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Pathophysiology of Adhesion Development 
MatWeb                           Pelvic Adhesions

Michael P. Diamond, MD
Professor, Department of Obstetrics & Gynecology, Wayne State University, USA
Director, Division of Reproductive Endocrinology & Infertility

Diaa M. EI-Mowafi, MD
Associate Professor, Department of Obstetrics & Gynecology, Benha Faculty of Medicine, Egypt
Researcher & Educator, Wayne State University, USA
Fellow, Geneva University, Switzerland

Pelvic adhesions observed in gynecologic patients are a major contributing factor to infertility, pelvic pain and/or intestinal obstruction. Such adhesions may be the sequelae to inflammatory processes, endometriosis, and prior surgical intervention. The latter will be the main topic of this article.
It has been recognized that pelvic adhesions occur in 55-95% of women following a laparotomy.1 This occurs in clinical trials in spite of different meticulous methods used to achieve this goal, including microsurgical technique, operative laparoscopy, the use of carbon dioxide laser and the use of medical and surgical adjuvants.2 This chapter explores the pathophysiology of adhesion formation and the different methods of its prevention or reduction. These different methods include: different ways to get into the abdomen (i.e. via laparotomy or laparoscopy), the variable surgical methods used either during the initial pelvic surgery or adhesiolysis which include macrosurgery, microsurgery, laser surgery and endoscopic surgery, and lastly, the different medical and/or surgical adjuvants used to prevent adhesion formation.
Pathophysiology of Adhesion Development
Adhesion development represents a disruption in the normal physiological process of peritoneal healing, although it is probably incorrect to call it abnormal healing since adhesion development can be thought of teleologically as a way for the body to resupply oxygen and nutrients to devascularized tissues. Following peritoneal injury, the process of healing without adhesions is initiated by release of histamine and vasoactive kinins causing an increase in capillary permeability with subsequent outpouring of serosanguinous fluid within three hours. This proteinacious fluid will coagulate, producing fibrinous bands between the denuded areas.3
A variety of inflammatory cells, including monocytes, plasma cells, polymorphonuclear cells, and histiocytes migrate to these fibrinous bands. Importantly, the fibrinolytic system is triggered to lyse these bands, usually within 72 hours. The denuded area of peritoneum is then reepithelized, probably within three to five days, with healing completed within 3 to 4 weeks. In contrast to skin which reepithelizes from the edges in, reepithelization of the peritoneal injury begins with, mesothelial migration from underlying primitive cells to line the denuded area into the peritoneal supportive matrix. If a disturbance in this equilibrium between fibrin deposition and fibrinolytic activity occurs, the fibrinous strands will persist, and will subsequently be infiltrated by proliferating fibroblasts, and later, new angiogenesis will take place and if tissue ischemia exists, thus an adhesion is created.
In fact, the definite etiology of pelvic adhesion formation is not clearly well known, but the following risk factors have been incriminated in this process: 
Intrabdominal infection. 
Tissue hypoxia or ischemia. 
Tissue drying. 
Rough manipulations of tissues during surgery. 
Presence of reactive foreign body. 
Presence of intraperitoneal blood. 
Dissection of prior adhesions. 
Ischemia of the tissues may result from excessive or rough tissue handling, ligating, suturing, crushing, cauterizing or stripping of the peritoneum. These may cause adhesion formation via inhibition of the fibrinolytic activity (which resides in peritoneal tissue) and stimulation of angiogenesis from a non-ischemic area to that devoid of its adequate blood supply. In addition, desiccation of the peritoneal tissue during prolonged surgical procedures may result in mesothelial cell desquamation with a resultant raw basement membrane and fibrin deposition.5
The common reactive foreign bodies that may be introduced into the field during surgery include: sutures, talc powder from surgical gloves, lint from drapes, cans, gowns, masks or laparotomy pads. Such foreign bodies lead to niduses excessive formation of the fibrin mass, which may result in adhesion formation. Interestingly, however, adhesions are less likely to develop in the presence of foreign body without coincidental peritoneal injury.6
The presence of intraperitoneal blood has been proposed to cause adhesions formation, although its actual role is not well understood.5 In general, intraperitoneal blood usually does not cause adhesion formation, except in the presence of tissue ischemia.7
It was a common concept that the mechanism of de novo adhesions formation and reformation after adhesiolysis is the same, although there is no experimental data supporting this. Nevertheless, in both experimental and clinical investigations the probability for adhesion reformation was greater than its de novo formation.1 This may be attributed to the higher degree of tissue ischemia in the previously damaged tissues than the native one.

Staging of Adhesions
Staging or classification of any medical or surgical disorder is the cornerstone to reach a univocal understanding facilitates communication among physicians and investigators, give a true judgment on the different modalities of treatment and clarify the expected prognosis for every individual case. Going into a medical or surgical disorder without staging or classification is like looking for luggage without an identification tag at Heathrow Airport.
In 1982, Hulka8 published a prognostic classification after five years of surgery for infertile patients in his institute. His classification was based upon 2 main factors; the extent of ovarian involvement and the nature of adhesions, whether filmy or dense. The poorest prognoses for achieving a spontaneous conception were in those patients with dense adhesions covering more than 50% of the ovarian surface visible at laparoscopy. The American Fertility Society (AFS) classification of adnexal adhesions (1985) had a great acceptability and became a universal one for many years. 
Recently, the Adhesion Scoring Group (1994)1 published their more comprehensive adhesion scoring system based on evaluation of 23 individual locations in the abdominal cavity for severity (0, none; 1, filmy, avascular; 2, dense and/or vascular; 3, cohesive) and extent of total area or length (0, none; 1£ 25%; 2, 26-50%; 3, >50%;4). 
The Adhesion Scoring Group reported that although the AFS adhesion scoring method generated significant agreement between pairs of surgeons, the use of the more comprehensive adhesion scoring method specifically demonstrating locations, severity, and the extent of adhesions produces a marked increase in reproducibility between surgeon pairs in scoring pelvic adhesions.
Unfortunately, none of these systems have been validated with clinical outcomes, and it is unlikely that they ever will be. 
The latter is because at second-look to score adhesions, additional surgical intervention is usually conducted; thus, clinical outcomes reflect the results of the second look procedure as opposed to the status of the pelvis at the beginning of the procedure.
As the previous classifications need the usage of an invasive procedure (usually laparoscopy) to achieve it, 
ultrasonography as a non-invasive tool was used recently to attempt to classify the pelvic adhesions.4

Surgery or Assisted Reproductive Techniques?
For many decades, surgical adhesiolysis was the only realistic option for an infertile patient with pelvic adhesions. After the birth of the first "test tube" baby, Louise Lesley Brown, in 1978 in England, a revolution in the use of assisted reproductive techniques (ART) took place. These techniques include9: in vitro fertilization and embryo transfer (IVF-ET), gamete intrafallopian transfer (GIFT) and zygote intrafallopian transfer (ZIFT). Microinjection (micro-manipulation), which entails mechanical transfer of sperm into the oocyte by a special micropipette is the most recently introduced assisted reproductive technique if there is an additional contributing factor for infertility such as severe oligospermia or athenospermia, or inability of sperm to penetrate the oocyte due to immunologidal factors. The main procedure for microinjection is intracytoplasmic sperm injection (ICSI), where the micropipette carrying the sperm is introduced through the zona pellucida into the oocyte cytoplasm and one sperm deposited. Now, the question is, which is more beneficial to the infertile female with pelvic adhesions; surgery or ART? Reported pregnancy rates after surgical treatment of pelvic adhesions vary from 25% to 75%. Rock et al.,10 reported normal pregnancy rates after surgery on severe, moderate and mild distal tubal obstruction to be 5%, 17% and 80% respectively, while the ectopic pregnancy rates were 0%, 13% and 6% respectively. The 17% rate of normal pregnancy reported after surgical treatment of moderate disease is comparable to the clinical pregnancy rate of 16% per retrieval for IVF-ET which was reported consistently over four years by the United States National IVF-ET registry.11 However, the 13% rate of ectopic pregnancy seen after surgical repair of moderate disease is nearly three times the approximately 5% rate expected after IVF-ET.12
Before choosing between surgery or ART, one must consider the severity of adhesions (the more extensive and dense, the poorer the prognosis of surgery)13, the patient's age, previous reproductive surgery, coexistent infertility factors as poor semenogram, suspected cervical or immunological cause and last, but not least, the financial constraints.
If the surgical approach is the wisest decision, the rational now is to reduce adhesion formation following both the primary reproductive surgery and/or adhesiolysis. This rationale passes through the following three main stations:
I. Getting into the abdomen.
II. Surgery inside the abdomen.
III. Adjuvants for adhesion reduction.

Getting into the abdomen:
Laparoscopy versus Laparotomy
The era of operative laparoscopy started in the 1980s and expanded to involve most of the previous traditional pelvic surgery. The advantages of endoscopic surgery are claimed to be reduction of hospital stay, postoperative pain, length of abdominal incision, and expense. One of the claims is the reduction of subsequent postoperative adhesion formation. This view is supported in theory by the concepts of lack of retractors and packs usage at laparoscopy, maintaining a closed abdomen with presumed reduction in peritoneal drying, less likelihood of introduction of foreign bodies, decreased possibility of blind dissection of adhesions during abdominal exploration and less tissue damage at the abdominal wall incision(s) compared to that of laparotomy. Luciano and co-worker14 have demonstrated no intra-abdominal adhesions in rabbits with the lesions created laparoscopically, whereas those lesions created at laparotomy were consistently followed by adhesion formation. Furthermore, the investigators then assigned those animals with adhesions to adhesiolysis at laparotomy or laparoscopy and demonstrated greater reduction in adhesion reformation following laparoscopic 
adhesiolysis. In their study, Nezhat and co-worker15 reported no de novo adhesion formation at non-operated sites at a second look laparoscopy done 4-8 months after laser laparoscopy for the treatment of endometriosis associated infertility in 157 patients. An overall 60-79% reduction in adhesions in patients undergoing adhesiolysis was observed. Diamond and co-workers16 described in a multicenter study a high (97%) incidence of adhesion reformation seen at early (90 days) second-look laparoscopy following laparoscopic adhesiolysis. Moreover, adhesion reformation occurred regardless of the consistency or vascularity of the initial adhesion.
This incidence is consistent with that previously reported following adhesiolysis at laparotomy, therefore they concluded that adhesion reformation would not be able to be eliminated by utilization of endoscopic surgery per se. Their report also pointed to a 12% of patients who developed de novo adhesions.
At this time, it seems that there is no clear and convincing evidence that laparoscopic adhesiolysis in humans is superior to microsurgical lysis of adhesions at laparotomy in terms of adhesion reformation or subsequent pregnancy.

Surgery inside the Abdomen
The use of microsurgery in reproductive pelvic surgery was first described by Swolin in 1967.17 The term microsurgery basically implies the use of magnification to allow close visualization, differentiation between healthy and pathologic tissues, handling the small caliber microsurgical instruments, and use of fine sutures. The fine sutures should be non-reactive, such as Vicryl, Dexon, or non-absorbable. The other main principles of microsurgery have included: minimization of tissue handling, prevention of tissue desiccation, avoidance of introduction of foreign bodies such as talc into the operative field, precise reapproximation of tissue planes and meticulous hemostatis.18 However, probably of greater controversy among these dictums is the benefit of precise approximation of tissue planes. Tulandi and his colleagues19 reported that leaving the anterior abdominal wall peritoneum unsutured after laparotomy results in less postoperative adhesions than its closure. However, they used chromic suture for closure; if a less reactive suture had been used, more difference might be noticed. Moreover, several studies recently suggested that ovarian bisection in animals results in fewer adhesions when the ovary is left open rather than closed. 20,21
In general, the use of microsurgical technique for adhesiolysis has improved the pregnancy outcome. It is difficult to interpret the results of the reports in the literature because of the variation in adhesion extent, consistency, and vascularity in addition to the personal skill variation. However, the following table shows a comparison between the results of use of macrosurgery versus microsurgery for adhesiolysis.

Table (1) Comparison between the results of macrosurgery versus microsurgery for adhesiolysis.

Macrosurgery/ Microsurgery
Total No. of Patient
Ongoing Pregnancies (%)
   Wallach & co-workers 22
Jansen 23
26 (41)
O’Brien & co-workers 24
16 (39) 
Betz & co-workers 25
20 (69)
Grant 26
94 (35)
Diamond 27
55 (25)
80 (57)
Caspi & co-workers 13
38 (38)
Donnex & Casanas-Roux 28
27 (64)
Tulandi 29
17 (52)
Frantzen & Schlosser 30
20 (41)
Laser Endoscopic Surgery:
Different types of laser now used in the reproductive pelvic surgery include argon, potassium-titanyl-phosphate 
(KTP-532), neodymium:yttrium-aluminum-garnet (Nd:YAG); but the most frequently used to date is the carbon dioxide, employed for its superficial site of action and variable spot size. It has been postulated that laser surgery will decrease dramatically the incidence of adhesion formation and reformation by virtue of making precise incisions, minimization of tissue handling, maintenance of meticulous hemostasis and reduction in operative time. However, in rabbits and rats, no reduction in post-operative adhesion was seen when the CO2 laser was compared with fine needle cautery.31,32
In a multicenter prospective study, an early (within 12 weeks) second-look laparoscopy was performed by Diamond and his colleagues 33to assess tubal patency and adhesion formation after intra-abdominal laser surgery. Procedures performed included neosalpingostomy, fimbrioplasty, lysis of adhesions, vaporization of endometriosis, and ovarian wedge resection. The results were compared with those of another multicenter prospective study that utilized non-laser reconstructive pelvic surgery. Use of CO2 laser was found to result in a greater tubal patency rate and adhesions were reduced from initial presentation at most sites. However, non-laser infertility surgery appeared to have equal or greater efficacy in the prevention of adhesion formation. It was concluded that the CO2 laser does not appear to be a panacea for the treatment of tuboperitoneal causes of infertility.
Dunn 34 examined 11 patients at second-look laparoscopy 12 to 21 days following laser laparoscopic adhesiolysis. No intraoperative agents were used for adhesion prevention. Fifteen sites were evaluated for adhesions. All patients had adhesion reformation in at least one site. Fifty-six percent of available sites had adhesions at second-look laparoscopy, which was not a significant change from the 60% of sites with adhesions of initial laparoscopy. De novo adhesions formed in seven of the patients at 23% of available sites.
McLaughlin35 utilized early second-look laparoscopy, done 6 to 12 weeks postoperatively, to evaluate recurrent adhesion formation following laser ovarian wedge resection. Forty-nine ovaries in 25 consecutive infertile patients underwent laser surgery for deep endometriosis or polycystic ovarian disease, refractory to medical treatment. On second-look laparoscopy, 36.7% of the ovaries had recurring adhesions; 83.3% of these adhesions were mild and filmy, and 16.7% were moderate and dense. Additionally, 2 ovaries that had mild and filmy adhesions lysed at 6 weeks during the second-look laparoscopy, have been found to have no recurrent adhesions when viewed one year later postoperatively. The actual pregnancy rate in this study is 60%, with 15 of the 25 patients conceiving at least once and two patients conceiving twice. The majority of pregnancies occurred within the first six months postoperatively, with the longest initial pregnancy occurring 22 months postoperatively. The author concluded that laser ovarian surgery, coupled with early second-look laparoscopy, appears efficacious in minimizing adhesion reformation and seems to have little adverse effect on subsequent conception.
Sutton36 stated that CO2 laser remains the most precise laser, especially in the ultrapulse mode, for the division of adhesions and the accurate and safe vaporization of deposits of endometriosis. The neodymium:YAG laser, because of its greater depth of penetration, is more suited to hysteroscopic surgery. Carbon dioxide laser energy is strongly absorbed by the water molecule and is rendered ineffective in the presence of blood, so the visible light lasers, argon and KTP-532, are more suitable for the treatment of ovarian endometriomas and ectopic pregnancies. The author concluded that the main advantage of the various lasers is that they allow fertility surgeons to perform operative surgery by the minimally invasive approach of laparoscopy rather laparotomy.
To summarize these and other studies appearing in the literature, it appears that lasers are useful for the performance of gynecological procedures when utilized by surgeons experienced in their use. However, it does not appear that use of a laser per se reduces postoperative adhesions or the complications they cause as compared to other surgical modalities. Furthermore, it appears that the use of lasers is generally decreasing, as surgeons become more experienced with alternative means of incising/excising tissue and in establishing hemostasis

The principle of SSL was first introduced by Swolin to evaluate the result of some surgical procedures.1 This principle soon became a routine used by many gynecological surgeons and investigators allowing a chance to perform adhesiolysis for the de novo or recurrent adhesions encountered during SLL. This is assumed to give the infertile patient a better opportunity to get pregnant. Trimbos-Kemper and co-worker37 went to further "third-look laparoscopy" in patients who had undergone an early second-look procedure with adhesiolysis at that time. They reported that more than half of the adhesions that were separated at the second-look laparoscopic procedure did not recur. The same was shown by Jansen38, who reported that second-look laparoscopy resulted in a significant reduction in adhesions at the time of a "third-look laparoscopy". The next logical question is: does the second-look laparoscopy provide benefit in terms of increasing the incidence of intrauterine pregnancies and/or decreasing that of ectopic pregnancy? Trimbos-Kemper37 reported a reduction in the incidence of ectopic pregnancy in women who had undergone SLL, although the intrauterine pregnancy rate was unchanged. Surry and colleagues39 reported a 52.1% intrauterine pregnancy in 31 patients who had undergone early SLL after reconstructive pelvic surgery. Unfortunately, none of these studies have been properly designed to provide a definitive answer to the value of second-look laparoscopy.
Other potential advantages of second-look laparoscopy include the ability of the surgeon to assess the efficacy of surgical techniques or adjuvants, as well as to provide the patient a reasonable assessment of likely prognosis. If the patient is among the approximately ten percent of subjects in whom adhesions worsen, that patient may benefit from early referral to ART as opposed to protracted lengths of time spent trying to conceive against very long odds.
What is the reasonable time for SLL? Even now, it is still a matter of personal opinion and controversy, varying from few days 37,38,40 to three years41 postoperatively. Swolin's opinion encouraged 6 weeks postoperatively as an optimum period for SLL42. Some surgeons feel that adhesiolysis performed via SLL carried out less than 2 weeks after the initial surgery is associated with increased bleeding from granulation tissue at adhesion sites; others prefer this interval because it is before patients have fully recuperated from their initial surgery and they anecdotally feel adhesions are easier to separate at this early time. Clinical studies, however, have not been able to identify differences in the frequency or severity of adhesions from intervals of 1-2 weeks to 3-4 months between the two procedures. Importantly, this suggests that if adhesions are going to develop postoperatively as a consequence of the surgical procedure that they will do so during the initial week after surgery.1 On the other hand, bleeding will also be considerable if the procedure is done more than 12 weeks after surgery as the adhesions become more dense and vascular.38

Adjuvants for Adhesion Reduction
Adhesion formation and reformation are still an unavoidable event in reproductive pelvic surgery in spite of the variable skills in microsurgery, endoscopic or laser surgery. This fact necessitates the search for an adjuvant(s) that can be used in the perioperative period. The field of these adjuvants becomes large enough to require a classification.
Table (2): Classes of adhesion-reduction adjuvants and their proposed mechanism of action

I. Fibrinolytic agents (fibrinolysis, stimulation of plasminogen activators)
Plasminogen activators 
II. Anticoagulants (prevention of clot and fibrin formation)
III. Anti-inflammatory Agents (reduce vascular permeability, reduce histamine release and, stabilize lysozomes)
Nonsteroidal anti-inflammatory agents 
Calcium channel blockers 
VI. Antibiotics (prevent infection)
V. Mechanical Separation (surface separation, hydroflotation)
A. Intra-abdominal Instillates: 
Mineral oil 
Crystalloid solutions 
Hyaluronic acid 
Chelated hyaluronic acid 
B. Barriers: 
Endogenous tissues: 
Omental grafts 
Peritoneal grafts 
Bladder strips 
Fetal membranes 
Exogenous materials: 
Fibrin glue 
Oxidized cellulose 
Oxidized regenerated cellulose 
Rubber sheets 
Metal foils 
Plastic hoods 

Modified from Diamond MP, DeCherney AH: Pathogenesis of adhesion formation/reformation: Application to 
reproductive pelvic surgery. Microsurgery 1987: 8: 103 and Diamond MP, Hershlag A: Adhesion formation/reformation: in Treatment of postsurgical Adhesions, Wiley-Liss, Inc. 1990: 23-33.

Fibrinolytic Agents
Fibrinolytic agents act directly by reducing the fibrinous mass and indirectly by stimulating plasminogen activator activity.43
Plasminogen activator is a serine protease that converts plasminogen into plasmin, which causes fibrin degradation. Recombinant tissue plasminogen activator (rtPA), delivered locally, was investigated by Vipond and colleagues44 in rats and found to be successive in reduction of adhesion formation significantly. It was even superior to carboxymethylcellulose (CMC) gel used in another group in the same study. CMC is another chemical component widely investigated for prevention of adhesions. Again, LeGrand and co-workers45 reported in their study on a rabbit model that imidazole, a thromboxane synthetase inhibitor, showed significant efficacy in prevention of adhesion formation to theuterine horn. They also found that Ridagrel, an inhibitor of thromboxane synthetase as well as a thromboxane A2 receptor blocker, also showed significant efficacy in reducing peritoneal adhesion severity. These results were contradictory to that of two other studies. The first was carried out by Gehlbach and others on rabbits46. They concluded that the combination of intraperitoneal rtPA and carboxymethylcellulose (CMC), did not reduce postsurgical adhesion reformation, and was associated with hemorrhagic complications. The second study was carried out by Bothin47 on rats 
and reported the rtPA and oxidized regenerated cellulose (ORC), which is an exogenous barrier, were unable to decrease adhesion formation. Nevertheless, rtPA mitigated the adhesion-increasing effect of ORC. Another worse drawback was reported by Evans and colleagues48 as they noticed that the levels of rtPA reguired to alter or prevent intra-abdominal adhesion formation also produce a significant impairment of the early phase of wound healing as measured by the wound content of hydroxyproline. Prior investigations have shown a strong correlation between wound-bursting strength and hyroxyproline content. The use of fibrinolytic agents in humans awaits investigation.
Heparin is the most widely investigated anticoagulant used for prevention of adhesions. Its mechanism of action is probably through one of the following: first, heparin may interact in the clouding cascade by a combination with antithrombin III.49 Second, heparin directly stimulates the activity of plasminogen activators, thereby promoting breakdown of fibrin clots once they form.50 Lastly, heparin may act by binding to fibroblast growth factor (FGF) leading to considerable improvement in healing of cutaneous wounds.51 Heparin has been added to peritoneal irrigants with concentrations around 5U/ml.52 In animal studies, this route of administration proved its efficacy.53,54 In rat uterine horn model, Sahin and Saglam55 added the low molecular weight heparin to the sodium carboxymethylcellulose solution instilled at laparotomy. They reported that this combination is highly effective in reducing postoperative adhesions in this animal model. Heparin has also been added to the local mechanical barriers to enhance its anti-adhesive benefit. Tayyar and co-worker56 added heparin to the amniotic membrane used to cover experimentally injured rabbit uterine horns. They showed that this combination was effective in reducing adhesion formation. In a rabbit uterine horn model study, Diamond and co-workers57 reported that heparin delivery by intraperitoneal lavage, intravenous injection, or intra-abdominal instillation failed to reduce adhesion formation. Similarly, heparin delivery with other intraperitoneal instillates as 
carboxymethylcellulose or 32% Dextran 70 failed to demonstrate efficacy. In their study, a significant reduction in adhesion formation was only observed with the combination of Interceed (TC7) and heparin where Interceed was utilized as a carrier to deliver heparin to traumatized surfaces. In another study, the same group of investigators reported that combination of the Interceed plus heparin in a dose of 500 and 1000 USP units per rabbit uterine horn resulted in a significant reduction of the adhesion reformation scores.58 This improvement in efficacy was not able to be demonstrated in a clinical trial done by Reid and co-workers59 where, after ovarian cystectomy and/or ovariolysis at laparotomy, one ovary was wrapped in Interceed TC7, and the contralateral ovary was wrapped in Interceed TC7 saturated with a heparin solution (1,000 U/ml). They noted that addition of heparin did not enhance significantly the adhesion-reducing capacity of the Interceed TC7 barrier when applied to ovarian surfaces.
However, it should be noted that the efficacy of Interceed alone in the trial exceeded its efficacy in another recent clinical trials.60
Anti-inflammatory agents
This group of agents was used to reduce the initial inflammatory response to tissue injury and hence, subsequent adhesion formation. This goal is probably achieved through the capability of these agents to reduce vascular permeability, inhibit synthesis and release of histamines and/or stabilize lysosomes. Anti-inflammatory agents that have been investigated included corticosteroids, nonsteroidal agents, progesterone and progestogens, antihistaminics and calcium channel blockers. 
Corticosteroids have been shown to decrease adhesion formation in small animals.61,62 Because of the large dosages required, the high risk of immunosuppression, infection and wound disruption have been noted.63 Corticosteroids were probably used on a large scale in clinical practice following Swolin's report that intraperitoneal hydrocortisone reduced adhesion formation as proved at SLL.64 But it is of importance to mention that all patients who received adjuvant for adhesion reduction were operated by Swolin, whereas those who did not receive corticosteroids had other primary surgeons. In fact, most of the animal studies failed to prove any reduction in adhesion formation with corticosteroid therapy.
diZerega and Hodgen65 found perioperative dexamethasone and promethazine to be ineffective in preventing adhesion formation after trauma to the fallopian tube. Seitz and co-workers66 investigated adhesion reformation after adhesiolysis in monkeys. Normal saline, low molecular weight dextran and dexamethasone/promethazine are three different adjuvant therapies given for separate groups. Adhesion reformation was similar in each of the three groups. The other few clinical trials for corticosteroid usage failed to prove its efficacy in reduction of adhesion formation.67
Nonsteroidal anti-inflammatory drugs (NSAIDs) are acting through several postulated mechanisms. NSAIDs have an anti-prostaglandins effect, thereby blocking the adhesiogenic action of prostaglandins instillated intraperitonealy.68 They have also been shown to inhibit platelets’ aggregation, leucocyte migration and phagocytosis, and lysosome release.5 Tolmetin, an NSAID was presumed to enhance macrophage function, and hence, allow rapid phagocytosis of tissue debris or fibrin.69 Tolmetin and ibuprofen have also been shown to increase fibrinolysis through decreasing the secretion of plasminogen inhibitors resulting in enhanced plasmin production.70,71 Most of the animal studies showed the effectiveness of NSAIDs in prevention of adhesions. Perioperative administration of oxyphenbutazone,72 and interaperitoneal instillation of indomethacin73 or tolmetin70 have been reported to reduce postoperative adhesion formation in rats and monkeys. In a recent study45, a rabbit uterine horn adhesion model was used to directly compare several commonly used NSAIDs of different chemical classes in a single animal study to evaluate their ability to prevent adhesion formation, Tolmetin, ibuprofen, aspirin and indomethacin all showed significant and comparable efficacy. These results support the view that there is a common mechanism through which NSAIDs act to prevent adhesions. In spite of that, other studies failed to prove any beneficial effect of intramuscular or intraperitoneal administration of ibuprofen in reduction of peritoneal adhesions in rat and rabbit models.73,74 Unfortunately, no clinical trials with NSAIDs have been published up until now, although several have been conducted.
Antihistamines, such as promethazine, inhibit the inflammatory response, stabilize lysosomal membranes and inhibit fibroblast proliferation. The use of antihistamines to prevent adhesions was in conjunction with corticosteroids and has not been shown to be effective in human studies.75
Progesterone was investigated for reduction of postoperative adhesions after the initial observation that adhesions were less after ovarian wedge resection if that ovary was containing an active corpus luteum at time of operation.76 Actually, the previous laboratory studies have elicited the anti-inflammatory and immunosuppressive effects of the progesterone. It was also shown that progesterone inhibits leukocyte migration77, and T-cell activation78, and reduces humoral antibody production. In addition, progesterone was found to decrease vascular permeability and the resulting volume of transudate in rats.80 Maurer and Bonaventura81 reported a decrease in adhesion formation if progesterone has been given by interaperitoneal and intramuscular route. Other studies were contradictory, finding an increase in adhesion development after intraperitoneal instillation of progesterone.82,83 In addition, intraperitoneal and intramuscular medroxyprogesterone acetate (MPA) has also resulted in an increase in postoperative adhesion formation82,84despite a significant reduction in antibody titers to peritoneum and myometrium.84 This concept was present until Montanino-Oliva85 and others published their recent study showing that preoperative IM administration of 15mg MPA into a rat model results in the most significant reduction of postoperative adhesion formation, even when it has been compared to leuprolide acetate and Ringer's lactate. They postulated that the action of MPA might be mediated by the induction of both a progestational and a hypoestrogenic milieu.
Calcium channel blockers have been shown to inhibit the release of vasoactive inflammatory mediators such as histamine and prostaglandins E and F.86 Tjssue ischemia is reduced as well by calcium antagonists.87 In addition, they have been demonstrated to inhibit platelet aggregation88, protect against granulocyte-mediated tissue injury89, and inhibit fibroblast migration into fibrin matrices.90 In a hamster animal model, Steinleitner and co-workers91 have demonstrated a reduction in pelvic adhesions with the use of subcutaneous verapamil, nifedipine, and diltiazam. Continuous intraperitoneal verapamil instillation was as effective as subcutaneous administration in the reduction of primary adhesion formation92, as well as adhesion reformation after lysis of peritoneal adhesions.93 These findings were unable to be confirmed in an animal study (Diamond and Linsky, Unpublished data).
Colchicine, which is known to inhibit histamine secretion, mitotic activity, and collagen synthesis and secretion, has been shown to decrease adhesion formation in two studies using a rat model.94,95 Unfortunately; no further studies have been carried out in this field.
The rationale behind the use of antibiotics is prophylaxis against infection, and hence the inflammatory response, that leads to adhesion development. Systemic broad-spectrum antibiotics, particularly cephalosporins, were widely used in the past. Nowadays, tetracyclines are commonly used to protect from chlamydia, a potentially infectious organism in the female genital tract.96
Unfortunately, there is no sufficient published data from animal or human studies supporting this practice. In contrast, intraperitoneal irrigation with antibiotic-containing solutions has been demonstrated to increase peritoneal adhesion formation in rat model.
Mechanical Separation
Mechanical separation of peritoneal surfaces of the pelvic organs during the early days of the healing process 
postoperatively was a practical way to prevent postoperative adhesions. This separation may be accomplished by intra-abdominal instillates and barriers whether endogenous tissue or exogenous material.
Crystalloid solutions were the most commonly used instillate put into the abdominal cavity after completion of the surgical procedure. In addition to its mechanical action in separation of the raw peritoneal surfaces, crystalloid solutions dilute fibrin and fibrinous exudate released from the traumatised surfaces.12
Unfortunately, crystalloid solutions are absorbed from the peritoneal cavity at an estimated rate of 35 ml/hr. Thus a volume of 500 ml will be absorbed within about 14 hours and 5 liters of crystalloid solution are needed to cover the first six days postoperatively. The process of peritoneal repair, fibrin deposition, and adhesion formation extends quite beyond the time during which a reasonable volume of crystalloid persists. The other drawback is the possible increased risk of infection with instillation of such a large volume of fluid into the peritoneal cavity.3 In an attempt to prolong the period of instillate persistence inside the peritoneal cavity, more viscous solutions have been tried in both experimental and clinical studies. A 32% dextran-70 solution (Hyskon) was among the most commonly used viscous solutions. Usually 200 ml of it is instilled into the posterior cul-de-sac at completion of the surgery. Hyskon acts as a siliconizing agent, coating raw surfaces. As an osmotic agent, it results in hyrdroflotation of the pelvic viscera, and additionally it stimulates plasminogen activators.52 Hyskon was investigated in four large clinical trials; the first initial two reports demonstrated a significant reduction in postoperative adhesions.99,100 The subsequent two studies failed to detect a beneficial effect to Hyskon.101,102 Complications from its use in humans have been reported, including anaphylaxis, pleural effusion, vulvar edema, transient liver function abnormalities, wound separation, disseminated intravascular coagulation, and abdominal bloating after its instillation.3
Carboxymethylcellulose (CMC) is a high molecular weight polysaccharide that acts as an adjuvant for prevention of adhesion by coating the intraperitoneal surfaces and creating hydroflotation of intra-abdominal structures. Using the rabbit uterine horn model, Diamond and co-workers found that intraperitoneal instillation of CMC significantly reduced postoperative adhesion formation and reformation.103,104 Yaacobi and colleagues105 reported that tissue coating with CMC prior to cecal abrasion in rat significantly reduced the formation of postoperative adhesion while coating following cecal abrasion failed to inhibit adhesion formation. A novel CMC sponge has been developed for prevention of surgical wound adhesions. It has been investigated by Ryan and Sax106 by performing by performing cecal denudation in rats. 
They concluded that CMC sponge was more effective than Interceed in preventing postoperative adhesions. Its action was not due to inhibition of cytokine transforming growth factor beta (TGF-beta) expression or macrophage-derived fibrogenic factors. 
Hyaluronic acid is a glycosaminoglyucan that under aqueous conditions forms a viscous solution. In rat studies, 
instillation of hyaluronic acid before cecal abrasion reduced adhesion formation107 while coating serosa surfaces after tissue injury was ineffective.108
Grainger and others109used the hyaluronic acid polymers at three different molecular weights and in form of a polymer slab to prevent adhesions in a rabbit animal model. None of the formulations of hyaluronic acid solutions resulted in a reduction of ovarian adhesions. Only the polymer slab significantly reduced adhesion formation. In a recent study110, a modified hyaluronate-carboxymethylcellulose gel was effective for reduction of adhesion formation in rat and rabbit models after surgery in the abdominal cavity. Treatment with this bioabsorbable gel increased the number of animals without any adhesions by 70% in a rat cecal abrasion model and by >70% in a rabbit sidewall defect bowel abrasion model compared with non-treatment control animals.
Poloxamers are groups of surfactants characterized by their ability to convert from a liquid state at room temperature to a gel form at temperatures higher than 25oC. If recooled, the polymer returns to its liquid state and conversion can be repeated. Poloxamer 407 of Flowgel is derived from a 4000 Kd hydrophobe and is composed of polyoxythylene and polyoxypropylene. Rice and colleagues111 used 0.5-1.5 ml of this poloxamer solution to cover uterine and sidewall defects in rabbit models. They noted a significant reduction in primary postsurgical adhesions; 95% of the control side had adhesions compared to 40% of the treated side.
Endogenous barriers as human amniotic membrane graft was tried to cover the traumatized surfaces for prevention of adhesions. In a rabbit-uterine horn model, Arora and co-workers112 showed that amniotic membrane graft failed to have the preventive effect on adhesion formation it is claimed to possess. Even worse amniotic membrane graft resulted in higher adhesion scores and subserosal inflammation score than the uncovered control side. Other data showed that when heparin was added to the amniotic membrane, it was an effective combination in reducing adhesion formation.56
Exogenous barriers such as metal foils, plastic hoods, silk and rubber sheets were used in the past to reduce postoperative adhesions. However, these substances have been abandoned because of lack of success and the need for its removal by a second surgical procedure.113
Gore-Tex surgical membrane is an exogenous barrier. It is composed of a polytetrafluoroethylene (PTFE) which is nontoxic, non-reactive and antithrombogenic; it is not absorbed and is unaffected by tissue enzymes.114 Therefore, it is a permanent membrane unless it is surgically removed later on. Placement requires suturing or some other form of fixation. 
In the animal studies, Gore-Tex has been proven to be an effective barrier for reducing primary adhesions, as well as reformation of adhesions.115 This encouraged its clinical trials. March and colleagues116 carried out their study where 18 patients with extensive pelvic adhesions and 10 with myomas had Gore-Tex applied over the adhesiolysis or myomectomy sites. At second-look laparoscopy, the membranes were removed easily with minimal adhesions to the traumatized site noted. However, it is common for a membrane to envelop the PTFE. In a multicenter nonblinded randomized clinical trial, Haney and his co-operatives117 studied 32 women with bilateral pelvic sidewall adhesions undergoing reconstructive surgery and second-look laparoscopy. They found that Gore-Tex was associated with fewer postsurgical adhesions to the pelvic sidewall and even superior to oxidized regenerated cellulose (Interceed TC7). To date, third-look studies to assess operative sites after removal of the enveloping membrane at second-look have not been systematically performed.
Fibrin glue is a combination of highly concentrated fibrinogen, thrombin, calcium, and factor VIII. It is postulated that fibrin glue acts by separating the raw surfaces through its rapid sealant effect.
In a rat model, a reduction in intra-abdominal adhesion formation was demonstrated with the administration of fibrin glue with a high fibrinogen concentration (from cryoprecipitate) but not when the fibrinogen concentration was low (from fresh frozen plasma).118 Obviously, the use of human blood products for fibrin glue production limits its attractiveness as a surgical adjuvant. Using rat models, a recent randomized, controlled study was carried out by Evrard and co-workers,119 showed that although the mean adhesion score was reduced by >50% with application of fibrin glue, there was no statistically significant difference concerning adhesion formation or peritoneal healing with the use of fibrin glue.
Surgicel is an oxidized regenerated cellulose (ORC) that was initially designed as a hemostatic agent. It was investigated as an adjuvant for prevention of adhesions because it is easy to apply and becomes a gel within hours after application. 
Initial studies showed that Surgicel is effective in preventing adhesions in rat cecal trauma model.l20,121 However, other studies failed to realize any reduction in adhesion formation in the same animal.122 The same controversy has been found with the use of a uterine horn model. In spite of most studies123 that found Surgicel to be effective in preventing adhesion formation, some124 did not confirm this observation.
Interceed (TC7) is an "altered relative" to Surgicel also composed of oxidized regenerated cellulose but differs in several characters including its degree of oxidation, weave, and smaller pore size. Interceed becomes a gel about eight hours after its intra-abdominal application. The material usually cannot be identified in the field within 3-4 days, and usually is degraded by the body without evidence of a foreign body reaction at the site of application.124 Interceed is metabolized into glucose and glucoronic acid within a few days.125
Initial rabbit studies using a uterine horn model showed a decrease in adhesion formation.126 This observation was confirmed by Diamond et al,127 using a sidewall model in which each animal could be its own control. These encouraging results initiated a human clinical trial conducted by multicenters. This study showed a significant reduction in the incidence and area of postoperative adhesion reformation in an actual report of 74 patients,128 and a follow up report of 134 patients.130 The use of Interceed necessitates meticulous hemostasis in the area prior to its application, otherwise it becomes ineffective. Wiseman et al129 used thrombin to achieve hemostasis in a rabbit uterine horn adhesion model facilitating the effect of interceed barrier. They added that the efficacy of Interceed was further enhanced by adding heparin to the fabric. A large multicenter study included 134 patients who underwent bilateral pelvic wall microsurgical adhesiolysis. In this study, Interceed was shown to further reduce the incidence, extent and severity of postoperative adhesion reformation and 90% of the patients benefits from the use of Interceed.130 To evaluate the efficacy of Interceed in prevention of postsurgical ovarian adhesions many studies were carried out. Franklin and The Ovarian Adhesion Study Group131 published a multicenter randomized study including 55 patients with bilateral ovarian disease. One ovary was randomly wrapped with Interceed at the completion of laparostomy and the other was left uncovered. At the time of second-look laparoscopy, they found that treatment of ovaries with Interceed significantly reduced the occurrence and severity of postsurgical ovarian adhesions. As regards laparoscopic ovarian surgery, Interceed was found to be safe and effective also in reducing the incidence of postoperative adhesion formation in patients undergoing laparoscopic ovarian cystectomy.132 These results are consistent with those of Larsson et al.,102 who also reported the ability of Interceed to reduce adhesions to the fallopian tubes. In contrast, in a small study (n=21), Saravelos et al.,133 were able to demonstrate a difference in reduction of adhesions on the Interceed-treated and control side after laparosopic electro-surgical treatment of polycystic ovarian syndrome.
In more studies, Haney and Doty134 found that Interceed, but not Gore-Tex surgical membrane has a localized injurious effect on the peritoneum of the mouse, resulting in de novo adhesions. However, in these studies the Interceed wasn't moistened and a 1 cm2 piece was used in the small abdominal cavity of the mouse. In spite of that, a recent report from the Nordic Adhesion Prevention Study Group135 showed in a randomized, multicenter, controlled study that by using a protocol in which other adjuvants have been shown not to be efficacious, Interceed was shown to significantly reduce the incidence and severity of adhesion reformation to the ovary, fallopian tube, and fimbria after infertility surgery.
A modified version of Interceed is neutralized Interceed (nTC), that is blood insensitive, has also proved efficacious in reducing adhesion formation and reformation in animal studies.136 The results using the nTC7 Interceed are comparable to those obtained with Interceed in combination with heparin. Further animal and human studies are needed, but the results thus far appear quite promising.
Seprafilm is a bioresorbable membrane composed of chemically modified sodium hyaluronate/carboxymethylcellulose. It has been investigated recently by Diamond and The Seprafilm Adhesion Study Group137 in a large randomized multicenter study, which includes 127 women who underwent uterine myomectomy with at least one posterior uterine incision 11 cm in length. In this study treatment of patients after myomectomy with Seprafilm significantly reduced the incidence, severity, extent, and area of postoperative uterine adhesions. Additionally, Seprafilm treatment was not associated with an increase in postoperative complications.

Pelvic adhesion development after gynecological operations and their reformation after adhesiolysis still, up until now, a problem that presents itself in the form of infertility, pelvic pain and/or intestinal obstruction. The following questions still need more investigations to be answered: Why some patients are more susceptible for adhesion formation and others are not? Can those patients be identified pre-operatively? Which stage of adhesion formation is more suitable to interfere with by an agent to reduce it?

Diamond MP: Surgical Aspects of Infertility. In: Sciarra JJ, ed.Gynecology and Obstetrics. Philadelphia: Harper & Row 1995; p 1-26. 
Diamond MP et al: Adhesion reformation and de novo adhesion formation following reproductive surgery. Fertil Steril 1987;47:864. 
diZerega GS: Contemporary adhesion prevention. Fertil Steril 1994; 61:219-235. 

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5. **
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132. Haney AF, Doty E: Murine peritoneal injury and de novo adhesion formation caused by oxidized-regenerated cellulose Interceed (TC7) but not expanded polytetrafluoroethylene (Gore-Tex Surgical Membrane). Fertil Steril 1992; 57:202. 
133. Nordic Adhesion Prevention Study Group: The efficacy of Interceed (TC7) for prevention of reformation of postoperative adhesions on ovaries, fallopian tubes, and fimbriae in microsurgical operations for fertility: a multicenter study. Fertil Steril 1995; 63:709. 
134. Wiseman DM, Kamp LF, Saferstein L et al.: Improving the efficacy of Interceed barrier in the presence of blood using thrombin, heparin or a blood insensitive barrier, modified Interceed (nTC7). Gynecological Surgery and Adhesion Prevention, Wiley-Leiss, New York, 1993; p 205;212. 
135. Diamond MP, The Seprafilm Adhesion Study Group: Reduction of adhesions after uterine myomectomy by Seprafilm membrane (HAL-F): a blinded, prospective, randomized, multicenter clinical study. Fertil Steril 1996; 66:904. 

 Michael P. Diamond, MD 
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