Adhesion Prevention: A Standard of Care

At a symposium held during the Annual Meeting of the American Society of Reproductive Medicine, a panel of speakers discussed the relationship of adhesions to infertility and reviewed methods for adhesion prevention.

This program was supported by an educational grant from Gynecare.

Surgical Techniques and Cost Effectiveness of Adhesion Prevention

“Ninety-three percent of patients who have abdominal surgery will have adhesions,” according to Togas Tulandi, MD, Professor of Obstetrics and Gynecology, The Milton Leong Chair in Reproductive Medicine, McGill University, Montreal. “Adhesions cause infertility, pain, and bowel obstruction,” he explained.

The National Hospital Discharge Survey of hospitalizations between 1998 and 2002 found that out of 281,982 hospitalizations, 51,100 were related to adhesions and adhesions were one of the problems for 227,882 other hospitalizations. All together, adhesions were directly or indirectly responsible for 948,000 hospital days, costing $1.18 billion (U.S.).

Another financial consideration is intestinal injury during adhesiolysis. One study found that 52 out of 270 patients had inadvertent injury during adhesiolysis. Risk is related to body mass index and the number of operations. “More injury occurs because of previous abdominal and pelvic surgery,” Dr. Tulandi said.

“There is an association between infertility and adhesions,” he continued. He described research he conducted to test whether removing adhesions would enable women to get pregnant faster. If a patient was not able to achieve pregnancy within one year, Dr. Tulandi would do laparoscopic surgery to remove adhesions. He found that women who had adhesions removed got pregnant faster than those who had adhesions that were not removed.

Pain is another critical aspect of pelvic adhesions. He described an old study that looked at pain in patients who had stage IV adhesions, local adhesions, or adhesions that had been removed. The study found that there was much greater reduction of pain in the group with stage IV adhesions that had been removed.

Small bowel obstruction is another critical aspect of adhesions. “Post-surgical adhesion is the most common cause of bowel obstruction,” Dr. Tulandi said. Within one year following surgery, 1% of patients with adhesions develop bowel obstruction. He explained that gynecologists rarely see patients with bowel obstruction because it can occur years after the initial surgery. When symptoms occur, the patients usually go to the emergency room or to a general surgeon. He added that there is a slightly higher risk of small bowel obstruction in patients who underwent peritoneal closure. “Peritoneal closure is unnecessary and can be harmful,” said Dr. Tulandi.

Dr. Tulandi reviewed measures that surgeons can take to decrease adhesion formation. For example, measures should be taken to avoid tissue dessication and necrosis. Non-reactive suture material should be used. Liberal irrigation should be employed. Carbon material, necrotic debris, and dermoid material should be removed. The surgeon should use good technique and microsurgical principles.

Adhesion preventing agents can be divided into two categories: intra-peritoneal instillates and adhesion barriers. Intra-peritoneal instillates include Ringer’s lactate, dextran-70 (Hyskon®), and Intergel®. Adhesion barriers include Interceed® (TC7) Absorbable Adhesion Barrier, Preclude®, Seprafilm®, and SprayGel™.

“Hyskon therapy is back but two or three randomized studies have shown that it doesn’t work,” Dr. Tulandi said. Randomized studies have shown that Intergel®, Interceed®, Preclude®, and Seprafilm® work in preventing adhesions. Experimental adhesion barriers include Surgisis® (porcine submucosal layer), pericardial dome patch, siliconized nylon sheet, hyaluronate-based bioresorbable membrane, polypropylene mesh, and collagen membrane/fleece composite film.

In conclusion, Dr. Talundi stated: “We still don’t have a surgical adhesion prevention substance that is great, but good surgical technique along with adhesion prevention might be helpful.”

Current Modalities for the Prevention of Adhesions

Gere S. diZerega, MD, Professor, Department of Obstetrics and Gynecology, University of Southern California Keck School of Medicine, spoke about FDA-approved technologies for adhesion prevention. “They do not affect peritoneal repair for the duration of time that they remain in the peritoneal cavity,” Dr. diZerega said. “They function as adhesion prevention barriers by preventing formation of fibrin bridges to adjacent tissues.”

Dr. diZerega began by reviewing the peritoneal repair process. Initial repair is a result of coagulation. Peritoneal cells implant on the surface and proliferate over a five- to seven-day period. “This five- to seven-day time period then becomes a target for us,” said Dr. diZerega. Fibrin bridges are formed as a byproduct of coagulation. These fibrin bridges become adherent between the adjacent peritoneal surfaces, leading to the formation of the surgical adhesions. “From a strategic point of view you can effectively separate peritoneal repair from adhesion formation,” Dr. diZerega said.

The most commonly used adhesion prevention method, which is not approved by the FDA, is hydroflotation using crystalloid solutions such as lactated Ringer’s solution or saline. However, “hydroflotation does not work because of the rapid rate of absorption,” explained Dr. diZerega. He listed several studies that have all shown that crystalloids do not prevent adhesions.

There are three devices approved by the FDA for adhesion prevention: the site-specific Interceed® and Seprafilm®, and the broad-covering Intergel®. These devices are FDA-approved for laparotomy use. “There are no approved devices in the United States for adhesion prevention by a laparoscopic instillation,” Dr. diZerega said. Numerous studies have demonstrated the effectiveness of these adhesion prevention devices. More and more physicians, both gynecologists and general surgeons, are utilizing these devices on a routine basis.

Seprafilm® is a site-specific device that is made out of hyaluronic acid and carboxymethylcellulose, and it achieves good results, according to Dr. diZerega. Seprafilm® is very tacky and surgeons must hold the film in its special packaging. The surgeon needs to make sure that the field is dry and easily accessible. Applying Seprafilm® to the posterior pelvis is very challenging. “Studies have provided compelling evidence that Seprafilm® works,” he said.

Interceed® is made of oxidized regenerated cellulose. It is the same material as Surgicel; however, Interceed® lasts longer in the peritoneal cavity. Dr. diZerega reviewed six studies on the efficacy of Interceed®. The results of the studies were fairly consistent and showed that Interceed® is twice as good at preventing adhesions as surgical technique alone. He cited a study by Sawada and colleagues in which patients in a general infertility practice who received Interceed® became pregnant more frequently than the surgical controls (J Repro Med. 2000;45(5):387-9).

Dr. diZerega said that there are two problems with Interceed® that compromise efficacy. First, Interceed® turns black when placed on bleeding tissue because hemoglobin has touched the oxidized cellulose. If a spot of black appears, it is not of concern. However, if the spot enlarges, Interceed® should be removed and better hemostasis established. The second problem is related to the presence of residual irrigation fluid. In the Trendelenburg position, the excess fluid goes into the upper abdomen. Once the patient is out of this position, the excess fluid flows down into the cul-de-sac and washes off the Interceed® (or Seprafilm®). “This is a very major consideration in using this technology,” said Dr. diZerega. He recommended that, when using these site-specific barriers, the patient be placed in reverse Trendelenburg and the fluid in the cul-de-sac removed until there is less than 10 milliliters remaining.

Intergel®, the most recently approved adhesion prevention device, is made of hyaluronic acid, iron, and water. Hyaluronic acid is naturally found in the human body — it fills the eye chamber and is used routinely in ophthalmologic procedures. The hyaluronic acid molecule is absorbed very quickly across the peritoneal membrane.

In Intergel®, the hyaluronic acid is ionically crosslinked by iron, which slows absorption by the peritoneum. Intergel® provides a transient, viscous, lubricious coating on peritoneal surfaces following surgery. It is packaged in an accordion-like bottle for easy instillation to the surgical site. “You don’t need to be concerned about where you put Intergel® because intraperitoneal circulation will distribute the material along the peritoneal surfaces,” Dr. diZerega said. However, because Intergel® is distributed, the entire bottle must be instilled so that efficacy is not compromised.

Dr. diZerega described a randomized, controlled, multicenter study, conducted by Johns and associates on 265 female patients undergoing laparotomy (Fertil Steril. 2001;76:595-604). Patients were treated with either Intergel® or lactated Ringer’s solution. Follow-up laparoscopies were conducted and effectiveness was measured at 24 different abdominal and pelvic sites. The American Fertility Society (AFS) classification of adnexal adhesions was utilized to measure efficacy. The tube and ovary from each adnexum were evaluated and scored. This score, which is the most widely used adhesion scoring system, correlates with pregnancy outcome. Intergel® reduced the AFS adhesion score by 59%, whereas patients who received lactated Ringer’s solution had an increase in AFS adhesion score. The difference was statistically significant.

A modified AFS (mAFS) adhesion score was calculated using the efficacy data from throughout the abdomen and pelvis. Patients who received Intergel® had about a 50% reduction in their mAFS adhesion score compared to controls for all types of adhesions (reformed, de novo, surgical site, and so forth). The majority of patients in this study had myomectomies or adhesiolysis. “With different surgical procedures, Intergel® worked very consistently, causing about a 50% reduction in the mAFS score,” said Dr. diZerega.

Another way to analyze the study data is to look at the outcome of individual patients using a shift table. “A shift table demonstrates efficacy via individual patient results,” explained Dr. diZerega. The shift table was designed to demonstrate a change in adhesion classification from the initial condition at first surgery (baseline) to the condition at second-look laparoscopy. “You can ask questions; for example, if the patient had no adhesions at the time of initial surgery, what happened to her at laparoscopy?” he said. “Using shift-table analysis, these things match very nicely.”

Dr. diZerega next discussed the clinical outcome of the Intergel® study. Patients with moderate to severe AFS adhesion scores and/or difficulty conceiving naturally constitute a bad outcome or failed surgical therapy. No patients in the Intergel® group had a severe mAFS adhesion score at second-look laparoscopy compared to seven patients in the control group. When including patients with moderate mAFS adhesion scores, nine in the Intergel® group and 32 patients in the lactated Ringer’s group had a bad outcome, or failed surgical therapy.

Dr. diZerega concluded by summarizing the safety of Intergel®. In the FDA pivotal study, the safety of Intergel® was the same as lactated Ringer’s solution. Intergel® was launched in Europe about three years before it was approved in the United States. There have been reports of late onset postoperative pelvic pain associated with Intergel® use. About 1 in 1,000 patients develops diffuse pelvic pain about three or four days after surgery. Noninfectious peritoneal inflammation is sometimes evident on follow-up surgery. Laboratory tests and vital signs are often normal. This adverse event is self-limited and may be associated with foreign body reaction. This very rare, late onset peritoneal inflammation has occurred with Seprafilm® also.

“We cannot predict who is going to form adhesions,” Dr. diZerega explained. But “now we have available to us FDA approved devices that may prove beneficial in terms of adhesion reduction and improved clinical outcome,” he concluded.

Future Modalities and the Treatment Avenues of Investigation in Adhesion Prevention

“Adhesion formation is actually a defect of the healing process,” said Nasser Chegini, PhD, Professor, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Institute for Wound Research, University of Florida, Gainesville.

He presented a review of the basic research conducted in recent years, along with current research that is intended to improve the outcome of the peritoneal healing process. “The devices that are currently available for postsurgical application with the intention of reducing or preventing adhesion formation are at best 50% effective,” said Dr. Chegini. “Therefore there is a need for better understanding of the peritoneal wound environment in order to design effective therapies to achieve near normal wound healing,”

Dr. Chegini presented data from a paper by Lower and colleagues that was a 10-year follow-up review of over 54,000 patients’ medical records from the Scottish National Health Service Registrar Database. They clearly showed the immediate and long- term scope of peritoneal-adhesion-associated morbidity following gynecological and lower abdominal surgeries. They concluded that 30% to 35% of all hospital readmissions were associated with potential adhesion-associated complications, of which 4.5% to 5.1% were directly related to adhesions. Patients who underwent gynecological surgery involving ovaries and fallopian tubes were at the highest relative risk of hospital readmission for complications directly related to adhesions.

Lower also found that 2,931 patients were readmitted to the hospital at least one time because of adhesions. Readmissions were broken down into categories based on whether they were directly related to adhesions (n = 245), possibly related to adhesions (n = 2,479), or potentially complicated by adhesions (n = 2,709).

Dr. Chegini continued with a review of current knowledge of peritoneal wound repair. Cell or tissue injuries cause a local inflammatory response with increased cellular migration, angiogenesis, and matrix deposition. “If these processes proceed normally to control wound healing, we have adhesion-free repair,” explained Dr. Chegini. Adhesions are formed when these processes become altered. Peritoneal adhesion formation is influenced by platelet-derived growth factor and a secretory product of inflammatory and immune related cells. Growth factors, cytokines, chemokines, and eiconsanoids play a role. “Extracellular matrix, adhesion molecules, and proteases are key factors in the outcome of scar formation,” he explained.

Dr. Chegini reviewed the common characteristics and differences between healing at the dermal level and the peritoneal level. In both wounds, during the inflammatory phase, a fibrin clot is formed and the wound site contains neutrophils and macrophages, which release growth factors such as vascular endothelial growth factor (VGEF), transforming growth factor (TGF), and platelet-derived growth factor (PDGF). Reepithelialization and neovascularization processes which occur at a later stage are influenced by urinary plasminogen activator, tissue plasminogen activator, and matrix metalloproteinases (MMP) that are released in the wound. The peritoneum is composed of mesothelial cells, fibroblasts, and adipocytes; their continuous exposure to peritoneal fluid make peritoneal wound healing proceed differently from dermal wound healing.

Immediately following wounding a vascular response, blood coagulation, and the inflammatory process occur. The vascular response lasts a few days, whereas blood coagulation is completed on the first day. Inflammation lasts throughout the healing process, but peaks a few days following injury. On the second day post injury, new tissue is formed and epithelialization occurs. New tissue formation occurs throughout the whole healing process; however, epithelialization is completed within about 12 days. Contraction occurs between the third and 20th days of the healing process.

Dr. Chegini reviewed data from a study that looked at several chemical messengers that are key factors in adhesion formation and the wound healing process. It was found that different abdominal and pelvic tissues have different levels of these key factors. For instance, adhesions have a greater amount of TGF-beta mRNA than the intact peritoneum. And adhesions have lesser amounts of MMP-1, tissue inhibitor of metalloproteinases-1 (TIMP-1), and integrins mRNAs than the peritoneum. These differences may explain, at least in part, why adhesions develop at one site rather than another.

“When you have an injury, many of these factors get altered, and the additional impact of inflammation results in more scar formation at the injury site,” said Dr. Chegini. There are no data to understand why some patients are prone to developing adhesions and why some develop severe adhesions.

He concluded by summarizing what he believes will reduce the incidence of adhesions. Better surgical training and tools are important considerations. Research designed to define the peritoneal wound environment would identify target molecules. This information would be used to design devices carrying wound-modifying factors to alter the wound healing process.

“I think for the next 10 years or so we have to go for 100% reduction in the adhesion,” concluded Dr. Chegini.

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