The Extremity War Injury symposium is an annual meeting in Washington, DC, that brings together researchers and clinicians with a shared interest in the treatment of high-energy trauma patients with applicability to the combatinjured patient. This year’s meeting focused on the sequelae of combat-related injuries, including posttraumatic osteoarthritis (PTOA), amputations, and infections.
The symposium was held over 2 days, following an additional day devoted to committee meetings for the Major Extremity Trauma Research Consortium (METRC). Lectures were given during three separate sessions, moderated by military and civilian faculty with recognized expertise on their respective topics. Six small group discussions were also held, allowing direct interaction between participants and faculty in a more intimate setting. There were two guest speakers at the meeting: Surgeon General of the Army Lieutenant General Patricia D. Horoho and Representative C. A. “Dutch” Ruppersberger III (D-MD). Presentations by these distinguished visitors helped to apply the topic of combat casualty research to strategic and political contexts.
PTOA is the most common injuryrelated cause of medical discharge from military service. Chondrocyte death initially occurs near fracture edges, but in succeeding days there is a spreading wave of cell death indicating a progressive deleterious biologic process. The nature and origin of this process has been the focus of recent research suggesting that cell death may trigger posttraumatic synovitis through stimulation of the immune system. The existence of a biologic process lends the possibility that biologic mediators could be used to ameliorate or prevent this process. In cell culture and in vitro tissue-level cartilage-impact models, the use of antioxidants and anti-inflammatories has been shown to decrease cell death. However, there is a need for research using animal models or well-designed human clinical trials.
One of the fundamental difficulties with prospective clinical research on articular fractures is the inability to measure and accurately assess clinically important mechanical factors associated with the acute injury and with chronic posttraumatic contact stress from articular malreduction. Recent advances in techniques of image analysis and contact stress analysis based on preoperative and postoperative CT scans suggest that these variables can now be accurately measured and quantified in order to stratify these mechanical risk factors. Prospective clinical research on articular fractures and new biologic interventions can now include suitably mechanically stratified patient cohorts.
Despite these advances, there remain many challenges to prospective research. One of the fundamental barriers is a lack of a suitable outcome measure. Long-term follow-up is usually required to identify arthritis on plain radiographs, and many other variables can affect clinical outcomes. In the future, research should concentrate on developing biomarkers from the blood, urine, or synovial fluid that may be predictive of cartilage degeneration. Further work is needed to understand and characterize the intra-articular response to joint injury in humans. This should include the study of the cellular response of all tissues in the joint, the nature of bioactive compounds found in synovial fluid, and an understanding of the time course of the response following injury. In addition, the use of imaging markers with various MRI sequences holds promise as an aid to early outcome assessments.
There appear to be few circumstances in which a definitive arthroplasty should be performed in an acutely injured and open joint. The two main concerns are the inability to obtain secure fixation for the arthroplasty components and the potential for subsequent infection. If arthroplasty is contemplated, then management should include the use of an antibiotic cement spacer until all soft-tissue injuries are healed and the joint is ready for implantation of components. Arthroplasty for PTOA is associated with a higher rate of complication and poorer outcomes compared with primary arthroplasty for degenerative arthritis.
Much remains to be learned about PTOA, particularly in the young patient. First, the true impact of mechanical alignment on cartilage wear is not fully understood. Potential risk factors and biologic markers for disease progression warrant investigation, and development of a large-animal model may help with this. The synovium may or may not play a role in the disease process, and there may be some benefit to pursuing biologic interventions that could alter the natural history of the disease. Finally, treating previously infected joints which have progressed to end-stage arthritis remains a challenge without a straightforward solution.
Complex Upper Extremity Injuries
Severe upper extremity war injuries continue to present a unique challenge for treatment and require creative thinking and a multidisci-plinary approach to ensure the best possible outcomes. At present, the severely injured elbow joint and major peripheral nerve injuries present the biggest challenges in the surgical management of upper extremity war injuries.
In research on regeneration for tissue regeneration, Christopher Allen, MD, from the University of Washington extracted adult digit tip-derived cells from amputated human digits, identified a host of progenitor cell markers, and ultimately was able to drive these cells in the proper environment toward bone, fat, and cartilage phenotypes. His studies suggest that adult human digits retain regenerative multipotent cells of the limb.
Vascularized composite allotransplants can provide an opportunity to restore touch, more normal function, and a more normal appearance for a patient with a devastating loss as compared to prosthesis. Prevention of rejection by the host is an absolute requirement and has been particularly difficult for a composition tissue allograft.
Joseph Kutz, MD, co-principal investigator in the Louisville, Kentucky, Hand Transplant Program, was part of the surgical team that completed the first hand transplant in the United States in 1999. They have now transplanted nine hands in eight patients. They use a standard immunosuppressant regimen used for kidney transplants. After modifications of their protocol, they now use dual therapy of tacrolimus (1 to 3 mg/d) and sirolimus (1 to 4 mg/d). Their longest survival is 15 years; only one transplant failed at 9 months due to an aggressive graft vasculopathy. Complications related to immunosuppression included hip osteonecrosis requiring bilateral hip replacement. Intrinsic muscle control returned “at same level” in six patients, and sensation continues to improve as long as 10 years after transplantation.
W. P. Andrew Lee, MD, chairman of the Department of Plastic and Reconstructive Surgery at Johns Hopkins, reported on his experience with a new immunosuppressive program that he developed after years of animal research. He led the surgical teams that performed the first bilateral hand transplant and the first above-elbow transplant in the United States. He has pioneered donor bone marrow cell-based strategies to modulate rather than suppress immune rejection to minimize the need for immunosuppressive medications. He has successfully treated six patients with 10 transplants. Patients are initially treated with alemtuzumab and methylprednisolone, followed by tacrolimus monotherapy (initially, 12 to 15 mg/mL; later, 6 to 10 mg/mL). In five patients, the dose has been decreased to 3 to 10 mg/mL. Donor bone marrow is also transplanted initially to the recipient. All early rejections have been reversed.
Peter C. Amadio, MD, reported his research on new biologic approaches to minimize scar formation. He discussed pharmaceutical interventions that block transforming growth factor-β, a primary mediator of fibrosis, as well as other agents that act as physical barriers to scar formation and lubricants to allow soft-tissue gliding. As an additional adjunct for treatment of adhesions and tendon scarring, Captain Eric P. Hofmeister, MD, presented new research completed by him and his colleagues at the Naval Medical Center San Diego on the use of the fractionated carbon dioxide laser. The laser effects include improved dermal appearance and pliability, decreased work of the musculotendinous unit, and decreased tendon adhesions, especially under skin graft and when located in the forearm or palm.
Although the last decade has seen tremendous advances in the treatment of combat upper extremity injuries, many questions remain unanswered. Use of nerve transfers is currently limited in the combatinjured upper extremity because of the length of nerve gaps and zone-ofinjury considerations. Continued research focusing on improving reconstruction of large segmental defects remains critical. Technologies that enhance nerve regeneration and preservation of the neuromuscular junction and its target muscle will greatly aid reconstructive efforts. Future research protocols directed toward prevention, modification, and elimination of stiffness and contracture need continued support. Laser treatment of scar contracture and tendon adhesions show promise, and studies of this treatment technique are required. Greater understanding of the peripheral vascular system and methods to modify and enhance blood flow to damaged tissues may prove to be beneficial for improving the rate and quality of overall healing and for the prevention of scar contracture and stiffness.
The success of most upper extremity prostheses, especially myoelectric ones, depends on comfort to the user, the ease of the bioprosthetic interface, and self-perceived functional utility. Further work will involve improvement in the biologic interfaces, with possible areas of focus anywhere from the cortical level to the skin-prosthesis interface. Better suspension techniques, reduced prosthetic weights, and the use of techniques such as osseointegration may continue to improve function in the upper extremity amputee. Composite tissue allotransplantation remains an exciting direction in the treatment of the upper extremity amputee, currently limited by the rate of nerve regeneration and the risks and morbidities historically associated with immunosuppression protocols. Further focus on these two critical areas may improve outcomes and expand the indication for this procedure in the future.
Several topics were raised during the infection panel and breakout session. First, several participants discussed a need for novel methods to reduce the bacterial load following the initial débridement procedures. This is an important topic, given the extensive zone of injury and high degree of contamination seen in blast wounds. In fact, a recent analysis of wounds resulting from the current conflicts found that more than 30% were critically colonized (>105 colonyforming units) on presentation to the tertiary referral center. This number is likely to grow as we transition from a “mature” theater of operations, in which timely casualty evacuation is the norm, to future areas of operations that are likely to take place in more austere locations. In the latter scenarios, evacuation to facilities with surgical and critical care support may take days—and means to modulate the inflammatory response and control bioburden become, at least in theory, more important. With this in mind, we discussed novel methods of delivering antimicrobial therapy (not necessarily using traditional “antibiotics” or “antifungals”) and anti-inflammatory medications directly to the wound, using a “foam” or similar material that could be applied in combination with traditional gauze dressings or negative-pressure wound-therapy devices. In addition, alternative therapies such as local hypothermia, which has had promising results controlling bioburden in large animal studies, could be used alone or in combination with other methods.
Defining the microbiome of wounds is also important. Existing techniques such as quantitative cultures and histopathologic analysis typically require days to generate usable information. Still, organisms within biofilms are underrepresented by these means. There is a need for near real-time assessment of bacterial and fungal burden (both planktonic and within biofilms) to guide treatment. In addition, other means of prevention and treatment of biofilm formation, such as vaccines, implant coatings/tethered antibiotics, and electrical current, stimulated a significant amount of discussion given their potential to have widespread impact.
Finally, we discussed the importance of animal models to test the therapies listed above as a bridge to clinical studies and regulatory approval. Large-animal models, which can be tailored to the research question at hand, are preferred. The host response to injury is arguably one of the most attractive targets for intervention, given its association with various complications, including wound failure, critical bacterial colonization, angioinvasive fungal infections, and heterotopic ossification (HO). Methods to modulate this response could be developed and tested in the proposed large-animal model. Other requisite conditions for a successful model include the use of metal and nonmetal implants, which could be used for fracture fixation in this setting. The use of multiple strains of bacteria should be selectively considered, and the resulting increased cost and effort was also recognized. Given the young age of patients and higher rate of PTOA, it was recognized that joint arthroplasty infection may also become problematic in later years. Invasive fungal infections were also noted to lack adequate treatment options.
Focus Group: Junctional Injuries
The term junctional hemorrhage refers to a vascular injury too proximal to be controlled by conventional tourniquets, for example, near the axilla or groin. In the spectrum of combat injury, junctional injury is characterized as injury secondary to explosion associated with high lower or upper extremity amputation or amputations, with or without intracorporeal vascular injury, pelvic bony and soft-tissue trauma, and other high energy-associated injuries. Although this constellation of injuries is most prevalent on the battlefield, it has been noted in the civilian environment, particularly in scenarios distinguished by a high-energy mechanism, such as motorcycle crashes and motor-pedestrian and industrial injuries.
Junctional injury was responsible for 6.5% (n = 93) of nonsurvivable injuries and 11.7% (n = 104) of potentially survivable injuries on the battlefield.1 The differentiation between nonsurvivable and survivable injury was largely related to an open pelvic fracture component with abdominopelvic exsanguination. Survival from this injury pattern was possible, particularly in circumstances in which prehospital hemorrhage was minimized or controlled. Personal protective gear has been only marginally effective at mitigating perineal soft-tissue and urogenital injury.
The concepts of Tactical Combat Casualty Care have globally improved outcomes in the prehospital phase of care.2 Junctional hemorrhage-control devices were reviewed. These included the Combat Ready Clamp (CRoC [Combat Medical Systems]), Abdominal Aortic Tourniquet (AAT [Speer Operational Technology]), and the Junctional Emergency Treatment Tool (JETT [North American Rescue]). The CRoC has recently been deployed to Afghanistan but has few documented uses and minimal data on efficacy. The currently fielded device attends to major junctional vascular injury only and not pelvic stabilization. Rapid evacuation has been associated with increased survival.3 Acute care is optimized by the tenets of early surgical hemorrhage control and damagecontrol resuscitation to concomitantly correct the coagulopathy of trauma.4 In conjunction with trauma surgical interventions, orthopaedic intervention is directed at pelvic ring stabilization and débridement of bony and soft-tissue injuries of the lower extremities, according to the principles of extremity war surgery.5 Sequential débridement at least every 24 to 48 hours is vital to minimize contamination and infection. Particularly problematic with this mechanism of injury and contamination are multidrug-resistant and invasive fungal infections.
There is a continuing need for improved prehospital care, including field junctional hemorrhage control devices/techniques that may extend the survival time window from point of injury to medical treatment facility. The development of intracorporeal hemostatic agents and the utilization of freeze-dried plasma and tranexamic acid may aid acute resuscitation. Improving infection control and long-term outcomes after orthopaedic reconstruction continue to be areas of ongoing research.
Focus Group: Multiligamentous Injuries
This focus group was organized after recognition of a knowledge gap in the prompt diagnosis and treatment of combat veterans with multiligament knee injuries, particularly in the setting of a transtibial amputation. Several unique challenges were identified in dealing with combat transtibial amputees. These challenges include the inability to easily obtain an MRI of the knee because of the high frequency of implanted metal about the knee as well as incompatible metal fragments throughout the body. Prompt diagnosis is further hindered by nonspecific knee complaints and difficulties with the physical examination of the knee after below-knee amputation. These factors can result in a delay in diagnosis of a significant knee ligament injury of up to 33 weeks on average in this patient population. This is 3.5 times greater than in the noncombatinjured below-knee amputee.
The focus group recommended the regular use of bilateral knee fluoroscopic stress views early after injury in an attempt to identify ligamentous knee injuries early in the treatment process. Gait analysis was mentioned as an adjunct to identifying ligamentous knee injuries because an alteration in the knee flexion moment was noted to correct after ligament reconstruction in at least one patient. More information is needed before recommending the regular use of gait analysis to diagnose knee ligament injuries. Patients who underwent ligament reconstruction, including multiligament knee reconstruction, functioned very well with the transtibial amputation and were significantly helped by the procedure. The moderators and lecturers identified optimal strategies for surgical repair and/or reconstruction of the ligaments as well as optimizing rehabilitation.
Focus Group: Long-term Sequelae of Amputations
The amputation focus group presented original research regarding bone mineral density (BMD) loss and HO following combat-related amputations, as well as overviews of residual limb problems related to the bony platform and soft-tissue envelope.
Despite efforts at early weight-bearing activity and aggressive, open-access rehabilitation, low hip BMD (Z-score < -1.0) is present in 42% of combat-related lower extremity amputees, with severely low BMD (Z-score < -2.0) developing in 15% of patients. On multivariate analysis, more proximal amputation level, bilateral amputations, and delayed rehabilitation (ie, longer time to first ambulation, regular ambulation, time to dual-energy x-ray absorptiometry scanning) all contribute to the process of BMD loss, which appears related to, but is not entirely explained by, disuse osteopenia.
HO affects up to 64% of combat-related amputations. Many patients are asymptomatic or can be managed nonsurgically. However, surgical excision, which is fraught with relatively high blood loss and frequent wound complications, is ultimately required in more than 25% of these patients. Recent research has identified specific local gene expression and local and systemic biomarkers associated with HO following combat trauma, and two different groups have identified local osteoprogenitor cells that represent the putative cells of HO origin in these patients. Using artificial neural networks and bayesian belief network modeling or early vibrational spectroscopy imaging, eventual HO formation can be accurately predicted in most patients, which may permit risk stratification and selective prophylactic intervention.
Despite myriad breakthroughs in microprocessor, powered, and myoelectric prosthetic technologies in recent years, prosthetic sockets remain remarkably conventional, and socket-related problems frequently limit function. Accurate assessment of load transmission and residual limb shear forces at the socket-limb interface remain problematic, and failure to accurately measure and understand this interface seems to represent the rate-limiting step in socket-related technologic advances. Osseointegration, which has shown both substantial promise and worrisome long-term limitations in European patients, may represent the future of prosthetic attachment through direct coupling, which can provide stable residual limb control with concomitant direct load transmission and improved proprioceptive feedback. A critical limitation of osseointegration techniques is the skin-implant interface, which serves as a chronic conduit for potential infectious complications.
The soft-tissue envelope remains at least as important as the bony platform in terms of overall residual limb health, particularly in the absence of widespread osseointegration. The goals of any amputation surgery should include the provision of a healthy, robust soft-tissue envelope with adequate padding and durability to tolerate socket load transmission and regular, prolonged prosthesis wear. In select cases of traumatic loss, atypical flaps, such as viable distal fillet (eg, “fillet of foot,” turn-up plasty) and local rotational flaps may provide a durable solution. Free-tissue transfer, while typically insensate, remains a viable and important option for salvaging joint levels at risk. When adjacent joints are not salvageable, end-bearing levels (eg, Syme, knee disarticulation, Gritti-Stokes transfemoral amputations) are appealing to enhance socket fit and load transmission. Although preferred in appropriately selected cases by the moderators, these levels remain somewhat controversial, as was evident during discussion and, at a minimum, require that specific preoperative requisites be met, such as a viable heel pad or gastrocnemius for the Syme and knee disarticulation levels, respectively.
Many areas exist for potential research on this subject. There is a need for a prospective analysis of BMD loss following amputation and/or limb salvage and the efficacy of short-term pharmacologic intervention to mitigate BMD loss. Mechanistic and physiologic model studies of HO should be developed to evaluate novel therapeutic interventions and confirm or refute similar pathologic processes between combat-related and civilian HO. Also, real-time analysis of pressure and shear forces at the limb-prosthesis interface within conventional prosthetic sockets, along with investigating osseointegration longevity and solutions for the skin-implant interface to mitigate infection concerns, will further the quest for an optimal user-prosthesis interface. Other long-term amputee concerns, such as utility of targeted muscle reinnervation, osteoarthritis development, and obesity, received limited discussion but persist as knowledge gaps.
The knowledge and research gaps identified will require continued funding to support ingenuity and innovation within this discipline. As we continue to characterize blastand other high-energy wounds, new questions arise. However, it is clear that these injuries are not unique to the combat zone and may, unfortunately, occur in the civilian setting. It is also clear that our cumulative knowledge after 10 years of war is not a panacea, and research intended to benefit blast victims (both military and civilian) must continue.