Surgical Biology for the Clinician Biologie chirurgicale pour le clinicien

Adhesive small : epidemiology, biology and prevention

Jo-Anne P. Attard, MD; Anthony R. MacLean, MD

Intraabdominal adhesions develop after abdominal as part of the normal healing processes that occur after damage to the . Over the last 2 decades, much research has gone into under- standing the biochemical and cellular processes that lead to formation. The early balance be- tween fibrin deposition and degradation seems to be the critical factor in adhesion formation. Although adhesions do have some beneficial effects, they also cause significant morbidity, including adhesive small bowel obstruction, infertility and increased difficulty with reoperative surgery. Several strategies have been employed over the years to prevent adhesion formation while not interfering with wound healing. This article summarizes much of our current understanding of adhesion formation and strategies that have been employed to prevent them.

Les adhérences intra-abdominales font leur apparition après une chirurgie à l’abdomen dans le cours des mécanismes de guérison normaux suivant un dommage au péritoine. Au cours des deux dernières dé- cennies, on a effectué beaucoup de recherches afin de comprendre les phénomènes biochimiques et cel- lulaires à l’origine de la formation d’adhérences. L’équilibre précoce entre le dépôt de fibrine et sa dégradation semble jouer un rôle critique dans la formation d’adhérences. Même si les adhérences ont certains effets bénéfiques, elles causent aussi une morbidité importante, y compris l’occlusion de l’in- testin grêle, l’infécondité et les difficultés accrues dans le cas d’interventions chirurgicales ultérieures. On a suivi au fil des ans plusieurs stratégies pour prévenir la formation d’adhérences sans nuire à la guérison de la plaie. Cet article résume une grande partie des connaissances actuelles au sujet de la for- mation d’adhérences, ainsi que les stratégies que l’on a suivies pour les prévenir.

ostoperative adhesions form af- the current available methods of It is estimated that 93% to 100% Pter trauma to the peritoneal cav- prevention. of patients who undergo transperi- ity and are a result of the biochemi- toneal surgery will develop postoper- cal and cellular response that occurs Background ative adhesions.5 The extent of adhe- in an attempt to repair the peri- sion formation varies from one toneum. Although there are benefi- Peritoneal adhesions can be defined patient to another and is most depen- cial effects to adhesions, they are the as abnormal fibrous bands between dent on the type and magnitude of leading cause of small intestinal ob- organs or tissues or both in the ab- surgery performed, as well as whether struction after dominal cavity that are normally sep- any postoperative complications de- and can be the source of significant arated.1–3 Adhesions may be acquired velop.6 Another surgical factor that morbidity, in some cases leading to or congenital; however, most are ac- has been shown to contribute to ad- mortality. This review aims to pro- quired as a result of peritoneal injury, hesion formation is intraperitoneal vide general surgeons with a broad the most common cause of which is foreign bodies, including mesh, glove overview of what is currently known abdomino-pelvic surgery.4 Less com- powder, suture material and spilled about adhesions, the cellular and monly, adhesions may form as the .7 Fortunately, most pa- molecular events that are involved result of inflammatory conditions, in- tients with adhesions do not experi- in their formation, the latest re- traperitoneal infection or abdominal ence any overt clinical symptoms. For search developments in this area and trauma.4 others, adhesions may lead to any

Department of Surgery, University of Calgary, Calgary, Alta. Accepted for publication June 17, 2005 Correspondence to: Dr. Anthony R. MacLean, Department of Surgery, Foothills Medical Centre, 1403–29th St. N.W., Calgary AB T2N 2T9; [email protected]

© 2007 Canadian Medical Association Can J Surg, Vol. 50, No. 4, August 2007 291 Attard and MacLean

one of a host of problems and can be hesions, but it is not the only one, over a 10-year period were found to the cause of significant morbidity and and the adverse effects of adhesions be directly related to adhesions, and mortality.8 are not limited to the gut.4 For ex- 3.8% of these admissions required ample, in the gynecological litera- operative management.8 In 1994, the Adhesions and small bowel ture, it has been found that adhe- estimated financial impact for direct obstruction (SBO) sions are a leading cause of secondary patient care owing to adhesion- infertility in women (responsible for related disorders in the United States Intraabdominal adhesions are the 15%–20% of cases)18 and, although was US$1.3 billion.22 In Sweden, it is most common cause of SBO in in- controversial, there is evidence to estimated that the health care burden dustrialized countries, accounting for suggest that they may be a cause of owing to adhesive disease reaches approximately 65% to 75% of cases.5 longer-term abdominal and pelvic $13 million annually.23 As the cost of There is a wide range of values re- pain.19 For patients with chronic re- health care continues to escalate and ported in the literature for the risk of nal failure, adhesions may make peri- the number of patients requiring sur- developing adhesive SBO after toneal dialysis impossible, and their gical care increases with the aging transperitoneal surgery, depending presence may preclude the use of in- population, the financial burden of on the series of patients, how they traperitoneal chemotherapy in those adhesions will continue to expand. were evaluated and the types of sur- patients who are candidates.4,6 For Given the far-reaching consequences gical procedures performed. In gen- general surgeons, the presence of ad- of postoperative adhesions, it is im- eral, procedures in the lower ab- hesions often makes reoperative portant that they not be viewed as an domen, or both and those surgery difficult and may increase the inevitable consequence of surgery for resulting in damage to a large peri- complication rate of the intended which little can be done.24 This toneal surface area tend to put pa- surgical procedure.20 In the current knowledge should provide the impe- tients at higher risk for subsequent era of advanced laparoscopic surgery, tus for further research in this area, adhesive obstruction.4 It is estimated adhesions have taken on an even to improve our understanding of the that the risk of SBO is 1% to 10% af- greater significance, frequently mak- pathophysiology of adhesions and to ter appendectomy,9,10 6.4% after open ing laparoscopic approaches more enable the development of methods cholecystectomy,9 10% to 25% after difficult and, in some cases, entirely to alter the biological events that are intestinal surgery11,12 and 17% to 25% impossible.4 Even with open reopera- necessary for their formation. after restorative proctocolectomy tive surgery, extensive adhesiolysis is (IPAA).13–16 often necessary to ensure adequate Understanding the The relation between postoperative exposure, not uncommonly resulting pathophysiology of adhesion adhesions and intestinal obstruction is in prolonged operating times, in- formation not a new concept. In 1872, Thomas creased blood loss and other compli- Bryant described a fatal case of intesti- cations.4,20,21 Inadvertent enterotomy Holmdahl and Ivarsson25 have sug- nal obstruction caused by intra- is probably the best recognized com- gested that the inability to discover abdominal adhesions that developed plication of adhesiolysis, with an inci- effective ways to reduce or abolish after removal of an ovarian tumour.17 dence of approximately 20% in reop- adhesion formation over the years Since Bryant’s report, a significant erative surgery.20 These cases result in has been due to a lack of insight into amount of time and money has been a poorer outcome for the patient, the basic tenets of peritoneal tissue invested into research on intraabdom- with prolonged hospitalization and a repair. Only in the last 15 to 20 years inal adhesions, with a primary focus higher incidence of intensive care have researchers started to unravel on the development of methods to unit admissions.20 the complexities of this process, prevent their formation. Despite sub- which involves several different cell stantial work in this area, little Socioeconomic burden of types, cytokines, coagulation factors progress has been made; to this day, adhesive SBO and proteases, all acting together to no clinical standard exists for any pre- restore tissue integrity.25 Although ventive measure, either surgical or The consequences of postoperative our understanding is far from com- pharmacological, to control the for- adhesion formation have become a plete, studies of adhesion formation mation of postoperative adhesions.4 significant burden socioeconomi- thus far have determined what is be- cally, and the treatment of adhesion- lieved to be the central pathophysio- Other complications of related disease uses a significant por- logical mechanism leading to ad- adhesions tion of health care resources and hesion development.24,26 This is dollars.8 From a large-scale epidemi- discussed below. If effective preven- SBO is probably the most severe ological study in Scotland, for exam- tative and treatment strategies are to consequence of intraabdominal ad- ple, 5.7% of hospital readmissions be developed, a more comprehensive

292 J can chir, Vol. 50, No 4, août 2007 Adhesive small bowel obstruction understanding of this process at both nism, however, the response of the thrombin, which is necessary for the the cellular and the molecular level, peritoneum to surgical trauma is the conversion of fibrinogen to fibrin.27 as well as the identification of inflam- same25 (Fig. 1). Immediately after in- Fibrin functions to restore injured tis- matory mediators involved, is essen- jury, there is bleeding and an increase sues and, once generated, is de- tial. The key to preventing post- in vascular permeability with fluid posited along peritoneal surfaces. operative adhesions will most likely leakage from injured surfaces.21,25,28 Si- Fibrin is a tacky substance and causes be based on selective inhibition of multaneously, a posttraumatic inflam- adjacent organs or injured serosal sur- one or more of the critical factors re- matory response occurs, with infiltra- faces to coalesce.24 Under normal cir- quired for their formation. tion of inflammatory cells, release of cumstances, the formation of a fibrin Peritoneal wound healing differs pro-inflammatory cytokines and acti- matrix during wound healing is only from skin in both the mode of ep- vation of the complement and coagu- temporary, and degradation of these ithelialization and the consequences lation cascades.25,27 filmy fibrinous adhesions by locally of fibrin deposition. To understand The fluid exudate released from released proteases of the fibrinolytic how the peritoneum responds to in- injured peritoneal surfaces is rich in system occurs within 72 hours of in- jury, some basic knowledge about its plasma proteins — especially fibrino- jury.2 Thus the process of fibrinolysis structure is required. The peri- gen.4,27 Activation of the coagulation is not confined to the degradation of toneum consists of a single outer cascade results in the formation of intravascular thrombi; it also has a key layer of mesothelial cells that are loosely anchored to a basement Peritoneal injury membrane and that detach readily with even the slightest trauma.21,25,27 The submesothelial layer consists of components of the extracellular Bleeding matrix, along with capillaries and , platelets, Coagulation cascade lymphatics.21,23,25 Fluid resorption and lymphocytes diffusion occurs freely across these Fibrinogen layers.21 The fluid in the contains several different cell Peritoneal fluid types, including leukocytes and + Proteins, cytokines, Thrombin Amino acid metabolites macrophages.25 These cells, along with the mesothelium, secrete vari- ous cellular mediators that have roles Fibrin in peritoneal healing, enabling mod- ulation of the inflammatory response 21 Plasminogen over a large surface area. Impaired fibrinolysis Fibrinolysis The process of postoperative adhe- PAI-1 sion formation constitutes a complex tPA PAI-2 interaction of biochemical events in- uPA volved in inflammation, tissue repair, 28 Plasmin angiogenesis and innervation. Peri- PAI-1 tPA toneal injury occurs at the site of the PAI-2 uPA actual procedure and in areas remote from the operative field, as a result of tissue and retraction during the Fibrin degradation products course of surgery.1 Surgical trauma to Fibrin matrix the peritoneum can occur by various mechanisms: cutting, abrasion, is- Collagen chemia, desiccation and coagulation.4 The latter 2 types of injury are unique Organization in that they are directly toxic to the Resolution of injury and mesothelial cells that line the peri- Mature adhesions peritoneal repair toneal cavity and to the underlying 4 connective tissue. Ischemic injury is FIG. 1. Biological events involved in peritoneal tissue repair and adhesion formation. typically the result of tissue and organ PAI-1 = plasminogen activator inhibitors group 1; tPA = tissue plasminogen activa- retraction. Regardless of the mecha- tor; uPA= urokinase-like plasminogen activator.

Can J Surg, Vol. 50, No. 4, August 2007 293 Attard and MacLean

role in tissue remodelling and repair.25 tively referred to as plasminogen acti- PAI-1 and have depressed tPA activ- Fibrinolysis allows mesothelial cells to vator inhibitors (PAI). Two groups of ity.31,32 Further, after surgery, tPA proliferate and the peritoneal defect PAIs exist: PAI-1 and PAI-2. How- knockout mice seem to be more sus- to be restored within 4 to 5 days, ever, PAI-1 is recognized as the dom- ceptible to adhesion formation, com- preventing the permanent attachment inant inhibitor of fibrinolysis in pared with uPA-deficient or wild- of adjacent surfaces.2,29 Adequate plasma.27,31,32 PAI-1 specifically pre- type mice.2 Although the specific blood supply is critical for fibrinolysis, vents the formation of plasmin by di- molecular and biochemical events and since peritoneal injury results in rectly binding to and inhibiting the mediating the change in fibrinolytic ischemia, it also interferes with fibri- activities of tPA and uPA, thereby activity have yet to be fully eluci- nolysis.6 If fibrinolysis does not occur preventing the degradation of fibrin.21 dated, it appears that cytokines, within 5 to 7 days of peritoneal in- If fibrinolysis is a normal part of growth factors and angiogenesis fac- jury, or if local fibrinolytic activity is peritoneal healing, one may ask, tors, all of which are released by acti- reduced, the fibrin matrix persists.25 If “what allows fibrin to become orga- vated macrophages and other inflam- this occurs, the temporary fibrin ma- nized and fibrous adhesions to per- matory cells in response to peritoneal trix gradually becomes more orga- sist?” In 1983, Moore and col- injury, may have important roles in nized as collagen-secreting fibroblasts leagues33 demonstrated that the regulating this change. and other reparative cells infiltrate the peritoneum has powerful coagula- Elucidating the role of inflamma- matrix.4,24 The organization of fibrin tion and fibrinolytic capacity. As tory mediators in adhesion formation bands over time and their transforma- discussed above, under normal con- has become the main current focus of tion into mature fibrous adhesions is ditions (i.e., in an undisturbed ab- research in this area. It is known that what enables them to persist.2 These dominal cavity), fibrinolytic capacity specific cytokines and growth factors “mature” adhesions are not simply exceeds coagulation.33 Additional are responsible for upregulating the composed of connective tissue; stud- studies have shown that, in condi- expression of genes whose products ies have demonstrated that, over tions where there is peritoneal in- may help to initiate adhesion forma- time, they become highly organized jury, relative ischemia or both (such tion, likely by coordinating the events cellular structures that contain arter- as when a patient has or is responsible for the decline in fibrinol- ioles, venules, capillaries and nerve fi- undergoing surgery), peritoneal fib- ysis.21,25 Examples include genes for bres in addition to collagen.30 rinolytic capacity is depressed,31 and the neurokinin-1 (NK-1) receptor, As described above, the fibri- the relation between fibrinolysis and transforming growth factor beta nolytic system has a key role in peri- coagulation is reversed. Further, the (TGF-β), substance P (SP), intracel- toneal wound healing, and disruption reduction in peritoneal fibrinolysis lular adhesion molecule (ICAM-1) of this system results in adhesion for- after an operation seems to be in- and vascular cell adhesion molecule mation. In addition to activators of versely correlated to the degree of (VCAM-1). An increase in the levels fibrinolysis, there are also inhibitors adhesion formation.34 Given these of mRNA transcribed from each of that exist to maintain balance in the findings, it is believed that the these genes has been found in the system (that is, to prevent excessive decline in peritoneal fibrinolytic ca- peritoneal tissue of rats early after sur- fibrin deposition and degradation). pacity after surgery is the common gical trauma.28 There are 2 major activators in the central pathway leading to adhesion TGF-β is the most thoroughly fibrinolytic system: tissue plasmino- formation.26,31 studied cytokine in adhesion forma- gen activator (tPA) and urokinase- Both animal and human studies tion.25 TGF-β is a potent cytokine like plasminogen activator (uPA), have shown that 2 major changes and growth factor that initiates, mod- both of which are capable of activat- mediate the decline in fibrinolysis: a ulates and terminates tissue repair, ing plasminogen to plasmin.2 Plasmin decrease in local tPA activity31 and an and both TGF-β and its receptor are is a broad-range protease capable of increase in PAI-1 locally and system- elevated in peritoneal tissue and fluid degrading various molecules in the ically.35 The reason for decreased ac- after transperitoneal surgery.36 In extracellular matrix (ECM), including tivity of tPA appears to be 2-fold: a vitro studies suggest that TGF-β con- fibrin.21,25 Of the 2 plasminogen acti- reduction in the absolute amount of tributes to a decrease in peritoneal vators, tPA is the most important in tPA released by the injured peri- fibrinolytic capacity and may have a peritoneal wound healing because it toneum and the result of quenching role in preventing the early dissolu- has a specific affinity for fibrin that any remaining tPA activity by PAI- tion of fibrinous adhesions.37 In vivo uPA lacks; it is responsible for 95% of 1.25,32 The importance of tPA and evidence for a role of TGF-β in pro- the plasmin generated in the response PAI-1 in adhesion formation is fur- moting adhesion formation comes to peritoneal injury.31 There is also a ther supported by studies in which it from studies using an animal model group of glycoproteins that act as in- was discovered that patients with the of surgically induced adhesions, in hibitors of fibrinolysis and are collec- most sever