Review
Topical non-barrier agents for postoperative adhesion prevention in animal models

https://doi.org/10.1016/j.ejogrb.2009.12.026Get rights and content

Abstract

Pelvic adhesion can form as a result of inflammation, endometriosis or surgical trauma. Most surgical procedures performed by obstetrician–gynecologists are associated with pelvic adhesions that may cause subsequent serious sequelae, including small bowel obstruction, infertility, chronic pelvic pain, and difficulty in postoperative treatment, including complexity during subsequent surgical procedures. An increasing number of adhesion reduction agents, in the form of site-specific and broad-coverage barriers and solutions, are becoming available to surgical teams. The most widely studied strategies include placing synthetic barrier agents between the pelvic structures. Most of the adhesions in the barrier-treated patients develop in uncovered areas in the abdomen. This fact suggests that the application of liquid or gel anti-adhesive agents to cover all potential peritoneal lesions, together with the use of barrier agents, may reduce the formation of postoperative adhesions. This article introduces the topical choices available for adhesion prevention mentioned in preliminary clinical applications and animal models. To date there is no substantial evidence that their use reduces the incidence of postoperative adhesions. In combination with good surgical techniques, these non-barrier agents may play an important role in adhesion reduction.

Introduction

Postoperative adhesion formation is the most frequent complication of surgery, although often not recognized as such [1], [2], [3]. With an incidence of 55% to 100% in all abdominal operations, adhesions are responsible for an increased risk of small bowel obstruction, chronic abdominal pain, and infertility [1], [2], [3]. Various strategies, such as application of liquids and membranes, are used in an attempt to prevent adhesion formation. There are three methods approved by the US Food and Drug Administration for the prevention of postoperative adhesions, including Adept®, Interceed®, and Seprafilm®[4]. Some surgical barriers have been demonstrated to be effective for reducing postoperative adhesions, but there is no substantial evidence that their use improves fertility, decreases pain, or reduces the incidence of postoperative bowel obstruction [5].

With the barrier technique, surgically traumatized surfaces are kept covered during peritoneal regeneration, thus preventing adherence of adjacent structures and reducing adhesion formation. Most of the adhesions in the barrier-treated patients develop in uncovered areas in the abdomen. As yet, no strategy is capable of complete prevention. This fact underlines the necessity of using liquid anti-adhesive agents to cover all potential peritoneal lesions. The purpose of this article is to review topical methods to prevent postoperative adhesion formation in animal models, as summarized in Table 1. The use of non-barrier agents effectively reduces postoperative peritoneal adhesions in the preliminary clinical applications and animal models.

Section snippets

Adhesion formation mechanism

Surgical trauma to the peritoneum is the main cause of postoperative adhesion formation (Fig. 1). Peritoneal damage induces an inflammatory response that ultimately leads to up-regulation of the expression of tissue factor by macrophages and peritoneal cells [1]. This causes activation of the extrinsic pathway of the coagulation cascade, eventually leading to the formation of a fibrinous exudate [6]. Under normal circumstances, this fibrinogenesis is in balance with fibrinolysis. The process of

Statins

HMG-CoA reductase inhibitors (statins) inhibit the rate-limiting enzyme in the production of cholesterol. This class of drugs has a well-studied lipid lowering benefit; however, recent studies have elucidated additional effects of statins beyond their impact on serum cholesterol levels [12], [13]. Various experimental studies have shown statins to have antioxidant, anti-inflammatory, and pro-fibrinolytic properties [11], [14], [15], all of which may play a role in the process of adhesion

Gonadotropin-releasing hormone agonists (GnRHa)

GnRHa have beneficial effects on the size and symptoms of endometriosis and uterine myomas by suppressing ovarian steroidgenesis [19], [20]. GnRHas are also the preferred drugs for postoperative adhesion prevention. Experimental and clinical studies have demonstrated various mechanisms of action to be involved in adhesion prevention when GnRHas are used for treatment [21]. In studies involving uterine surgery in monkeys, postoperative utero-omental adhesions were reduced with preoperative

Melatonin

Oxidative stress may also be involved in the formation of intraperitoneal adhesions (Fig. 1) [30]. Therefore, intraperitoneal antioxidant treatment may be hypothesized to reduce adhesion formation and reformation [30]. Melatonin (N-acethyl-5-methoxytryptamine) was initially thought to be produced exclusively in the pineal gland. However, melatonin production in the retina is well documented and there is evidence for its formation in the ovary, lens and gastrointestinal tract [31], [32].

Collagen

Type I collagen is an extracellular matrix protein, expression of which is increased by hypoxia [36]. Hypoxia resulting from tissue injury has been suggested to play an important role in wound healing, and may therefore be a critical factor in the development of postoperative adhesions. Collagen has been reported as having multiple functions in healing process, such as fibroblastosis activity and re-epithelization. Collagen is chemotactic to fibroblasts, which control the restoration of new

Phosphatidylcholine

The surface-active material coating the peritoneum is chemically similar to pulmonary surfactants, consisting mainly of phospholipid phosphatidylcholine (PC) [6]. The local formation of fibrin might be prevented by the lubricant action of PC since the tissue defects are covered [39]. Phospholipids are composed of both hydrophobic and hydrophilic parts; it has been suggested that phospholipids adhere to the negatively charged peritoneum by their positively charged head-group in such a way that

Linezolid

Linezolid is a new class of oxazolidinone antibiotics, and inhibits protein synthesis by a mechanism not shared by other antibiotics. Linezolid binds to 23S ribosomal RNA, inhibiting translation in the early phase and preventing the proper binding of formyl-methionine transfer RNA. Linezolid also inhibits mammalian mitochondrial protein synthesis and serves as an antioxidant [40]. A recent trial examined the effects of linezolid in prevention of adhesion formation in the rat uterine horn model

Anti-inflammatory agents

Some local and systemic anti-inflammatory drugs and adhesion-reducing substances such as dexamethasone and promethazine have been evaluated. However, none has been found effective for reducing adhesions [5].

Honey

Honey has been used as a method of wound treatment for more than 2000 years. Honeybees produce honey from the nectar of flowers or secretions from other parts of the plant. It is rich in flavonoid components, such as luteolin, quercetin, apigenin, fisetin, kaempferol, isorhamnetin, acacetin, tamarixetin, chrysin and galangin, and thus exhibits antioxidant activity. Honey inhibits the growth of both gram-positive and gram-negative bacteria and provides anti-bacterial, anti-inflammatory,

Adept solution

Icodextrin 4% solution (Adept®, Baxter Healthcare S.A.) is a high-molecular-weight α-1,4-glucose polymer that is approved in Europe for use as an intra-operative lavage to reduce adhesion formation following abdominopelvic laparotomy or laparoscopy. Due to the high-molecular-weight of icodextrin and the absence of amylase, the enzyme by which it is metabolized within the human peritoneal cavity, the agent has a prolonged peritoneal residence time of at least 4 days [45]. This enables it to

Conclusion

Post-surgical adhesion formation is a significant clinical problem for every surgical specialty. Evaluation of the cause and means of prevention of adhesion formation has been the major goal of many investigations. Following the basic surgical principles of minimizing tissue trauma with meticulous hemostasis, minimization of ischemia and desiccation, and prevention of infection and foreign body retention may help to decrease postoperative adhesions. Several drugs and substances are used locally

Conflict of interest

Neither author has any conflict of interest.

Acknowledgements

We thank Drs. Stephanie L. Pierce and Syed Mahfuzul Alam for their language editing in the preparation of this manuscript.

References (51)

  • H. Wiczyk et al.

    Pelvic adhesions contain sex steroid receptors and produce angiogenesis growth factors

    Fertil Steril

    (1998)
  • M. Diamond et al.

    Regulation of transforming growth factor-beta, type III collagen, and fibronectin by dichloroacetic acid in human fibroblasts from normal peritoneum and adhesions

    Fertil Steril

    (2003)
  • C. Ara et al.

    Protective effect of melatonin against oxidative stress on adhesion formation in the rat cecum and uterine horn model

    Life Sci

    (2005)
  • O. Koc et al.

    Intraperitoneal administration of single dose type I collagen or low dose melatonin to prevent intraperitoneal adhesion formation: a comparative study

    Eur J Obstet Gynecol Reprod Biol

    (2009)
  • G. Saed et al.

    Hypoxia-induced irreversible up-regulation of type I collagen and transforming growth factor-beta1 in human peritoneal fibroblasts

    Fertil Steril

    (2002)
  • A. Ar’Rajab et al.

    Phosphatidylcholine prevents postoperative peritoneal adhesions: An experimental study in the rat

    J Surg Res

    (1991)
  • E. Aysan et al.

    The role of intraperitoneal honey administration in preventing postoperative peritoneal adhesions

    Eur J Obstet Gynecol Reprod Biol

    (2002)
  • A. Emre et al.

    Comparison of intraperitoneal honey and sodium hyaluronate-carboxymethylcellulose (seprafilm) for the prevention of postoperative intra-abdominal adhesions

    Clinics (Sao Paulo)

    (2009)
  • R. Lang et al.

    Polyvinyl alcohol gel prevents abdominal adhesion formation in a rabbit model

    Fertil Steril

    (2007)
  • C. Coddington et al.

    Gonadotropin-releasing hormone agonist pretreatment did not decrease postoperative adhesion formation after abdominal myomectomy in a randomized control trial

    Fertil Steril

    (2009)
  • Z. Alpay et al.

    Postoperative adhesions: from formation to prevention

    Semin Reprod Med

    (2008)
  • V. González-Quintero et al.

    Preventing adhesions in obstetric and gynecologic surgical procedures

    Rev Obstet Gynecol

    (2009)
  • J. van der Wal et al.

    The use of statins in postoperative adhesion prevention

    Ann Surg

    (2007)

  • The Society of Reproductive Surgeons: Pathogenesis, consequences, and control of peritoneal adhesions in gynecologic surgery

    Fertil Steril

    (2007)
  • V. Shavell et al.

    Review: cellular metabolism: contribution to postoperative adhesion development

    Reprod Sci

    (2009)

    • Cited by (22)

    • Recombinant human lubricin for prevention of postoperative intra-abdominal adhesions in a rat model

      2017, Journal of Surgical Research
      Citation Excerpt :

      Despite numerous previous animal experimental studies and clinical trials demonstrating a degree of reduction of severity and frequency of postoperative intraperitoneal adhesion formation, not one product has been demonstrated to effectively and safely reduce adhesions without significant side effects. There is also a lack of products that are suitable for use in all types of operations.16-18 Many experimental models have been used in previous literature to form peritoneal adhesions such as bowel abrasion model, large bowel anastomosis model, bacterial peritonitis model, suturing model, ileal transection model, uterine horn model, and electrocautery model.

    • Preventing intraperitoneal adhesions with linezolid and hyaluronic acid/carboxymethylcellulose: A comparative study in cecal abrasion model

      2014, American Journal of Surgery
      Citation Excerpt :

      Proposed mechanisms to reduce the formation of adhesions are as follows: 1, to reduce the 1st inflammatory response and the release of exudate; 2, to block the coagulation of the exudate; 3, to enhance fibrinolysis; 4, to separate mechanically fibrin-coated surfaces; and 5, to prevent the proliferation of fibroblasts. The most effective way to reduce intraperitoneal adhesions is perhaps a meticulous hemostasis, to follow basic surgical principles to minimize the tissue trauma and ischemia, and to prevent infections.13–15 There are many experimental models to form peritoneal adhesions: the damaged uterine horn model, the ileal transection model, the large bowel anastomosis model, the peritoneal damage model, the bacterial peritonitis model, the scraping model, the suturing model, and the electrocautery model.

    • Regional treatment with liquid barrier agents: A novel therapeutic option for intraperitoneal endometriosis?

      2013, Medical Hypotheses
      Citation Excerpt :

      In case of endometriosis, these liquid barrier agents may prevent the attachment of endometrial fragments to the peritoneum and the formation of peritoneal adhesions in the course of the disease. Moreover, some of these agents have been shown to exhibit anti-inflammatory, anti-oxidant and anti-tumoral effects [24]. Thus, they may be used as pleiotropic compounds, directly targeting multiple mechanisms involved in the pathogenesis of endometriosis, including local formation of reactive oxygen species [25], activation of inflammatory cells [26] as well as vascularization and proliferation of endometrial tissue [27].

    • Efficacy of melatonin in the treatment of endometriosis: A phase II, randomized, double-blind, placebo-controlled trial

      2013, Pain
      Citation Excerpt :

      It is important to investigate other therapeutic options, such as melatonin, which has been shown to have a beneficial effect in experimental models of endometriosis [65]. Mounting evidence indicates that melatonin should be tested in this setting, considering its analgesic, antioxidant [27,32], and antiinflammatory effects. In fact, the antinociceptive effect of melatonin has been demonstrated in animal models of acute pain [20,39], inflammatory pain [5,6,19], and neuropathic pain [60].

    • Adhesion Prevention in Endometriosis: A Neglected Critical Challenge

      2012, Journal of Minimally Invasive Gynecology
      Citation Excerpt :

      The fibrinous adhesions organize into fibrous adhesion because of in-growth of fibroblasts and endothelial cells that is followed by capillary formation and incorporation of collagen. An abdominal surgery aimed at removing endometriotic lesions and nodules is unlikely to repair the equilibrium between fibrinogenesis and fibrinolysis, and, because the environment is already compromised toward an inflammatory condition, it may disturb further the balance [29]. Prevention of adhesions, whether de novo or by re-formation, is one of the most important and surprisingly neglected aspect of treatment [30,31].

    • Current Management of Small Bowel Obstruction

      2011, Advances in Surgery
    View all citing articles on Scopus
    View full text
    Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.