Surgical Adhesions Summit Launches Ambitious Improvement Project

The ACS gathered 100 experts from around the world for its first Surgical Adhesions Improvement Project Summit last month. The 2-day event, held in Washington, DC, aimed to generate momentum in effective prevention, assessment, and treatment for surgical adhesions.

The reason to meet was simple, if ambitious. Surgical adhesions occur in approximately 90% of patients who undergo abdominal or pelvic surgeries, triggering nearly 300,000 additional surgical procedures and $2.3 billion in costs each year. But despite their prevalence, there are few effective means to prevent or treat adhesions.

This group of experts is determined to change that.

The assembly included surgeons, biologists, engineers, and researchers from nearly a dozen countries—a team brought together with the help of Peter and Marshia Carlino, who donated $1 million to the ACS Foundation to help fund surgical adhesions research. In a speech, Mr. Carlino explained that his family’s motivation was personal: one of their sons, a Crohn disease patient, has required extensive treatment for surgical adhesions and had suggested that the family’s philanthropy should include attention to this problem. Movingly, Mr. Carlino thanked the experts present for “your willingness to join us in this shared mission.”

The mission was indeed shared; in addition to expressing gratitude to the Carlino family, multiple speakers commented on their pleasure at finding a rare receptive audience for the topic. Richard ten Broek, MD, PhD, a medical researcher at Radboud University Medical Center in Nijmegen, the Netherlands, as well as leader of the Dutch Adhesions Group, said, “There has never been a dedicated conference on adhesions, so it is good that there is one now.”

With that dearth of prior attention in mind, the conference took a comprehensive approach. Samuel P. Carmichael II, MD, FACS, a trauma surgeon at Wake Forest University School of Medicine in Winston-Salem, North Carolina, and one of the event’s key organizers, later said, “If you came to this meeting not knowing anything about adhesions, you will leave with a holistic understanding of where we've been, where we are, and where we're going, and that’s been our goal from the beginning.”

Where We’ve Been

Some of the atmosphere of inattention to adhesive disease reflects the sheer difficulty of addressing this problem. Attendees described a basic conundrum: adhesions form as wounds heal and, therefore, efforts to inhibit adhesion formation also may inhibit wound healing. Similarly, efforts to remove existing surgical adhesions create new wounds and thus can provoke more extensive adhesions to form. As a result, avoiding adhesions requires simultaneously helping healthy tissue to form while avoiding excessive or pathological growth.

Several steps toward prevention and treatment remain undone. These include finding ways to effectively assess, measure, and record surgical adhesions. Laboratory research elucidating how adhesion tissue forms, plus engineering to create useful prevention and treatment options, are also crucial. “A particularly frustrating thing about this is the pathobiology of why these adhesions form is not wholly worked out, which is why they’re so difficult to treat,” said speaker Melinda Maggard Gibbons, MD, MSHS, FACS, a general surgeon from UCLA Health in Los Angeles, California.

Where We Are: Assessment and Patient-Reported Outcomes

With that background in mind, the summit’s first panel presented a literature review of research on surgical adhesions, particularly focused on prevention, measurement, and patient-reported outcomes. The review, led by Dr. Maggard and Tara Russell, MD, MPH, PhD, a colorectal surgeon at UCLA Health, clarified how complex approaches had proven ineffectual.

A review of 132 studies showed 54 unique tools for intraoperative measurement of adhesions, including just seven that had been used in more than three studies. The review also included nonoperative approaches to measurement, including ultrasonography and computed tomography. Drs. Maggard and Russell said the tools captured a wide range of adhesion attributes, and most had minimal validation, moderate interrater reliability, and no clear standard as to the timing of measurements.

Approaches to patient-reported outcomes were similarly scattered; 192 research articles showed 87 instruments used in studies, only 10 of which were specific to adhesive disease and related quality of life. “A bunch of siloed tools that don't talk to each other is what we basically have now,” Clifford Y. Ko, MD, MS, MSHS, FACS, Director of the ACS Division of Research and Optimal Patient Care, later summarized, noting that the upshot is limited clarity and forward momentum in creating effective care.

In discussions, attendees affirmed the need for a well-validated, highly reliable, widely used instrument to assess adhesions and associated outcomes.

Where We Are: Prophylaxis

Drs. Maggard and Russell also presented evidence that adhesion barriers, which aim to prevent the formation of adhesions, had varying effectiveness. They described a meta-analysis of randomized clinical trials on adhesion prophylaxis that found smaller likelihood of small bowel obstruction (SBO) for more than 30 days after surgery (0.76, relative to nonuse). Outcomes varied between products, with Guardix shown to be effective and Seprafilm ineffective against SBOs.

In a later talk, Dr. ten Broek described research on barriers as ongoing but incomplete: “A problem with using adhesion barriers in bowel surgery is that most barriers have never been tested in proximity of bowel anastomosis or colon tumor cells.”

With that said, much is known. Nearly every speaker on the summit’s first day described at least one prophylactic agent or approach. Like measurement tools, these ran the gamut of effectiveness, reflecting active but uncoordinated development.

The progress includes a fair number of negative results. Rudy Leon de Wilde, MD, PhD, the medical director of the Clinic for Obstetrics and Gynecology at Pius-Clinic Oldenburg in the University of Gottingen, in Gottingen, Germany, described a range of drugs, including nonsteroidal anti-inflammatory drugs, antibiotics, corticosteroids, and fibrinolytics, that appeared not to reach the right sites or not stay long enough in the abdomen or pelvis, and/or negatively impact epithelial regrowth. He also noted that a product called SprayShield had been shown to elicit allergic reaction in some patients. Another speaker, David Wiseman, PhD, MRPharmS, from the International Adhesions Society, described a failed product called Intergel, which was launched in 2002 despite issues with infectivity and withdrawn from the market a year later.

Other options, Dr. de Wilde said, do work. They include the absorbable barrier gel HyaRegen; 4Dryfield PH Powder, a starch that can be jellified into an effective barrier; and intraoperative approaches, including pneumoperitoneum humidification, use of absorbable sutures, and peritoneal cooling during surgery.

Where We Are: Microbiology and Engineering

Developing effective adhesion prevention and treatment depends on understanding the environment in which adhesions form and what agents can treat them. To that end, the summit included multiple sessions on microbiological and material sciences.

Here again, the picture was complex. Steve Mutsaers, MD, PhD, a professor of pharmacology and toxicology in School of Biomedical Sciences at The University of Western Australia in Perth, has examined the peritoneal environment and determined the role of macrophages in regeneration of mesothelium. Joel Zindel, MD, PhD, from the Department of Visceral Surgery and Medicine at Inselspital in Bern, Switzerland, further explained that macrophages and mesothelial cells are part of a pathway that generates thrombin, which can combine with fibrin to generate fibrous adhesions. Jessica C. Cardenas, PhD, a researcher associated with the Department of Surgery at the University of Colorado in Aurora, added her insights on the connections between inflammation and coagulation—aspects of wound healing known to have implications for adhesion formation.

Dr. Cardenas underlined the complexity of adhesion formation and, like other speakers, evinced enthusiasm for a focused, incisive solution. “Maybe what we really need is just new, better agents—one drug that can perform multiple functions,” she said, noting her laboratory is working on an option based on heparin sulfate.

In addition to the right drug, the right delivery mechanism is important. Eric Appel, PhD, an associate professor of materials science and engineering at Stanford University in California, walked through his research on hydrogels, a form of matter between liquids and solids that can be sprayed, injected, and spread over tissue, remains in place for relatively long periods, and can carry pharmaceutical agents.

In addition, researcher Deshka Foster, MD, PhD, a surgical oncology fellow from Memorial Sloan Kettering Cancer Center in New York, New York, shared her research in mouse models of abdominal adhesion formation. Dr. Foster’s work has shown that the JUN gene, which is conserved across several species, promotes adhesion formation and is activated early after injury. In in vivo experiments with mice and pigs, she has found that applying a small molecule, T-5224, in hydrogel decreases abdominal adhesion formation by inhibiting JUN signaling after surgery. “Suspended released packaging in advanced hydrogel really shows promise,” Dr. Foster commented.

Where We’re Going

The second day of the summit focused on the future. In interviews, several interviewees noted the key ambition was to bring an effective preventive agent into clinical practice. To that end, developing connections to the National Institutes of Health (NIH) and US Food and Drug Administration (FDA) for research funding and regulatory approval is highly compelling.

Steven Bauer, MD, PhD, a scientist formerly with the FDA and now at Wake Forest Institute for Regenerative Medicine in Winston-Salem, North Carolina, detailed the regulatory pathway for investigative new drugs. Dana K. Andersen, MD, FACS, from the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, described the NIH funding process, focusing on advising the younger investigators in attendance. “My transparent objective in this business is to put more money in the hands of surgeon researchers,” Dr. Andersen said.

The final summit session addressed what the attendees would do collectively. Before the meeting, most had completed a survey on how and when to measure adhesions and what patient-reported outcomes are most relevant to care. This survey was one of a series the group will complete as part of a modified Delphi process,¹ a research methodology in which experts complete anonymous surveys about their opinions, then review aggregated scores and modify their responses based on their colleagues’ views. Aimed to giving all voices equal weight, the method is useful for aligning group opinion—a natural fit for a situation in which development has been meaningful but scattered. Discussion and re-surveying at the summit advanced the group toward consensus.

“How do we keep this momentum going?” Mr. Carlino asked before answering with respect to his family’s philanthropic role. “We’re committed, not just for this year, but down the road, to make sure that we complete this, hopefully with a lot more progress and a lot more cohesiveness.”

The Carlino family provided a second round of funding for three grants of $100,000 each for research on surgical adhesions.

As another step toward that goal, Dr. Ko said the group will generate multiple academic papers, including “the results of the Delphi to suggest a way to standardize description classification of adhesions in the operating room.”

Additional papers remain under discussion and are likely to include summit proceedings, a literature review, and a white paper summarizing the expert input generated so far—“a small foundational library that puts all that conversation, robust discussion, and enthusiasm down on paper for reference moving forward,” Dr. Carmichael said.

Beyond that, the aim is clear. Dr. Carmichael said that bringing a “happy ending” to patients like Mr. Carlino’s son is highly motivating: “Certainly, the overall objective is cure. One thing we really want to remain centered around is developing something to treat patients with this disease process on a practical level.”

M. Sophia Newman is the Medical Writer and Speechwriter in the ACS Division of Integrated Communications in Chicago, IL.

References

1. Nasa P, Jain R, Juneja D. Delphi methodology in healthcare research: How to decide its appropriateness. World J Methodol. 2021 Jul 20; 11(4): 116–129.