by Gabriel Miller
New York—Adhesions, particularly those following common procedures like appendectomy or hernia repair, are among the oldest and most common surgical complications encountered. Despite more than 150 years of published clinical insight into adhesions, they remain one of the most troublesome aspects of modern surgery.
“Preventing postsurgical adhesions remains truly an art rather than a science,” said Charles E. Miller, MD, clinical associate professor of obstetrics and gynecology at the University of Illinois College of Medicine, in Chicago.
“I second that,” said Stephen Kavic, MD, assistant professor of surgery at the University of Maryland School of Medicine, in Baltimore. “This is the one area where I find my colleagues wax poetic. There was a ‘forest of adhesions’; ‘I was wading through a sea of adhesions’; ‘the adhesions looked bad but they were mere cobwebs.’ You don’t get descriptive terms like this when you talk about the colon, but you find it often with adhesions.”
Drs. Miller and Kavic were two members of a panel of experts tackling the issue of adhesions and hernia mesh, during a plenary session at the 2010 annual meeting of the Society of Laparoendoscopic Surgeons.
“Healing Gone Awry”
Every surgeon is familiar with adhesions—fibrous bands connecting tissues and organs, typically bound to the peritoneum.
The key to understanding adhesions, and the newest approaches in preventing them, said Dr. Kavic, is that they are “an abnormal variant of a normal healing process initiated by trauma.” In other words, adhesions result from healing gone slightly awry.
“When tissue is traumatized the first thing that happens is the mast cells degranulate, causing an edema and the release of histamine and a variety of cytokines that initiate an inflammatory response,” said Kathleen Rodgers, PhD, director of research in obstetrics and gynecology at the University of Southern California, Los Angeles.
After this inflammatory phase, tissue formation begins with the recruitment of fibroblasts to create an extracellular matrix at the wound site.
“With the addition of these cellular elements—fibrinogen and thrombin onto the viscera—what can happen over time is the migration of myofibroblasts that can lead to fibrin deposition and a permanent adhesion,” said Dr. Kavic.
Because adhesions are a natural process, they may be instigated by any one of many postoperative conditions. “You have a number of issues, including infection, inflammation, a foreign body, tissue injury, necrosis—all of these contribute to postoperative adhesion formation. So the point is that it’s not a one-size-fits-all or simple mechanism,” said Ray Lanzafame, MD, MBA, associate professor of surgery at the University of Rochester School of Medicine in Rochester, N.Y.
Fibrinous adhesions are temporary and disappear over time, usually without incident. However, if inflammation is continuous—which is typical in the presence of a foreign body like mesh—fibrinous material is converted to fibrous material that forms permanent adhesions of the variety that “plague us and cause a terrific amount of grief,” Dr. Kavic said.
A Common Problem
Equally familiar to the surgical community is the variety of complications that can occur as a result of permanent adhesions, most notably small bowel obstruction, chronic pain and increased operative times in subsequent procedures.
Adhesions are so common, in fact, that they are not perceived as a legitimate complication worthy of informed consent, but instead as natural sequelae that occur in more than 90% of patients following major abdominal surgery, according to one review of peritoneal adhesions (Colorectal Dis 2007;Suppl 2:35-38).
However, a recent study found that 11% of patients are hospitalized within five years of an appendectomy for suspected adhesions, Dr. Kavic said. “That’s an alarmingly high number for a common clinical condition,” he added.
For the hernia patient, there is, perhaps not surprisingly, disagreement among surgeons about the best approach to prevent adhesions. “Generally speaking, it’s still felt that the incidence of adhesions after laparoscopy is lower than [after] open procedures, and certainly is least when the mesh surface is covered in some way,” said Dr. Lanzafame. “Adhesions are more likely with TAPP [transabdominal preperitoneal] and IPOM [intraperitoneal onlay mesh] repairs as opposed to a TEP [totally extraperitoneal] type of laparoscopic herniorrhaphy,” he added.
Nevertheless, adhesions can result from any type of hernia operation. “When we take a look at any mesh and any fixation method, we can find adhesions if we look at it hard enough; so adhesions are ubiquitous when it comes to mesh placement,” said Dr. Kavic.
Strategies and Products for Adhesion Prevention
Currently, there are three main approaches to prevent adhesions, and in particular, mesh and point-fixation adhesions in hernia patients:
•new approaches to affixing mesh to tissue
•composite materials that combine traditional mesh with a nonadhering surface
•resorbable liquid barriers that dissolve after the risk for adhesions has passed.
Recognizing that many current meshes allow aggressive tissue ingrowth in the first weeks after hernia repair such that permanent fixation is no longer necessary in some cases, companies introduced absorbable fixation tacks. These products, which are made from polylactic acids, show significant absorption within six months and nearly complete absorption within a year.
Although several studies have shown that absorbable tacks generally reduce postoperative pain, there are fewer data on adhesion formation using absorbable tacks. One early study of laparoscopic ventral hernia repair in a pig model found no difference in tack adhesions between metal and absorbable devices (Hernia 2004;8:358-364); in contrast, a much more recent study comparing Covidien’s metal and absorbable tacks in a rat model of laparoscopic incisional hernia repair found that adhesions were significantly reduced with absorbable tacks (Surg Endosc 2010;24:1318-1324).
Lately, hernia surgeons have eschewed point fixation altogether. The most well studied of these techniques involves fixation with resorbable biologic “glues,” most of which are tissue sealants first approved for use in thoracic or cardiovascular settings.
Much of the early research with biodegradable glues was done in inguinal hernia patients, where mesh placement within tissue planes provided a more favorable environment for glue fixation. However in the past year, three studies compared glues with other fixation methods in porcine models of laparoscopic ventral or incisional hernia repair.
The first study, conducted at the University of Southern California, found no difference in tensile strength or adhesions between four fixation methods: fibrin glue alone, transfascial sutures with tacks, fibrin glue with tacks and tacks alone (Surg Endosc 2010; July 31:Epub ahead of print).
More recently, a group at Washington University School of Medicine, in St. Louis, found that three absorbable tacking devices (PermaSorb, SorbaFix and I-Clip) were significantly stronger than fibrin glue (Surg Innov 2010;17:285-290).
Finally, in a study published in January, surgeons in Vienna demonstrated that fibrin glue fixation did not differ significantly from absorbable tacks provided that specific open-porous meshes were used. Fibrin glue did not work as well with polyester mesh coated with a resorbable collagen or condensed PTFE mesh (J Am Coll Surg 2011;212:80-86).
Covidien has introduced a self-affixing mesh that uses resorbable polylactic acid “microgrips” and adheres evenly to tissue within 60 seconds, according to the company.
“They’ve actually designed it to stick, so you’ve got these polylactic acid prongs in polypropylene, where sooner or later, the polylactic acid is resorbed and you have the underlying matrix,” said Dr. Lanzafame. “It’s the surgical equivalent of Velcro.” But currently, this mesh is not configured for laparoscopic use, he said.
Laser Tissue Welding
At the forefront of fixation is laser tissue welding or soldering, a technique that Dr. Lanzafame pioneered as a result of research funded by a National Institutes of Health (NIH) grant in collaboration with Conversion Energy Enterprises at the Laser Research Laboratory at Rochester General Hospital, in Rochester, N.Y. In this approach, mesh is welded to tissue using a collagen-based solder, which is then spread completely over the mesh material. In animal models, Dr. Lanzafame demonstrated that laser soldering can be used without increasing inflammation or adhesions compared with staples.
There are several obstacles that will need to be surmounted before surgeons can use laser-welding prosthetics intraperitoneally. “There are a couple of different issues, not the least of which is getting the [collagen-derived solder] where you want it, holding it in position and having minimal trauma to the tissue,” said Dr. Lanzafame. “This process is no small trick.”
Even if point fixation is abandoned in favor of fibrin glues or tissue welding, surgeons still will have to deal with adhesions forming on the mesh itself, or more commonly, around the perimeter of the mesh.
The current chapter in the long-running battle to reduce adhesions began 30 years ago with the work of Scott Jenkins, MD, who performed seminal comparisons of different mesh products. In 1983, Dr. Jenkins sought to characterize adhesion formation among five different materials, most of which still are used today.
The most recent leap forward involves the creation of barrier meshes, usually comprised of a solid anti-adhesive surface bound to a standard macroporous mesh. Dr. Jenkins’ original ideal of finding a material so chemically inert that adhesions would never form is probably unrealistic, but the practical difference between placing a standard macroporous mesh and a barrier mesh intraperitoneally is the difference between bluntly dissecting thin, flimsy adhesions that are easily swept off a mesh and getting bogged down in dense, vascularized fibrotic bands that require a half-hour or longer to clear.
With the introduction of microporous mesh in the early 1980s, the market for barrier meshes exploded and at least 11 barrier meshes are being manufactured for use in the United States.
As an extension of the barrier concept, more recently liquid barrier coatings have been recommended for use in hernia repairs. Last fall, a multinational, interdisciplinary consensus conference published recommendations for adhesion prevention that included advocating use of FDA-approved adhesion barriers when appropriate.
Currently, there are three FDA-approved adhesion barriers: Seprafilm (Genzyme), Adept (Baxter) and Interceed (Gynecare), each of which has benefits and drawbacks, according to the surgeons interviewed for this article.
Seprafilm, a sodium hyaluronate/carboxymethylcellulose, was the first approved by the FDA to prevent adhesions in patients undergoing laparotomy.
“It has been shown to decrease severity of adhesions—incidence has been a little bit more questionable—and adhesion reduction seems to be what it is marketed for and what it delivers,” said Dr. Kavic.
However, in a Cochrane review of published studies, reviewers found that even though adhesions were reduced, there may have been an increased risk for leaks when Seprafilm was wrapped around anastomoses, and furthermore it did not ultimately affect rates of small bowel obstruction or morbidity and mortality.
With Seprafilm, Dr. Kavic said, “we may be preventing adhesions, but at a bit of a price.”
Less well studied are the two other adhesion barriers, Adept and Interceed.
Interceed is an oxidized, regenerated cellulose barrier approved by the FDA in 1998 for reducing adhesions in open gynecologic pelvic surgery. However, Interceed has a black box warning against use in laparoscopic surgery and is specifically contraindicated as a hemostatic agent.
“It has been shown to reduce adhesions, but it doesn’t work well when there is blood,” said Dr. Kavic. “There are very few operations that I do that involve zero blood loss; most are minimal, but there is some present.”
Finally, there is Adept, a 4% icodextrin solution approved in 2006 to reduce adhesions in patients undergoing laparoscopic gynecologic surgery. The most significant point about Adept is that it carries more contraindications than the other adhesion barriers, including infection, laparotomy incision, bowel resection, appendectomy, and uniquely, allergy to cornstarch.
Although adhesion barriers represent a step forward, by no means are they the ideal agent, said Dr. Kavic.
“We have properties of the ideal anti-adhesive—it eliminates adhesions, it’s inert, it’s cheap, it’s pliable, it’s easy to apply, but we really don’t have that agent as of yet,” he said. “Seprafilm probably comes closest to the mark for general surgery, but we do not have this for the laparoscopic setting.”
Drug Therapies: The Future?
At the farthest reaches of the adhesion prevention spectrum lie systemic or medical treatments that support normal healing while limiting adhesion formation.
Drug therapies under investigation work in one of three ways, said Dr. Rodgers, the research scientist at the University of Southern California: They reduce fibrin deposition, accelerate fibrin removal or decrease the anti-inflammatory process.
“They accelerate the healing process by reducing the inflammatory response or they reduce the scaffold that adhesions are built upon,” she said. However, many of these agents affect clotting and Dr. Rodgers said there is some risk for bleeding at a time when clotting is paramount.
Dr. Rodgers said that several other agents have shown promise, including recombinant human activated protein C, a polysaccharide similar to heparin, and a recombinant tissue plasminogen activator. But like earlier medical therapies, these agents can affect blood clotting and wound healing.
“I’ve worked with most of these kinds of drugs, and again, what I’ve noticed in my animal models when I’ve given them is there is bruising and bleeding at the incision site, and there is a very low therapeutic index between efficacy and some toxicity with their use,” Dr. Rodgers said.
The problem is that these drugs are largely systemic, rather than localized, and when they are given locally, they are diluted in a wash that’s quickly removed from the wound site.
Ultimately, Dr. Rodgers believes the future of adhesion prevention is a combination of adhesion barriers and pharmacologic therapies.
“This is where the research is going,” she said. “It’s still at very early stages, and clinically no drug yet has been shown to reduce adhesions. There are barriers that are being used clinically to prevent adhesions, and they can be effective, but they are minimally effective and they have complications. We have to find something that steps up the ability of these barriers to be effective, and my recommendation would be a drug that is safe and prevents the inflammatory events that lead to the adhesion formation.”
Currently, the general surgeon, particularly for hernia repair, has an incredible armamentarium when it to comes to preventing adhesions. Despite this, adhesions continue to proliferate.
“There is a terrific volume of research that is going into the study of preventing adhesions, but there is nothing that has really been elevated above the rest as of yet,” Dr. Kavic said.
Kathleen Rodgers, PhD, is a consultant for FzioMed and has been a consultant for Atrium Medical.
Ray Lanzafame, MD, MBA, reports grant funding from the National Institutes of Health Small Business Innovation Research (SBIR) program and research equipment from Conversion Energy Enterprises, Inc. Dr. Lanzafame also is or has been a consultant for General and Plastic Surgery Devices and other panels of the Medical Devices Advisory Committee of the FDA’s Center for Devices and Radiological Health; he has done medicolegal consulting for various law firms and entities; and he has served as a consultant for various biomedical technology companies including Carestream Health, Conversion Energy Enterprises (CEE), Eastman Kodak, Lucid, Surgicon and business and venture capital groups.
Stephen Kavic, MD, reports no disclosures and no business or financial relationships that apply to hernia fixation or to adhesion prevention.
Charles Miller, MD, reports grant/research funding from Covidien and Femasys; he has served as a consultant for Ferring Pharmaceuticals, Ethicon Endo-Surgery, Ethicon Women’s Health and Urology, Boston Scientific, Care Fusion Interlace Medical, Covidien and Femasys; he serves on the speaker’s bureau for Ferring Pharmaceuticals, Ethicon Endo-Surgery, Ethicon Women’s Health and Urology, Merck and Femasys.