Peritoneal Adhesions: Etiology, Pathophysiology, and Clinical Significance

Transcription

1 Review Dig Surg 2001;18: Peritoneal Adhesions: Etiology, Pathophysiology, and Clinical Significance Recent Advances in Prevention and Management Theodoros Liakakos a Nikolaos Thomakos c Paul M. Fine c Christos Dervenis b Ronald L. Young c a 3rd Academic Department of Surgery, University of Athens Medical School, Athens, and b 1st Department of Surgery, Konstantopoulion Agia Olga Hospital, Athens, Greece; c Department of Obstetrics and Gynecology, Division of Gynecology, Baylor College of Medicine, Houston, Tex., USA Key Words Adhesions, pathophysiology W Pelvic surgery W Prevention/treatment, adhesions Abstract Aim: To summarize the most common etiologic factors and describe the pathophysiology in the formation of peritoneal adhesions, to outline their clinical significance and consequences, and to evaluate the pharmacologic, mechanical, and surgical adjuvant strategies to minimize peritoneal adhesion formation. Methods: We performed an extensive MEDLINE search of the internationally published English literature of all medical and epidemiological journal articles, textbooks, scientific reports, and scientific journals from 1940 to We also reviewed reference lists in all the articles retrieved in the search as well as those of major texts regarding intraperitoneal postsurgical adhesion formation. All sources identified were reviewed with particular attention to risk factors, pathophysiology, clinical manifestations, various methods, and innovative techniques for effectively and safely reducing the formation of postsurgical adhesions. Results: The formation of postoperative peritoneal adhesions is an important complication following gynecological and general abdominal surgery, leading to clinical and significant economical consequences. Adhesion occur in more than 90% of the patients following major abdominal surgery and in % of the women undergoing pelvic surgery. Small-bowel obstruction, infertility, chronic abdominal and pelvic pain, and difficult reoperative surgery are the most common consequences of peritoneal adhesions. Despite elaborate efforts to develop effective strategies to reduce or prevent adhesions, their formation remains a frequent occurrence after abdominal surgery. Conclusions: Until additional information and findings from future clinical investigations exist, only a meticulous surgical technique can be advocated in order to reduce unnecessary morbidity and mortality rates from these untoward effects of surgery. Introduction Copyright 2001 S. Karger AG, Basel Adhesion formation after abdominal and pelvic operations remains extremely common and is a source of considerable morbidity. Adhesion formation occurs following any procedure, including cholecystectomy, gastrectomy, appendectomy, hysterectomy, colectomy, abdominoperineal resection, and abdominal vascular operations. ABC Fax karger@karger.ch S. Karger AG, Basel /01/ $17.50/0 Accessible online at: Christos Dervenis, MD 1st Department of Surgery Konstantopoulion Agia Olga Hospital 3 5 Agias Olgas Street Athens (Greece)

2 The incidence of intraperitoneal adhesions ranges from 67 to 93% after general surgical abdominal operations and up to 97% after open gynecologic pelvic procedures [1 3]. In clinical and autopsy studies of patients who had prior laparotomies, the incidence of intra-abdominal adhesions was 70 90% [4, 5]. Adhesions may be classified as either congenital or acquired [6]. Congenital adhesions are present from birth as embryological anomaly in the development of the peritoneal cavity (vitellointestinal bands, adhesions seen across the lesser sac). Acquired adhesions are subdivided into inflammatory or postsurgical. Inflammatory adhesions arise after intra-abdominal inflammatory processes, such as appendicitis, acute cholecystitis, acute diverticulitis, pelvic inflammatory disease, and the previous use of an intrauterine contraceptive device. The true proportion of each of these types is not known, but it has been reported [7] that the majority of adhesions are postsurgical. Postsurgical adhesions are a consequence resulting when injured tissue surfaces, following incision, cauterization, suturing or other means of trauma, fuse together to form scar tissue. Recently, it was found [8] that all patients who had undergone at least one prior abdominal surgery developed one to more than ten adhesions. Factors associated with the formation of postsurgical adhesions include trauma, thermal injury, infection, ischemia, and foreign bodies. Multiple other factors, including tight suturing, where tension within the sutured peritoneum produces ischemia, abrasions, exposure to foreign bodies such as talc and powders from gloves, lint from abdominal packs, or fibers from disposable paper items, reactive sutures, intestinal contents, overheating by lamps, or irrigation fluid, may contribute to postoperative adhesion formation [6, 9, 10]. Such adhesions often contain multiple foreign body granulomas. This suggests a relationships between foreign material, foreign-body granulomas, and adhesion formation. Microscopic examination of adhesions showed in a large proportion both suture and starch granulomas. Suture granulomas are often found in patients who recently underwent surgery [8]. Clinical Significance Importance and Complications from Intraperitoneal Adhesions Postsurgical adhesions severely affect the quality of life of millions of people worldwide, causing small-bowel obstruction [6, 7, 9 11], difficult reoperative surgery [12], chronic abdominal and pelvic pain [13], and female infertility [14]. Complications and risks for those patients with postoperative adhesions after surgical procedures are substantial. Adhesions form between the wound and the omentum in over 80% of the patients, and they may involve the intestines in 50% of the patients [1]. Intra-abdominal adhesions are almost inevitable after major abdominal surgery. Reoperating through a previous wound can be extremely difficult, risky, and potentially dangerous. Also, adhesiolysis extends operating time, anesthesia, and recovery time and causes additional risks to the patient such as blood loss, visceral damage including injury to the bladder, enterocutaneous fistulas, and resection of damaged bowel [15]. Adhesions are the most common cause of large and small intestinal obstructions in the Western world and account for approximately one third to one half of all intestinal and for 60 70% of the small-bowel obstructions [9, 16]. Congenital or inflammatory adhesions rarely give rise to intestinal obstructions, except for malrotation [17]. However, between 49 and 74% of the small-bowel obstructions are caused by postsurgical adhesions [6, 13, 18]. Small-bowel obstructions from adhesions are responsible for a large proportion of general surgical admissions and unavoidable operations in current surgical practice. Approximately 1% of all surgical admissions and 3% of laparotomies are the result of intestinal obstruction from adhesions [1]. In pediatric patients bowel obstruction from adhesions is most prevalent; 8% of the neonates undergoing abdominal surgery require a future laparotomy for this complication [19]. Extensive soft adhesions will form within 72 h after laparotomy. These seem most extensive at about 10 days to 2 weeks, by which time they become dense and vascular. Over 20% of adhesive obstructions occur within 1 month of surgery, and up to 40% occur within 1 year [6]. Obstruction by adhesions is usually the result of kinking or angulation or by creating bands of tissue that compress the bowel [20]. Impairment of the local circulation of the small intestine due to strangulation is caused by adhesions in 30% of the cases. Patients presenting with strangulated or gangrenous obstructions have overall mortality rates ranging between 6 and 8% after different surgeries [21]. At long-term follow-up, about 5% of the patients who underwent laparotomy develop adhesive obstruction; 10 30% of these will suffer additional episodes [16]. Although it is not clear how often adhesive obstruction recurs after conservative or surgical treatment, it is well known that adhesions create a lifetime risk of intestinal obstruction. An operation for obstruction due to adhe- Adhesions: Pathogenesis and Prevention Dig Surg 2001;18:

3 sions carries a higher likelihood of recurrence than a laparotomy for other indications. When obstruction recurs, the possibility of a cause other than adhesions is lower, and according to recent surveys, there is more justification for a nonoperative management without surgical intervention [20]. The problem of postsurgical adhesions increases with the patient s age, the number of laparotomies, and the complexity of surgical procedures [21]. The number of prior episodes a patient has experienced is the strongest predictor of recurrence. Operative strategies appear useful for patients experiencing second episodes, but nonoperative management for patients in a stable condition during their first episode appears reasonable [22]. Simple adhesive obstruction may be resolved without surgical intervention in the majority of the cases, in contrast to other forms of obstruction. According to recent series, up to 80% of episodes of partial small-bowel obstruction caused by adhesions resolve nonoperatively [16]. The operations that frequently lead to adhesive obstruction include colon and rectal surgery, gynecologic procedures, and nonelective appendectomy. Patients with a relatively low risk of adhesion formation are those who have undergone an elective appendectomy through a small incision or a cesarian section via a Pfannenstiel incision [17]. Prior laparotomy through a midline vertical incision has significantly increased the frequency of anterior abdominal wall adhesions. These adhesions may later cause injury to bowel or omentum during laparoscopic cannula insertion through the umbilicus [23]. Adhesions more likely to become obstructive are those involving the small intestine; however, intestinal adhesions occur less frequently than those involving the omentum. Most of the patients with adhesive intestinal obstructions have been found to have had surgery in the infracolic part of the abdomen, where the loops of small intestine adhere and become obstructed [17]. Gynecologic Considerations and Sterility Postoperative adhesions are an important topic for gynecologic surgeons, gynecologic oncologists, and those who treat infertile women. The gynecologist has a significant role in the management of conditions that may later result in adhesion formation. Gynecologic and obstetric events have been a major source of intraperitoneal adhesions. Gynecologists manage more than 20% of all female patients with intestinal obstruction. It has been reported that abdominal hysterectomy is among the most commonly performed operations contributing to intestinal obstruction associated with postoperative adhesions [18]. Myomectomy is associated with a high degree of adnexal adhesions, especially after incision performed on the posterior uterine wall [24]. Surgical treatment of gynecologic malignancy, such as ovarian cancer debulking surgery, may commonly be associated with intestinal obstruction either by persistent tumor growth or by postoperative adhesions [13, 25, 26]. Extensive pelvic surgery, such as radical hysterectomy and pelvic exenteration, has been documented to cause postoperative adhesions and subsequent small-bowel obstruction. The incidence of adhesions can increase with postoperative radiation therapy [27 29]. Also, postoperative adhesions have been implicated in inadequate distribution of chemotherapeutic regimens when they are given interaperitoneally for treatment of ovarian carcinoma [30]. Voiding dysfunction and nonspecific gastrointestinal complaints have been associated with postgynecologic surgery adhesion formation. Endometriosis, one of the most common causes of pelvic pain and infertility in women of reproductive age [14], is associated with fibrous adhesion formation following conservative surgical procedures and excision of ovarian endometriomas. Fibrous adhesions often form as a response to chronic irritation of the peritoneal surface by the endometriotic implant and its secretory products. Fifteen to 20% of female infertility is caused by adhesions [8]. Pregnancy rates are increased by 38 to 52% among previously infertile patients following laparotomy with adhesiolysis [31]. Paraovarian peritubal adhesions inhibit follicular growth [32] by possible ovarian entrapment from adhesions around the ovaries. Induction of ovulation during assisted reproductive technologies, such as in vitro fertilization and embryo transfer, were found to fall in a larger percentage of patients with severe postinflammatory adhesions [33]. Peritubal as well as intratubal adhesions may affect tubal motility and ovum transport. The slowing of or preventing the embryo from reaching the uterus may lead to either infertility or an ectopic pregnancy. Ectopic pregnancies have been implicated as possible sequelae of peritubal or intratubal adhesions. Infertility may be caused not only by tubal dysfunction but also by adhesion formation following treatment of an ectopic gestation either by laparotomy or laparoscopy [34]. Chronic pelvic pain is one of the sequelae of intraperitoneal adhesions [35]. Pelvic adhesive diseases, either postoperative or from pelvic inflammatory reactions, and endometrioses are the most common morphologic changes seen in women with pelvic pain [35]. They were thought to be caused from increased tension, stretching, 262 Dig Surg 2001;18: Liakakos/Thomakos/Fine/Dervenis/Young

4 and traction of pelvic organs which stimulate peritoneal pain receptors and from the restriction of the mobility or expansibility of pelvic organs [36, 37]. Analysis of eleven studies showed that adhesions were the most common pathology in patients suffering from pelvic pain [31]. The association between adhesions and pain is well supported by relief and reduction of pain following adhesiolysis in 60 90% of the cases [35]. Pelvic pain in patients with endometriosis is due to adhesion formation which results in nerve injury, tissue destruction, and scar formation. Laparoscopy There has been considerable work done for adhesion formation after laparoscopy. Laparoscopic surgery with the development of endoscopic techniques seems to be less traumatic on the serosal surfaces, causing less reaction and less adhesions. But, on the other hand, the laparoscopic instruments appear to cause at least as much intra-abdominal trauma as do the surgeon s fingers in laparotomy [10]. At the time of early second-look laparoscopy in women after reproductive pelvic surgery by laparotomy, numerous studies have described postoperative adhesions both de novo and recurrent in % of the patients, despite using microsurgical techniques, surgical adjuvants, and lasers [3]. It does not appear that laparoscopic adhesiolysis results in a greater reduction of postoperative adhesion reformation than is able to be achieved by laparotomy [3]; however, it has been hypothesized in a rabbit study that laparoscopic lysis of adhesions was associated with significant reduction in adhesion scores [38]. De novo adhesion formation after operative laparoscopy has been reported to occur in only 12% the of cases versus 50% after laparotomy [3, 39, 40]. However, laparoscopic reproductive pelvic surgery as compared with laparotomy procedures has been shown in various animal and clinical studies to result in less recurrent and the novo adhesion formation [14]. (De novo adhesions are observed at the time of early second-look procedures at sites within the pelvis that did not have adhesions at the time of initial laparotomy.) The benefits of laparoscopy in reduction of adhesion formation have been demonstrated in the surgical treatment of ectopic pregnancy, where it was found that the incidence of periadnexal adhesions was significantly less after laparoscopic surgery as compared with laparotomy [41]. Also, after laparoscopic myomectomy, adhesion formation appears to be less than after the same operation by laparotomy [42, 43]. Pathogenesis and Biochemical Events in Adhesion Formation Peritoneal healing differs from that of skin. Skin reepithelialization takes place through proliferation of epithelial cells from the periphery toward the center of the skin wound. By contrast, the peritoneum becomes mesothelialized simultaneously, and regardless of the size of the injury, with new mesothelium developing from islands of mesothelial cells which later proliferate into sheets of cells. Consequently, large skin injuries take longer to reepithelialize than do small skin injuries. Larger peritoneal wounds remesothelialize about as quickly as small peritoneal wounds, within 5 6 days for the parietal peritoneum and within 5 8 days for both the visceral mesothelium covering the terminal ileum and the mesothelial layer of the parietal peritoneum [21, 31]. The key site in adhesion formation is the surface lining of the peritoneum. The delicacy of the peritoneal surface and its subsequent susceptibility to damage as well as the rapid rate of remesothelialization within 5 8 days are important factors in adhesion formation. Injury or inflammation of the peritoneum triggers a coagulative state at the beginning of postsurgical peritoneal repair that releases multiple chemical messengers at the injury site that lead to a series of events. Leukocytes, mesothelial cells, and fibrin play a major role in this cascade of events. Also present in the peritoneal cavity prior to surgery is a small amount of fluid that contains macrophages and plasma proteins containing a large amount of fibrinogen [31, 44, 45]. Following surgery, the macrophages increase in number and change function. These postsurgical macrophages are entirely different from the resident macrophages and secrete variable substances, including cyclooxygenase and lipoxygenase metabolites, plasminogen activator, plasminogen activator inhibitor (PAI), collagenase, elastase, interleukins (IL) 1 and 6, tumor necrosis factor (TNF), leukotriene B 4, prostaglandin E 2 etc. [10, 44, 45]. Postsurgical intraperitoneal macrophages recruit new mesothelial cells onto the surface of the injury. These mesothelial cells later and in response to cytokines and other macrophage-secreted mediators form small islands which proliferate into sheets of mesothelial cells on the injured area which will lead to peritoneal remesothelialization [6]. The organization of the fibrin gel matrix is of major importance in adhesion formation. This matrix forms in several steps, beginning from fibrinogen to fibrin monomer, then to soluble fibrin polymer, and finally through Adhesions: Pathogenesis and Prevention Dig Surg 2001;18:

5 rinsing tissues with irrigating solutions (during surgery) becomes insoluble fibrin polymer. This last product interacts with proteins, including fibronectin, to form the fibrin gel matrix. A number of different amino acids is involved in this last interaction and is the basis of much new research in adhesion prevention. The fibrin gel matrix includes leukocytes, erythrocytes, platelets, endothelium, epithelium, mast cells, and cellular and surgical debris. Two damaged peritoneal surfaces coming into apposition while covered with fibrin gel matrix may form an adhesion, not only at the time of surgical injury, but also during the next 3 5 days [31]. Peritoneal fibrinolytic activity has been hypothesized to play an important role in the pathophysiology of adhesiogenesis [46]. Tissue plasminogen activator (tpa) found in mesothelial cells is an important natural defense against postsurgical adhesion formation. The active enzyme plasmin, which is produced from the inactive plasminogen by the tpa and the urokinase-type plasminogen activator, degrades the fibrin gel matrix into fibrin split products which have no effect on adhesion formation. Fibrinous adhesions are lysed, if local fibrinolysis is sufficient; however, if inadequate, may lead to connective tissue formation and adhesion development [46]. A strong correlation between hypofibrinolytic activity and increased adhesion formation has been demonstrated in animal studies. Reduced plasminogen activator activity from surgical trauma in rabbits and correction by fibrinolytic activation with recombinant tpa (rtpa) was shown to prevent the formation of fibrinous adhesions to both the injured bowel and the parietal peritoneum, confirming the significant role of fibrinolysis in adhesion formation [46]. At sites of surgical or inflammatory injury, increased levels of PAI 1 and PAI 2 prevent tpa and urokinase plasminogen activator from stimulating plasmin to remove the fibrin gel matrix. Inadequate blood supply and reduced tissue oxygenation, occurring frequently with surgical injury, inhibit fibrinolysis and decrease fibrinolytic activity, allowing the fibroproliferative structure to persist, leading to fibrovascular adhesion development [31, 47]. Various other traumatic factors such as ischemia caused by grafting or suturing of peritoneal defects, the use of retractors by their mechanical effects of pressure, crushing, stripping, excessive handling of the peritoneum, the presence of foreign materials (starch powder), inflammation-induced peritonitis, intraperitoneal blood, and serosal drying can inhibit fibrinolysis and lead to adhesion formation [46, 48, 49]. Finally, adhesions will mature into fibrous bands containing collagen, elastin fibers, and blood vessels and may be lined by mesothelial cells [5]. Adhesion formation at the molecular level constitutes a complex interaction of cytokines, growth factors, components secreted by platelets, macrophages, and other cells at or near the injured area. More studies and research are needed in order to unterstand clearly all these factors and their interrelationships in the process of adhesion formation. Management and Strategies for Adhesion Prevention The need to reduce the development of postoperative surgical adhesions is pronounced. More than 440,000 procedures for abdominopelvic peritoneal adhesiolysis are performed each year [50] in the United States, creating a serious health risk to patients at a cost of more than 1.2 billion annually [51]. Propensity to form adhesion appears to be patient specific. Various individual factors such as nutritional status, disease states like diabetes, and the presence of concurrent infectious processes, which alter leukocyte and fibroblast function, affect adhesion formation [52]. In the search for effective methods for preventing adhesions, a variety of clinical techniques and agents have been advocated for the prevention of both primary and secondary postoperative adhesion formation. The main approaches in preventing adhesions include adjusting surgical techniques, limiting trauma to intra-abdominal structures, and applying adjuvants to decrease adhesion formation [53]. Postsurgical coalescing adhesions will form only when both contacting peritoneal surfaces have been traumatized during surgery. Methods, which minimize peritoneal trauma, and the exclusion of foreign-body material from the abdominal cavity may lead to less adhesion formation. Halstedian principles of gentle tissue handling and meticulous hemostasis are necessary to avoid the presence of free blood and ischemic tissues which provide a source of fibrin and also result in adhesion formation by releasing thromboplastin with subsequent activation of the clotting cascade. Other effective measures include careful and delicate handling of the bowel in order to reduce severe trauma, keeping tissues moist with irrigation, avoiding large abdominal wounds and unnecessary dissection, and using micro and atraumatic instruments to reduce serosal injury. Adjuvant therapy falls into two main categories: administering drugs that alter the adhe- 264 Dig Surg 2001;18: Liakakos/Thomakos/Fine/Dervenis/Young

6 sion-producing inflammatory cascade and separating serosal surfaces during the early stages of wound repair with barriers [54]. Surgical Techniques The relationships between surgical techniques and adhesion formation are shown in table 1. Tissue Injury During surgical procedures the peritoneum is susceptible to crush, thermal, electrical, laser, mechanical, hypoxic, and strangulation injury, resulting in denudation of the superficial mesothelial layer. Disrupting the underlying connective tissue and associated microvasculature elicits the inflammatory response, depresses fibrinolytic activity, and promotes adhesion formation [55]. Surgeons should pursue general principles of atraumatic, gentle, and bloodless surgery during either laparoscopy or laparotomy. Forceps, retractors, and clamps should not be placed on structures not intended for dissection, reducing serosal denudation and vascular trauma. Peritoneal Suturing Considerable experimental evidence indicates that peritoneal suturing increases adhesion formation [56]. Grafting or suturing of peritoneal defects increases ischemia, devascularization, and necrosis, predisposing the site to decreased fibrinolytic activity and increased adhesion formation [57]. The presence of suture material and tightening the sutures to the point of ischemia potentiate adhesion formation [8]. The suture materials elicit foreign-body reactions of varying degrees. Braided versus monofilament sutures contain microscopic pores that can harbor bacteria and lead to infection. A catgut suture, though rapidly absorbed, leads to greater tissue reaction, whereas polyglycolic acid derivatives and monofilament synthetics are less reactive [55]. Numerous studies show no significant differences in complications, wound healing, and adhesions to the laparotomy incisions with or without parietal peritoneal closure by suturing when evaluated by second-look laparoscopy. Current data support improved outcome with nonclosure of the peritoneum. Peritoneal closure may induce ischemia and adhesion formation. It is thus unnecessary during closure of abdominal wounds and especially in the presence of intraperitoneal bacterial contamination or infection which may result in postoperative peritoneal adhesions. Regrowth of peritoneum from mesothelial cells occurs within h. Table 1. Surgical techniques 1 Tissue injury 2 Peritoneal suturing 3 Foreign material 4 Sponges 5 Intraperitoneal blood deposits 6 Minimally invasive surgery Areas at higher risk of adhesion development may be covered with omentum, peritoneal flaps, falciform ligament, and broad ligament. In infertility patients and those in whom preservation of childbearing potential is desirable, in order to minimize adnexal or peritubal adhesions, it is sometimes necessary to reapproximate the peritoneum with 3 0 or 4 0 nonreactive absorbable sutures without producing significant tension. The practice of omitting the closure of the peritoneum is well supported in the literature [18, 58 61]. Foreign Materials Foreign materials such as glove powder (talc and starch), fluff from surgical packs (gauze lint), sutures, and material extruded from the digestive tract cause peritoneal inflammatory reaction. This inflammatory response potentiates adhesion formation with multiple foreignbody granulomas, suggesting a strong relationship between foreign material, foreign-body granulomas, and adhesion formation. Using powder-free gloves should prevent starch granuloma-induced adhesions. Interestingly, powdered gloves when washed can lead to clumping of starch granules, generating more intense tissue reaction [8]. Sponges A recognized association exists between adhesion formation and use of sponges in the peritoneal cavity. Wetting of sponges is performed routinely to prevent de novo adhesion formation when using sponges in the abdominal cavity, but controversy exists over the benefits of this technique [21]. When the bowel needs to be packed outside of the operative field, an atraumatic bag might reduce injury to the serosa [21]. Intraperitoneal Blood Deposits The presence of intraperitoneal blood deposits in inducting adhesions is still controversial. In animal models large clots produced adhesion, but small clots did not in Adhesions: Pathogenesis and Prevention Dig Surg 2001;18:

7 Table 2. Drugs 1 NSAIDs 2 Corticosteroids 3 Antihistamines 4 Progesterone/estrogen 5 Anticoagulants 6 Fibrinolytics 7 Antibiotics the absence of peritoneal injury [62]. Hemostasis is essential, and blood should be aspirated in irrigation solution. If pinpoint electrocautery cannot provide adequate hemostasis, then the smallest gauged synthetic suture should be used, with special consideration to avoid tissue strangulation [63]. Minimally Invasive Surgery Using minimally invasive/laparoscopic surgical techniques should be encouraged, since de novo adhesion formation occurs more frequently in patients undergoing laparotomy. Adhesion reformation can occur with laparoscopy, and it has not been shown that laparoscopy is superior to microsurgical adhesiolysis at the time of laparotomy in terms of subsequent pregnancy rates. A policy, during operations for small-bowel obstruction, of dividing only those adhesions that are either obstructing the bowel or hindering the surgeon, appears prudent. Pharmacological Adjuvant Therapy Pharmacological agents (table 2) can be directed against various causes and components of the inflammatory process (e.g., infection, endotoxin, exudation) and/or of adhesion formation (e.g., coagulation, fibrin deposition, and fibroblastic activity and proliferation). A number of obstacles must be surmounted before agents can be used in adhesion prevention. First, ischemic sites are vulnerable to adhesion formation, but are cut off from the bloodstream and, therefore, from systemic drug delivery. Second, the peritoneal membrane has an extremely rapid absorption mechanism, limiting the half-life and efficacy of many intraperitoneally administered agents. Third, any antiadhesion agent needs to act specifically against adhesion formation and not normal wound healing processes; these processes of adhesion formation and remesothelialization use the same cascade (exudation, coagulation, fibrin deposition, and fibroblastic activity and proliferation) [53]. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) NSAIDs alter arachidonic acid metabolism by changing cyclooxygenase activities, inhibiting the formation of end products, including prostaglandins and thromboxane. By inhibiting prostaglandin and thromboxane synthesis, NSAIDs decrease vascular permeability, plasmin inhibitor, platelet aggregation, and coagulation and enhance macrophage function. NSAIDs modulate a number of aspects of inflammation and have reduced peritoneal adhesion formation in many, but not all, animal models [5, 53, 64, 65]. Glucocorticoid and Antihistamine Therapy Corticosteroid therapy attenuates the inflammatory response by reducing vascular permeability and liberation of cytokines and chemotactic factors. This therapy is met with mixed results [53]. Corticosteroids, such as dexamethasone, hydrocortisone, and prednisolone, were studied alone or with antihistamines, such as promethazine, by intraperitoneal administration [64 66]. Antihistamines, often used in conjunction with glucocorticoids, inhibit fibroblast proliferation. Potential side effects, initiated by immunosuppression and delayed wound healing (e.g., infection, incisional hernia, and wound dehiscence), argue that these agents should be used with extreme caution [44, 53, 62, 64 66]. Progesterone/Estrogen Progesterone shows a decreased adhesion formation in animal models. Human studies have either failed to confirm this finding or noted an increase in adhesion formation when medroxyprogesterone acetate was used intramuscularly or intraperitoneally [64, 65]. Estrogen has been associated with increased adhesions in animal models. In animal studies fat necrosis and fibrotic changes were found less often in anestrogenic subjects. Primates treated with gonadotropin-releasing hormone agonists formed fewer adhesions than untreated animals, implicating estrogen in promoting adhesion formation. It remains unknown whether a hypoestrogenic state leads to less postsurgical adhesions in humans [67]. Anticoagulants Crystalloid isotonic irrigation containing heparin sulfate reduces intra-abdominal adhesion formation by inhibiting fibrin coagulation. But this use of heparin was associated with hemorrhages and delayed wound healing. Low-dose intraperitoneal heparin irrigation (2,500/5,000 U/l) showed no benefit in adhesion reduction [44, 57, 64, 65]. 266 Dig Surg 2001;18: Liakakos/Thomakos/Fine/Dervenis/Young

8 Fibrinolytics Fibrinolytic agents caused hemorrhagic complications, although recombinant tpa, when applied locally, reduced adhesions in animal models without increasing complication rates [44, 62, 64, 65]. A promising approach in postsurgical adhesion prophylaxis was described with the use of tpa. The effectiveness of rtpa with production of tpa by recombinant DNA techniques has been investigated in the prevention of initial as well as recurrent adhesion formation in animal studies. As discussed earlier, decreased plasminogen activator activity is believed to be a possible pathogenic factor in the development of adhesions. In experimental models, this activity has been reduced in the presence of thermal or mechanical trauma, ischemia, and inflammatory factors known to lead to adhesion formation. Although the administration of rtpa succeeded in reducing adhesion formation when studied in a rabbit model, continued research is needed to establish safety and effectiveness of rtpa use in human subjects. The evidence from clinical and animal trials suggests that all these approaches have had only limited success, impeded by lack of safety, efficacy, and many adverse effects without eliminating the problem of postoperative adhesion formation [6, 11, 68 70]. Antibiotics Broad-spectrum antibiotics are commonly used for prophylaxis against postoperative infections and adhesion formation. Antibiotics in intra-abdominal irrigation fluid actually caused adhesion formation and are not recommended as a single agent for adhesion prevention [64, 65]. Adjuvant Barrier Therapy Antiadhesion barriers basically fall under two main categories: macromolecular solutions and mechanical devices (table 3). In recent years both kinds of barriers have demonstrated real progress in adhesion prevention [5, 53]. The ideal barrier, besides being safe and effective, should be noninflammatory, nonimmunogenic, persist during the critical remesothelialization phase, stay in place without sutures or staples, remain active in the presence of blood and be completely biodegradable. In addition, it should not interfere with healing, promote infection, nor cause adhesions. Barrier Solutions Crystalloids. Absorption of water and electrolytes from the peritoneal cavity is rapid, with up to 500 ml of isosmo- Table 3. Barriers Solutions 1 Crystalloids 2 32% dextran 70 3 Hyaluronic acid 4 HA-PBS/Sepracoat 5 Carboxymethylcellulose Solids 1 Autologous peritoneal transplants 2 PTFE (Gore-Tex) 3 Oxidized-regenerated cellulose (Interceed) 4 HA-CMC (Seprafilm) lar sodium chloride absorbed in less than 24 h [71]. Because it takes 5 8 days for peritoneal surfaces to remesothelialize, a crystalloid solution should be absorbed well before the processes of fibrin deposition and adhesion formation are complete. From a theoretical point of view, intraperitoneal crystalloid instillates are not expected to prevent adhesion formation. Studies have shown an adhesion reformation rate of approximately 80% in patients who received crystalloid instillates [21, 72]. Whether used in surgery performed by laparotomy or laparoscopy, the risks of leaving large volumes of fluid in the peritoneal cavity after surgery may substantially reduce the ability of the host to eliminate infection. Increasing the intraperitoneal volume facilitates the accumulation of Escherichia coli by retarding the clearance of E. coli from the peritoneal cavity. Animal studies have shown that increasing the delivery of fluid contaminated with bacteria from 1 to 10 ml in the rat peritoneum increases the lethality from 20 to 60%. Dilution of opsonic proteins and increasing the surface area, on which phagocytes can trap and ingest unopsonized bacteria, and a decrease of the phagocyte-to-bacteria ratio by increasing the intraperitoneal volume are theorized as the basis for this increased morbidity. Decreasing the ratio of phagocyte-to-bacteria or diluting the opsonin source diminishes phagocytosis. Leaving large volumes of crystalloid in the peritoneal cavity after surgery may not benefit the patient s postoperative course [21, 73]. The postsurgical peritoneal cavity is acidic, and consideration should be given to the irrigation solution used in surgery [21, 73]. Ringer s lactate is safe, inexpensive, readily available, and has a better buffering capacity than normal saline. Intraperitoneal instillation of lacted Ringer s solution in animal models decreases adhesion formation and reformation [74, 75]. The mechanism of action is Adhesions: Pathogenesis and Prevention Dig Surg 2001;18:

9 unclear, but it seems that the presence of a great volume of Ringer s lactate in the abdominal cavity separates raw peritoneal surfaces and prevents adhesion formation. It is also possible that Ringer s lactate cleanses the newly formed fibrin exudate that can serve as a matrix for fibroblast and capillary formation. This initial fibrin, if not removed by fibrinolysis or absorption, produces an inflammatory response, fibroblast proliferation, and adhesion formation. But this solution is rapidly absorbed. The efficacy of Ringer s lactate in clinical situations has not been clinically proven [67]. 32% Dextran % dextran 70 (Hyskon, Pharmacia, Uppsala, Sweden), is a frequently used solution for adhesion prevention. By hydroflotation of intra-abdominal structures with the dextran solution, a physiological separation occurs between peritoneal surfaces [5, 66]. Through dilution, dextran diminishes local fibrin concentration, preserves local plasminogen activators, and interferes with polymorphonuclear neutrophil expression of adhesion molecules [6, 66]. The dextran solution is slowly absorbed and draws fluid into the abdominal cavity. It also decreases clot formation [62, 64 66]. Follow-up studies of the initial observation did not show a reduction in adhesions [5, 66]. Moreover, significant side effects, such as ascites, weight gain, pleural effusion, labial edema, liver function abnormalities, and, albeit rare, disseminated intravascular coagulation and anaphylaxis, were noted [5]. Although instillation of high-molecular-weight dextran (32% dextran 70) was popular, the results have been inconsistent [76]. Hyaluronic Acid (HA). HA is a naturally occurring glycosaminoglycan and a major component of the extracellular matrix, including connective tissue, skin, cartilage, and vitreous and synovial fluids. HA is biocompatible, nonimmunogenic, nontoxic, and naturally bioabsorbable. Like carboxymethylcellulose, it is negatively charged at physiological ph and freely soluble [21]. HA coats serosal surfaces and provides a certain degree of protection from serosal desiccation and other types of injury. However, its use after tissue injury is ineffective [67, 77]. HA Combined with Phosphate-Buffered-Saline (HA- PBS). HA has been combined with PBS into a macromolecular solution to prevent adhesion formation, called Separacoat (Genzyme, Cambridge, Mass., USA). HA- PBS is applied intraoperatively, prior to dissection, to protect peritoneal surfaces from indirect surgical trauma (e.g., abrasion and desiccation) rather than postoperatively to separate surfaces after they are traumatized [78]. In animal models, this solution effectively reduced serosal damage, inflammation, and postsurgical adhesions [78]. In human studies HA-PBS solution safely and significantly decreased incidence, extent, and severity of de novo adhesion in multiple sites indirectly traumatized by complex, multiple gynecologic pelvic procedures via laparotomy [79]. Carboxymethylcellulose. Carboxymethylcellulose is a derivative of cellulose. Carboxymethylation of the glucosidic hydroxyl groups makes the polymer hydrophilic. It is negatively charged at physiological ph and freely soluble. Clearance is less clear than that of HA, but it is spontaneously broken down. Carboxymethylcellulose works by separating raw surfaces and allowing independent healing of traumatized peritoneal surfaces [21, 67]. Solid Barriers Autologous Peritoneal Transplants. Experimental studies have demonstrated that covering lesions of the parietal peritoneum with microsurgically applied autologous peritoneal transplants can completely prevent severe adhesion formation. More significantly was the decrease of visceral peritoneal adhesions with the use of autologous peritoneal transplants, i.e., injuries to the serosa of the uterine horn. This suggests that the risk is higher for adhesion formation stemming from the visceral than from the parietal peritoneum after gynecologic surgery. The visceral peritoneum should be generally covered at the conclusion of surgery, either with autologous peritoneal grafts or a synthetic barrier. The advantage of a synthetic barrier is that the material does not need to be obtained surgically and can be cut to size outside of the abdomen and then applied without sutures [80]. Synthetic Solid Barriers A great number of natural and synthetic graft materials have been employed in an effort to reduce adhesion formation on traumatized surfaces. Natural materials have included peritoneum, omentum, HA, fat, amnion, as well as amnion plus chorion [10, 81 92]. Synthetic materials, including polyvinyl alcohol film and tantalum foil, were used in the past [84, 93]. Recently, interest has focused on mechanical barriers placed over traumatized tissues at the conclusion of surgery, in order to separate tissue surfaces. Such synthetic barriers included Gelfilm and Gelfoam paste (Upjohn, Kalamazoo, Mich., USA), Surgicel (Johnson & Johnson, New Brunswick, N.J., USA), Silastic (Dow-Corning, Midland, Mich., USA), meshes of polytetrafluorethylene (PTFE, Gore-Tex ; Gore & Associates, Flagstaff, Ariz., USA), Interceed (TC7) oxidized regenerated cellulose (ORC; Johnson & Johnson), and Seprafilm bioresorbable membrane chemically deriva- 268 Dig Surg 2001;18: Liakakos/Thomakos/Fine/Dervenis/Young

10 tized sodium hyaluronate and carboxymethylcellulose (HA-CMC; Genzyme) [10, ]. Gore-Tex. Expanded PTFE is a nonreactive, antithrombogenic, nontoxic synthetic fabric with small pores that inhibit cellular transmigration and tissue adherence. The use of PTFE is strictly reserved for noncontamination operations. When placed over traumatized tissue it has been shown to reduce adhesion formation [104]. A PTFE barrier prevents adhesion formation and reformation regardless of the type of tissue injury or whether hemostasis is achieved. Expanded PTFE was found to decrease postmyomectomy adhesions and pelvic sidewall adhesions in a randomized study [101]. It was found that expanded PTFE was associated with fewer postsurgical adhesions to the sidewall than oxidized-regenerated cellulose [105]. The use of PTFE in laparoscopy is cumbersome and not easy to handle [67]. PTFE also needs to be secured in place physically and is nonabsorbable. Therefore, it must be either left in place permanently or removed surgically. Whether it is necessary to remove the PTFE barriers when placed in such a manner that the adnexal anatomy is not distorted remains to be determined. PTFE is one of the least reactive polymers and causes little or no morphologic alterations to the adjacent peritoneum and resists chemical and biological degradation even after several years in vivo. However, it generates the formation of pseudocapsules. PTFE has also been successfully used in cardiovascular surgery as a pericardial patch with minimal adhesion formation and foreign-body reaction [67, ]. The very act of removal involves some degree of surgical trauma which might lead to adhesion formation. Laparoscopic removal should minimize the surgical trauma. Fragments of the PTFE membrane remain attached to the peritoneum after barrier removal, but they do not lead to adhesion formation in animal models. While a small amount of bleeding at the suture sites may occur at removal, incomplete hemostasis does not alter the effectiveness of PTFE barriers. Theoretically, the barrier removal itself most likely will occur at the time of repeat cesarean section after a myomectomy in which a PTFE barrier was used to prevent adhesion formation [105]. Interceed. ORC is the only adjuvant approved for the specific purposes of postsurgical adhesion prevention. ORC has been shown in both animal and human studies to reduce adhesion formation by forming a barrier and physically separating adjacent raw peritoneal surfaces, preventing adhesion development between these surfaces. ORC appears to decrease adhesion formation-reformation beyond that achieved with meticulous surgical technique. ORC reduces both raw surface area and the occurrence of adhesion formation-reformation by a margin of 20%. When applied to a raw peritoneal surface, it becomes gel within 8 h [44, 53, 66, 107]. ORC can be applied easily by laparoscopy, follows the contour of the organ, and does not need suturing. It is essential that complete hemostasis is achieved before ORC is placed on the peritoneal surface, as the presence of intraperitoneal blood negates any beneficial effect [108]. Clinical observation indicates that small amounts of bleeding at the time that ORC is applied results in blood permeating the weave of the material. Fibroblasts grow along the strands of clotted blood with subsequent collagen deposition and vascular proliferation [21, 66]. This explains the appearance of adhesions despite the use of the adhesion barrier. The most important steps to maximize the efficacy of ORC barriers are to remove intraperitoneal irrigants thoroughly, inspect the operative site to ensure that adequate hemostasis has been achieved, and use a sufficiently large piece of the ORC barrier. It hemostasis has not been achieved, the ORC barrier turns black or brownish black. In these cases the material must be removed, hemostasis achieved, and a new piece of ORC barrier applied [5, 21, 66, 94]. ORC reduces incidence, extent, and severity of postoperative pelvic adhesions, but does not prevent them [94]. This evidence extended to patients with severe endometriosis [109]. ORC has been shown to act in synergy with heparin. In animal models, the application of heparin-treated ORC adhesion barriers significantly reduced adhesion scores. Although adhesion reduction was also seen in human studies, it did not reach statistical significance when compared to nontreated ORC [110]. Rather than support bacterial growth, ORC exhibits antibacterial properties in vivo [111]. Interceed appears to play an important role and may provide beneficial effects in preventing and reducing postoperative adhesion development [94, 95, 112]. Seprafilm. HA-CMC is a nontoxic, nonimmunogenic, biocompatible material effective in reducing incidence and extent of severe postoperative adhesions. It turns to a hydrophilic gel approximately 24 h after placement and provides a protective coat around traumatized tissue for up to 7 days during remesothelialization. Like ORC, the HA component is completely cleared from the body within 28 days; less clear is the removal of the CMC component. HA-CMC can be used in the presence of blood [113]. Adhesions: Pathogenesis and Prevention Dig Surg 2001;18:

11 HA-CMC reduced the incidence of postoperative adhesions to the incision line by greater than 50%, and the mean adhesion rate was 40% less when compared to controls undergoing laparotomy. Patients receiving HA- CMC also had less severe adhesions as compared with controls. The incidence of incisional adhesions associated with omentum, stomach, small bowels, abdominal wall, and bladder was significantly reduced in patients who had an abdominal operation performed by midline incision and had HA-CMC placed. A higher incidence of pulmonary emboli and intraperitoneal abscess formation has been reported in patients treated with HA-CMC, but these findings were not statistically significant [54, 102]. The mechanism for these complications is unknown. The relative differences in clearance of HA and CMC may lead to fragmentation of the film and increased emboli or abscess formation [21]. Despite recent advances that have led to substantial enthusiasm for the development of an ideal barrier agent, several major obstacles must be overcome for this type of adhesion prevention to be effective. A variety of questions need to be addressed. Why under the same circumstances do some patients form adhesions and others do not? Does abdominopelvic surgery itself result in the same type of adhesions as in endometriosis, infection, and malignancy? Further Research Further studies are required to completely define at a molecular and cellular level the components involved in adhesiogenesis and to more precisely determine the role of fibrin and the regulation of fibrinolysis and coagulation in adhesion formation. Also, by understanding the biochemical and morphological mechanisms of normal peritoneal healing and its repair processes, we will be able to develop strategies to separate damaged peritoneal surfaces and enforce fibrinolysis. In various animal models with different levels of tpa and response to fibrinolytic stimulation among them [ ], factors that stimulate adhesion formation, sites of adhesion development, and dose and administration of antiadhesive agents, need to be carefully assessed in laboratory studies. Identification and comparison of adhesion formation in different anatomical areas with adhesive complications and a better understanding of adhesions that are more likely to cause complications are other important areas of adhesion prevention research. The type (newly formed de novo reformed), the extent, and the severity of postsurgical adhesions need to be carefully defined. The Operative Laparoscopy Study Group [3] has described the reformation of adhesions of different severity at different rates after operative laparoscopy procedures. Filmy avascular adhesion reformation lysed at the initial procedure was identified in 45% during second-look laparoscopy, cohesive adhesions in 79%, and dense and/or vascular adhesions were followed by adhesion reformation in 60%. More research is needed on development of new selected agents, focusing on adhesion prevention and further diagnostic techniques to visualize adhesions that form after abdominal surgery. Adhesion formation involves migration and proliferation of infiltrating cells that release cytokines such as IL-1, TNF-, transforming growth factor beta, etc., related well to both the normal healing response and the response to peritoneal injury that leads to postoperative adhesion formation. It has been proven in animal studies that IL-1 and TNF- are important mediators of postsurgical adhesion formation [117, 118], and by using neutralizing antibodies against IL-1 and TNF-, the adhesion rates could be reduced [119]. Higher levels of serum IL-1 and TNF- levels in humans during the early intraoperative period have been demonstrated to correlate with postoperative adhesion formation [120]. Thus, cytokine antibodies to these biological markers may further play an important role in reduction and prevention of peritoneal adhesions. Experimental results in rat studies with intraperitoneal instillation of phosphatidylcholine upon abdominal closure seemed to reduce adhesion formation [ ]. phosphatidylcholine as a component of phospholipids which are natural ingredients of abdominal fluid and cell membranes may reduce the risk of adhesion development by diminishing fibrin formation between peritoneal surfaces and defects [53]. The efficacy of phosphatidylcholine in humans remains to be seen with further research. It has been described a technique of using ultrasound to examine the sliding motion of the abdominal viscera [124]. Normal sliding motion was termed viscera slide and occurred either spontaneously, during respiratory movements, or was induced by manual palpation of the abdomen. Restricted viscera slide was shown as an accurate indication of intra-abdominal adhesions [125]. Viscera slide ultrasound is a promising noninvasive diagnostic technique that may be useful in identifying and mapping abdominal wall adhesions prior to laparascopic or open surgical procedures. Preoperative ultrasound examination would help to identify patients with adhesions 270 Dig Surg 2001;18: Liakakos/Thomakos/Fine/Dervenis/Young