Reduction of postoperative adhesions by N,O-carboxymethylchitosan: a pilot study

Transcription

1 FERTILITY AND STERILITY VOL. 80, NO. 3, SEPTEMBER 2003 Copyright 2003 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A. Reduction of postoperative adhesions by N,O-carboxymethylchitosan: a pilot study Michael P. Diamond, M.D., a Anthony Luciano, M.D., b D. Alan Johns, M.D., c Randall Dunn, M.D., d Phillip Young, M.D., e and Eric Bieber, M.D. f Wayne State University/Detroit Medical Center, Detroit, Michigan; New Britain General Hospital, New Britain, Connecticut; University of Texas Southwestern Medical Center, Fort Worth, Texas; Obstetrical and Gynecological Associates, Houston, Texas; IGO Medical Group, San Diego, California; and Geisinger Clinic, Danville, Pennsylvania Received September 11, 2002; revised and accepted February 21, Supported by Chitogenics, Chatham, New Jersey. Two of the authors (M.P.D. and E.B.) are consultants to Chitogenics, the sponsor of the study. Reprint requests: Michael P. Diamond, M.D., Hutzel Hospital, Department of Obstetrics and Gynecology, 4707 Saint Antoine Boulevard, Detroit, Michigan (FAX: ; a Wayne State University/ Detroit Medical Center. b New Britain General Hospital. c University of Texas Southwestern Medical Center. d Obstetrical and Gynecological Associates. e IGO Medical Group. f Geisinger Clinic /03/$30.00 doi: /s (03) Objective: To examine the logistics, safety, and efficacy of N,O-carboxymethylchitosan (NOCC) in reducing adhesions in women. Design: Multicenter, prospective, randomized, reviewer-blinded clinical trial. Setting: Gynecologic practices. Patient(s): Thirty-four patients were enrolled; 17 in each group were available for the safety analysis and 16 for the efficacy analysis. Intervention(s): Adhesion reduction by administration of NOCC vs. Ringer s lactate at the conclusion of the initial surgical procedure, as assessed at second-look laparoscopy. The NOCC was applied as 200 ml of a 1% NOCC gel that was tamped in place, followed by 100 ml of 2% NOCC solution. Efficacy was assessed by covariate analysis. Main Outcome Measure(s): Safety and postoperative adhesion formation. Result(s): Groups did not differ in age, ethnicity distribution, height, weight, or body mass index. No deaths or serious adverse events were attributable to NOCC, and no adverse events were definitively or probably related to NOCC administration. Adhesions recurred at 61% of sites in controls and 38% of sites in NOCC recipients. De novo grade 1a and 1b adhesions tended to occur more commonly in controls than NOCC recipients. Adhesion extent and severity at second look were also less in NOCC recipients. Conclusion(s): Intraperitoneal use of NOCC gel and solution appears to be safe. Despite the small sample, strong trends were identified for reduction of occurrence, extent, and severity of adhesion recurrence and de novo adhesion formation. (Fertil Steril 2003;80: by American Society for Reproductive Medicine.) Key Words: Adhesions, N,O-carboxymethylchitosan, laparoscopy The sequelae of postoperative adhesion development can be multifaceted, lifelong, and pronounced. Such adhesions are found in 55% to 97% of men and women undergoing intraabdominal surgery, and adhesions result in variable clinical manifestations (1). In a report from Scotland, women undergoing an initial abdominal surgery had a 5% likelihood of being rehospitalized because of adhesions over the next 10 years, and adhesions may have contributed to rehospitalization in an additional 20% of patients (2). Adhesions involving the tubes and ovaries are a well-recognized cause of infertility and contribute to the occurrence of ectopic pregnancies (3). Postsurgical adhesions, which can occur days to decades after the initial surgery, are the leading noncancerous cause of bowel obstruction (4). Abdominopelvic pain is frequently attributed to adhesions and can persist years after definitive surgery for the initial pathologic condition (3). Among approximately 25,000 laparoscopic surgeries in the Netherlands in 1994, more than half of the complications occurred during entry into the abdominal cavity; many of these complications were due to adhesions of the bowel and other structures to the anterior abdominal wall (5). The financial cost of adhesions is estimated to be $1.2 to $1.3 billion yearly in the United States alone (6, 7). 631

2 Despite an unquestionable clinical need (8), limited options are available over and above good surgical technique for reduction of postoperative adhesions. The U.S. Food and Drug Administration approved three products for reduction of postoperative adhesions after intraabdominal surgery. Two of these methods, Intercede (Gynecare, Somerville, NJ) and Seprafilm (Genzyme, Cambridge, MA), are barriers that provide efficacy only at the anatomic sites where placed and are approved for use only at laparotomy, not after laparoscopy (9, 10). The third method (Intergel; Lifecore, Canasta, MN) is a solution that is also only approved for use after laparotomy (11). While beneficial, its use resulted in a reduction of only fewer than one site per patient. Thus, more efficacious agents that are proven to be effective in laparoscopic procedures are needed. N,O-carboxymethylchitosan (NOCC) is a purified derivative of chitin obtained from the exoskeleton of shrimp (12). The molecule has structural similarities to hyaluronic acid and carboxymethylcellulose, which have been shown to be beneficial in adhesion reduction both in its native and derivative forms. N,O-carboxymethylchitosan is effective in reducing adhesions in rats and rabbits and has a high level of safety in cardiac and bowel anastomosis models (12 15). We present findings from the first human pilot trial of NOCC after laparoscopic surgery for the purpose of reduction of postoperative adhesion development. MATERIALS AND METHODS Study Design This prospective, randomized multicenter placebo-controlled parallel group, reviewer-blinded was conducted at four clinical sites. The aim was to assess the safety of intraabdominal instillation of NOCC in humans and to obtain preliminary evidence of the effectiveness of NOCC in reducing development of postoperative adhesions. Approval was obtained from the institutional review boards of the participating surgeons clinics. All participants provided informed written consent. To qualify for participation, women had to be at least 18 years of age and scheduled to undergo laparoscopic surgery with a planned second-look laparoscopy. Indications for the initial surgery included infertility, pelvic pain, a pelvic mass, uterine fibroids, or endometriosis. Women were excluded if they were pregnant or lactating; had previously undergone salpingectomy, oophorectomy, or hysterectomy; had a known cancer; had active pelvic inflammatory disease; or had received hormonal therapy within 1 month of the initial surgery. At completion of the initial surgery, once hemostasis was achieved (as evidenced by inspection after deinsufflation and reinsufflation) and just before closure, patients were randomized to undergo instillation of 300 ml of Ringer s lactate (controls) or 200 ml of NOCC gel plus 100 ml of NOCC solution (total volume, 300 ml). The NOCC gel was placed at sites of adhesiolysis and at surgical sites by extrusion from a laparoscopic irrigation instrument. The NOCC gel was tamped in place by using the laparoscopic instrument. Subsequently, the NOCC solution was placed at the same sites; excess flowed to the dependent portions of the abdominal cavity. Participants returned for a follow-up office visit 2 to 9 days later and underwent second-look laparoscopy 2 to 10 weeks after the initial surgery. This time frame for secondlook studies was chosen because adhesion development does not appear to vary over this time interval (9, 16 19). At the conclusion of each surgical procedure, the surgeon scored each of 23 anatomical sites by using a previously validated scoring system. Each site was scored for the presence or absence of adhesions, adhesion severity, extent of involvement of each site, and raw surface area at each site. Adhesion severity was scored as follows: 0, no adhesions; 1, filmy, vascular adhesions; 2, dense or vascular adhesions; or 3, cohesive adhesions. Adhesion extent was scored as follows: 0, no adhesions; 1, up to 25% of total area of site; 2, 26% to 50% of total area of site; or 3, 50% of total area of site. Each surgical procedure was videotaped in its entirety. After editing to remove application of the test or study agent, the video of each procedure was reviewed by an evaluator who was blinded to group assignment. The reviewer applied the same scoring system as the surgeons. The data presented in this report are those from this single-blinded evaluator. Surgery The attending surgeon determined surgical procedures conducted at each operation and used their own standard surgical care and practices. To minimize variation in the conduct of the surgeries, the investigators agreed to use lactated Ringer s solution for all intraoperative irrigation, to limit sutures in contact with the peritoneal cavity to 2-0 to 4-0 polydioxanone surgical (PDS), and to place patients in the reverse Trendelenberg position for suctioning of fluids from the abdominal cavity before confirmation of hemostasis. Statistical Analysis Clinical data were double entered by using an SAS database (SAS Software, Inc., Cary, NC). Statistical analysis was performed by using SAS software for PC. Safety and efficacy variables were summarized by descriptive statistics, including number, mean, median, SE, and range for continuous variables and the number and percentages for categorical variables. Baseline characteristics were compared by using the Student t-test for continuous variables and the Fisher exact or 2 test for categorical variables. All comparisons were two-tailed. Data are expressed as means ( SE). P.05 was considered significant. Because of baseline and demographic variations between the study 632 Diamond et al. NOCC reduction of adhesions Vol. 80, No. 3, September 2003

3 TABLE 1 Demographic characteristics. Characteristic Controls NOCC recipients Age (y) Race Caucasian African-American 2 1 Hispanic 2 1 Other 0 1 Height (cm) Weight (kg) Body mass index (kg/m 2 ) Note: Data with the plus/minus sign are the mean ( SE). NOCC N,Ocarboxymethylchitosan. TABLE 2 Baseline characteristics and surgical variables. Variable Controls NOCC recipients Sites with adhesions Adhesion extent Adhesion severity Previous intraabdominal surgery (%) Yes 6 (35.3) 13 (76.5) No 11 (64.7) 4 (23.5) Duration of surgery (h) Days between surgeries Total raw surface area (cm 2 ) Note: Data with the plus/minus sign are means ( SE). NOCC N,Ocarboxymethylchitosan. Diamond. NOCC reduction of adheions. Fertil Steril groups, covariate analysis was performed for efficacy determinations controlling for number of sites with adhesions and the severity of adhesions at the initial procedure. Efficacy analysis was determined for de novo adhesion formation at nonsurgical (type IA) or surgical (type IB) sites, for adhesion recurrence at sites of adhesiolysis alone (type IIA), and at sites of adhesiolysis plus treatment of other pathology (type IIB), as well as for all sites. In each of these categories, a proportion was by using the number of sites with adhesions at second-look as the numerator and the number of sites of that type available for adhesion development after the initial surgical procedure as the denominator. RESULTS Thirty-four women (17 in each group) were enrolled. All but 1 woman in the NOCC group underwent second-look laparoscopy; this patient developed a reaction that was subsequently attributed to her preexisting rheumatoid arthritis. A videotape was not made for one participant in the control group and thus was not available for blinded review. Consequently, efficacy data are available from 16 participants in each group. The groups did not differ in baseline characteristics, including age, race, height, weight, and body mass index (Table 1). There were no deaths or serious adverse events attributable to NOCC, and no adverse events were definitively or probably related to NOCC. All patients had at least one adverse event; there was no significant difference in the incidence of any category of adverse events. The most common adverse events in each group were postoperative pain and nausea. No persistent changes in serum chemistry occurred in either group. Surgery-related demographic characteristics at baseline varied greatly between the two groups (Table 2). Recipients of NOCC at the initial surgery had 41% more sites with adhesions, a 53% greater extent of adhesions, and 77% greater severity of adhesions; were more than twice as likely to have had previous abdominal surgery; and had a 50% increase in the duration of surgery and an 84% increase in the total new surface area at the completion of the initial surgery. To control for these baseline differences, efficacy analysis was performed by covariate analysis. In the control group, the proportion of sites at which adhesions recurred was 0.61, which was 61% greater than the proportion of 0.38 in the NOCC group (P not significant) (Fig. 1). When all participants were considered, the extent and severity of adhesion recurrence decreased nonsignificantly, but the decrease was greater in the NOCC group (Fig. 2). Occurrence of both type 1A and 1B de novo adhesion tended to be less in NOCC recipients (Fig. 3). DISCUSSION In vitro and in vivo studies demonstrate that NOCC has many of the characteristics of an ideal antiadhesion barrier. In cell culture studies, NOCC inhibits attachment of contactdependent cells. (Lee T. Personal communication). In vivo studies in animals have demonstrated that NOCC is safe and efficacious (12 15). Both the gel and solution forms of NOCC can be delivered from a syringe or a laparoscopic irrigation device. The material is clear, allowing identification of anatomical structures and bleeding sites, but it is not readily miscible with blood. Efficacy of NOCC has been demonstrated in many different animal models. In a pericardial adhesion model in rats in which adhesion formation was induced by application of a talc slurry, Krause et al. (12) demonstrated that NOCC gel plus solution reduced adhesions to less than 20% of the scores in either the control or saline-treated animals. In a gauze cecal abrasion model, the same investigators demonstrated that NOCC gel plus solution resulted in an even FERTILITY & STERILITY 633

4 FIGURE 1 Adhesion recurrence at second-look laparoscopy after operative laparoscopy in controls (gray bar) and women receiving N,O-carboxymethylchitosan (NOCC) (black bar). greater reduction in cecal adhesions compared with control or saline-treated rats (12). Kennedy et al. assessed the efficacy of NOCC in two additional models (13). In the first model, a 5-mm 2 area of rat uterine horn serosa was excised and positioned adjacent to a 5-mm 2 abraded retroperitoneal area with a 6.0 Prolene suture. The NOCC gel plus solution reduced the mean planar width ( mm vs mm in controls; P.001) and the strength of the adhesion ( vs in controls). The second model consisted of complete incision of the ileum portion of the small bowel with anastomosis. At necropsy, omental adhesions were observed in 80% of control animals but only 20% of NOCC-treated rats, whereas the incidence of cecal adhesion was reduced from 90% in controls to 40% in NOCC rats (13). The efficacy of NOCC was evaluated by Costain et al. (14) in three additional rat models. In the first model, rats underwent abdominal aortic transection and repair; the NOCC group experienced reductions in the percentage and severity of liver adhesions and a reduction in the severity of retroperitoneal adhesions (14). In a large-bowel anastomosis healing model, bursting strength of the anastomosis was assessed 4, 7, and 14 days after surgery. No significant difference was noted between NOCC-treated rats and control FIGURE 2 Adhesion extent and severity at second-look laparoscopy after operative laparoscopy in controls (gray bar) and women receiving N,O-carboxymethylchitosan (NOCC) (black bar). 634 Diamond et al. NOCC reduction of adhesions Vol. 80, No. 3, September 2003

5 FIGURE 3 Occurrence of de novo adhesions at second-look laparoscopy after operative laparoscopy in controls (gray bar) and women receiving N,O-carboxymethylchitosan (NOCC) (black bar). rats (14). Finally, healing was tested in an abdominal skin wound model, in which NOCC was applied to the peritoneal cavity and to the skin incision. Fourteen days later, the tension required to rupture the healed skin wound was found to not differ. Histologic examination by hematoxylin eosin staining yielded no information that could be used to discriminate between the two groups (14). Krause et al. recently conducted a study comparing adhesion formation after sternotomy in the rabbit (15). Animals had NOCC or saline applied to the heart and retrosternal surfaces after these surfaces were abraded with sponges and desiccated by oxygen. Two weeks later, the control animals had extensive thoracic and mediastinal adhesions. The pericardial adhesion score was markedly lower in the NOCC group than the control group ( vs ; P.01), and NOCC induced no serious cardiac side effects (15). Thus, in animals, use of NOCC appears to be both safe and efficacious for reduction of postoperative adhesion development. In view of the promising potential for NOCC as an antiadhesion technique, we performed this pilot clinical trial to determine the safety of NOCC in humans and to collect preliminary efficacy data on NOCC that could be used to power a subsequent pivotal trial. We found that use of NOCC in humans appears to be safe; no deaths or severe adverse events could be attributed to NOCC, and no adverse events occurred with significantly greater frequency in NOCC recipients compared with controls. In addition, NOCC recipients had no persistent changes in serum chemistry. Baseline surgical characteristics of the NOCC and control groups differed greatly. Significant among these were the number of sites with adhesions, the severity and extent of adhesions at the beginning of the first surgical procedure, the raw surface area at the conclusion of the initial surgical procedure, the number of previous surgical procedures, and the duration of the initial surgery. All of these factors, each of which would be expected to increase postoperative adhesion development, were worse in the NOCC group. To correct for these differences and thereby allow better interpretation of the efficacy of NOCC, covariate analysis was performed in which we controlled for initial adhesion occurrence and severity. Use of NOCC appeared to reduce adhesion recurrence, de novo adhesion formation, and the severity and extent of adhesions observed at second-look laparoscopy, although none of these changes reached statistical significance. Adhesions recurred at 61% of available sites in the control group and 38% of available sites in NOCC recipients. Use of NOCC also reduced the extent and severity of recurring adhesions. De novo adhesions, which was a less frequent event than adhesion recurrence, also tended to be reduced to a greater extent for both type 1A and type 1B adhesions in NOCC recipients. In summary, our findings extend the promising efficacy results from animal studies of NOCC in reducing postoperative adhesion development and demonstrates the ability of NOCC to reduce the occurrence, extent, and severity of adhesions in humans. When combined with the clinical safety profile of NOCC described in the report, these observations suggest that NOCC may offer great benefit for reduction of postoperative adhesion development. Further clinical investigation is warranted. FERTILITY & STERILITY 635

6 References 1. Diamond MP. Surgical aspects of infertility. In Sciarra JJ (ed). Gynecology and obstetrics. vol. 5. Philadelphia: Harper and Row, Lower AM, Hawthorn RJ, Ellis H, O Brien F, Buchan S, Crowe AM. The impact of adhesions on hospital readmissions over ten years after 8849 open gynaecological operations: an assessment from the surgical and clinical adhesions research study. Br J Gynecol 2000;107: Diamond MP, Freeman ML. Clinical implications of post-surgical adhesions. Hum Reprod Update 2001;7: Ellis H, Moran BJ, Thompson JN, Parker MC, Wilson MS, Menzies D, et al. Adhesion-related hospital readmissions after abdominal and pelvic surgery: a retrospective cohort study. Lancet 1999;353: Jansen FW, Kapiteyn K, Trimbos-Kemper T, Hermans J, Trimbos JB. Complications of laparoscopy: a prospective multicenter observational study. Br J Obstet Gynecol 1997;104: Ray NF, Larsen JW, Stillman RJ, Jacobs RJ. Economic impact of hospitalizations for lower abdominal adhesiolysis in the United States in Surg Gynecol Obstet 1993;176: Ray NF, Denton WG, Thamer M, Henderson SC, Perry S. Abdominal adhesiolysis: inpatient care and expenditures in the United States in New York: Elsevier Science, 1998: Wiseman DM, Trout JR, Franklin R, Diamond MP. Metaanalysis of safety and efficacy of oxidized regenerated cellulose adhesion barrier (TC7) in laparotomy. J Reprod Med 1999;44: Diamond MP. Reduction of adhesions after uterine myomectomy by Seprafilm (HAL-F): a blinded, prospective, randomized, multicenter clinical study. Seprafilm Adhesion Study Group. Fertil Steril 1996;66: Becker JM, Dayton MT, Fazio VW, Beck DE, Stryker SJ, Wexner SD, et al. Prevention of postoperative adhesions by a sodium hyaluronatebased bioresorbable membrane: a prospective, randomized doubleblind multicenter study. J Am Coll Surg 1996;183: Johns DB, Keyport GM, Hoehler F, dizerega GS. Intergel adhesions prevention study group: reduction of postsurgical adhesions with intergel adhesion prevention solution. A multicenter study of safety and efficacy after conservative gynecologic surgery. Fertil Steril 2001;76: Krause TJ, Zazanis GA, McKinnon RD. Prevention of postoperative adhesions with the chitin derivative N,O-carboxymethylchitosan. Wound Repair Regen 1996;4: Kennedy R, Costain DJ, McAlister VC, Lee TD. Prevention of experimental postoperative peritoneal adhesions by N,O-carboxymethyl chitosan. Surgery 1996;120: Costain DJ, Kennedy R, Ciona C, McAlister VC, Lee TD. Prevention of postsurgical adhesions with n, o-carboxymethyl chitosan: examination of the most efficacious preparation and the effect of N,O-carboxymethyl chitosan on postsurgical healing. Surgery 1997;121: Krause TJ, Zazanis G, Malatesta P, Solina A. Prevention of pericardial adhesions with N,O-carboxymethyl chitosan in the rabbit model. J Invest Surg 2001;14: Linsky CB, Diamond MP, Cunningham T, Constantine B, DeCherney AH, dizerega GS. Adhesion reduction in a rabbit uterine horn model using TC-7. J Reprod Med 1987;32: Diamond MP, Daniell JF, Feste J, Surrey MW, McLaughlin DS, Friedman S, et al. Adhesion reformation and de novo adhesion formation following reproductive pelvic surgery. Fertil Steril 1987;47: Azziz R, Cohen S, Curole DN, Diamond MP, Franklin RR, Haney AF, et al. Pelvic sidewall adhesion reformation: microsurgery alone or with interceed absorbable adhesion barrier. Surg Gynecol Obstet 1993;177: Diamond MP. Reduction of de novo postsurgical adhesions by intraoperative precoating with Sepracoat (HAL-C) solution: a prospective, randomized, blinded, placebo-controlled multicenter study. Sepracoat Adhesion Study Group. Fertil Steril 1998;69: Diamond et al. NOCC reduction of adhesions Vol. 80, No. 3, September 2003