Postoperative Adhesions: From Formation to Prevention

Zeynep Alpay, MD; Ghassan M. Saed, PhD; Michael P. Diamond, MD

Disclosures

Semin Reprod Med. 2008;26(4):313-321. 

In This Article

Prevention

Antiadhesion Adjuvants and Other Approaches to Reduce Adhesions

Over the years, several measures including microsurgical techniques, specialized equipment, unpowdered gloves, extensive irrigations, adhesion-reducing agents such as anti-inflammatory agents, peritoneal instillates, and surgical barriers have been used for the prevention of adhesions. Among these measures, some barriers have proved beneficial, but none of them have been found to completely prevent adhesion development in all patients.

Barriers

Oxidized regenerated cellulose, Interceed (Johnson & Johnson Medical, Inc., New Brunswick, NJ), is commonly used as a barrier agent. After placement, it gelates and physically separates tissue layers during tissue healing, thereby contributing to the prevention of postoperative adhesions. It has been shown that Interceed increased the tPA/PAI-1 ratio in fibroblasts isolated from adhesion tissues to levels observed in fibroblast isolates from normal peritoneum obtained from the same patient(s).[40] Also, it has been demonstrated that Interceed altered the inflammatory response by acting on macrophages and causing a diminished immunologic response with the potential to decrease adhesion formation.[41] Interceed has been studied in animal models and has been shown to reduce adhesion formation and re-formation significantly in rabbit uterine horn.[42,43] In a meta-analysis done to evaluate the safety and efficacy of Interceed use in pelvic laparotomy surgery to prevent adhesions, 10 studies including 560 patients were evaluated.[44] There was a significant reduction in the incidence and extent of adhesions in Interceed-treated patients. Adhesion-free outcomes were reported to be 1.5 to 2.5 times more at sites treated with Interceed.

Seprafilm (Genzyme Corp., Cambridge, MA) is a commonly used barrier agent composed of modified hyaluronate and carboxymethylcellulose (HA-CMC). The antiadhesive nature of modified sodium hyaluronate and carboxymethylcellulose bioresorbable membrane has been evaluated in a study involving 11 centers that enrolled 183 patients with ulcerative colitis and familial polyposis who had colectomy with ileal pouch-anal anastomosis with diverting-loop ileostomy.[45] The patients were randomly assigned to receive Seprafilm membrane placed under the midline incision just before abdominal closure. These patients have been reevaluated in terms of the incidence, extent, and severity of the adhesion formation to the midline incision with a second-look laparoscopy 8 to 12 weeks after surgery. There was a significant difference in the patients who received Seprafilm as opposed to the ones who did not (51% adhesion free in the users vs. 6% in the nonusers; p < 0.001). The dense adhesion incidence was also significantly lower in the Seprafilm-treated group (15% vs. 58%; p < 0.001). The Seprafilm treatment was also found to be associated with a decrease in the incidence and extent of adhesion formation in women undergoing myomectomy,[46] as well as in radical oophorectomy cases,[47] after second-look surgeries. In animal studies, the adhesion formation in rats with abdominal wall defects has been compared between the use of polypropylene mesh, Sepramesh (polypropylene mesh with HA-CMC; Genzyme Corp.), and Sepramesh plus Seprafilm. The adhesion scores were significantly better with Sepramesh plus Seprafilm than with Sepramesh or polypropylene mesh alone.[48]

Currently, laparoscopy is a commonly used surgical approach for many gynecologic procedures. However, Interceed and Seprafilm are not approved for laparoscopic use, and such delivery is not easily performed. A liquid or gel that serves as a barrier, as opposed to a material barrier, would be easier to apply and deliver endoscopically. Recently, a multicenter, prospective, randomized, double-blinded study has studied Adept (icodextrin w/v 4% solution; Baxter Healthcare, Deerfield, IL).[49] This adhesion-reducing agent has been used in Europe in both laparoscopy and laparotomy and has recently been approved by the U.S. Food and Drug Administration (FDA) for laparoscopic use in the United States. It is a nonviscous, iso-osmotic, clear solution containing icodextrin (a biodegradable α-1,4-linked glucose polymer) at a concentration of 4% in a buffered solution. In this study, a comparison of Adept to lactated Ringer's solution (LRS) in 410 patients who underwent gynecologic laparoscopic surgery including adhesiolysis was performed. A second-look laparoscopy was performed 4 to 8 weeks postoperatively, at which time the adhesion scores were determined in the two groups. It was shown that there was a reduction of at least three sites with adhesions, or 30% of the number of preexisting sites with adhesions between the initial surgery and the follow-up laparoscopy in the Adept group in comparison with the LRS group (49% vs. 38%, respectively; p = 0.018). This reduction was significant in the nonrandomized subgroup of patients with infertility (55% vs. 33%; p < 0.001). American Fertility Society (AFS) score was found to be lower in the Adept-treated infertility patients than in the LRS group (53% vs. 30%, respectively; p = 0.001). When the subgroups of infertility patients were compared, patients with endometriosis and pelvic pain showed a significant decrease in AFS score in the Adept group above that of the LRS group (54% vs. 25%, respectively, in endometriosis group; 51% vs. 23%, respectively, in pelvic pain group; p = 0.003, p = 0.006, respectively). Unfortunately, significant differences in the overall reduction of extent and severity of adhesions per patient and the AFS adnexal adhesion score between the two groups were unable to be identified. The reduction in the number of visceral site adhesions in the Adept group was significant compared with that of the LRS group (p = 0.046). The difference in abdominal wall adhesions was not significant (p = 0.184).

There are several other antiadhesion adjuvants that have been evaluated in human clinical trials, including the agents that will be described below. NO-carboxymethylchitosan (NOCC) is a purified derivative of chitin obtained from the exoskeleton of shrimp.[50] There is a structural similarity of NOCC to HA-CMC, which has been shown to be an effective antiadhesive agent in animal studies. In rabbit and rat studies, both NOCC gel and solution have been shown to reduce the incidence and severity of postoperative adhesions, as well as adhesion formation and re-formation.[51,52] NOCC has been used to provide a physical barrier between surgically damaged surfaces. A pilot, prospective, multicenter, randomized clinical study has shown promising results on the safety and efficacy of NOCC in reducing adhesions in women who had gynecologic laparoscopy. It has been demonstrated that intraperitoneal NOCC gel and solution is safe and exhibits a trend in the reduction of occurrence, extent, severity of adhesion recurrence, and de novo adhesion formation.[53]

SprayGel (Confluent Surgical, Waltham, MA) is another material that as of yet is not approved in the United States but has been used in Germany and Australia in laparoscopic and hysteroscopic procedures to prevent adhesions. This sprayable tissue adherent and synthetic gel material has been studied in humans with successful results. After laparoscopic myomectomies, the overall reduction in adhesion was 27% in treated patients.[54] The same agent has also been used in a multicenter, randomized, prospective controlled study in both laparoscopic and open myomectomies. The mean adhesion score was 64.7% less in treated patients (p = 0.001).[55] SprayGel has also been studied in the Asherman syndrome treatment for intrauterine adhesion prevention and has shown promising results in pregnancy outcomes.[56]

Oxiplex-AP gel (FzioMed, San Luis Obispo, CA) is another agent undergoing investigation for gynecologic use and is specifically formulated for laparoscopic applications with tissue adherence and persistence sufficient to prevent adhesion formation. Oxiplex-AP gel is composed of carboxymethylcellulose and polyethylene oxide, which are well studied in rabbits and found to be promising in reducing postoperative adhesions.[57,58,59] Furthermore, it was demonstrated that Oxiplex-AP gel decreases the incidence of adnexal adhesion development after laparoscopic gynecologic surgery in humans.[60] Eighteen patients received Oxiplex-AP gel and 10 patients received surgical therapy alone. There was no difference in AFS score in the treated group; however, it was increased in the control group. In the second-look surgery, 66.7% of the control group had increased AFS score compared with 34.5% of the treated group (p < 0.091). In another study, 49 patients had laparoscopic gynecologic surgery. Twenty-four of the 49 patients had surgery with viscoelastic (Oxiplex-AP) gel placement on their adnexal area and the remaining 25 received only surgery. After the second-look surgeries, the AFS scores in control group were significantly increased (8.8 to 15.8) compared with those of the treated group (11.9 to 9.1).[61]

Sepracoat (HAL-C; Genzyme Corp.), a diluted solution of hyaluronic acid, was used in a multicenter study to prevent de novo type 1A adhesion in gynecologic laparotomy and yielded beneficial results,[62] but use of the product was not approved by the FDA. To attempt to improve efficacy and to expand benefit to sites at risk for type 1B and type 2 adhesions, methods to increase dwell time within the abdominal cavity have been evaluated.

Other Agents

The estrogenic environment has been proposed to have an important role in adhesion formation. A hypoestrogenic environment induced by gonadotropin releasing hormone (GnRH) agonist (GnRH-a) or by noncompetitive estrogen antagonist mifepristone treatment has been shown to decrease the incidence of postoperative adhesions in primate and rat models.[63,64,65] The activities of the proteolytic and fibrinolytic enzymes were studied in rats before and after GnRH-a therapy. The short-term and long-term effects were compared between treated and untreated groups. In the short-term, PAA and PAI activities were decreased in the treated group. However, in the long-term, both PAA and MMP levels were decreased whereas the expression of matrix metalloproteinase inhibitor (MMPI) and PAI were increased, which is one of the proposed mechanisms of postoperative adhesions development that was discussed.[65] However, GnRH analogues have not been shown to be effective in human clinical trials. In a randomized, double-blinded, prospective study involving 20 patients who had myomectomy via laparotomy, 10 patients received GnRH analogues for 3 months prior to surgery and 10 patients received a placebo. These patients were also evaluated by second-look laparoscopies 2 to 3 weeks after prior surgeries to evaluate postoperative adhesion formation. The severity and extent of adhesions were statistically non-significant.[66] Recently, aromatase inhibitors such as anastrozole and tamoxifen have shown promising results in rat studies.[67] Tamoxifen significantly reduces collagen-1 formation through downregulation of transforming growth factor-β (TGF-β1), which is well-known to promote extracellular matrix production and fibrosis in fibroblasts from the peritoneum and skin.[68]

Excess production or impaired elimination of free radicals leads to increased oxidative stress that has been implicated in the development of several different disease processes including postoperative adhesions.[24] Nitric oxide (NO) has been shown to decrease collagen synthesis and fibrosis in both human cell cultures and animal studies.[3,69,70] Lower NO levels have been demonstrated in normal peritoneal fibroblasts after exposure to hypoxia, which is a characteristic of adhesion fibroblasts.[71]

Contrary to these findings, NO stimulates guanyl cyclase to produce cyclic guanosine monophosphate (cGMP) and activate protein kinase G. Inhibition of phosphodiesterase-5 enzyme helps the breakdown of cGMP, which leads to reduced collagen synthesis and increased apoptosis of fibroblasts.[72,73] Sildenafil, a potent phosphodiesterase-5 inhibitor, has been studied in rats with promising results in the prevention of postoperative adhesions development.[74]

Similarly, methylene blue, a NO synthase inhibitor, has been shown to decrease postoperative adhesion formation in animals. It has been shown that while methylene blue decreases the intraperitoneal adhesions, it also impairs the anastomotic wound healing.[75] It has been claimed that methylene blue acts in a dose-dependent manner in adhesion prevention. In lower doses it is preventive, whereas in higher doses it increases the extent of adhesions.[76]

Opioid use has been shown to reduce the severity and extent of postoperative adhesions in animal models.[77] There is no known mechanism how opioids reduce adhesions, but proposed actions include affecting the known steps that promote the adhesion formation such as decreasing inflammation through the inflammatory cells, macrophages, mesothelial cells, platelets, or bioactive substances, and changing the fibrinolysis balance.

Several studies have been conducted to understand the mechanisms of adhesion development after surgical procedures in addition to its prevention. The results have been somewhat controversial without leading to a clear understanding of factors that affect postoperative adhesions formation. Despite initial promising results of different measures in postoperative adhesions prevention, none of them have become a standard application. Future studies focusing on the biological differences between individuals who develop postoperative adhesions and those who do not may bring a new understanding of the pathophysiology of postoperative adhesions and hopefully result in more effective preventive measures.

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