylaxis on infectious morbidity at cesarean section. Obstet Gynecol 1986; 67: 545-8. 14. Sauven P, Playforth MJ, Smith GMR, Evans M, Pollock AV. Single-dose antibiotic prophylaxis of abdominal surgical wound infection: a trial of preoperative latamoxef against preoperative tetracycline lavage. JR See Med 1986; 24: 240-2. 15. Lally KP, Shorr LD, Nichols RL. Aminoglycoside peritoneal lavage: lack of efficacy in experimental fecal peritonitis. J Pediatr Surg 1985; 20: 541-2. 16. Rambo WM. Irrigation of the peritoneal cavity with cephalo thin. Am J Surg 1972; 123: 192. 17. Conover WB, Moore TB. Comparison of irrigation and intravb nous antibiotic prophylaxis at cesarean section. Obstet Gynecol 1984; 63: 787. 18. Ericsson CD, Duke JH, Pickering LK. Clinical pharmacology of intravenous and intraperitoneal aminoglycoside antibiotics in the prevention of wound infections. AM Surg 1978; 188: 66-70. 19. Ericsson CD, Duke JI-I, Pickering LK, Hussain SM. Systemic absorption of bacitracin after peritoneal lavage. Am J Surg 1979; 137: 65-7. 20. Weinstein AJ, McHemy MC, Gavan TL. Systemic absorption of neomycin irrigating solution, JAMA 1977; 238: 152-3. 21. Majeski JA, McClellan MS, Alexander JW. Evaluation of leukocyte chemotactic response in the presence of antibiotics. Surg Forum 1975; 16: 83. 22. Phillips RKS, Dudley HAF. The effect of tetracycline lavage and trauma on visceral and parietal peritoneal ultrastructure and adhesion formation. Br J Surg 1984; 71: 537. 23. Ellis H. Internal overhealing: the problem of intraperitoneal adhesions. World J Surg 1980; 4: 303. 24. Jewett TC, Ambrus JL, Ambrus CM, Mink IB. Effects of fibrinolytic enxymes on experimentally induced peritoneal adhesions. Surgery 1965; 57: 280-4. 25. Fredericks CM, Kortry I, Holtx G, Askalani AH, Serour GI. Adhesion prevention in the rabbit with sodium carboxymethlicellulose solution. Am J Obstet Gynecol 1986; 155: 667-70. 26. Bergqvist JE, Arfors KE. Effect of dextran and hyahrronic acid on the development of postoperative peritoneal adhesions in experimental animals. Eur Surg Res 1977; 9: 321-5.
THE AMERICAN JOURNAL OF SURGERY
VOLUME 158 NOVEMBER 1989
437
T
he efficacy of antibiotic peritoneal lavage in the prevention of postoperative infection is controversial. A number of authors cite reduction in infectious complications after intraabdominal surgery [1-I I]. others have noted no difference in infection rates when antibiotic irrigation was compared with the intravenous route [22171. In addition, toxicity from peritoneal irrigation has been reported [22,28-201. One area which has not been previously addressed is the role of antibiotic irrigation in the formation of intraabdominal adhesions. With adhesions being the most common cause of bowel obstruction, identification of contributing factors should prove helpful in prevention. MATERIAL AND METHODS Thirty-two Sprague-Dawley rats weighing between 240 to 300 g were divided into 3 groups. All operations were performed using Innovar@anesthesia. After preparFrom the Department of Surgery and the Section of Surgical Biology, University Arizona Health !3cienaa Center, Tucson, Arizona. Requests for reprints should be addrcsecd to Wii D. Rappaport, MD, Deportment of Surgery, University of Arizona Health Sciences Center, 1501 North Campbell Avenue, Tucson, Arizona 85724.
of
THE AMERICAN
MD,
ing the abdomen, a 3-cm midline laparotomy incision was made. After entering the abdomen, one of the three irrigation fluids was administered. Group 1(16 rats) underwent peritoneal cavity irrigation with 10 ml of normal saline solution (0.9 percent). Group 2 (8 rats) were irrigated with 10 ml of 0.2 percent cefaxolin in normal saline solution. Group 3 (8 rats) underwent irrigation with 0.2 percent tetracycline in normal saline solution. The abdomen was closed with a running 3-O prolene. The animals were sacrificed after 2 weeks when repeat laparotomy was performed. The system employed by Siegler et al was used for grading adhesions [Za]. This was performed in a blinded fashion. The grading system was as follows: 0, no adhesion; 1, thin, few, filmy; 2, thick, avascular; 3, thick, vascular, and extensive. A sample of the peritoneum away from the suture line was harvested for histologic evaluation. All data were subjected to analysis of variance. RJBULTS
There were no deaths, therefore all 32 rats were included in the study. When the incidence and score of adhesions in Group 1 was compared with Group 2, there was a statistically significant greater adhesion grade in the antibiotic-irrigated group (p
JOURNAL
OF SURGERY
VOLUME
158
NOVEMBER
1989
4%
of normal saline solution. Other investigators have demonstrated similar beneficial results with intraabdominal antibiotic irrigation [3,4,5,10]. A number of investigations have shown no benefit of antibiotic lavage in reducing infectious complications. Hau et al [9] showed no beneficial effect of peritoneal irrigation with cephalothin solution in the rat model with fecal peritonitis. Rambo [Z6] compared saline with cephalothin irrigation in patients with diffuse peritonitis and found no difference in patient survival. Other investigators have also demonstrated no benefit of intraabdominal antibiotic irrigation when compared with intravenous antibiotics [13,17]. Intraperitoneal antibiotic administration is not without complications. Rapid absorption occurs after instillation, with peak serum concentration at about 15 to 30 minutes [4,13,15,18]. Renal failure and ototoxicity have been reported after irrigation with aminoglycosides [4,22,28,20]. Majeski et al [21] have shown that certain commonly used antibiotics inhibit chemotactic response of leukocytes. The first report suggesting that antibiotics may cause adhesions was by Phillips and Dudley [22] who showed peritoneal damage as judged by electron microscopy. In the present study, we have shown that two commonly used antibiotic irrigants, tetracycline and cefazolin, produce parietal peritoneal damage and adhesion for-
mation in the rat model. As Ellis [23] points out, various chemicals and irritants produce varying effects on the serosal surfaces. Some initiate ischemia which leads to the formation of adhesions [24]. Others are cytotoxic by interfering with protein synthesis or other metabolic cell function. In this respect, some antibiotics (bacitracin) are less toxic than others (tetracycline). The nature of posttraumatic peritoneal adhesions is believed to be secondary to an outpouring of fibrin onto the traumatized surface. This causes a fibrin bond between intraabdominal organs. After 5 days, much of the fibrin has been absorbed, and collagen deposition by fibroblasts has begun [23]. In a final stage, the collagenous adhesion be comes crosslinkcd and a stable, rigid adhesion is formed. A number of both experimental and clinical measures have been tried to reduce adhesion formation [23-24. The majority of these attempts have met with limited success. Currently, the only accepted method of reducing adhesion formation is strict adherence to Halsted principles of meticulous handling of tissue and prevention of infection. In conclusion, we believe that until large prospective controlled studies are performed to investigate the role of antibiotic irrigation, these agents should be used cautiously. This is especially true in the low-risk elective surgery patient, since these agents may play a role in adhesion formation.
a6
158
THE AMERICAN
JOURNAL
OF SURGERY
VOLUME
NOVEMBER
1989
ANTIBIOTIC IRBIGATION AND INTBAABDOIWNALADHESIONS
The issues of peritonitis and peritoneal contamination continue to be in theforefront of both clinicalpracticeproblems and surgical research. The favorable and unfavorable effects of treatment directed to the site of injury, that is, the peritoneal cavity, have both clinical and further investigativerelevance. RElwwNcE!S 1. Silv~ SH, Ambrose NS, Youngs DJ, Shepherd AFI, Rob erts AP, Keighly MRB. The effect of peritoneal lavage with tetracycline solution on pcstoperative infection: a prospective, randomized, clinical trial. Dis Colon Rectum 1986; 29: 165-9. 2. Nomikos IN, Katsouyamri K, Papaioamtou AN. Washing with or without chloramphenicol in the treatment of peritonitis: a prospective clinical trial. Surgery 1986; 99: 20-5. 3. Bourgeois FJ, Pinkerton JA, Andersen W, Thiagrarjah S. Antibiotic irrigation prophylaxis in the high-risk ccsarean section patient. Am J Obstet Gynecol 1965; 153: 197-201. 4. Freissschlag JF, M&rattan M, Bussutil RW. Topical versus systemic cephalosporin administration in elective biliary operations. Surgery 1984; %: 686-93. 5. Grr JD. Antibiotic peritoneal lavage in childhood appendicitis. JR Coll Surg Edinb 1984; 29: 307-9. 6. Benjamin JB, Volx RG. Efficacy of a topical antibiotic irrigant in decreasing or eliminating bacterial contamination in surgical wounds. Clin Grthop 1984; 184: 114-7. 7. Lord JW. Intraoperative antibiotic wound irrigation. Surg Gyne co1 Obstet 1983; 157: 357-61. 8. Lord JW, LaRaja RD, Daliana M, Gordon MT. Prophylactic antibiotic wound irrigation in gastric, biliary, and colonic surgery. Am J Surg 1983; 145: 209-12. 9. Hau T, Niihikawa R, Phuangsab A. Irrigation of the peritoneal cavity and local antibiotics in the treatment of peritonitis. Surg Gynecol &&et 1983: 156: 25-30. 10. Saha SK. Peritoneal lavage with metronidaxole. Surg Gynecol Obstet 1985; 160: 335-8. 11. Anderson MG. Neomycin ototoxicity associated with wound irrigation in the local treatment of osteomyelitis. J Fla Med Assoc 1978; 65: 20-l. 12. Richardson H, Mueller CB. Topical neomycin. Can J Surg
1979; 22: 199-200. 13. Gonen R, Samberg I, Levi&i R, Levitan Z, Sharf M. Effect of irrigation or intravenous antibiotic prophylaxis on infectious morbidity at cesarean section. Obstet Gynecol 1986; 67: 545-8. 14. Sauven P, Playforth MJ, Smith GMR, Evans M, Pollock AV. Single-dose antibiotic prophylaxis of abdominal surgical wound infection: a trial of preoperative latamoxef against preoperative tetracycline lavage. JR See Med 1986; 24: 240-2. 15. Lally KP, Shorr LD, Nichols RL. Aminoglycoside peritoneal lavage: lack of efficacy in experimental fecal peritonitis. J Pediatr Surg 1985; 20: 541-2. 16. Rambo WM. Irrigation of the peritoneal cavity with cephalo thin. Am J Surg 1972; 123: 192. 17. Conover WB, Moore TB. Comparison of irrigation and intravb nous antibiotic prophylaxis at cesarean section. Obstet Gynecol 1984; 63: 787. 18. Ericsson CD, Duke JH, Pickering LK. Clinical pharmacology of intravenous and intraperitoneal aminoglycoside antibiotics in the prevention of wound infections. AM Surg 1978; 188: 66-70. 19. Ericsson CD, Duke JI-I, Pickering LK, Hussain SM. Systemic absorption of bacitracin after peritoneal lavage. Am J Surg 1979; 137: 65-7. 20. Weinstein AJ, McHemy MC, Gavan TL. Systemic absorption of neomycin irrigating solution, JAMA 1977; 238: 152-3. 21. Majeski JA, McClellan MS, Alexander JW. Evaluation of leukocyte chemotactic response in the presence of antibiotics. Surg Forum 1975; 16: 83. 22. Phillips RKS, Dudley HAF. The effect of tetracycline lavage and trauma on visceral and parietal peritoneal ultrastructure and adhesion formation. Br J Surg 1984; 71: 537. 23. Ellis H. Internal overhealing: the problem of intraperitoneal adhesions. World J Surg 1980; 4: 303. 24. Jewett TC, Ambrus JL, Ambrus CM, Mink IB. Effects of fibrinolytic enxymes on experimentally induced peritoneal adhesions. Surgery 1965; 57: 280-4. 25. Fredericks CM, Kortry I, Holtx G, Askalani AH, Serour GI. Adhesion prevention in the rabbit with sodium carboxymethlicellulose solution. Am J Obstet Gynecol 1986; 155: 667-70. 26. Bergqvist JE, Arfors KE. Effect of dextran and hyahrronic acid on the development of postoperative peritoneal adhesions in experimental animals. Eur Surg Res 1977; 9: 321-5.
THE AMERICAN JOURNAL OF SURGERY
VOLUME 158 NOVEMBER 1989
437