Guest Feature by Gere diZerega, MD
Click here to see Dr. Sinervo's update on adhesions.
Many people have re-examined what we know about peritoneal repair. Several studies have shown conclusively that microsurgical techniques alone cannot prevent adhesion formation. In six studies from 1982 to 1987, from 55 to 100% of patients had pelvic adhesions at second-look surgery.
In addition to causing pain, adhesions are expensive. Costs include subsequent surgeries to free adhesions, doctor visits, pain medication and millions of dollars in lost work time.
A fairly recent approach to adhesion formation has been the use of a physical barrier, such as Interceed. In order to understand this approach, it is first necessary to understand how the peritoneum heals.
In 1919, it was shown that peritoneum heals differently from skin. If you scrape your knee, healing occurs from the outside edges. Gradually, the raw spot in the center becomes smaller as the skin regenerates. In the peritoneum, islands of regenerated peritoneum occur over the entire surface at once. This means that large peritoneal wounds heal as quickly as small ones.
How long does it take? Most investigators agree that regeneration is complete within three to eight days.
Inflammation is an integral part of post-surgical repair. A major challenge in identifying drugs and physical barriers is the requirement that they do not further inflame an already inflamed area.
How Adhesions Are Formed
Typically, adhesions begin with a fibrin matrix that occurs during coagulation. Over the next few days (in the rat model) a variety of cellular elements become encased in fibrin matrix, which are gradually replaced by vascular granulation tissue containing macrophages, fibroblasts and giant cells. By four days post-injury, most of the fibrin is gone and more fibroblasts and collagen are present. Through days five through ten, fibroblasts align within the adhesion. At two weeks, the relatively few cells present are predominantly fibroblasts. At one to two months, the collagen fibrils organize into discrete bundles.
Eventually, the adhesion matures into a fibrous band, often holding small calcifications. Extensive adhesions often contain blood vessels.
Click the slide to see the image in full color and larger.
Historical Approaches to Adhesion Prevention
Most studies that looked at using corticosteroid drugs to help prevent adhesions reported little success. The pharmacologic properties of corticosteriods (they are anti-inflammatories) suggests they would be helpful in adhesion prevention. Why is this not the case? One possibility is that peritoneal surgery simply overwhelms the therapeutic benefits of the dose. If a higher dose is used, the effects on other organs (immunosuppression and delayed wound healing) outweighs any positive benefit.
Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of drugs that ease the post-surgical inflammatory response. Some studies have shown a marked reduction in adhesion formation in animal models when the drug was given peri-operatively. Another study showed that two doses of Ibuprofen post-operatively did not help, but a five-dose barrage did. When the NSAIDs were administered intraperitoneally, adhesions reduction resulted.
Areas devascularized by surgery are hypoxic, thus permitting fibrin persistence and adhesion formation. Devascularized sites are prime adhesion candidates. However, these sites are not readily available to drugs given systemically. Perhaps another method of drug delivery would help.
Dextran is a water-soluble glucose polymer originally used as a plasma expander. The weight most often considered in adhesion studies is a 32% solution of dextran 70 suspended in glucose. Hyskon is the best known brand name. Hyskon is slowly absorbed in five to seven days. Hyskon draws fluid equal to 2-1/2 to 3 times the original volume into the pelvis.
Animal studies were split. Some found that using Hyskon reduced the number and severity of adhesions. Other studies did not show positive results.
In people, Hyskon studies were also mixed. Some found that patients treated with Hyskon had fewer and less severe adhesions than patients treated with saline (Ringer's lactate). Other studies found no differences between treatments.
Hyskon carries with it side effects that include temporary weight gain, vulvar edema, leg edema, pleural effusion, and coagulopathy. Rarely, a patient may be allergic to it.
Barrier agents include mechanical barriers and viscous solutions. Many different mechanical barriers have been tried, but they are generally inadequate because they interfere with the blood supply or produceforeign body reaction. However, there are some exceptions.
Ideally, a barrier agent for adhesion prevention should be non-reactive, maintain itself during the critical stages of peritoneum regeneration, and then be absorbed by the body. Oxidized regenerated cellulose (Surgicel and Interceed) appear to satisfy these criteria. In addition, they do not support bacterial growth.
The first surgical studies were done with Surgicel. A few days after placement with sutures, Surgicel changes to a gelatinous mass and is absorbed. Some animal studies were very promising, but others were not. Surgicel was altered by its manufacturer with some positive studies then resulting.
Interceed is a newer product of the same type. It was designed to last longer in the pelvis than Surgicel. In addition, it didn't require sutures, if the pelvis were kept very dry. Animal studies yielded mixed results.
Early clinical studies were very positive, and Interceed was approved by the FDA in 1989 as the first product specifically indicated for reduction of postsurgical adhesions. Many studies since then have shown that the proper use of Interceed is useful in reducing formation of adhesions after surgery.
Gore-Tex has also been tested for adhesion prevention. Unlike Interceed and Surgicel, Gore-Tex is not absorbed by the body and must be anchored in place. It is used in heart surgery. However, its use in gynecological procedures is far from certain. A comparison study of Interceed and Gore-Tex showed that both reduced adhesions, although Interceed performed better.
Studies have shown that it is not necessary to suture the peritoneum to help it heal after surgery. Indeed, two studies showed that using stitches made the adhesions worse. Therefore, it is better to leave the peritoneum unsutured after surgery. It will heal satisfactorily on its own.
The most common method used to try to prevent adhesion formation after surgery is to use a crystalloid solution. The best known are Ringer's and plain saline. However, several studies have shown that these solutions do not help prevent adhesion formation. The most common amount of solution used is 200mL. This is absorbed by the body in about six hours. Peritoneal repair takes many more hours. Adding more solution isn't the answer, either. Five thousand mL of solution takes about five days to absorb. However, such a large amount may reduce the body's ability to fight infection.
Although many clinicians assume that laparoscopic surgery will reduce post-operative adhesion formation, the data is not compelling. However, de novo adhesion formation was substantially reduced by laparoscopic surgery.
Much progress has been made. Use of barrier methods, however, is limited to surgical situations where the area in question can be completely covered. In addition, Gore-Tex needs to be anchored, and Interceed requires hemostasis and removal of excess peritoneal fluid.
The development of new aids to prevent postsurgical adhesion formation is encumbered by the way the peritoneum heals, access to the peritoneal cavity, limitations of animal models, and the complexities of interperitoneal circulation and transperitoneal transport.
Important Questions Remain:
Why do some patients form adhesions after trauma while others do not?
What are the differences between adhesion reformation and de novo adhesions?
What are the different potential for adhesion formation due to general surgery, endometriosis, cancer, infection and ovulation?
A direct cause-and-effect relationship between adhesions prevention and outcome measures is difficult to establish. Screening of potential tools is time consuming and expensive. For a company to invest in this therapeutic area only to find a disparity between preclinical animal results and clinical trials is disappointing and costly. Soon, regulatory agencies must set guidelines of "effectiveness" and delineate clinical settings for definitive evaluation of usefulness.
To date, no treatment has proven uniformly effective in preventing postoperative adhesions formation. Surgical techniques that preserve good blood flow as well as the use of mechanical barriers, provide clinical benefits to the patient today.
Dr. Albee Responds
Dr. diZerega's article is thorough and objective. His expertise in this area is evidenced by his huge list of publications. I am very impressed by his work. And, as he makes clear, pelvic adhesions can cause terrible problems.
I'll spend the rest of this space explaining what I do here at the Center for Endometriosis Care to minimize adhesion formation.
In my opinion, the single most important thing I do to lessen the chance for adhesion formation is our thorough, painstakingly meticulous approach to the surgery. That approach includes the following items:
I aim for complete hemostasis. This means I accept absolutely no bleeding or oozing from any surface area.
I handle all tissues with atraumatic instruments so there is no crushing of tissues.
Because all abnormal tissue is excised instead oflaser ablated, fulguration or cautery, I minimize the amount of devitalized tissue left behind. This greatly reduces adhesion formation.
Bleeding vessels that cannot be controlled with the laser are bipolar cauterized intermittently to minimize heat accumulation.
If an ovarian capsule that has been opened to remove endometriosis does not naturally fall into an opposed position, I suture it closed to lessen the exposed raw surface.
I do float the pelvic tissues with saline at the end of the procedure.
When I think it will be advantageous, I use Interceed on the uterus or ovary.
I acknowledge Dr. diZerega's report that a published study that proves laser dissection creates fewer adhesions has not yet been seen. However, it has been my experience that laser dissection can cause less tissue trauma and less heat-related injury, if it is used according to the principles outlined above. Any technique is only as good or bad as the surgeon using it, which helps explain the wide disparity of results at the hands of different surgeons who use similar techniques.
At the Center for Endometriosis Care, the majority of our problems with adhesions have come from our stage III and IV patients. We routinely remove all adhesions we see when we operate on a patient. Because endometriosis can hide beneath adhesions, it is vital to completely excise the scar tissue to be certain no endometriosis is left behind.
Occasionally, I will perform a second surgery on a patient I have operated on before. Should those cases reveal adhesions, it is usually a straightforward process to cut through them with the laser and remove the source of pain. If all the endometriosis was removed at the first surgery, the resulting adhesions were formed post-operatively. Without deep dissection or endometriosis to cause re-formation, I feel the chance for de novo adhesions is minimal. This lets us safely cut through them, restoring the anatomy to normal and relieving any ongoing pain.