Adhesion Prevention

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Chapter 52 Adhesion Prevention

Mohamed F. Mitwally, Michael P. Diamond

INTRODUCTION

The relevance of pelvic and peritoneal adhesions to the practice of reproductive endocrinology and infertility clearly relates to their association with infertility and chronic pelvic pain. In addition, postoperative adhesions are also responsible for significant complications, most notably adhesive bowel obstruction, and increase the difficulty of subsequent surgical procedures, which enhances the potential for intraoperative complications. Interestingly, the first case report of fatal intestinal obstruction caused by intra-abdominal adhesions was a woman who developed adhesions after removal of an ovarian tumor.¹ Although the peritoneal cavity is of interest to the reproductive surgeon, postoperative adhesions also occur in other spaces, such as the pleural and pericardial cavities.

This chapter first describes the scope and impact of pelvic adhesions, as well as the patholophysiology of their formation. This is followed by a careful examination of the complications and clinical conditions associated with adhesions. The final section is a thorough look at what is known about prevention.

HISTORICAL PERSPECTIVE

Ancient Egyptians, known for their detailed descriptions of human anatomy, described pelvic adhesions several thousands years ago. Pleural adhesions were first described in the Babylonian Talmud in 440 A.D.² Although adhesions caused by peritonitis have been recognized since the early 1700s, it was not until the widespread use of anesthesia in the mid-1800s when invasive abdominal procedures became more prevalent that the extent of the problems caused by intra-abdominal adhesions was realized.

By the 1880s, the first published reports describing the use of adjuvants for adhesion prevention began to appear in the surgical literature. Over the next 100 years, a plethora of scientific reports and anecdotal accounts described the use of everything from amniotic fluid, bovine cecum, gold-beater’s skin, shark peritoneum, fish bladder, vitreous of calf’s eyes, various gums, lubricants, fluids, gels, polymers, physical barriers, and a host of mechanical separation methods to prevent adhesions. Unfortunately, the results of most of these studies were equivocal, with no more than a small percentage of success. Even in this age of surgical sophistication and new operating room technology, our age-old nemesis, the intra-abdominal adhesion, remains a significant, long-term, and recurrent postoperative problem.³

DEFINITION, TYPE, AND EXTENT OF DISEASE

Intra-abdominal adhesions are strands or membranes of fibrous tissue that can be attached to the various intra-abdominal organs, sometimes connecting them together (Fig. 52-1). The term adhesion in the medical field refers to the abnormal joining of anatomic structures at sites where no such anatomic attachment should exist. Adhesions usually develop in conjunction with surgery at sites of adhesiolysis and other operative sites, but also occur at “distant” sites where no surgical procedure was done.

Figure 52-1 Pelvic adhesions involving the uterus and bowel. This patient had a previous myomectomy.

There are two general categories of adhesions, de novo and reformation. De novo adhesions occur at sites that did not previously have adhesions; reformation refers to adhesion formation at sites of previous adhesiolysis.

To accurately describe the extent of peritoneal adhesions during clinical investigations, various scoring systems have been developed. Systematic assessment of adhesions is mandatory to decrease interobserver variation and to provide quantitative data corresponding to their extent and clinical significance.⁴ Most of the available scoring systems incorporate adhesion location, vascularity, and type (thickness). However, the current scoring systems suffer from the lack of validation for outcomes such as fertility, pain, and bowel obstruction, which makes the interpretation of the results of research related to adhesion development and prevention difficult. Thus, the question is often asked that if a study demonstrates a significant change in an adhesion score, does that reflect true clinical relevance in the extent of adhesive disease?

PREVALENCE OF DISEASE

Despite the application of microsurgical technique and use of surgical adjuvants by experienced surgeons, the development of intraperitoneal postoperative adhesions is common. Currently, no serum marker or scanning technique is consistently able to identify adhesions, and a repeat operative procedure is required for evaluation.⁵

In a postmortem study of victims of motor vehicle accidents, intra-abdominal adhesions were encountered in 67% of individuals who had a history of abdominal operation.⁶ The prevalence among patients who had undergone major operations and multiple procedures was 81% and 93%, respectively. Most studies have shown that after an intra-abdominal operation, most patients developed adhesions. One study found that after merely one previous abdominal operation, 93% of patients had adhesions.⁷ On the other hand, intra-abdominal adhesions among patients who had never experienced a laparotomy were found in only 10.4%.

Within 1 year of laparotomy, 1% of patients develop adhesion-related intestinal obstruction;⁷ 11% to 12% of them will suffer from recurrence later.⁸ In reports based on data from laparoscopies⁹ and autopsies,⁶ 60% and 69% of women, respectively, had pelvic adhesions after previous abdominopelvic operations. Variation in the incidence of postoperative adhesions may be explained by differences in the extent of surgery, differences in the incidence or severity of prior surgery or other etiologic events, and in what each investigator considered to be a “significant” adhesion. It is important to emphasize that although some investigators believe all adhesions may not be clinically significant, others would emphasize that you cannot tell which adhesions will cause pain or contribute to bowel obstruction.

ECONOMIC IMPACT OF ADHESIONS

The economic impact of adhesions as a complication of surgery is enormous. In the United States, 446,000 procedures were performed annually to remove abdominopelvic adhesions.¹⁰ This included 347,000 operations to release peritoneal adhesions and approximately 100,000 procedures to liberate intestinal adhesions. The cost of morbidity associated with adhesions is large.¹¹ Few studies have been conducted to evaluate the financial impact of adhesion-related problems on the medical budget, and many of the studies could have underestimated the actual financial impact of adhesive disease by not considering the costs of performing diagnostic tests, consultations with other services such as gastroenterology, the increase in operative time required to free adhesions, and the complications due to inadvertent injury to other vital structures while freeing adhesions. In addition, a significant number of planned laparoscopic surgeries are converted to laparotomy because of failure to safely enter the abdomen and achieve adequate pneumoperitoneum. Finally, there are costs associated with long-term morbidity such as adhesion-related infertility and repeated admissions for bowel obstruction. The psychological impact of adhesion-related conditions that lead to loss of work might add to the economic burden.

In the United States, an analysis of all hospitalizations for adhesions was performed using the 1988 National Hospital Discharge Survey. Of a total 281,982 hospitalizations, 51,100 were adhesion-related admissions. In total, there were more than 948,000 hospital-days of care, accounting for a cost of approximately $1.18 billion.¹⁰ In 1994, the same authors updated their database and found the annual overall cost to be approximately $1.3 billion. They also reported that lysis of adhesions was responsible for 1% of hospitalization in the United States.¹²

In a study that evaluated hospital discharge for adhesion-related bowel obstruction between 1990 and 1996, the total number of patients increased from 115,067 in 1990 with a total length of hospitalization of 962,642 days to 139,716 patients with a total length of hospitalization of 885,396 days in 1996.¹³ The total costs increased steadily from $924 million in 1990 to $1.4 billion in 1996. Among those who were treated medically, there were 88,601 hospitalizations in 1990 and 110,817 in 1996, with a parallel increase of cost from $261 million in 1990 to $386 million in 1996.

In the United Kingdom, Menzies and coworkers ¹⁴ reviewed 110 hospital admissions resulting from adhesion-related small-bowel obstruction over a 2-year period. Of 110 admissions, surgical treatment was performed in 37% of patients and conservative management in the remaining patients. The total costs per admission were $7,521.28 (£4,677.41) and $2582.69 (£1,606.15) for the surgical and conservative treatment groups, respectively.

In Sweden, Holmdhal and Riseberg ¹⁵ conducted a cost analysis study on adhesion-related admission among all general surgeons. Collection of data was performed after the authors analyzed the questionnaire sent to all department heads of Swedish surgical units. There were a total of 6200 patients requiring hospitalizations, accounting for 3.5% of all laparotomies. They found that the total cost for adhesion-related hospitalization was $6.1 million US annually or close to $1 million US per million Swedish inhabitants (the population of Sweden is 8.5 million).

Because of the difference in medical costs in various countries, meaningful comparisons are difficult. However, all studies suggest a huge financial impact of adhesion-related conditions to the healthcare system. Recently, Wilson ¹⁶ calculated that a low-cost product with a 25% efficacy in preventing surgical adhesions could potentially generate a cost saving of £55 million over a 10-year period in the UK. In a prior study, they concluded that demonstrating the clinical effectiveness of adhesion reduction products in a randomized, controlled setting is unlikely to be feasible due to the large number of patients required. They suggested that products costing £200 (around $300 US) or more are unlikely to pay back their direct costs.¹⁷

COMPLICATIONS OF ADHESIONS

Postoperative adhesions develop after virtually every transperitoneal operation, ranging from minimal scarring present on serosal surface to dense agglutination of nearly all structures. However, postoperative adhesions are much more common than symptoms would suggest; therefore, most adhesions probably do not lead to acute symptoms or clinical sequelae.

In certain situations, adhesions may be of benefit. They may serve as adjuncts to the body’s natural defenses against intra-abdominal insults and can be lifesaving in the postoperative period by localizing leakage from suture lines, isolating an inflammatory collection, or preventing the spread of infection. Other potential benefits include neovascularization of ischemic structures such as anastomoses. However, adhesions are associated with significant morbidity such as infertility, pain, and bowel obstruction.¹⁸

Reproductive Problems

Adhesions play a significant role in the etiology of several reproductive disorders, including infertility, ectopic pregnancy, and recurrent pregnancy loss (intrauterine adhesions). From 15% to 20% of female infertility is caused by adhesions.¹⁹ Adhesions causing infertility or ectopic pregnancy may originate from endometriosis, infection such as pelvic inflammatory disease, appendicitis, or tuberculosis, as well as inflammatory bowel disease and surgery. More details on adhesions and infertility, ectopic pregnancy, and recurrent pregnancy loss are provided in other chapters of this text (see Chapters 34, 41, 47 and 48).

Intestinal Obstruction

Adhesive intestinal obstruction is the most serious complication associated with peritoneal adhesions (Fig. 52-2). In addition to the significant pain, the condition can be life-threatening and in some cases fatal. In the early 20th century, most of the cases of intestinal obstruction were due to strangulated external hernias. As abdominal and gynecologic surgeries began to be performed more routinely, the number of intestinal obstructions caused by postsurgical adhesions increased and now has surpassed those produced secondary to hernias. This statistic, however, only holds true for the western world. In poorer regions of the world, the percentage of obstruction from hernias is still greater than that caused by adhesions.²⁰ In advanced countries, adhesions account for intestinal obstructions in 49% to 74% of cases.²¹ Intestinal surgeries involving the left side of the colon and rectum, appendectomies, and gynecologic procedures are the three most common surgical procedures accounting for adhesion-related intestinal obstruction.⁷

Figure 52-2 Radiograph of intestinal obstruction-related bowel adhesions. This patient presented within 1 week of surgery with nausea and vomiting. Plain film of the abdomen in the supine and upright positions was obtained. The classic signs of a mechanical bowel obstruction are seen: large loops of bowel in ladder pattern with no gas in the colon. The gas–fluid levels are the classic sign of a small bowel obstruction.

Both the extent and indication (e.g., cancer) of a gynecologic operation correlate significantly with the risk of postoperative intestinal obstruction. A Japanese group looked at the type of adhesions that caused intestinal obstruction and found that in 29% of cases, obstructive adhesions were small bowel to small bowel; in 48% the adhesions were small bowel to other abdominopelvic structures.²²

Gynecologic malignancy increases the incidence of intestinal obstruction because more extensive operations are often required, and blockage by a tumor mass can occur. A report on 283 gynecologic patients treated for mechanical small-bowel obstruction showed that 175 (61.8%) were due to a primary or recurrent gynecologic malignancy, almost exclusively arising from the ovary.²³ However, the second most common cause of obstruction was postoperative adhesions (41 patients, 14.5%), most of which followed an operation performed for a gynecologic cancer.²³ Intestinal obstruction occurring in the immediate postoperative period and those that follow treatment for early-stage ovarian cancer usually are related to adhesions, whereas delayed obstruction, especially that which occurs in the presence of advanced disease, is usually tumor-related, particularly if radiotherapy is administered.²⁴

Although small-bowel obstruction on a gynecology service occurs most frequently in women with ovarian cancer, it can occur after other extensive pelvic operations, particularly ones associated with significant pelvic infection, such as surgery for tubo-ovarian abscess. It has been suggested that the two structures most commonly involved in adhesions associated with gynecologic surgery are the omentum and the distal small intestine.¹⁸ Short, obese women have a particular tendency to develop omental and small-bowel postoperative adhesions, perhaps in part related to longer, more difficult operative procedures.⁶ Because colonic adhesions are less common and the restricted mesentery can preclude twisting and kinking of the lumen, the colon is involved in adhesive obstruction only 2% to 10% as frequently as the small bowel.⁶ Among gynecology patients colonic obstruction usually is related to recurrent or persistent pelvic tumor causing extrinsic compression of the rectosigmoid colon.^23,²⁴

Adhesive intestinal obstruction after previous surgery can be early or late. According to the general surgery literature, 17% to 29% of intestinal obstruction cases occur within 1 month,^25,²⁶ whereas the rest of the cases develop later, from 1 month to several decades after the surgery. After definitive operative management of an intestinal obstruction, the incidence of recurrence is approximately 14%. The factors contributing to occurrence or recurrence of intestinal obstruction are poorly understood.^26,²⁷

Fevang and colleagues studied a series of patients that included 500 patients who had a median follow-up of 10 years and a maximum follow-up time of 40 years after adhesive small-bowel obstruction.²⁸ The cumulative recurrence rate for patients operated once for adhesive intestinal obstruction was 18% after 10 years and 29% at 30 years. For patients admitted several times for adhesive intestinal obstruction, the relative risk of recurrent adhesive intestinal obstruction increased with increasing number of prior episodes. The cumulative recurrence rate reached 81% for patients with four or more admissions. Other factors influencing the recurrence rate were the method of treatment of the last previous adhesive intestinal obstruction episode (conservative versus surgical) and the number of abdominal operations before the initial adhesive intestinal obstruction operation. Most recurrent adhesive small-bowel obstruction episodes occurred within 5 years after the previous one, but a considerable risk is still present 10 to 20 years after an adhesive small-bowel obstruction episode.²⁸

The Conundrum of Chronic Pain Syndromes and Adhesions

The issue of adhesion-related pain, including chronic pelvic and abdominal pain, dysmenorrhea, and dyspareunia, has been the subject for intense debate.²⁹ There are three important questions that need to be addressed: Do adhesions cause pain? If yes, does the extent of adhesions correlate with the nature and severity of pain? Does adhesiolysis relieve adhesion-related pain?

Adhesions May or May Not Cause Pain

The question as to whether or not adhesions cause pain does not have an entirely satisfactory answer. In favor of this relationship are the findings that adhesions contain nerve fibers ³⁰ and are innervated with substance P-containing sensory neurons, suggesting that adhesions themselves are capable of generating pain stimuli and perhaps finally suggesting a mechanism to explain the pain associated with adhesions.³¹ However, some have criticized reports such as this because of the potential for “tenting” of normal peritoneum during adhesion excision, such that the nerves may have been in normal peritoneum. Additionally, the apparent absence of pain in some patients with massive adhesions in contrast to claims of intense pain by patients with only minimal adhesive disease has led many clinicians to doubt that adhesions alone are “enough” pathology to “cause” pain.

Contributing to the confusion is the subjective nature of pain, the intrinsic difficulty in establishing reliable measures of clinical pain, and the lack of behavioral and psychological assessment in reports of pelvic pain in the gynecologic literature. Add to this the lack of noninvasive techniques for accurately observing or quantifying postoperative adhesion development.

The magnitude of the problem is great. As many as 20% of patients with acute pelvic inflammatory disease will have chronic pain, much of which is felt to be associated with adhesions.³² It is possible that adhesions that restrict the free movement of pelvic organs would be implicated as a cause of chronic pelvic pain.³³ Approximately 20% to 50% of patients with chronic pain have pelvic adhesions.^33,³⁴

Adhesion Extent Does Not Correlate with Nature and Severity of Pain

Although several studies have suggested a significant association between adhesions and chronic pelvic pain, and the location of pain to reflect the site of adhesions, most of these studies failed to show a significant correlation between the extent of adhesions and the severity of pain.²⁰ Similar observations have been made for the relationship between endometriosis and pain.

Adhesiolysis Does Not Always Relieve Adhesion-Related Pain

Lysis of adhesions has been proposed as the therapeutic modality of choice for patients suffering from pelvic pain in association with adhesions, and some investigators report the resolution of chronic pain in individuals after lysis of adhesions, whereas others have not noted this effect consistently or have noticed only a very short period of benefit.^35,³⁶ Obviously, the “gold standard” study to determine the utility of adhesiolysis for pain relief would be a double-blinded, randomized trial with a control arm, which would control for adhesion reformation and de novo adhesion formation, and follow-up occurring past the point of the expected placebo effect of adhesiolysis surgery. Not surprisingly, such a study would be difficult to execute because of the need to recruit a large number of patients, to perform a second-look procedure to ascertain whether adhesion reformation occurred in those patients having pain relapse after adhesiolysis, and to debate the method to use to quantify patient pain.²⁰

Probably the closest to this ideal study are reports by Swank and colleagues,^37,³⁸ who conducted both laparotomy and laparoscopy. Neither of these studies was able to demonstrate a significant benefit of adhesiolysis to the patient population as a whole, although trends were identified. Although each of these studies was randomized, the length of follow-up was limited, and neither included second-look laparoscopy so as to allow correction for new or persisting adhesions.

PATHOPHYSIOLOGY OF ADHESION FORMATION

Peritoneal Cavity Repair

The abdominal cavity is lined by the peritoneum, which consists of a single layer of mesothelial cells, supported by a basement membrane and an underlying sheet of connective tissue. When it covers the abdominal wall it is called the parietal peritoneum and when it covers viscera it is called the visceral peritoneum.

Peritoneal trauma results in mesothelial damage and is accompanied by inflammation. Mesothelial cells balloon and detach from the basal membrane, thereby creating denuded areas.⁴⁰ Peritoneal injury due to surgery, irradiation, infection, or irritation initiates an inflammatory reaction that increases peritoneal fluid, including proteins and cells. This fibrinous exudate leads to formation of fibrin⁴¹ by activation of the coagulation cascade.⁴² Within this fibrinous exudate, polymorphonuclear cells, macrophages, fibroblasts, and mesothelial cells migrate, proliferate, or differentiate (Table 52-1).

Table 52-1 The Temporal Relationship of Different Cell Types and Products in the Peritoneal Cavity (Days) after Surgical Injury

Macrophages increase in number and change functions from mainly phagocytosis into secretion of a variety of substances that cause differentiation of progenitor cells into mesothelial cells on the injured surface. Mesothelial cells form islands throughout the injured area, proliferate, and cover the denuded area in short periods of time, usually estimated to be within 5 to 7 days of injury.⁴³ It is important to realize that this process occurs, not just at the edge of the denuded peritoneum, but throughout the surface of the injured area. All these cells, as well as fibroblasts that migrate from underlying tissues, release a variety of substances such as plasminogen system components, arachidonic acid metabolites, reactive oxygen species, cytokines, and growth factors such as interleukins, tumor necrosis factor-α, and transforming growth factors α and β. These factors modulate the process of peritoneal healing and adhesion development at different stages.⁴⁴

Abnormal Repair

The fibrinous exudate and fibrin deposition is an essential part of normal tissue repair, but its complete resolution is required for normal healing without adhesions. The degradation of fibrin is regulated by the plasminogen system. The inactive pro-enzyme plasminogen is converted into plasmin by tissue-type plasminogen activator or urokinase-type plasminogen activator in peritoneum (primarily tissue plasminogen activator [tPA]), which are inhibited by the plasminogen activator inhibitors 1 and 2. Plasmin degrades fibrin into fibrin degradation products. Plasmin can be directly inhibited by plasmin inhibitors (i.e., α₂-macroglobulin,α₂-antiplasmin, and α₁-antitrypsin), but their role in peritoneal fibrinolysis is not well defined. Inhibition of plasminogen activator results in decreased fibrinolysis and allows formation of fibrin gel matrix, the scaffolding for the formation of an adhesion. This usually occurs over 5 to 8 days.

Fibroblasts will invade the fibrin matrix with extracellular matrix deposition, leading to peritoneal adhesions. In addition to fibroblast invasion and extracellular matrix deposition, the formation of new blood vessels has been universally claimed to be important in adhesion development as a means of resupplying oxygen and nutrients and removing metabolic waste.⁴⁴

During peritoneal healing, cell–cell interactions between mesothelial cells, macrophages, and fibroblasts contribute to the healing of the peritoneum. Adhesion fibroblasts have developed a specific phenotype. Compared with normal peritoneal fibroblasts, adhesion fibroblasts have increased basal levels of collagen I, fibronectin, and other adhesion substances and decreased levels of tPA.⁴⁵ Readers with greater interest in this area of investigation are referred to a more detailed review.⁴⁶

To conclude, the balance between fibrin deposition and degradation in the initial days after surgery is critical in determining normal peritoneal healing or adhesion development. If fibrin is completely degraded, remesothelialization leading to normal peritoneal healing without adhesions will occur. In contrast, if fibrin is not completely degraded, it will serve as a scaffold for fibroblast ingrowth with subsequent extracellular matrix deposition and angiogenesis. After abdominal surgery and infection, however, the equilibrium between coagulation and fibrinolysis is disturbed in favor of the coagulation system.⁴⁷^–⁵⁰

Risk Factors for Developing Adhesions

As mentioned earlier, peritoneal repair and adhesion development is the net result of a balance between fibrin deposition as an outcome of the inflammatory process associated with peritoneal injury and fibrinolysis. Fibrinolysis plays a central role in the resolution of the inflammatory exudate, thereby minimizing the risk of adhesion development. This process has primarily been thought to be initiated by mesothelial cells in the region of tissue injury because fibrinolytic activity has been documented within normal mesothelium.⁵¹ However, tPA occurs in fibroblasts from human peritoneum and adhesions as well.^52,⁵³ Adequate blood supply is critical for normal fibrinolysis to occur. Peritoneal injury associated with ischemia interferes with fibrinolysis and leads to organization rather than resolution of the fibrin–cellular matrix.⁴³ In the absence of ischemia, even large denuded areas of peritoneum usually will heal normally without developing adhesions.^54,⁵⁵

Agents that compromise blood flow within the area of tissue injury increase adhesion development. Thermal injury,⁵⁶ infection,⁵⁷ foreign body reaction (i.e., suture),^57,⁵⁸ radiation-induced endarteritis,⁵⁹ and any other impediment to fibrin degradation increase intraperitoneal adhesions. The effect of electrocautery devoid of significant thermal injury or incomplete hemostasis on fibrinolysis and ultimately on adhesion development has not been adequately studied. Thus, the necessity to control small bleeding vessels and the optimal method to do such (cautery or suture) has yet to be defined. Only conflicting reports concerning these issues exist in the infertility literature.^56,⁶⁰ Fibrinolysis in the abdominal cavity is even more depressed in the presence of infection.⁶¹

Intraoperative tissue damage, infections, tissue ischemia, and intra-abdominal presence of foreign material, blood, or bile ^62,⁶³ all have been shown to be potent causes of peritoneal adhesions. Foreign materials, such as glove powder,⁶⁴ fluff from surgical packs (gauze lint),⁶⁵ sutures,^58,⁶⁶ and material extruded from the digestive tract, cause a peritoneal inflammatory reaction, hence increasing the chance of adhesions.⁶⁷

PREVENTION OF ADHESION DEVELOPMENT

Although gynecologic surgery has been a major source of intraperitoneal adhesions and associated morbidity over the past century, most related complications, including adhesions, have been traditionally managed by general surgeons and related surgical subspecialties.⁶⁸ However, with the establishment of the gynecologic subspecialties of reproductive endocrinology and infertility and gynecologic oncology, gynecologic surgeons developed a directed interest in adhesion development, prevention, and management. This interest is stimulated particularly for reproductive endocrinologists by the relationship between adhesions and impaired fertility⁴ and for gynecologic oncologists by the increased aptitude to perform all aspects of intestinal surgery,⁶⁹ as well as the ability to deal with adhesion-related intestinal complications. As residency training programs in obstetrics and gynecology universally provide exposure to both of these subspecialties, all obstetricians and gynecologists should be familiar with the principles of adhesion development and their management.⁷⁰

The focus of this review is on the pathophysiology of surgically induced adhesions and their prevention. The discussion on pathophysiology and the various approaches to decrease the chance of adhesions may not apply to adhesions that result from specific disease processes such as endometriosis, pelvic inflammatory disease, inflammatory bowel disease, and other adhesiogenic diseases.

Surgical Techniques

Prevention of adhesion development starts by adopting adequate surgical techniques involving the application of microsurgical principles that enhance postoperative healing and minimize tissue insults that exacerbate inflammatory reactions. Such principles of microsurgical techniques, including gentle tissue handling, meticulous hemostasis, copious irrigation, prophylaxis against infection, limiting foreign body reaction, and preventing thermal injury, have all been described as means of decreasing adhesion development.

These surgical principles apply to all types of operations because they can influence the risks of most complications associated with surgical procedures, not just adhesion development. Of course, application of these principles must be done in the context of the surgical procedure that needs to be conducted and appreciation of other surgical principles such as the need for adequate exposure and use of traction and countertraction.

Surgery for, or associated with, peritonitis requires meticulous and thorough elimination of the source of contamination, treatment of infection, and debridement of the abdominal cavity; these are the cornerstones of such types of surgery for the prevention of surgical adhesions as well as intraperitoneal abscess formation.

Hemostasis and Tissue Handling

Achieving meticulous hemostasis and minimizing tissue handling without doubt constitute the two most important surgical principles in minimizing adhesions. Although the presence of blood at the operative site increases postoperative adhesion development, it is important that hemostasis be achieved in a manner that devitalizes as little surrounding tissue as possible. When possible, the size of pedicles should be minimized and use of electrosurgery should be restricted to the actual bleeding site. With regard to tissue handling, manipulation of structures is required to achieve exposure and perform the procedure. However, tissue damage can often be minimized by the use of atraumatic graspers, moist (not dry) pads and, when feasible, grasping of tissue structures to be excised.⁴

Value of Precise Tissue Approximation

The value of tissue approximation, including peritoneal closure, is still a subject of intense debate without clearcut recommendations to be generalized. Traditionally, closure of the peritoneum was thought to possibly allow for (1) restoration of anatomy and approximation of tissues for healing; (2) reestablishment of the peritoneal barrier to reduce the risk of infection; (3) reduction of the risk of wound herniation or dehiscence; and (4) minimization of adhesion development.⁷¹

The Cochrane database examined the issue of peritoneal closure versus nonclosure in cesarean section. They concluded that there was “no significant difference in short-term morbidity from nonclosure of the peritoneum in cesarean section.”⁷² It is, however, important to appreciate that the conclusions drawn from cesarean section may not be applicable to general gynecologic surgery due to the obvious differences in the nature of the two surgery types. Although suturing the peritoneum appears to have a more anatomic result than leaving it to heal by secondary intention, the presence of ischemic tissue by sutures causes a predisposition to adhesion development.⁵⁵ In animal models,^73,⁷⁴ laparotomy closure without peritoneal suturing healed with a lower incidence of adhesions to the wound compared with animals with peritoneal suturing. Postoperative adhesions at the site of closure of the pelvic peritoneum were responsible for bowel obstruction in 85% of cases, with adhesions to the anterior abdominal wall occurring in another 15%.⁷⁵ Tulandi⁷⁶ suggested that the currently available evidence suggests that peritoneal suturing is not only unnecessary, but could also be associated with a greater risk of small-bowel obstruction.

Another important issue involving whether to precisely approximate tissues together or not is the ovarian cortex closure, such as in surgeries involving the removal of ovarian cysts and masses. In animal studies, suture closure of the ovarian cortex was associated with greater, not lesser, adhesion development.⁷⁷

Use of Laparoscopy

It had been suggested, anecdotally, that procedures performed by laparoscopy, as opposed to laparotomy, might be less likely to be followed by the postoperative development of pelvic adhesions. Potential explanations included reductions in tissue drying, tissue manipulation, introduction of foreign materials, and abrasion of peritoneal sutures, as well as lack of packing of bowel.^78,⁷⁹ However, in a multicenter study evaluating adhesion reformation at a second-look procedure after laparoscopic adhesiolysis, adhesion reformation was identified in 66 of 68 subjects (97%).⁸⁰ Laparoscopic adhesiolysis was able to significantly reduce the extent of pelvic adhesions to approximately half of what was present initially. De novo adhesion development occurred in only 8 (12%) of these 68 women, and in 11 (23%) of 47 available sites in those affected. This suggests that de novo adhesion development (not adhesion reformation) may occur less frequently after laparoscopic surgery, but confirmation of this hypothesis will require properly controlled studies.

A recent study made the observation that the increased use of laparoscopy for abdominal procedures between 1988 and 1994 did not appear to be associated with a concomitant reduction in the hospitalization rate for adhesive intestinal obstruction, suggesting that although minimally invasive techniques may offer advantages such as decreased morbidity, whether such procedures actually reduce adhesion development remains unclear at this time.¹²

Laparoscopic adhesiolysis for adhesive intestinal obstruction has also come to the forefront ⁸¹ and obviously offers similar advantages over laparotomy. However, there are no long-term results; thus, the question concerning decreased recurrence after laparoscopy compared with laparotomy requires further investigation.

CO₂ Pneumoperitoneum-Enhanced Adhesion Development

Recently, the effects of carbon dioxide (CO₂) pneumoperitoneum have become increasingly scrutinized.⁸²^–⁹⁰ It has been hypothesized that CO₂ pneumoperitoneum induces adverse effects, including hypercarbia, acidosis,⁸⁸ hypothermia, and desiccation,⁸⁹ as well as altered peritoneal fluid⁹⁰ and morphology of the mesothelial cells.⁹¹ Adhesions have been found to increase with the duration of the pneumoperitoneum and with increased insufflation pressure in rabbits⁸² and mice.⁸³ Potentially, such adhesions may be due to drying or cooling of tissues from insufflation gas flow; however, this remains controversial. Cooling has been suggested both to cause⁸⁹ and reduce adhesions,⁸⁴ while humidification of insufflation gas has been implicated in adhesion reduction⁸⁵ or having no effect. The pneumoperitoneum-enhanced adhesion development has been suggested to be mediated by mesothelial hypoxia because similar effects were observed with helium pneumoperitoneum, and because the addition of 2% to 4% oxygen to both CO₂ and helium pneumoperitoneum decreased adhesion development.^83,⁸⁶

Use of Energy Source

In general, there has been no evidence that use of a specific energy source per se (e.g., CO₂ laser, bipolar electrocautery, unipolar electrocautery, harmonic scalpel) results in a greater reduction of adhesions or improvement in pregnancy outcome, compared with other surgical modalities.⁹²^–⁹⁴ However, individual surgeons, based on their own experience, equipment availability, and preference, may find use of a particular modality to be most advantageous for the performance of these procedures.⁹⁵^–⁹⁸

Technique for Treatment of Existing Adhesions to Prevent Adhesion Reformation

There is no single best method of dividing adhesions, in spite of dogma to the contrary. In some situations, particularly when the adhesions are flimsy and are easily separable, gentle blunt dissection may be the safest method. In other situations, when adhesions are dense and especially when important adjacent structures such as the urinary bladder are involved, blunt dissection or pulling on the small intestine results in tears of the bowel or adherent viscus. This happens primarily because the tensile strength of the adhesions exceeds that required to maintain bowel or other visceral seromuscular layer intact. Consequently, when adhesions are dense, it is generally safer to use a sharp method of dissection (Fig. 52-3).

Figure 52-3 Sharp dissection of dense adhesion of tube to the pelvic sidewall.

Adhesion Development versus Adhesion Reformation

Three groups have demonstrated fundamental differences between adhesion development and adhesion reformation in animal models. Holtz and associates ^100,¹⁰¹ described reduction in adhesion development with 32% dextran 70, but a similar inhibition of adhesion reformation could not be achieved with higher doses of dextran. Similarly, Elkins and coworkers^102,¹⁰³ observed a greater extent of adhesion reformation than adhesion formation after dextran treatment. Finally, Diamond and associates^104,¹⁰⁵ compared adhesion formation and reformation models and noted a greater extent of adhesions in the latter. Consistent with these observations, Diamond and Nezhat have proposed a classification of postsurgical adhesion development that differentiates de novo adhesion formation (type I) from adhesion reformation (type II) and subcategorizes each of these groups as to whether there was a lack of or presence of treatment of pathology¹⁰⁶ at sites during the initial procedure. Importantly, a recent meta-analysis has validated this classification system by demonstrating increasing risk of adhesions in association with advanced stages.¹⁰⁷ Such a system provides a method to assess efficacy of surgical techniques, new instrumentation, and antiadhesion adjuvant therapy.

Second-Look Laparoscopy

The value of second-look laparoscopy to promote fertility remains controversial. Multiple series have demonstrated that adhesiolysis in patients with preexisting adhesions results in pregnancy outcomes in inverse correlation with the extent/severity of the initial adhesions (i.e., the more adhesions initially, the less likely pregnancy will occur). Additionally, in other series, adhesiolysis has been shown to reduce the amount of adhesions, which will be identified in the future.

The logical deduction from these statements is that second-look laparoscopies will increase the pregnancy rate. However, well-designed studies examining the effect of early second-look laparoscopies on subsequent pregnancy outcome have not been performed. Advocates of second-look procedures propose several advantages: the ability to assess the efficacy of new surgical techniques, equipment, or adjuvants; the opportunity for the surgeon to assess the outcome of the surgical procedure; and a better opportunity for the patient to be counseled regarding next steps (e.g., recommending in vitro fertilization for patients with extensive adhesions).

Nonetheless, these outcomes do not prove clinical benefits regarding pregnancy. Although Tulandi and colleagues were unable to identify a benefit of second-look laparoscopy 1 year after reproductive surgery, this study was limited by the lack of randomization and the differences in the initial surgeons.¹⁰⁸ In contrast, when looking at adhesions as the endpoints, early second-look laparoscopy has been shown to reduce the presence of adhesions at the time of a “third-look” procedure.¹⁰⁹ Additionally, reduced rates of ectopic pregnancy have been reported in women having second-look laparoscopies.¹¹⁰

If second-look laparoscopy is to be performed for assessment and possible management of postoperative adhesions, Swolin ¹¹¹ recommended that it be done early (6 to 8 weeks) to improve the possibility of lysis of postoperative adhesions. Subsequently, Raj and Hulka¹¹² examined second-look laparoscopies performed up to 2 years after the initial procedure and demonstrated that bleeding was more common if the procedure was performed more than 12 weeks after surgery or sooner than 2 weeks after surgery. In the former case, bleeding was attributed to increased density and vascularity of the adhesions; in the latter, bleeding was attributed to granulation tissue.

Adjuvant Therapy

In addition to adopting microsurgical principles and optimal surgical techniques to reduce adhesion development, several other approaches have been suggested to help prevent and reduce the severity of adhesion development. Such approaches include the application of intraoperative devices and agents as well as the use of adjuvant medications to prevent adhesions. Table 52-2 includes a list of characteristics possessed by the ideal antiadhesive adjuvant.

Table 52-2 Characteristics of an Ideal Antiadhesive Adjuvant

Highly efficacious over range of conditions for which it will be utilized

High safety profile

No interference with tissue healing

Easy to handle

Easy to deliver

Stays where placed

Remains in abdominal cavity for sufficient time

Will not promote infection

Will not interfere with surgical procedure

Treats large area

Utilizable at open and endoscopic procedures

Biosorbable

Inexpensive

When reviewing the potential applications of adhesion barriers, it is important to distinguish the prevention of adhesions at the injury site versus other sites. It is not clear whether applying physical barriers to reduce adhesions at site of application can provide protection in areas other than the site of application.¹¹³ It has been shown that adhesions can readily develop at uninjured peritoneal sites distant from the midline incision and that a midline laparotomy initiates a generalized peritoneal inflammatory response.¹¹⁴ Hence, a single preventive measure, such as a physical barrier alone applied to one area, may not completely eliminate adhesion development throughout the abdominal cavity. In fact, the antiadhesion material barrier trials have used, as their endpoint, adhesion development at the site of barrier placement rather than at distant sites.

Potential Mechanisms for Antiadhesion Barriers

There are several different classes of antiadhesion barriers (Table 52-3). Approaches that have been suggested to minimize adhesion development involve one or more of the following mechanisms of action:

1. Reducing fibrin formation (anticoagulants and anti-inflammatory agents such as corticosteroids and nonsteroidal anti-inflammatory medications)

2. Enhancing fibrin elimination (peritoneal lavage with fluids, and enzymatic degradation by fibrinolytic agents such as urokinase and recombinant plasminogen activator)

3. Mechanical separation of injured surfaces (peritoneal floatation by lavage fluid and instillation of high molecular-weight liquids and application of mechanical barriers such as Interceed, Gore-Tex Surgical Membrane, and Seprafilm)

4. Indirect mechanisms such as enhancement of intestinal motility to prevent establishment of adhesions and other agents under investigations that modulate mediators of the inflammatory response to peritoneal injury, such as immunomodulator, melatonin, and biodegradable polymers, as well as the use of antibiotics to reduce and eliminate infection.

Table 52-3 Classes of Antiadhesion Agents

Fibrinolytic agents

Anticoagulants

Anti-inflammatory agents

Antibiotics

Mechanical separation

Table 52-4 gives some examples of various adjuvants that are generally used to prevent surgical adhesions.^115,¹¹⁶ Several substances and materials have been studied and used over the years. These commercial adhesion-reducing substances are relatively expensive, with their cost ranging between $100 and $300 per unit. Although much has been written about use of these agents to prevent adhesion development, too little is known about the economic impact of adhesion-reducing agents on the healthcare system.

Table 52-4 Examples of Antiadhesion Barriers

Oxidized regenerated cellulose (Interceed)

FDA approved for laparotomy but not laparoscopy

Requires meticulous hemostasis and removal of all irrigant fluids

Hyaluronic acid and carboxymethylcellulose (Seprafilm)

FDA approved

Difficult application by laparoscopy

4% Icodextrin (Adept)

FDA approved for laparoscopy but not laparotomy

Expanded polytetrafluoroethylene (Gore-Tex surgical membrane)

Not approved by the FDA for preventing pelvic adhesions

Not biodegradable

Requires suturing

Ringer’s lactate

Not approved by the FDA for preventing adhesions

No studies showing human efficacy

Dextran 70 (32%)

Not FDA approved for preventing adhesions

Significant complications such as coagulopathy

It is important to stress the fact that a great deal of the available “evidence” involving prevention of adhesions comes from numerous animal studies that have examined various means of preventing postoperative intraperitoneal adhesions, usually in relation to tuboplasties and other infertility-related operations rather than extensive pelvic surgery. In addition, most of the controlled clinical trials of adhesion prevention in humans exist in the infertility literature rather than the gynecologic oncology literature. Although the relevance of these studies to the prevention of adhesions associated with extensive gynecologic surgery is unclear, one may conclude that adjuvants effective in the prevention of adhesions in one clinical setting (infertility surgery) may also be effective in another setting (extensive gynecologic surgery). Such an assumption awaits confirmation but may be false if there are differences in the metabolic, hemostatic, and infectious parameters associated with extensive surgery from those associated with infertility surgery. Moreover, with limited procedures, such as lysis of adhesions, there is no real injury to the underlying structures, as compared with radical operations, in which peritoneal trauma can be extensive.

Human trials have not investigated the use of surgical adjuvants in preventing adhesions after radical pelvic surgery; therefore, it remains only speculative that this potential exists. Adhesions may simply represent the normal healing process after peritoneal injury. Indeed, with the degree of tissue destruction associated with radical operations, adhesion development may be physiologic rather than pathologic. Fortunately, animal studies and second-look laparoscopies, once largely limited to the infertility arena, are now being used in gynecologic oncology research and operative procedures by other surgical specialties.¹⁸

Activation of the fibrinolytic system is considered beneficial in the prevention of intra-abdominal adhesions. In the late 19th century, agents with potential fibrinolytic capacity, including liquor thiosinamine with sodium salicylate ¹¹⁷ and oral phosphorus,² were advocated. Streptokinase and streptodornase were the first agents with proven fibrinolytic properties that were effective in preventing adhesion development in rabbits and rats.^118,¹¹⁹ The value of activation of the fibrinolytic system remains unproven in humans.

Plasminogen Activator

Tissue plasminogen activator, the main plasminogen activator, has often been studied for prevention of adhesions. Although tPA proved to be effective, the risk of hemorrhage has been the main obstacle to its routine use. Anticoagulants such as heparin are also effective in adhesion prevention, although the use of local heparin in abdominal surgery remains controversial because of the risk of bleeding.¹²⁰^–¹²⁴

Mechanical Separtion of Injured Surfaces

In the past decade several mechanical barriers have been developed. Membranes of oxidized regenerated cellulose,^125,¹²⁶ modified hyalouronic acid and carboxymethylcellulose, or expanded polytetrafluoroethylene¹²⁷ were found to prevent the development of adhesions. All three coat the trauma site for the time (>7 days) required for re-epithelialization. Johns has reviewed the literature for the available evidence-based prevention of postoperative adhesions.¹²⁸ He concluded that level 1 evidence supports the efficacy of three barrier methods for the prevention of postoperative adhesions: Interceed, Seprafilm, and Gore-Tex Surgical Membrane. Adhesions are not eliminated by these barriers, and the main debate is the clinical significance with the level of adhesions prevented. Furthermore, most of the efficacy is at the site of application.

All three have limitations. Gore-Tex Surgical Membrane does not resorb and requires surgical removal or must be left in place permanently. Interceed and Seprafilm are biodegradable but also have significant practical limitations. Neither are approved for laparoscopy and their efficacy with this access is unproven.

4% Icodextrim is a recently approved adhesion reduction device that is a cornstarch-derived, water soluble branched glucose polymer. It is a solution that is applied intraperitoneally and is retaired in the peritoneal cavity for 3 to 4 days. Its effect is believed to be by hydroflotation.

Hyaluronan

Hyaluronan-based agents have been shown to prevent adhesions after surgery. The potential of these agents to reduce intra-abdominal adhesion in abdominal sepsis is a new promising concept. Hyaluronan-based antiadhesive agents, including modified hyaluronan–carboxymethylcellulose bioresorbable membrane and 0.4% hyaluronan solution, have been shown to be effective and safe for clinical application. Only the membrane, however, has been approved by the U.S. Food and Drug Administration (FDA) for use in benign diseases under noninfectious conditions.¹²⁹

Methods of Unknown Benefit

Hydrofloatation, the use of large-volume isotonic solutions such as normal saline and Ringer’s lactate, has not been directly tested in randomized studies for preventing postsurgical adhesions. However, lack of benefit of crystalloids (and in fact statistically significant worsening) was demonstrated by a recent meta-analysis.¹⁰⁷ Failure of effectiveness of crystalloids is due, at least in part, from the rapid absorption time. Most crystalloids are absorbed at approximately 30 to 60mL/hour.

However, recent studies have suggested that these crystalloids remain in the peritoneal fluid longer.¹³⁰ After the instillation of 300mL of Ringer’s lactate solution, 78mL was still present in the peritoneal cavity after 48 hours, compared with 30mL in patients in the control group, in whom no Ringer’s lactate was left.¹³⁰ By 96 hours there was no difference between the two groups. However, this is still too short a time to have a beneficial effect on adhesion formation.

The disturbed equilibrium between fibrin synthesis and degradation leads to persistence of fibrinous adhesions. These will become ingrown with fibroblasts, and subsequent collagen deposition results in the development of permanent fibrous adhesions. Treatment with halofuginone, an inhibitor of collagen type I synthesis, decreases the development of experimentally induced surgical adhesions.¹³¹ Clinical trials have not been conducted yet.

Anti-inflammatory drugs, including corticosteroids and prostaglandin synthetase inhibitors, have been tested for their ability to prevent adhesions.¹³²^–¹³⁴ Down-regulation of the inflammatory response in this way, however, gave conflicting results. Swolin¹³⁵ successfully reduced adhesion development in patients by applying intraperitoneal steroids, but others have reported equivocal or even deleterious effects.¹³⁴