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Developing a predictive model for wound healing

By Jeffrey Mark Smith, MD

Lessons from military research can improve care for all

You did everything that you were trained to do as a surgeon. Your patient’s complex traumatic wound was treated with serial débridement and irrigations. The associated fracture was stabilized. Negative pressure therapy was applied and the wound was closed or covered with a flap. But instead of healing, the wound went on to dehisce. What went wrong?

“Despite seemingly appropriate tension-free wound closure following meticulous serial débridement and antibiotic therapy, some wounds dehisce (Fig. 1). Conversely, some wounds of a questionable appearance may possess the ability to heal,” said LCDR Jonathan Forsberg, MD, a Navy surgeon at Walter Reed National Military Medical Center. Speaking at the Extremity War Injuries IV (EWI-IV) symposium, Dr. Forsberg outlined the results of his research on “Biomarker Analysis of High Energy Extremity Wounds.”

Fig. 1 Despite meticulous serial débridements and clean appear­ing wounds, some wounds dehisce, necessitating a return to the operating room for repeat débridement, amputation, or revision of amputation. Courtesy of LCDR Jonathan Forsberg, MD

13 markers as clues
Imagine a biochemical assay as simple as a urinalysis that could be performed on wound drainage (effluent) to indicate if the wound is ready for closure. Traditionally, orthopaedists have used C-reactive protein, erythrocyte sedimentation rate, and albumin as guides to determine wound infection or healing potential. But neither these nor interleukin-6 (IL-6) have sufficient positive or negative predictive value to be clinically relevant. Additionally, these analyses are rarely used for the management of acute wounds.

Dr. Forsberg and his colleagues have been investigating cytokines and chemokines in the serum and effluent of traumatic wounds to guide decision-making for wound closure. Their pilot study, which was published in the Journal of Bone and Joint Surgery in 2008, found elevated procalcitonin, IL-13, and RANTES protein levels in wounds that proceeded to dehiscence.

Since that study, Dr. Forsberg and his team have developed a 13-marker assay of wound effluent that, combined with a computer calculation, provides a determination of the readiness of a wound for closure without subsequent dehiscence. With this information, orthopaedic surgeons can close traumatic wounds earlier with a substantially decreased risk of wound dehiscence. The potential benefits in minimizing patient morbidity and treatment costs could be significant.

Effluent analysis
In the pilot study, samples of wound effluent were collected directly after removal of a negative pressure wound dressing (Wound V.A.C.®, KCI, San Antonio, Texas) from 50 wounds in 20 patients who had sustained high-energy penetrating extremity wounds during military combat. Only serum procalcitonin levels correlated with wound dehiscence (P < 0.05). Concomitant closed head injury or arterial injury was also associated with increased risk of wound dehiscence.

Analysis of the effluent found that wounds that dehisced had increased concentrations of procalcitonin and decreased concentrations of both RANTES protein and IL-13 (P < 0.05) compared to wounds that healed.

Although this study involved high-energy penetrating blast wounds sustained in combat, in the future, orthopaedic surgeons may be able to use the same or similar markers in any severe open traumatic wound from high-energy mechanisms such as motor vehicle accidents.

In his report at EWI-IV, Dr. Forsberg shared the results of research conducted since the pilot study report. To predict wound healing with closure, he and a team of collaborators have further refined the database of cytokines and chemokines from the effluent of traumatic wounds and have added mRNA from débrided tissue. Initially, wound effluent was collected using a syringe around the wound. Now, they simply use an empty negative pressure therapy canister (one that does not contain the gel material that converts the fluid to a gel solid for human waste disposal purposes). The fresh fluid is then siphoned out of the canister and injected into a red top laboratory tube for spinning and analysis.

“We are discovering that the systemic and local inflammatory response may be much more important than we once thought,” Dr. Forsberg explained. Although the principles of establishing a stable, well-débrided wound still apply, “wound healing problems may stem from the fact that the systemic response drives the local response to injury.”

His group has also expanded the concept of analyzing local cytokines, chemokines, and mRNA to the development, and perhaps prevention, of heterotopic ossification (Fig. 2). The natural progression of this research is developing treatments that would control or limit the dysregulated inflammatory response, improve wound healing, and prevent heterotopic ossification.

Fig. 2 The study population had an observed rate of heterotopic ossification (HO) of 37.5 percent. Courtesy of LCDR Jonathan Forsberg, MD

Application for disaster preparedness
Most orthopaedic surgical care provided in major natural or man-made disasters comes from civilian surgeons who have not cared for many complex injuries, even at Level 1 trauma centers.

Many current standards of practice for the management of trauma, open fractures, and amputations were developed during previous wartime conflicts such as the Vietnam War. Scientific investigation, however, has been more pronounced in civilian care settings. Through the unfortunate casualties of the current conflicts in Iraq and Afghanistan, orthopaedic surgeons have the opportunity to take a more scientific approach that will teach us much more about caring for and treating traumatic injuries, healing bone defects, and combating wound and bone infections.

The Extremity War Injury and Disaster Preparedness (EWIDP) Workgroup created by the AAOS promotes collaborative relationships among military and civilian orthopaedic surgeons, as well as basic and clinical research scientists, to evaluate lessons learned in a combat arena and see if they can be applied to a civilian arena.

These efforts have resulted in the collaborative EWI research symposium series sponsored by the AAOS, the Orthopaedic Trauma Association, and the Society of Military Orthopaedic Surgeons. EWI-IV: Collaborative Efforts in Research, Host Nation Care, and Disaster Preparedness was held in Washington, D.C., Jan. 21–23, 2009. The EWI symposium series has also helped increase Congressional funding for such research by more than $115 million dollars over the past 4 years.

Jeffrey Mark Smith, MD, is an orthopaedic traumatologist and a member of the AAOS EWIDP Workgroup. He can be reached at jsmith@ucsd.edu

AAOS Now
March 2009 Issue
http://www.aaos.org/news/aaosnow/mar09/clinical1.asp