Systemic inflammation induced from remote extremity trauma is a critical driver of secondary brain injury.

Blast exposure, commonly experienced by military personnel, can cause devastating life-threatening polysystem trauma. Despite considerable research efforts, the impact of the systemic inflammatory response after major trauma on secondary brain injury-inflammation is largely unknown. The aim of this study was to identify markers underlying the susceptibility and early onset of neuroinflammation in three rat trauma models: (1) blast overpressure exposure (BOP), (2) complex extremity trauma (CET) involving femur fracture, crush injury, tourniquet-induced ischemia, and transfemoral amputation through the fracture site, and (3) BOP+CET. Six hours post-injury, intact brains were harvested and dissected to obtain biopsies from the prefrontal cortex, striatum, neocortex, hippocampus, amygdala, thalamus, hypothalamus, and cerebellum. Custom low-density microarray datasets were used to identify, interpret and visualize genes significant (p < 0.05 for differential expression [DEGs]; 86 neuroinflammation-associated) using a custom python-based computer program, principal component analysis, heatmaps and volcano plots. Gene set and pathway enrichment analyses of the DEGs was performed using R and STRING for protein-protein interaction (PPI) to identify and explore key genes and signaling networks. Transcript profiles were similar across all regions in naïve brains with similar expression levels involving neurotransmission and transcription functions and undetectable to low-levels of inflammation-related mediators. Trauma-induced neuroinflammation across all anatomical brain regions correlated with injury severity (BOP+CET > CET > BOP). The most pronounced differences in neuroinflammatory-neurodegenerative gene regulation were between blast-associated trauma (BOP, BOP+CET) and CET. Following BOP, there were few DEGs detected amongst all 8 brain regions, most were related to cytokines/chemokines and chemokine receptors, where PPI analysis revealed Il1b as a potential central hub gene. In contrast, CET led to a more excessive and diverse pro-neuroinflammatory reaction in which Il6 was identified as the central hub gene. Analysis of the of the BOP+CET dataset, revealed a more global heightened response (Cxcr2, Il1b, and Il6) as well as the expression of additional functional regulatory networks/hub genes (Ccl2, Ccl3, and Ccl4) which are known to play a critical role in the rapid recruitment and activation of immune cells via chemokine/cytokine signaling. These findings provide a foundation for discerning pathophysiological consequences of acute extremity injury and systemic inflammation following various forms of trauma in the brain.

The Scope and Distribution of Upper Extremity Nerve Injuries Associated With Combat-Related Extremity Limb Salvage.

PURPOSE: Chronic pain and functional limitations secondary to nerve injuries are a major barrier to optimal recovery for patients following high-energy extremity trauma. Given the associated skeletal and soft tissue management challenges in the polytraumatized patient, concomitant nerve injuries may be overlooked or managed in delayed fashion. Whereas previous literature has reported rates of peripheral nerve injuries at <10% in the setting of high-energy extremity trauma, in our experience, the incidence of these injuries has been much higher. Thus, we sought to define the incidence, pain sequelae, and functional outcomes following upper extremity peripheral nerve injuries in the combat-related limb salvage population. METHODS: We performed a retrospective review of all patients who underwent limb salvage procedures to include flap coverage for combat-related upper extremity trauma at a single institution between January 2011 and January 2020. We collected data on patient demographics; perioperative complications; location of nerve injuries; surgical interventions; chronic pain; and subjective, patient-reported functional limitations. RESULTS: A total of 45 patients underwent flap procedures on 49 upper extremities following combat-related trauma. All patients were male with a median age of 27 years, and 96% (n = 47) of injuries were sustained from a blast mechanism. Thirty-three of the 49 extremities (67%) sustained associated nerve injuries. The most commonly injured nerve was the ulnar (51%), followed by median (30%) and radial/posterior interosseous (19%). Of the 33 extremities with nerve injuries, 18 (55%) underwent surgical intervention. Nerve repair/reconstruction was the most common procedure (67%), followed by targeted muscle reinnervation (TMR, 17%). Chronic pain and functional limitation were common following nerve injury. CONCLUSIONS: Upper extremity peripheral nerve injury is common following high-energy combat-related trauma with high rates of chronic pain and functional limitations. Surgeons performing limb salvage procedures to include flap coverage should anticipate associated peripheral nerve injuries and be prepared to repair or reconstruct the injured nerves, when feasible. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Is the Lifetime Malignancy Risk in United States Military Personnel Sustaining Combat-related Trauma Increased Because of Radiation Exposure From Diagnostic Imaging?

BACKGROUND: Patients with complex polytrauma in the military and civilian settings are often exposed to substantial diagnostic medical radiation because of serial imaging studies for injury diagnosis and subsequent management. This cumulative radiation exposure may increase the risk of subsequent malignancy. This is particularly true for combat-injured servicemembers who receive care at a variety of facilities worldwide. Currently, there is no coordinated effort to track the amount of radiation exposure each servicemember receives, nor a surveillance program to follow such patients in the long term. It is important to assess whether military servicemembers are exposed to excessive diagnostic radiation to mitigate or prevent such occurrences and monitor for carcinogenesis, when necessary. The cumulative amount of radiation exposure for combat-wounded and noncombat-wounded servicemembers has not been described, and it remains unknown whether diagnostic radiation exposure meets thresholds for an increased risk of carcinogenesis. QUESTIONS/PURPOSES: We performed this study to (1) quantify the amount of exposure for combat-wounded servicemembers based on medical imaging in the first year after injury and compare those exposures with noncombat-related trauma, and (2) determine whether the cumulative dose of radiation correlates to the Injury Severity Score (ISS) across the combat-wounded and noncombat-wounded population combined. METHODS: We performed a retrospective study of servicemembers who sustained combat or noncombat trauma and were treated at Walter Reed National Military Medical Center from 2005 to 2018. We evaluated patients using the Department of Defense Trauma Registry. After consolidating redundant records, the dataset included 3812 unique servicemember encounters. Three percent (104 of 3812) were excluded because of missing radiation exposure data in the electronic medical record. The final cohort included 3708 servicemembers who had combat or noncombat injury trauma, with a mean age at the time of injury of 26 ± 6 years and a mean ISS of 18 ± 12. The most common combat trauma mechanisms of injury were blast (in 65% [2415 of 3708 patients]), followed by high-velocity gunshot wounds (in 22% [815 of 3708 patients]). We calculated the cumulative diagnostic radiation dose exposure at 1 year post-traumatic injury in patients with combat-related trauma and those with noncombat trauma. We did this by multiplying the number of imaging studies by the standardized effective radiation dose for each imaging study type. We then performed analysis of variance for four data subsets (battle combat trauma, nonbattle civilian trauma, high ISS, and high radiation exposure [> 50 mSv]) independently. To evaluate whether the total number of imaging studies, radiation exposure, and ISS values differed between battle-wounded and nonbattle-wounded patients, we performed a pairwise t-test. RESULTS: The mean radiation exposure for combat-related injuries was 35 ± 26 mSv while the mean radiation exposure for noncombat-related injuries was 22 ± 33 mSv in the first year after injury. In the first year after trauma, 44% of patients (1626 of 3708) were exposed to high levels of radiation that were greater than 20 mSv, and 23% (840 of 3708) were exposed to very high levels of radiation that were greater than 50 mSv. Servicemembers with combat trauma-related injuries had eight more imaging studies than those who sustained noncombat injuries. Servicemembers with combat trauma injuries (35 ± 26 mSv) were exposed to more radiation (approximately 4 mSv) than patients treated for noncombat injuries (22 ± 33 mSv) (p = 0.01). We found that servicemembers with combat injuries had a higher ISS than servicemembers with noncombat trauma (p < 0.001). We found a positive correlation between radiation exposure and ISS for servicemembers. The positive relationship between radiation exposure and ISS held for combat trauma (r 2 = 0.24; p < 0.001), noncombat trauma (r 2 = 0.20; p < 0.001), servicemembers with a high ISS (r 2 = 0.10; p < 0.001), and servicemembers exposed to high doses of radiation (r 2 = 0.09; p < 0.001). CONCLUSION: These data should be used during clinical decision-making and patient counseling at military treatment facilities and might provide guidance to the Defense Health Agency. These recommendations will help determine whether the benefits of further imaging outweigh the risk of carcinogenesis. If not, we need to develop interdisciplinary clinical practice guidelines to reduce or minimize radiation exposure. It is important for treating physicians to seriously weigh the risk and benefits of every imaging study ordered because each test does not come without a cumulative risk. LEVEL OF EVIDENCE: Level III, therapeutic study.

Effect of Targeted Cytokine Inhibition on Progression of Post-Traumatic Osteoarthritis Following Intra-Articular Fracture.

Intra-articular fractures (IAF) result in significant and prolonged inflammation, increasing the chances of developing post-traumatic osteoarthritis (PTOA). Interleukin-one beta (IL-1ß) and Tumor Necrosis Factor-alpha (TNF-α) are key inflammatory factors shown to be involved in osteochondral degradation following IAF. As such, use of targeted biologics such as Infliximab (INX), a TNF-α inhibitor, and Anakinra (ANR), an interleukin-one (IL-1) receptor antagonist (IL1RA), may protect against PTOA by damping the inflammatory response to IAF and reducing osteochondral degradation. To test this hypothesis, IAFs were induced in the hindlimb knee joints of rats treated with INX at 10 mg/kg/day, ANR at 100 g/kg/day, or saline (vehicle control) by subcutaneous infusion for a period of two weeks and healing was evaluated at 8-weeks post injury. Serum and synovial fluid (SF) were analyzed for soluble factors. In-vivo microcomputed tomography (µCT) scans assessed bone mineral density and bone morphometry measurements. Cationic CA4+ agent assessed articular cartilage composition via ex vivo µCT. Scoring according to the Osteoarthritis Research Society International (OARSI) guidelines was performed on stained histologic tibia sections at the 56-day endpoint on a 0-6 scale. Systemically, ANR reduced many pro-inflammatory cytokines and reduced osteochondral degradation markers Cross Linked C-Telopeptide Of Type II (CTXII, p < 0.05) and tartrate-resistant acid phosphatase (TRAP, p < 0.05). ANR treatment resulted in increased chemokines; macrophage-chemotractant protein-1 (MCP-1), MPC-3, macrophage inhibitory protein 2 (MIP2) with a concomitant decrease in proinflammatory interleukin-17A (IL17A) at 14 days post-injury within the SF. Microcomputed tomography (µCT) at 56 days post-injury revealed ANR Treatment decreased epiphyseal degree of anisotropy (DA) (p < 0.05) relative to saline. No differences were found with OARSI scoring but contrast-enhanced µCT revealed a reduction in glycosaminoglycan content with ANR treatment. These findings suggest targeted cytokine inhibition, specifically IL-1 signaling, as a monotherapy has minimal utility for improving IAF healing outcomes but may have utility for promoting a more permissive inflammatory environment that would allow more potent disease modifying osteoarthritis drugs to mitigate the progression of PTOA after IAF.

Functional Limb Restoration Through Amputation: Minimizing Pain and Optimizing Function With the Use of Advanced Amputation Techniques.

OBJECTIVE: To demonstrate the role of advanced orthoplastic techniques in harnessing the full potential of elective amputation as a functionally restorative procedure. SUMMARY OF BACKGROUND DATA: Once considered the unfortunate consequence of failed reconstructive efforts, recent outcomes studies have prompted a re-evaluation of the role of amputation in the management of complex extremity trauma. However, even as amputation is appropriately afforded greater consideration as part of the reconstructive algorithm, reconstructive techniques that are commonly utilized in pursuit of limb salvage are rarely applied to amputation. METHODS: The following case demonstrates the successful application of orthoplastic reconstructive techniques to achieve optimal pain and functional outcomes in a 41-year-old active duty soldier who underwent an elective transtibial amputation after prolonged, limb salvage. RESULTS: The patient presented with a large osteocutaneous proximal tibial defect secondary to trauma and subsequent osteomyelitis. The patient underwent a free scapular-parascapular fasciocutaneous flap to provide soft tissue coverage and facilitate the skeletal reconstruction necessary for either continued limb salvage or amputation. Due to tibial allodynia and severely limited ankle function, the patient subsequently elected for amputation in favor of continued limb salvage. Thus, a transtibial amputation was performed concurrently with a pedicled vascularized fibula to address the proximal tibial defect. A modified agonist-antagonist myoneural interface procedure was used to maximize post-amputation function, with creation of regenerative peripheral nerve interface constructs to prophylax against neurogenic pain. After the operation, the patient achieved improved function of the extremity with the use of a prosthesis and reported substantially improved pain while remaining on active duty in a warfighting military occupational specialty. CONCLUSIONS: By addressing all of the reconstructive components commonly considered in limb salvage, an orthoplastic approach to amputation surgery can minimize pain and maximize the rehabilitative potential of the amputee.

Survival in Pediatric, Adolescent, and Young Adult Patients With Sarcoma in the Military Health System: Comparison With the SEER Population.

BACKGROUND: We sought to compare survival outcomes of sarcomas in the pediatric and adolescent/young adult populations with universal care access in the Military Health System (MHS) to those from the United States general population. METHODS: We compared data from the Department of Defense's (DoD) Automated Central Tumor Registry (ACTUR) and the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) program on the overall survival of patients 24 years or younger with histologically or microscopically confirmed sarcoma between diagnosed between January 1, 1987, and December 31, 2013. The Kaplan-Meier survival curves were used to compare survival between the 2 patient populations. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) comparing ACTUR relative to SEER. RESULTS: The final analysis included 309 and 1236 bone sarcoma cases and 465 and 1860 soft tissue sarcoma cases from ACTUR and SEER, respectively. Cox proportional hazards analysis showed soft tissue sarcoma patients in ACTUR had significantly better overall (HR=0.73, 95% CI=0.55-0.98) and 5-year overall (HR=0.63, 95% CI=0.46-0.86) survival compared with SEER patients, but no significant difference in overall or 5-year overall survival between ACTUR and SEER patients with bone sarcoma. CONCLUSION: Survival data from the ACTUR database demonstrated significantly improved overall survival for soft tissue sarcomas and equivalent survival in bone sarcomas compared with that reported by SEER.

Institutional Experience and Orthoplastic Collaboration Associated with Improved Flap-based Limb Salvage Outcomes.

BACKGROUND: Flap-based limb salvage surgery balances the morbidity and complexity of soft tissue transfer against the potential benefit of preserving a functional limb when faced with a traumatized extremity with composite tissue injury. These composite tissue injuries are well suited for multidisciplinary management between orthopaedic and plastic surgeons. Thus, it makes intuitive sense that a collaborative, orthoplastic approach to flap-based limb salvage surgery can result in improved outcomes with decreased risk of flap failure and other complications, raising the question of whether this orthoplastic team approach should be the new standard of care in limb salvage surgery. QUESTIONS/PURPOSES: (1) Is there an association between increased annual institutional volume and perioperative complications to include free and local flap failure (substantial flap viability loss necessitating return to the operating room for debridement of a major portion or all of the flap or amputation)? (2) Is an integrated orthoplastic collaborative approach to managing combat-related traumatic injuries of the extremities individually associated with a decreased risk of flap failure and overall flap-related complications? (3) What other factors, such as location of injury, injury severity score, and initial inpatient length of stay, were associated with flap necrosis and flap-related complications? METHODS: We performed a retrospective review of the electronic medical records of all patients who underwent flap-based limb salvage for combat-related extremity trauma in the United States Military Health System's National Capital Region between January 1, 2003 and December 31, 2012. In total, 307 patients underwent 330 flap procedures. Of the 330 flaps, 59% (195) were local or pedicled flaps and 41% (135) were free flaps. Patients were primarily male (99% [303]), with a median (interquartile range) age of 24 years old (IQR 21 to 29), and 87% (267 of 307) of injuries were sustained from a blast mechanism. We collected data on patient demographics, annual case volume involving flap coverage of extremities, mechanism of injury, flap characteristics, perioperative complications, flap failure, flap revision, isolated orthopaedic management versus an integrated orthoplastic approach, and other salvage procedures. For the purposes of this study, orthoplastic management refers to operative management of flap coverage with microvascular surgeons present for soft tissue transfer after initial debridement and fixation by orthopaedic surgery. The orthoplastic management was implemented on a case-by-case basis based on individual injury characteristics and the surgeon's discretion with no formal starting point. When implemented, the orthoplastic team consisted of an orthopaedic surgeon and microvascular-trained hand surgeons and/or plastic surgeons. In all, 77% (254 of 330) of flaps were performed using this model. We considered perioperative flap complications as any complication (such as infection, hematoma, dehiscence, congestion, or necrosis) resulting in return to the operating room for re-evaluation, correction, or partial debridement of the flap. We defined flap failure as a return to the operating room for debridement of a major portion of the flap or amputation secondary to complete or near-complete loss of flap viability. Of the flap procedures, 12% (40 of 330) were classified as a failure and 14% (46 of 330) experienced complications necessitating return to the operating room. Over the study period, free flaps were not more likely to fail than pedicled flaps (11% versus 13%; p = 0.52) or have complications necessitating additional procedures (14% versus 16%; p = 0.65). RESULTS: Our multiple linear regression model demonstrated that an increased number of free flaps performed in our institution annually in any given year was associated with a lower likelihood of failure per case (r = -0.17; p = 0.03) and lower likelihood of reoperation for each flap (r = -0.34; p < 0.001), after adjusting for injury severity and team type (orthoplastic or orthopaedic only). We observed a similar relationship for pedicled flaps, with increased annual case volume associated with a decreased risk of flap failure and reoperation per case after adjusting for injury severity and team type (r = -0.21; p = 0.003 and r = -0.22; p < 0.001, respectively). Employment of a collaborative orthoplastic team approach was associated with decreased flap failures (odds ratio 0.4 [95% confidence interval 0.2 to 0.9]; p = 0.02). Factors associated with flap failure included a lower extremity flap (OR 2.7 [95% CI 1.3 to 6.2]; p = 0.01) and use of muscle flaps (OR 2.3 [95% CI 1.1 to 5.3]; p = 0.02). CONCLUSION: Although prior reports of combat-related extremity trauma have described greater salvage success with the use of pedicled flaps, these reports are biased by institutional inexperience with free tissue transfer, the lack of a coordinated multiservice effort, and severity of injury bias (the most severe injuries often result in free tissue transfer). Our institutional experience, alongside a growing body of literature regarding complex extremity trauma in the civilian setting, suggest a benefit to free tissue coverage to treat complex extremity trauma with adequate practice volume and collaboration. We demonstrated that flap failure and flap-related complications are inversely associated with institutional experience regardless of flap type. Additionally, a collaborative orthoplastic approach was associated with decreased flap failures. However, these results must be interpreted with consideration for potential confounding between the increased case volume coinciding with more frequent collaboration between orthopaedic and plastic surgeons. Given these findings, consideration of an orthoplastic approach at high-volume institutions to address soft tissue coverage in complex extremity trauma may lead to decreased flap failure rates. LEVEL OF EVIDENCE: Level III, therapeutic study.

Wartime Military Orthopaedics.

Military orthopaedic surgeons are faced with hardship and decreased morale. Surgeons have frequent deployments and practice inefficiencies resulting in poor retention rates. The purpose of this analysis is to report demographics and factors effecting military retention. A survey was sent to all members of the Society of Military Orthopedic Surgeons. The survey obtained demographic information, as well as factors affecting retention and termination of service. Data was compared between subset groups within the total respondent population. Of active-duty personnel, 38.5% plan on staying in the military until retirement. Most surgeons entered into the military due to a desire to serve their country, while most people leave service due to higher pay as a civilian. A minority of military orthopaedic surgeons achieve military retirement; however, increased pay, increased control over practice, and decreased frequency of deployments are factors that could improve retention rates. (Journal of Surgical Orthopaedic Advances 30(2):116-119, 2021).

The management of embedded metal fragment patients and the role of chelation Therapy: A workshop of the Department of Veterans Affairs-Walter Reed National Medical Center.

Exposure to retained metal fragments from war-related injuries can result in increased systemic metal concentrations, thereby posing potential health risks to target organs far from the site of injury. Given the large number of veterans who have retained fragments and the lack of clear guidance on how to medically manage these individuals, the Department of Veterans Affairs (VA) convened a meeting of chelation experts and clinicians who care for embedded fragment patients to discuss current practices and provide medical management guidance. Based on this group's clinical expertise and review of published literature, the evidence presented suggests that, at least in the case of lead fragments, short-term chelation therapy may be beneficial for embedded fragment patients experiencing acute symptoms associated with metal toxicity; however, in the absence of clinical symptoms or significantly elevated blood lead concentrations (greater than 80 µg/dL), chelation therapy may offer little to no benefit for individuals with retained fragments and pose greater risks due to remobilization of metals stored in bone and other soft tissues. The combination of periodic biomonitoring to assess metal body burden, longitudinal fragment imaging, and selective fragment removal when metal concentrations approach critical injury thresholds offers a more conservative management approach to caring for patients with embedded fragments.

Can Predictive Modeling Tools Identify Patients at High Risk of Prolonged Opioid Use After ACL Reconstruction?

BACKGROUND: Machine-learning methods such as the Bayesian belief network, random forest, gradient boosting machine, and decision trees have been used to develop decision-support tools in other clinical settings. Opioid abuse is a problem among civilians and military service members, and it is difficult to anticipate which patients are at risk for prolonged opioid use. QUESTIONS/PURPOSES: (1) To build a cross-validated model that predicts risk of prolonged opioid use after a specific orthopaedic procedure (ACL reconstruction), (2) To describe the relationships between prognostic and outcome variables, and (3) To determine the clinical utility of a predictive model using a decision curve analysis (as measured by our predictive system's ability to effectively identify high-risk patients and allow for preventative measures to be taken to ensure a successful procedure process). METHODS: We used the Military Analysis and Reporting Tool (M2) to search the Military Health System Data Repository for all patients undergoing arthroscopically assisted ACL reconstruction (Current Procedure Terminology code 29888) from January 2012 through December 2015 with a minimum of 90 days postoperative follow-up. In total, 10,919 patients met the inclusion criteria, most of whom were young men on active duty. We obtained complete opioid prescription filling histories from the Military Health System Data Repository's pharmacy records. We extracted data including patient demographics, military characteristics, and pharmacy data. A total of 3.3% of the data was missing. To curate and impute all missing variables, we used a random forest algorithm. We shuffled and split the data into 80% training and 20% hold-out sets, balanced by outcome variable (Outcome90Days). Next, the training set was further split into training and validation sets. Each model was built on the training data set, tuned with the validation set as applicable, and finally tested on the separate hold-out dataset. We chose four predictive models to develop, at the end choosing the best-fit model for implementation. Logistic regression, random forest, Bayesian belief network, and gradient boosting machine models were the four chosen models based on type of analysis (classification). Each were trained to estimate the likelihood of prolonged opioid use, defined as any opioid prescription filled more than 90 days after anterior cruciate reconstruction. After this, we tested the models on our holdout set and performed an area under the curve analysis concordance statistic, calculated the Brier score, and performed a decision curve analysis for validation. Then, we chose the method that produced the most suitable analysis results and, consequently, predictive power across the three calculations. Based on the calculations, the gradient boosting machine model was selected for future implementation. We systematically selected features and tuned the gradient boosting machine to produce a working predictive model. We performed area under the curve, Brier, and decision curve analysis calculations for the final model to test its viability and gain an understanding of whether it is possible to predict prolonged opioid use. RESULTS: Four predictive models were successfully developed using gradient boosting machine, logistic regression, Bayesian belief network, and random forest methods. After applying the Boruta algorithm for feature selection based on a 100-tree random forest algorithm, features were narrowed to a final seven features. The most influential features with a positive association with prolonged opioid use are preoperative morphine equivalents (yes), particular pharmacy ordering sites locations, shorter deployment time, and younger age. Those observed to have a negative association with prolonged opioid use are particular pharmacy ordering sites locations, preoperative morphine equivalents (no), longer deployment, race (American Indian or Alaskan native) and rank (junior enlisted).On internal validation, the models showed accuracy for predicting prolonged opioid use with AUC greater than our benchmark cutoff 0.70; random forest were 0.76 (95% confidence interval 0.73 to 0.79), 0.76 (95% CI 0.73 to 0.78), 0.73 (95% CI 0.71 to 0.76), and 0.72 (95% CI 0.69 to 0.75), respectively. Although the results from logistic regression and gradient boosting machines were very similar, only one model can be used in implementation. Based on our calculation of the Brier score, area under the curve, and decision curve analysis, we chose the gradient boosting machine as the final model. After selecting features and tuning the chosen gradient boosting machine, we saw an incremental improvement in our implementation model; the final model is accurate, with a Brier score of 0.10 (95% CI 0.09 to 0.11) and area under the curve of 0.77 (95% CI 0.75 to 0.80). It also shows the best clinical utility in a decision curve analysis. CONCLUSIONS: These scores support our claim that it is possible to predict which patients are at risk of prolonged opioid use, as seen by the appropriate range of hold-out analysis calculations. Current opioid guidelines recommend preoperative identification of at-risk patients, but available tools for this purpose are crude, largely focusing on identifying the presence (but not relative contributions) of various risk factors and screening for depression. The power of this model is that it will permit the development of a true clinical decision-support tool, which risk-stratifies individual patients with a single numerical score that is easily understandable to both patient and surgeon. Probabilistic models provide insight into how clinical factors are conditionally related. Not only will this gradient boosting machine be used to help understand factors contributing to opiate misuse after ACL reconstruction, but also it will allow orthopaedic surgeons to identify at-risk patients before surgery and offer increased support and monitoring to prevent opioid abuse and dependency. LEVEL OF EVIDENCE: Level III, therapeutic study.

Targeted Muscle Reinnervation Improves Residual Limb Pain, Phantom Limb Pain, and Limb Function: A Prospective Study of 33 Major Limb Amputees.

BACKGROUND: Targeted muscle reinnervation is an emerging surgical technique to treat neuroma pain whereby sensory and mixed motor nerves are transferred to nearby redundant motor nerve branches. In a recent randomized controlled trial, targeted muscle reinnervation was recently shown to reduce postamputation pain relative to conventional neuroma excision and muscle burying. QUESTIONS/PURPOSES: (1) Does targeted muscle reinnervation improve residual limb pain and phantom limb pain in the period before surgery to 1 year after surgery? (2) Does targeted muscle reinnervation improve Patient-reported Outcome Measurement System (PROMIS) pain intensity and pain interference scores at 1 year after surgery? (3) After 1 year, does targeted muscle reinnervation improve functional outcome scores (Orthotics Prosthetics User Survey [OPUS] with Rasch conversion and Neuro-Quality of Life [Neuro-QOL])? METHODS: Data on patients who were ineligible for randomization or declined to be randomized and underwent targeted muscle reinnervation for pain were gathered for the present analysis. Data were collected prospectively from 2013 to 2017. Forty-three patients were enrolled in the study, 10 of whom lacked 1-year follow-up, leaving 33 patients for analysis. The primary outcomes measured were the difference in residual limb and phantom limb pain before and 1 year after surgery, assessed by an 11-point numerical rating scale (NRS). Secondary outcomes were change in PROMIS pain measures and change in limb function, assessed by the OPUS Rasch for upper limbs and Neuro-QOL for lower limbs before and 1 year after surgery. RESULTS: By 1 year after targeted muscle reinnervation, NRS scores for residual limb pain from 6.4 ± 2.6 to 3.6 ± 2.2 (mean difference -2.7 [95% CI -4.2 to -1.3]; p < 0.001) and phantom limb pain decreased from 6.0 ± 3.1 to 3.6 ± 2.9 (mean difference -2.4 [95% CI -3.8 to -0.9]; p < 0.001). PROMIS pain intensity and pain interference scores improved with respect to residual limb and phantom limb pain (residual limb pain intensity: 53.4 ± 9.7 to 44.4 ± 7.9, mean difference -9.0 [95% CI -14.0 to -4.0]; residual limb pain interference: 60.4 ± 9.3 to 51.7 ± 8.2, mean difference -8.7 [95% CI -13.1 to -4.4]; phantom limb pain intensity: 49.3 ± 10.4 to 43.2 ± 9.3, mean difference -6.1 [95% CI -11.3 to -0.9]; phantom limb pain interference: 57.7 ± 10.4 to 50.8 ± 9.8, mean difference -6.9 [95% CI -12.1 to -1.7]; p ≤ 0.012 for all comparisons). On functional assessment, OPUS Rasch scores improved from 53.7 ± 3.4 to 56.4 ± 3.7 (mean difference +2.7 [95% CI 2.3 to 3.2]; p < 0.001) and Neuro-QOL scores improved from 32.9 ± 1.5 to 35.2 ± 1.6 (mean difference +2.3 [95% CI 1.8 to 2.9]; p < 0.001). CONCLUSIONS: Targeted muscle reinnervation demonstrates improvement in residual limb and phantom limb pain parameters in major limb amputees. It should be considered as a first-line surgical treatment option for chronic amputation-related pain in patients with major limb amputations. Additional investigation into the effect on function and quality of life should be performed. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Utilizing Precision Medicine to Estimate Timing for Surgical Closure of Traumatic Extremity Wounds.

BACKGROUND: Both the frequency and high complication rates associated with extremity wounds in recent military conflicts have highlighted the need for clinical decision support tools (CDST) to decrease time to wound closure and wound failure rates. METHODS: Machine learning was used to estimate both successful wound closure (based on penultimate debridement biomarker data) and the necessary number of surgical debridements (based on presentation biomarkers) in 73 service members treated according to military guidelines based on clinical data and the local/systemic level of 32 cytokines. Models were trained to estimate successful closure including an additional 8 of 80 civilian patients with similar injury patterns. Previous analysis has demonstrated the potential to reduce the number of operative debridements by 2, with resulting decreases in ICU and hospital LOS, while decreasing the rate of wound failure. RESULTS: Analysis showed similar cytokine responses when civilians followed a military-like treatment schedule with surgical debridements every 24 to 72 hours. A model estimating successful closure had AUC of 0.89. Model performance in civilians degraded when these had a debridement interval > 72 hours (73 of the 80 civilians). A separate model estimating the number of debridements required to achieve successful closure had a multiclass AUC of 0.81. CONCLUSION: CDSTs can be developed using biologically compatible civilian and military populations as cytokine response is highly influenced by surgical treatment. Our CDSTs may help identify who may require serial debridements versus early closure, and precisely when traumatic wounds should optimally be closed.

Targeted Muscle Reinnervation Treats Neuroma and Phantom Pain in Major Limb Amputees: A Randomized Clinical Trial.

OBJECTIVE: To compare targeted muscle reinnervation (TMR) to "standard treatment" of neuroma excision and burying into muscle for postamputation pain. SUMMARY BACKGROUND DATA: To date, no intervention is consistently effective for neuroma-related residual limb or phantom limb pain (PLP). TMR is a nerve transfer procedure developed for prosthesis control, incidentally found to improve postamputation pain. METHODS: A prospective, randomized clinical trial was conducted. 28 amputees with chronic pain were assigned to standard treatment or TMR. Primary outcome was change between pre- and postoperative numerical rating scale (NRS, 0-10) pain scores for residual limb pain and PLP at 1 year. Secondary outcomes included NRS for all patients at final follow-up, PROMIS pain scales, neuroma size, and patient function. RESULTS: In intention-to-treat analysis, changes in PLP scores at 1 year were 3.2 versus -0.2 (difference 3.4, adjusted confidence interval (aCI) -0.1 to 6.9, adjusted P = 0.06) for TMR and standard treatment, respectively. Changes in residual limb pain scores were 2.9 versus 0.9 (difference 1.9, aCI -0.5 to 4.4, P = 0.15). In longitudinal mixed model analysis, difference in change scores for PLP was significantly greater in the TMR group compared with standard treatment [mean (aCI) = 3.5 (0.6, 6.3), P = 0.03]. Reduction in residual limb pain was favorable for TMR (P = 0.10). At longest follow-up, including 3 crossover patients, results favored TMR over standard treatment. CONCLUSIONS: In this first surgical RCT for the treatment of postamputation pain in major limb amputees, TMR improved PLP and trended toward improved residual limb pain compared with conventional neurectomy. TRIAL REGISTRATION: NCT02205385 at ClinicalTrials.gov.

Intrawound Antibiotic Powder Decreases Frequency of Deep Infection and Severity of Heterotopic Ossification in Combat Lower Extremity Amputations.

BACKGROUND: Amputations sustained owing to combat-related blast injuries are at high risk for deep infection and development of heterotopic ossification, which can necessitate reoperation and place immense strain on the patient. Surgeons at our institution began use of intrawound antibiotic powder at the time of closure in an effort to decrease the rate of these surgical complications after initial and revision amputations, supported by compelling clinical evidence and animal models of blast injuries. Antibiotic powder may be useful in reducing the risk of these infections, but human studies on this topic thus far have been inconclusive. PURPOSE: We sought to determine whether administration of intrawound antibiotic powder at the time of closure would (1) decrease the risk of subsequent deep infections of major lower-extremity combat-related amputations, and (2) limit formation and decrease severity of heterotopic ossification common in the combat-related traumatic residual limb. METHODS: Between 2009 and 2015, 252 major lower extremity initial and revision amputations were performed by a single surgeon. Revision cases were excluded if performed specifically to address deep infection, leaving 223 amputations (88.5%) for this retrospective analysis. We reviewed medical records to collect patient information, returns to the operating room for subsequent infection, and microbiologic culture results. We also reviewed radiographs taken at least 3 months after surgery to determine the presence and severity of heterotopic ossification using the Walter Reed classification system. We grouped cases according to whether limbs underwent initial or revision amputations, and whether the limbs had a history of a prior infection. Apart from the use of antibiotic powder and duration of followup, the groups did not differ in terms of age, mechanism of injury, or sex. We then calculated the absolute risk reduction for infection and heterotopic ossification and the number needed to treat to prevent an infection. RESULTS: Overall, administration of antibiotic powder resulted in a 13% absolute risk reduction of deep infection (14 of 82 [17%] versus 42 of 141 [30%]; p = 0.03; 95% CI, 0.20%-24.72%). In revision amputation surgery, the absolute risk reduction of infection with antibiotic powder use was 16% overall (eight of 58 versus 17 of 57; 95% CI, 1.21%-30.86%), and 25% for previously infected limbs (eight of 46 versus 14 of 33; 95% CI, 4.93%-45.14%). The number needed to treat to prevent one additional deep infection in amputation surgery is eight in initial amputations, seven in revision amputations, and four for revision amputation surgery on previously infected limbs. With the numbers available, we observed no reduction in the risk of heterotopic ossification with antibiotic powder use, but severity was decreased in the treatment group in terms of the number of residual limbs with moderate or severe heterotopic ossification (three of 12 versus 19 of 34; p = 0.03). CONCLUSIONS: Our findings show that administration of intrawound antibiotic powder reduces deep infection in residual limbs of combat amputees, particularly in the setting of revision amputation surgery in apparently aseptic residual limbs at the time of the surgery. Furthermore, administration of antibiotic powder for amputations at time of initial closure decreases the severity of heterotopic ossification formation, providing a low-cost adjunct to decrease the risk of two complications common to amputation surgery.Level of Evidence Level III, therapeutic study.

Is Bone Loss or Devascularization Associated With Recurrence of Osteomyelitis in Wartime Open Tibia Fractures?

BACKGROUND: During recent wars, 26% of combat casualties experienced open fractures and these injuries frequently are complicated by infections, including osteomyelitis. Risk factors for the development of osteomyelitis with combat-related open tibia fractures have been examined, but less information is known about recurrence of this infection, which may result in additional hospitalizations and surgical procedures. QUESTIONS/PURPOSES: (1) What is the risk of osteomyelitis recurrence after wartime open tibia fractures and how does the microbiology compare with initial infections? (2) What factors are associated with osteomyelitis recurrence among patients with open tibia fractures? (3) What clinical characteristics and management approaches are associated with definite/probable osteomyelitis as opposed to possible osteomyelitis and what was the microbiology of these infections? METHODS: A survey of US military personnel injured during deployment between March 2003 and December 2009 identified 215 patients with open tibia fractures, of whom 130 patients developed osteomyelitis and were examined in a retrospective analysis. No patients with bilateral osteomyelitis were included. Twenty-five patients meeting osteomyelitis diagnostic criteria were classified as definite/probable (positive bone culture, direct evidence of infection, or symptoms with culture and/or radiographic evidence) and 105 were classified as possible (bone contamination, organism growth in deep wound tissue, and evidence of local/systemic inflammation). Patients diagnosed with osteomyelitis were treated with débridement and irrigation as well as intravenous antibiotics. Fixation hardware was retained until fracture union, when possible. Osteomyelitis recurrence was defined as a subsequent osteomyelitis diagnosis at the original site ≥ 30 days after completion of initial treatment. This followup period was chosen based on the definition of recurrence so as to include as many patients as possible for analysis. Factors associated with osteomyelitis recurrence were assessed using univariate analysis in a subset of the population with ≥ 30 days of followup. Patients who had an amputation at or proximal to the knee after the initial osteomyelitis were not included in the recurrence assessment. RESULTS: Of 112 patients meeting the criteria for assessment of recurrence, 31 (28%) developed an osteomyelitis recurrence, of whom seven of 25 (28%) had definite/probable and 24 of 87 (28%) had possible classifications for their initial osteomyelitis diagnosis. Risk of osteomyelitis recurrence was associated with missing or devascularized bone (recurrence, 14 of 31 [47%]; nonrecurrence, 22 of 81 [28%]; hazard ratio [HR], 3.94; 1.12-13.81; p = 0.032) and receipt of antibiotics for 22-56 days (recurrence, 20 of 31 [65%]; nonrecurrence: 37 of 81 [46%]; HR, 2.81; 1.05-7.49; p = 0.039). Compared with possible osteomyelitis, definite/probable osteomyelitis was associated with localized swelling at the bone site (13 of 25 [52%] versus 28 of 105 [27%]; risk ratio [RR], 1.95 [1.19-3.19]; p = 0.008) and less extensive skin and soft tissue injury at the time of trauma (9 of 22 [41%; three definite/probably patients missing data] versus 13 of 104 [13%; one possible patient missing data]; RR, 3.27 [1.60-6.69]; p = 0.001). Most osteomyelitis infections were polymicrobial (14 of 23 [61%; two patients with missing data] for definite/probable patients and 62 of 105 [59%] for possible patients; RR, 1.03 [0.72-1.48]; p = 0.870). More of the definite/probable patients received vancomycin (64%) compared with the possible patients (41%; p = 0.046), and the duration of polymyxin use was longer (median, 38 days versus 16 days, p = 0.018). Time to definitive fracture fixation was not different between the groups. CONCLUSIONS: Recurrent osteomyelitis after open tibia fractures is common. In a univariate model, patients with an intermediate amount of bone loss and those treated with antibiotics for 22 to 56 days were more likely to experience osteomyelitis recurrence. Because only univariate analysis was possible, these findings should be considered preliminary. Osteomyelitis recurrence rates were similar, regardless of initial osteomyelitis classification, indicating that diagnoses of possible osteomyelitis should be treated aggressively. LEVEL OF EVIDENCE: Level III, therapeutic study.

Proximal Femur Hounsfield Units on CT Colonoscopy Correlate With Dual-energy X-ray Absorptiometry.

BACKGROUND: Quantifying bone mineral density (BMD) on CT using commercial software demonstrates good-to-excellent correlations with dual-energy x-ray absorptiometry (DEXA) results. However, previous techniques to measure Hounsfield units (HUs) within the proximal femur demonstrate less successful correlation with DEXA results. An effective method of measuring HUs of the proximal femur from CT colonoscopy might allow for opportunistic osteoporosis screening. QUESTIONS/PURPOSES: (1) Do proximal femur HU measurements from CT colonoscopy correlate with proximal femur DEXA results? (2) How effective is our single HU measurement technique in estimating the likelihood of overall low BMD? (3) Does the relationship between our comprehensive HU measurement and DEXA results change based on age, sex, or time between studies? METHODS: This retrospective study investigated the measurement of HU of the femur obtained on CT colonoscopy studies compared with DEXA results. Between 2010 and 2017, five centers performed 9085 CT colonoscopy studies; of those, 277 (3%) also had available DEXA results and were included in this study, whereas 8809 (97%) were excluded for inadequate CT imaging, lack of DEXA screening, or lack of proximal femur DEXA results. The median number of days between CT colonoscopy and DEXA scan was 595 days; no patient was excluded based on time between scans because bone remodeling is a long-term process and this allowed subgroup analysis based on time between scans. Two reviewers performed HU measurements at four points within the proximal femur on the CT colonoscopy imaging and intraclass correlation coefficients were used to evaluate interrater reliability. We used Pearson correlation coefficients to compare the comprehensive (average of eight measurements) and a single HU measurement with each DEXA result-proximal femur BMD, proximal femur T-score, femoral neck BMD, and femoral neck T-score-to identify the best measurement technique within this study. Based on their lowest DEXA T-score, we stratified patients to a diagnosis of osteoporosis, osteopenia, or normal BMD. We then calculated the area under the receiver operator characteristic curves (AUCs) to evaluate the classification ability of a single HU value to identify possible threshold(s) for detecting low BMD. For each subgroup analysis, we calculated Pearson correlation coefficients between DEXA and HUs and evaluated each subgroup's contribution to the overall predictive model using an interaction test in a linear regression model. RESULTS: The Pearson correlation coefficient between both the comprehensive and single HU measurements was highest compared with the proximal femur T-score at 0.75 (95% confidence interval [CI], 0.69-0.80) and 0.74 (95% CI, 0.68-0.79), respectively. Interobserver reliability, measured with intraclass correlation coefficients, for the comprehensive and single HU measurements was 0.97 (95% CI, 0.72-0.99) and 0.96 (95% CI, 0.89-0.98), respectively. Based on DEXA results, 20 patients were osteoporotic, 167 had osteopenia, and 90 patients had normal BMD. The mean comprehensive HU for patients with osteoporosis was 70 ± 30 HUs; for patients with osteopenia, it was 110 ± 36 HUs; and for patients with normal BMD, it was 158 ± 43 HUs (p < 0.001). The AUC of the single HU model was 0.82 (95% CI, 0.77-0.87). A threshold of 214 HUs is 100% sensitive and 59 HUs is 100% specific to identify low BMD; a threshold of 113 HUs provided 73% sensitivity and 76% specificity. When stratified by decade age groups, each decade age group demonstrated a positive correlation between the comprehensive HU and proximal femur T-score, ranging between 0.71 and 0.83 (95% CI, 0.59-0.91). Further subgroup analysis similarly demonstrated a positive correlation between the comprehensive HU and proximal femur T-score when stratified by > 6 months or < 6 months between CT and DEXA (0.75; 95% CI, 0.62-0.84) as well as when stratified by sex (0.70-0.76; 95% CI, 0.48-0.81). The linear regression model demonstrated that the overall positive correlation coefficient between HUs and the proximal femur T-score is not influenced by any subgroup. CONCLUSIONS: Our measurement technique provides a reproducible measurement of HUs within the proximal femur HUs on CT colonoscopy. Hounsfield units of the proximal femur based on this technique can predict low BMD. These CT scans are frequently performed before initial DEXA scans are done and therefore may lead to earlier recognition of low BMD. Future research is needed to validate these results in larger studies and to determine if these results can anticipate future fracture risk. LEVEL OF EVIDENCE: Level III, diagnostic study.