Abdominal Adhesions: Current and Novel Therapies

Journal of Surgical Research 165, 91–111 (2011) doi:10.1016/j.jss.2009.09.015 RESEARCH REVIEW Abdominal Adhesions: Current and Novel Therapies Brian C. Ward, Ph.D.,*,† and Alyssa Panitch, Ph.D.*,1 *Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana; and †Indiana University School of Medicine, Indianapolis, Indiana Submitted for publication July 13, 2009 An adhesion occurs when two tissues that normally Abdominal adhesions place a tremendous burden on freely move past each other attach via a fibrous bridge. public health. Adhesions develop after nearly every ab- Abdominal adhesions place a tremendous clinical and dominal surgery. Multiple studies cite that of patients financial burden on public health. Adhesions develop who have abdominal surgery, 93% will have adhesions after nearly every abdominal surgery, commonly caus- [3, 4]. Many of these adhesions require a second opera- ing female infertility, chronic pelvic pain, and, most tion known as adhesiolysis to break the adhesion. A frequently, small bowel obstruction. A National Hospi- comprehensive study of inpatient care and expendi- tal Discharge Survey of hospitalizations between 1998 tures associated with adhesiolysis procedures in the and 2002 reported that 18.1% of hospitalizations were United States was conducted in 1994. This study found related to abdominal adhesions annually accounting for 948,000 days of inpatient care at an estimated cost that adhesiolysis accounted for 303,836 hospitaliza- of $1.18 billion. tions (1% of the hospitalizations in the United States), This review discusses the current or proposed thera- 846,415 days of inpatient care, and $1.33 billion in hos- pies for abdominal adhesions. While many therapies pitalization and surgeon expenditures. Furthermore, for abdominal adhesions have been attempted, the this enormous cost estimate did not include other need for a definitive therapy to prevent or even reduce expenditures such as laboratory tests, endoscopies, im- abdominal adhesions still exists. Ó 2011 Elsevier Inc. All rights aging, ambulance service, consulting physician costs, reserved. post-discharge costs, workday or productivity losses, Key Words: abdominal; adhesion; therapy; review; long-term morbidity costs, or the societal cost of early inflammation; fibrosis; cytokine. mortality [13]. Over the past decade, the number of adhesiolysis procedures has increased [14]. In 2004, over IMPORTANCE AND HEALTH RELEVANCE 342,000 procedures were performed to lyse peritoneal OF ABDOMINAL ADHESIONS adhesions [14]. Finally, litigation stemming from complications of intra-abdominal adhesions threatens to Surgical procedures are the primary cause of adhe- drive healthcare costs related to abdominal adhesions sions [1–5]. Moreover, adhesions can arise in many even higher [15]. Thus, the prevention of abdominal parts of the body. Adhesions commonly occur during ab- adhesions has the potential to save the United States dominal, gynecological, dental, thoracic, and cardiac healthcare market billions of dollars and improve the procedures [1, 2, 6–12]. While many of the therapies lives of hundreds of thousands of Americans. discussed will be applicable to all of these adhesion While female infertility and chronic pelvic pain are types, the focus of this review is preventing abdominal common complications of abdominal adhesions, small adhesions with an emphasis on small bowel adhesions bowel obstruction is often cited to have the highest due to their enormous clinical significance and market incidence among abdominal adhesion complications potential. [13]. In fact, adhesiolysis operations on the digestive system accounted for $1.1 billion in surgeon expendi- 1 To whom correspondence and reprint requests should be ad- tures and hospitalization costs as well as 94% of the dressed at Weldon School of Biomedical Engineering, Purdue Univer- inpatient days associated with adhesiolysis procedures sity, 206 Martin Jischke Drive, West Lafayette, IN 47907. E-mail: [email protected]. in the United States in 1994 [13]. Moreover, 54% to 59% 91 0022-4804/$36.00 Ó 2011 Elsevier Inc. All rights reserved. 92 JOURNAL OF SURGICAL RESEARCH: VOL. 165, NO. 1, JANUARY 2011 of bowel obstruction occurrences in the United States cytokines and extracellular matrix signals and also from 1979 to 1989 were due to abdominal adhesions, can actually develop a myofibroblastic phenotype and 60% to 70% of these adhesions involved the small [20–23]. Fibroblasts and myofibroblasts secrete mas- bowel [3]. According to a 2004 National Hospital Dis- sive amounts of extracellular matrix molecules includ- charge Survey, approximately 305,000 operations ing fibronectin, hyaluronic acid, glycosaminoglycans, were performed to treat intestinal obstruction [14]. and proteoglycans. This process establishes a weak Thus, 180,000 of these operations were probably due fibrous bridge between tissues. Vascularization and to abdominal adhesions. Even after adhesiolysis, recur- collagen deposition strengthen this bridge, forming rent obstruction is common (8% to 32%) [3]. Most impor- a tough adhesion between the two tissues [2]. tantly, patients may die from bowel obstruction; as Although the mechanism that shifts the normal heal- many as 3% to 5% die from a simple obstruction, and ing process to adhesion formation remains unclear, pos- as many as 30% die if the bowel becomes strangulated, sible culprits include ischemia, surgical trauma, necrotic, or perforated [3]. Clearly, abdominal adhe- inflammation, hemorrhage, thermal injury, chemical sions, particularly adhesions involving the bowel, rep- injury, allergic reaction, tissue desiccation, genetic pre- resent a clinically and financially significant problem. disposition, and reactions to foreign bodies introduced during the procedure such as glove powder, sutures, and gauze [13, 24, 25]. Regardless of the initiating PATHOGENESIS OF ABDOMINAL ADHESIONS factor, adhesions develop from the interplay of three Normal Peritoneal Healing intertwined processes in the body: the fibrinolytic system, extracellular matrix deposition and remodel- To understand how to prevent adhesions, one must ing, and the inflammatory system (Fig. 1). first understand how adhesions develop. Serosal surfaces are maintained by mesothelial cells. Mesothelial cells make a phospholipid-based surfactant that provides LITERATURE REVIEW OF CURRENT OR PROPOSED lubrication for sliding viscera, have fibrinolytic activity ABDOMINAL ADHESION PREVENTION THERAPIES that protects against adhesions and thromboses, and se- Methods of Literature Review crete cytokines that play an active role in tissue repair and extracellular matrix turnover [16].Whenmesothe- Because of the massive number of abdominal adhe- lial surfaces are injured, the coagulation cascade causes sion prevention strategies developed over the past sev- fibrin deposition. Fibrin monomers polymerize to form eral decades, this review organizes the strategies into a lattice of fibrin that can serve as a template for wound categories. The major categories selected are: solid bar- healing or as a tissue bridge for adhesion development. riers, fluid and gel barriers, surgical protocols, cellular The injured area is invaded by inflammatory cells strategies, pharmaceuticals, and combination prod- from the vasculature or peritoneal fluid. Polymorpho- ucts. First, the category as a whole is critically evalu- nuclear neutrophils (PMNs) appear first in the perito- ated. Some of the most notable strategies within the neum and persist 1–2 d [17]. Macrophages appear category are also evaluated in the text, and more anal- soon after PMNs and become the predominant cells in ysis is dedicated to products approved by the FDA and the peritoneal fluid. Macrophage concentration in the to strategies with more extensive efficacy data. Human peritoneal fluid peaks between ds 5 and 6 after surgery trial data is also given more consideration. Further- [17]. Macrophages adhere to the wound area within more, each category contains a comprehensive table 24 h after surgery [18]. At approximately d 3, mesothe- listing abdominal adhesion prevention strategies in lial cells begin to cover bound peritoneal macrophages this category along with notes concerning efficacy and at the injured area, and macrophages embed deeper special features associated with the individual strat- in the wound [18]. If normal healing occurs, the injured egy. Specific references listed in the table are not area, regardless of size, is restored to a continuous sheet always repeated in the text. of mesothelial cells in 7 to 10 d [2]. These categories and the literature and strategies comprising these categories are critically evaluated ac- When Peritoneal Healing Goes Wrong cording to several criteria. The most important criterion is efficacy. Each strategy in each category is evaluated Alternatively, the recovering mesothelial cells, fibro- for its ability or potential ability to reduce or prevent blasts, and peritoneal macrophages can signal the abdominal adhesions. Only papers that included statis- deposition of excessive extracellular matrix via cell tical analysis were selected to be included in the review growth factors and cytokines [2]. Adhesion fibroblasts of strategy efficacy. Furthermore, other performance develop a myofibroblast phenotype [19]. Recent evi- criteria are considered. These criteria include whether dence suggests that these mesothelial cells respond to the category/strategy targets the pathogenesis of WARD AND PANITCH: ABDOMINAL ADHESIONS: PATHOGENESIS AND SOLUTIONS

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