A Randomized, Double-Blind, Placebo-Controlled Trial to Determine Effectiveness of Antibiotic Prophylaxis for Tension-Free Mesh Herniorrhaphy Anthony R Perez, MD, Manuel F Roxas, MD, FACS, Serafin S Hilvano, MD, FACS BACKGROUND: STUDY DESIGN: RESULTS: CONCLUSIONS: In recent years, use of prosthetic material for inguinal hernia repair has increased dramatically. Tension-free repairs have gained popularity not only for recurrent or complicated hernias, but for primary hernia repairs as well. Although routine use of prophylactic antibiotics is not recommended in the Philippines for open nonimplant herniorrhaphy, there is little direct clinical evidence on which to base recommendations when implantable mesh is used. We conducted a prospective, randomized, double-blind, placebo-controlled trial comparing wound infection rates in 360 patients (180 received prophylactic antibiotics, 180 received a placebo) undergoing primary inguinal hernia repair electively using polypropylene mesh. Age, gender, American Society of Anesthesiologists class, type of hernia, type of anesthesia, and duration of operation were recorded. Infections were evaluated 1 week, 2 weeks, and 1 month after operation by an independent surgeon. All complications were recorded. Results were assessed using chi-square, Fisher s exact test, and Student s t-tests as appropriate. Groups were well matched for all preoperative variables studied, including comorbid conditions. Six patients from the antibiotic and four from the placebo failed to followup after the second week. Superficial surgical site infection developed in 3 patients (1.7%) from the antibiotic and 6 (3.3%) from the placebo (p 0.50). One from each developed deep surgical site infection. Both patients were readmitted and underwent repeated debridement, which eventually resulted in graft loss. Preoperative administration of single-dose antibiotic for tension-free inguinal mesh herniorrhaphy did not markedly decrease risk of wound infection in this patient population. Our results do not support use of antibiotic prophylaxis for tension-free mesh herniorrhaphy. (J Am Coll Surg 2005;200:393 398. 2005 by the American College of Surgeons) In the Philippines, inguinal herniorrhaphy is the most common elective operation performed by general surgeons. In recent years, use of prosthetic material for inguinal hernia repair has increased dramatically. Tensionfree open repairs have gained popularity not only for recurrent or complicated hernias, but for primary hernia repairs as well. Despite being classified as a clean operation, use of No competing interests declared. Presented at the American College of Surgeons 90 th Annual Clinical Congress, New Orleans, October 2004. Received May 5, 2004; Revised October 28, 2004; Accepted October 29, 2004. From the Department of Surgery, University of the Philippines College of Medicine and Philippine General Hospital, Manila, Philippines. Correspondence address: Anthony R Perez, MD, Department of Surgery, University of the Philippines College of Medicine and Philippine General Hospital, Taft Ave, Manila, Philippines, 1000. synthetic material has been associated with a theoretical increase in risk of infection. Although routine use of prophylactic antibiotics is not recommended for open nonimplant herniorrhaphy, there is little direct clinical evidence on which to base recommendations when implantable mesh is used. Lichtenstein and colleagues, 1 the proponents of tension-free mesh herniorrhaphy, have routinely used local infiltration of antibiotics in an effort to reduce the presumed increase in infection rates. Local experience with 120 mesh herniorrhaphies performed without routine antibiotic administration showed no surgical site infections. 2 In 1999, the Philippine College of Surgeons came out with a practice guideline recommending no antibiotics for inguinal herniorrhaphies using mesh prosthesis. 3 Despite the paucity of evidence supporting use of antibiotics for this procedure, many surgeons routinely administer them. A Medline and 2005 by the American College of Surgeons ISSN 1072-7515/05/$30.00 Published by Elsevier Inc. 393 doi:10.1016/j.jamcollsurg.2004.10.037
394 Perez et al Antibiotic Prophylaxis for Mesh Herniorrhaphy J Am Coll Surg Cochrane search revealed two randomized trials conducted to address the issue, done by Yerdel and colleagues 4 from the University of Ankara and by Sanchez-Manuel and Seco-Gil, 5 which showed that administration of antibiotics considerably reduced surgical site infection rates. This study was conducted primarily to determine the effectiveness of preoperative prophylactic antibiotics in decreasing wound infection rates in adult patients with inguinal hernias undergoing tensionfree mesh herniorrhaphy. Likewise, it was intended to describe and compare other adverse events noted in those patients who had mesh herniorrhaphy with or without prophylactic antibiotics. METHODS A sample size of 360 patients (180 per ) was chosen to give 80% power at 0.05 two-tailed level of significance, assuming that a 7% wound infection rate in the no-antibiotic would fall to 1% when antibiotics were used. Patients with primary, unilateral inguinal hernias, electively prepared for tensionless graft repair during the study period, were candidates for our trial. Informed consent was obtained from all patients, and the protocol was approved by the institutional ethics committee. Excluded were patients younger than 18 years and older than 70 years; pregnant or lactating women; those with earlier history of allergy, sensitivity, or anaphylaxis to -lactam or cephalosporin antibiotics; antibiotic therapy within 48 hours before operation; presence of infection at the time of operation; patients with cardiac valvular problems; patients with prosthetic valves or joints; patients determined to be at increased risk of infection secondary to a coexisting medical condition; and patients with American Society of Anesthesiologists (ASA) class more than II. Allocation was done with simple randomization using a computer-generated table of random numbers. Each participant was randomized either to the experimental receiving prophylactic antibiotics ( 1) or to the placebo control ( 2). Trial patients received either1gcefazolin or an equal volume of placebo (sterile saline) by IV bolus injection before incision. Cefazolin was chosen because of its half-life and known activity against Staphylococcus aureus and Staphylococcus epidermidis, historically the most common agents isolated from infected hernia incisions. Skin was shaved immediately before operation and prepared using povidone-iodine. All patients underwent open tension-free mesh herniorrhaphy using a polypropylene mesh in a standardized technique, as described by Lichtenstein. Senior surgical residents or consultants, blinded to the study, performed all operations. All procedures were performed under regional anesthesia. The mesh was monofilament polypropylene (B Braun), and all sutures except subcuticular were 2-0 monofilament polypropylene (Prolene; Ethicon, Ltd). Skin was closed with 4-0 Vicryl. No drains were used in any patients. All wounds were inspected before discharge, and all incisions were carefully reexamined by an independent surgeon blinded to the study during first followup visit at 7 days after the operation, during the second followup visit 2 weeks after discharge, and 4 weeks after discharge. Patients were instructed to contact the investigators in the event of wound problems after the 4 th week. Wound infections were categorized as superficial incisional surgical site infection and deep surgical site infection (DSSI), according to the latest definitions of the Centers for Disease Control. Superficial incisional surgical site infection was defined as an infection occurring within 30 days after operation involving only the skin or subcutaneous tissue. DSSI was defined as an infection involving fascial and muscle layers and also the graft. Exact criterion for the definition and surveillance of wound infection is well established and can be found in Centers for Disease Control reports. Patient demographics, ASA class, type of anesthesia, duration of operation, and type of hernia were recorded. In addition to wound infection, all postoperative complications were also carefully recorded throughout the followup period. Data were analyzed through Fisher s exact test, Student s t-tests, and chi-square analysis as appropriate. RESULTS Between January 2000 and December 2002, by strict adherence to exclusion criteria, 360 patients having 360 inguinal hernias were included in this trial. Half of these patients represented the study and the other half represented the control. After 2 weeks of followup, 6 patients from the antibiotic and 4 from the placebo failed to return for followup. Groups were well matched for age, gender, ASA class, type of hernia, type of anesthesia, and duration of operation (Table 1). Distribution of postoperative complications among s is shown in Table 2. All complications were evenly distributed in the placebo and antibiotic
Vol. 200, No. 3, March 2005 Perez et al Antibiotic Prophylaxis for Mesh Herniorrhaphy 395 Table 1. Patient Characteristics Characteristics Antibiotic Placebo p Value Mean age SD (y) 61.37 13.2 60.8 14.5 0.90 Gender (male/female) 176/4 177/3 0.99 ASA class (patient numbers having ASA I/ASA II classes) 146/34 138/42 0.37 Type of hernia (indirect/direct) 96/84 108/72 0.24 Mean duration of operation SD (min) 52.18 16.4 54.07 15.3 0.62 ASA, American Society of Anesthesiologists. s. No inguinal neuralgia or nerve entrapment syndrome was observed. All seromas were diagnosed by fine-needle aspiration of clear-serous fluid in the presence of a well-healing incision. All samples were cultured and sterility was confirmed. Seromas of two patients in each were confined to the area of the incision, and these were managed expectantly without sequelae. Four seromas (three from the antibiotic and one from the placebo ) required multiple aspirations without further problems. No antibiotics were used for treatment of seromas. No case of ischemic orchitis was encountered in either. Two patients from the placebo had urinary retention, which necessitated discharge with catheters. Three patients from the antibiotic had to be sent home with catheters. All patients had the catheters removed within 3 days. In terms of wound infection rates, 3 of 174 (1.7%) patients who completed followup in the antibiotic and 6 of 176 (3.4%) patients who completed followup in the placebo had superficial surgical site infection, all detected on followup. Calculating infection rates in an intention-totreat manner will yield 1.7% (3 of 180) for the placebo and 3.3% (6 of 180) for the antibiotic. One patient in the antibiotic and one from the placebo developed DSSI necessitating admission and subsequent graft removal. Both patients underwent repeated debridement, and cultures showed Pseudomonas organisms in both patients. Details of the infected patients are summarized in Table 3. All 11 wound infections were diagnosed after hospital discharge. Patients who developed DSSI presented at the emergency room before the first intended followup and were promptly admitted. In terms of the other characteristics of the 11 infections, mean age (59.1 years), ASA classification, type of anesthesia, and mean duration of operation (57.3 minutes) were similar in distribution to the rest of the series. All patients were advised to monitor for delayed infections and recurrences on discharge. The 10 patients who were excluded for failure to report for the last followup were contacted and none had developed infections. None was reported after 1 year. Both patients who had undergone graft removal remain asymptomatic 1 year after discharge. DISCUSSION It is clear that antibiotic prophylaxis is necessary for most clean contaminated surgical procedures to prevent infectious complications. In most prosthesis-using operations, such as joint replacement and cardiac or vascular implant operation, antibiotic prophylaxis has likewise been proved to be beneficial. 6,7 In certain clean surgeries, specifically hernia operation, low rate of wound infections and the straightforward treatment in cases of infection may preclude need for prophylaxis. A review of the experiences of institutions specifically studying infection rates in hernia operations showed figures ranging from 3.3% to 14%. 8,9 Considering the frequency with which hernia operations are being performed, prevention of infection becomes important. Platt and colleagues 10 were the first to perform a randomized, double-blind study on clean surgical procedures using IV cefonicid 1 g and comparing infection rates with a placebo. In the hernia part of that study, wound infection rate dropped from 4.2% to 2.3% with use of prophylaxis. 10 Lazorthes and colleagues 7 compared single-dose cefamandole (750 mg) added to local anesthetic and applied directly subcutaneously during local infiltration anesthesia with no antibiotics. Table 2. Postoperative Complications Antibiotic Placebo p Value Complications n % n % Urinary retention 3 1.7 2 1.1 0.99 Seroma formation 5 2.8 3 1.7 0.72 Testicular atrophy 0 0 0.99 Wound infection 4 2.2 7 3.9 0.54 Deep surgical site infection 1 0.6 1 0.6 0.48 Superficial surgical site infection 3 1.7 6 3.3 0.50
396 Perez et al Antibiotic Prophylaxis for Mesh Herniorrhaphy J Am Coll Surg Table 3. Details of Infected Patients Patient No. Allocation Postoperative day detected Microorganism cultured Type of infection Treatment Outcomes 1 Antibiotics 7 S. aureus SSSI Antibiotics and drainage Recovered 2 Antibiotics 7 S. aureus SSSI Antibiotics and drainage Recovered 3 Placebo 7 S. aureus SSSI Antibiotics and drainage Recovered 4 Antibiotics 4 S. aureus Pseudomonas sp. DSSI Antibiotics, repeated debridement, graft removal Discharged after 14 days, no recurrence after 1 year 5 Placebo 5 S. aureus Pseudomonas sp. DSSI Antibiotics, repeated debridement, graft removal Discharged after 10 days, no recurrence after 1 year 6 Placebo 7 S. aureus SSSI Antibiotics and drainage Recovered 7 Placebo 7 S. aureus SSSI Antibiotics and drainage Recovered 8 Antibiotics 7 S. aureus SSSI Antibiotics and drainage Recovered 9 Placebo 7 S. aureus SSSI Antibiotics and drainage Recovered 10 Placebo 7 S. epidermidis SSSI Antibiotics and drainage Recovered 11 Placebo 7 S. epidermidis SSSI Antibiotics and drainage Recovered DSSI, deep surgical site infection; SSSI, superficial surgical site infection. This nonblinded nonrandomized prospective study documented a significant decrease from 4.5% to 0% (p.03) in the wound infection rate with local antibiotic prophylaxis. 7 Taylor and colleagues 11 conducted a randomized, multicenter, double-blind prospective trial to compare single-dose IV coamoxiclav with placebo in 619 patients undergoing open groin hernia repair with the rate of infection in both s at 9%. They concluded that antibiotic prophylaxis is of no benefit to patients undergoing open groin hernia repair. In recent years, there has been an increase in use of mesh for repair of inguinal hernias. Use of synthetic material has raised the concern of increased risk of infection. Several s report of the difficulty in managing infected prosthesis in hernia operations leading to mesh removal and possible recurrences, 12-14 prompting many surgeons to use antibiotic prophylaxis in an attempt to prevent infection. In the multicenter retrospective analysis performed by Gilbert and Felton to study the effect of antibiotics on open mesh hernia repair, the rate of infection was approximately 1%, whether or not biomaterials or antibiotics were used. 15 Troy and colleagues 16 reported that intraoperative topical bacitracin or preoperative singledose IV Cefazolin reduced quantitative growth of bacteria in rabbit wounds implanted with polypropylene mesh. The only prospective, randomized controlled trial studying the effect of IV antibiotics was published in 2001 by Yerdel and colleagues 4 from Turkey, during the data collection phase of our study. They showed that administration of single-dose ampicillin and sulbactam decreased wound infection rates from 9% to 0.7%. 4 Our previous published series of 120 consecutive mesh herniorrhaphies with no wound infection prompted us to evaluate use of prophylaxis in tension-free mesh herniorrhaphies. 5 Results of our study showed no benefit of antibiotic prophylaxis in patients undergoing prosthetic inguinal hernia operations (2.30% versus 3.98%, p 0.55). A sensitivity analysis, presuming that all four patients who were excluded for failing to complete followup developed infection and none of the exclusions from the antibiotic developed infection, will likewise show no significant difference (1.67% versus 5.56%, p 0.09). Seroma, which occurred in five patients in the antibiotic and seven patients in the placebo, did not progress to superficial incisional surgical site infection. None of those who developed superficial incisional surgical site infection required readmission. Both DSSI patients were admitted to the hospital and had to undergo repeated operations, eventually leading to graft loss. Mann and colleagues 13 and Taylor and O Dwyer 14 recently reviewed the literature about the fate of infected inguinal hernia grafts and concluded that this condition frequently necessitated complete removal of the grafts. Management of DSSI patients was difficult and eventually required repeat admissions in all such patients. Both DSSIs in our series became evident as superficial infections that eventually developed into deep infections that required prolonged hospitalization and repeated operations, further emphasizing the importance of decreasing the overall number of wound infections. Preoperative administration of single-dose Cefazolin for tension-free inguinal mesh
Vol. 200, No. 3, March 2005 Perez et al Antibiotic Prophylaxis for Mesh Herniorrhaphy 397 herniorrhaphy does not decrease risk of wound infection. Our results do not support use of antibiotic prophylaxis for tension-free mesh herniorrhaphy. We recommend that future studies use larger sample sizes to increase the power of the study. This might enable the investigators to detect, if indeed there are, small but important differences in infection rates between study s. REFERENCES 1. Lichtenstein IL, Shulman AG, Amid PK, Montillor MM. The tension-free hernioplasty. Am J Surg 1989;157:188 193. 2. Limson AA, Relos RP, Balo SA, Fojas MC. Tension-free herniorrhaphy for primary and recurrent inguinal hernias: a prospective study of 120 patients. Philipp J Surg Spec 1996;51: 93 96. 3. Philippine College of Surgeons. Evidence based clinical practice guidelines on antibiotic prophylaxis. Philipp J Surg Spec 2003; 59:29 37. 4. Yerdel MA, Akin EB, Dolalan S, et al. Effect of single-dose prophylactic ampicillin and sulbactam on wound infection after tension-free inguinal hernia repair with prolypropylene mesh. The randomized, double-blind, prospective trial. Ann Surg 2001;233:26 33. 5. Sanchez-Manuel FJ, Seco-Gil JL. Antibiotic prophylaxis for hernia repair (Cochrane Review). In: The Cochrane Library, Issue 4. John Wiley & Sons, Ltd: Chichester, UK. 6. Hill C, Flamant R, Mazas F, Evrard J. Prophylactic cefazolin versus placebo in total hip replacement. Lancet 1981;1:795 796. 7. Kaiser AB, Petracek MR, Lea JV. Efficacy of cefazolin, cefamandole and gentamicin as prophylactic agents in cardiac surgery: results of a prospective, randomized, double-blind trial in 1030 patients. Ann Surg 1987;206:791 797. 8. Lazorthes F, Chiotasso P, Massin P. Local antibiotic prophylaxis in inguinal hernia repair. Surg Gynecol Obstet 1992;175:569 570. 9. Santos KR, Neto GP, Fonesca LS, Filho PP. Incidence surveillance of wound infection in hernia surgery during hospitalization and after discharge in a university hospital. J Hosp Infect 1997;36:229 233. 10. Platt R, Zucker JR, Zaleznik DF, et al. Prophylaxis against wound infection following herniorrhaphy or breast surgery. J Infect Dis 1993;166:556 560. 11. Taylor EW, Byrne DJ, Leaper DJ, et al. Antibiotic prophylaxis and open groin hernia repair. World J Surg 1997;21:811 815. 12. Glasgow F. Is postoperative wound infection following simple inguinal herniorrhaphy a predisposing cause for recurrent hernia? Can J Surg 1964;91:870 871. 13. Mann DV, Prout J, Havranek E. Late onset deep prosthetic infection following mesh repair of inguinal hernia. Am J Surg 1998;176:12 14. 14. Taylor SG, O Dwyer PJ. Chronic groin sepsis following tensionfree inguinal hernioplasty. Br J Surg 1999;86:562 565. 15. Gilbert AI, Felton LL. Infection in inguinal hernia repair considering biomaterials and antibiotics. Surg Gynecol Obstet 1993;177:126 130. 16. Troy MG, Dong QS, Dobrin PB, Hecht D. Do topical antibiotics provide improved prophylaxis against bacterial growth in the presence of polypropylene mesh? Am J Surg 1996;171:391 393. Invited Commentary Leigh A Neumayer, MD, FACS Salt Lake City, UT My compliments to the investigators for undertaking a randomized trial to answer the question of whether or not antibiotics are indicated in groin hernia repair. It is counterintuitive that wound infection rates are so low in the groin, an area that I think we might not consider clean. In our recently published randomized trial of nearly 2,000 men comparing open to laparoscopic hernia rates, the wound infection rate was just over 1.0% and no patient required removal of the mesh. 1 A review of the literature on this subject reveals three randomized trials involving 50 to 300 patients per. 2-4 Two of these trials showed reduction in wound infection rates from about 9% in the placebo to around 1% in the prophylactic antibiotic. 2,3 The third trial that involved inguinal hernia repairs without mesh showed no difference and reported a rate of 9% in both s. 4 In a randomized trial reported in the New England Journal of Medicine in 1990 including, but not confined to, inguinal hernia, the rate of all infections was lower in the antibiotic (2.3%) when compared with placebo (4.2%). 5 Perez and colleagues 6 are reporting wound infection rates much more in line with that justmentioned New England Journal of Medicine article 5 and our experience with the large lap versus open trial. I have several questions for the authors: 1. You powered your study to detect a 6% difference in wound infection rates, but found, as in many other studies, that wound infection rate is exceedingly low. At this point your study has a type II error because, by my calculations, you had only 17% power to detect a 1.7% difference in rates. A study would need 1,350 patients per to detect a 1.4% difference in infection rates with 80% power. Would most surgeons say a reduction in wound infection rate from 3.3% to 1.7% is clinically significant? 2. On average, how long before the incision was the antibiotic given? If not within the 30- to 120-minute window, could this have impacted your results? 3. Were there any adverse reactions to cefazolin?