A Two-Stage Approach Integrating Provisional Biomaterial-Mediated Stabilization Followed by a Definitive Treatment for Managing Volumetric Muscle Loss Injuries.

Treatment of volumetric muscle loss (VML) faces challenges due to its unique pathobiology and lower priority in severe musculoskeletal injury management. Consequently, a need exists for multi-stage VML treatment strategies to accommodate delayed interventions owing to comorbidity management or prolonged casualty care in combat settings. To this end, polyvinyl alcohol (PVA) was used at concentrations of 5%, 7.5%, and 10% to generate provisional muscle void fillers (MVFs) of varying stiffness values (1.125 kPa, 3.700 kPa, and 7.699 kPa) to stabilize VML injuries as part of a two-stage approach. These were implanted into a rat model for a duration of 4 weeks, then explanted and either left untreated (control) or treated through minced muscle grafting (MMG). Additional benchmarks included acute MMG and unrepaired groups. At the MVF explant, the 7.5% PVA group exhibited superior neuromuscular function compared to the 5% and 10% PVA groups, the least fibrosis, and the largest median myofiber size among all groups at the 12-week endpoint. Despite the 7.5% PVA's superiority amongst the two-stage treatment groups, neuromuscular function was neither improved nor impaired relative to acute treatment benchmarks. This suggests that the future success of a two-stage VML treatment strategy will necessitate a more effective definitive intervention.

The local and systemic effects of immune function on fracture healing.

The immune system plays an integral role in the regulation of cellular processes responsible for fracture healing. Local and systemic influences on fracture healing correlate in many ways with fracture-related outcomes, including soft tissue healing quality and fracture union rates. Impaired soft tissue healing, restricted perfusion of a fracture site, and infection also in turn affect the immune response to fracture injury. Modern techniques used to investigate the relationship between immune system function and fracture healing include precision medicine, using vast quantities of data to interpret broad patterns of inflammatory response. Early data from the PRECISE trial have demonstrated distinct patterns of inflammatory response in polytrauma patients, which thereby directly and indirectly regulate the fracture healing response. The clearly demonstrated linkage between immune function and fracture healing suggests that modulation of immune function has significant potential as a therapeutic target that can be used to enhance fracture healing.

Deep Surgical Site Infection after Fracture Has a Profound Effect on Functional Outcomes.

Background: Fracture-related infection is one of the most challenging complications in orthopaedic trauma surgery. However, the effect of infection on functional and pain-related outcomes has not been well established. The aims of this study were to evaluate functional recovery for patients with fracture and a deep surgical site infection compared with patients with fracture without infection and to evaluate whether pain severity, social support, and preinjury mental health have a moderating effect on the magnitude and direction of the relationship between deep surgical site infection and functional recovery. Methods: This is a secondary retrospective cohort study using prospectively collected data from the VANCO trial (Local Antibiotic Therapy to Reduce Infection After Operative Treatment of Fractures at High Risk of Infection) and the OXYGEN (Supplemental Perioperative Oxygen to Reduce Surgical Site Infection After High Energy Fracture Surgery) trial. In this study, 2,116 patients with tibial plateau, pilon, or calcaneal fractures at high risk for infection were included. Patients were divided into cohorts of patients who experienced a deep surgical site infection and those who did not. The primary outcome measure was the functional outcome using the Veterans RAND 12-Item Health Survey (VR-12). Results: After controlling for covariates, deep surgical site infection was independently associated with functional outcome, with a 3.3-point reduction in the VR-12 Physical Component Score, and pain severity was independently associated with functional outcome, with a 2.5-point reduction in the VR-12 Physical Component Score. Furthermore, the Brief Pain Inventory pain severity demonstrated an important moderating effect on the relationship between infection and functional outcome. In patients with lower pain scores, infection had a large negative impact on functional outcome, whereas, in patients with higher pain scores, infection had no significant impact on functional outcome. Furthermore, the functional outcome in the entire cohort remains at only 61% of baseline. Conclusions: This study documents the negative impact of postoperative infection on functional recovery after injury, as well as the novel finding of pain severity as an important moderating factor. This study emphasizes not only the importance of developing effective interventions designed to reduce postoperative infection, but also the role that factors that moderate pain severity plays in limiting recovery of physical function. Level of evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

The VANCO Trial Findings Are Generalizable to a North American Trauma Registry.

OBJECTIVES: To estimate the generalizability of treatment effects observed in the VANCO trial to a broader population of patients with tibial plateau or pilon fractures. METHODS: Design and Setting: Clinical trial data from 36 United States trauma centers and Trauma Quality Programs registry data from more than 875 Level I-III trauma centers in the United States and Canada.Patient Selection Criteria: Patients enrolled in the VANCO trial treated with intrawound vancomycin powder from January 2015 to June 2017 and 31,924 VANCO-eligible TQP patients admitted in 2019 with tibial plateau and pilon fractures.Outcome Measure and Comparisons: Deep surgical site infection and gram-positive deep surgical site infection estimated in the TQP sample weighed by the inverse probability of trial participation. RESULTS: The 980 patients in the VANCO trial were highly representative of 31,924 TQP VANCO-eligible patients (Tipton generalizability index 0.96). It was estimated that intrawound vancomycin powder reduced the odds of deep surgical infection by odds ratio (OR) = 0.46 (95% confidence interval [CI] 0.25-0.86) and gram-positive deep surgical infection by OR = 0.39 (95% CI, 0.18-0.84) within the TQP sample of VANCO-eligible patients. For reference, the trial average treatment effects for deep surgical infection and gram-positive deep surgical infection were OR = 0.60 (95% CI, 0.37-0.98) and OR = 0.44 (95% CI, 0.23-0.80), respectively. CONCLUSIONS: This generalizability analysis found that the inferences of the VANCO trial generalize and might even underestimate the effects of intrawound vancomycin powder when observed in a wider population of patients with tibial plateau and pilon fractures. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Incidence and risk factors for non-union of the superior ramus osteotomy when hip dysplasia is treated with periacetabular osteotomy.

Periacetabular osteotomy (PAO) is a well-established surgical treatment for hip dysplasia. Few studies report risk factors for the development of superior ramus osteotomy non-union. The purpose of this investigation was to document the incidence and risk factors for this complication. We identified 316 consecutive hips that underwent PAO for symptomatic acetabular dysplasia with a minimum 1-year radiographic follow-up. We developed and validated a technique to measure the superior ramus osteotomy location on anterior-posterior (AP) pelvis radiographs and computed tomography. Logistic regression with generalized estimating equations was used to evaluate the relationships between odds of non-union and potential demographic and radiographic predictor variables in univariate and multivariate analyses. Twenty-nine (9.2%) hips developed superior ramus non-union. Age {median [interquartile range (IQR)] 23 years (18-35) healed versus 35 years (26-40) non-united, P = 0.001}, pre-operative lateral center-edge angle (LCEA) [16° (11-20) healed versus 10° (6-13) non-united, P < 0.001] and the distance from the superior ramus osteotomy to the ilioishial line [15.8 mm (13.2-18.7) healed versus 18.1 mm (16.2-20.5) non-united, P < 0.001] varied significantly between groups. Using multivariate analysis, moderate-to-severe dysplasia [LCEA < 15°, odds ratio (OR) 5.95, standard error (SE) 3.32, 95% confidence interval (CI) 1.99-17.79, P = 0.001], increased age (5-year increase, OR 1.29, SE 3.32, 95% CI 1.105-1.60, P-value = 0.018) and distance from the ilioishial line (3-mm increase, OR 1.67, SE 0.22, 95% CI 1.29-2.18, P < 0.001) were at increased risk of developing non-union. Superior ramus osteotomy non-union is common after PAO. Older age, moderate-to-severe dysplasia, and more medial osteotomy location were independent risk factors for non-union. Consideration should be made in high-risk patients for a more lateral superior ramus osteotomy and adjuvant medical and surgical interventions.

In situ forming biomaterials as muscle void fillers for the provisional treatment of volumetric muscle loss injuries.

Volumetric muscle loss (VML) represents a devastating extremity injury which leads to chronic functional deficits and disability and is unrecoverable through normal healing pathways. When left untreated, the VML pathophysiology creates many challenges towards successful treatment, such as altered residual muscle architecture, excessive fibrosis, and contracture(s). As such, innovative approaches and technologies are needed to prevent or reverse these adverse sequelae. Development of a rationally designed biomaterial technology which is intended to be acutely placed within a VML defect - i.e., to serve as a muscle void filler (MVF) by maintaining the VML defect - could address this clinical unmet need by preventing these adverse sequelae as well as enabling multi-staged treatment approaches. To that end, three biomaterials were evaluated for their ability to serve as a provisional MVF treatment intended to stabilize a VML defect in a rat model for an extended period (28 days): polyvinyl alcohol (PVA), hyaluronic acid and polyethylene glycol combination (HA + PEG), and silicone, a clinically used soft tissue void filler. HA + PEG biomaterial showed signs of deformation, while both PVA and silicone did not. There were no differences between treatment groups for their effects on adjacent muscle fiber count and size distribution. Not surprisingly, silicone elicited robust fibrotic response resulting in a fibrotic barrier with a large infiltration of macrophages, a response not seen with either the PVA or HA + PEG. Taken together, PVA was found to be the best material to be used as a provisional MVF for maintaining VML defect volume while minimizing adverse effects on the surrounding muscle.

Minced muscle autografting improves bone healing but not muscle function in a porcine composite injury model.

Composite tissue injuries (CTIs) in extremities include segmental bone defects (SBDs) and volumetric muscle loss. The objective of this study was to determine if skeletal muscle autografting with minced muscle grafts (MMGs) could improve healing in an SBD and improve muscle function in a porcine CTI model that includes an SBD and adjacent volumetric muscle loss injury. Adult Yucatan Minipigs were stratified into three groups including specimens with an isolated SBD, an SBD with volumetric muscle loss (CTI), and an SBD with volumetric muscle loss treated with MMG (CTI + MMG). Bone healing was quantified with serial x-rays and postmortem computed tomography scanning. Muscle function was quantified with a custom in vivo force transducer. Muscle tissue content was determined by biochemical analyses and histology. Anterior cortex-modified Radiographic Union Score for Tibia fractures (mRUSTs) decreased from 2.7 to 1.9 (p = 0.003) in CTI versus SBD animals. MMG improved anterior mRUST scores to 2.5 in CTI + MMG specimens (p = 0.030 compared to CTI specimens) and overall mRUST scores increased from 9.4 in CTI specimens to 11.1 in CTI + MMG specimens (p = 0.049). Residual strength deficits at euthanasia were 42% in SBD (p < 0.001), 44% in CTI (p < 0.001), and 48% in CTI + MMG (p < 0.001) compared to preoperative values. There were no differences in strength deficits between the three groups. Biochemical and histologic analyses demonstrated scattered differences between the three groups compared to contralateral muscle. MMG improved bone healing. However, the primary cause of muscle dysfunction and biochemical changes was the presence of an SBD. Clinical significance: Early mitigation of SBDs may be necessary to prevent muscle damage and weakness in patients sustaining composite extremity trauma.

Application of Bayesian Methods to Help Interpret the VANCO Trial Results.

OBJECTIVE: To determine whether a Bayesian analysis changes the results of the VANCO trial. DESIGN: A secondary analysis of a randomized clinical trial using Bayesian methods. SETTING: Thirty-six US trauma centers. PATIENTS: Patients ages 18-80 years with a tibial plateau or pilon fracture deemed high risk of infection and definitively treated with plate and screw fixation. INTERVENTION: Patients were randomly allocated to receive 1000 mg of intrawound vancomycin powder at their definitive fixation or to a control group that received no topical antibiotics. MAIN OUTCOME MEASUREMENTS: A deep surgical site infection requiring operative treatment within 6 months of definitive fixation. Secondary outcomes included gram-positive and gram-negative-only deep surgical site infections. RESULTS: Of the 980 patients randomized, 874 (89%) had at least 140 days of follow-up and were included in this Bayesian analysis. The estimated probability that intrawound vancomycin powder reduces the risk of a deep surgical site infection is >98% [relative risk (RR), 0.66; 95% credible interval (CrI), 0.46-0.98]. There is a >99% chance intrawound vancomycin powder reduces gram-positive infections and an 80% chance the magnitude of this risk reduction exceeds 35% (RR, 0.52; 95% CrI, 0.33-0.84) exists. It is unlikely (44%) that intrawound vancomycin powder prevents gram-negative surgical site infections (RR, 1.06; 95% CrI, 0.48-2.45). CONCLUSIONS: There is a high probability (>98%) that intrawound vancomycin powder reduces deep surgical site infections in patients with tibial plateau or pilon fractures at high risk of infection and even more likely it reduces deep infections with gram-positive pathogens (>99%). LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Single-cell RNAseq provides insight into altered immune cell populations in human fracture nonunions.

Nonunion describes bone fractures that fail to heal, resulting in the fracture callus failing to fully ossify or, in atrophic cases, not forming altogether. Fracture healing is regulated, in part, by the balance of proinflammatory and anti-inflammatory processes occurring within the bone marrow and surface cell populations. We sought to further understand the role of osteoimmunology (i.e., study of the close relationship between the immune system and bone) by examining immune cell gene expression via single-cell RNA sequencing of intramedullary canal tissue obtained from human patients with femoral nonunions. Intramedullary canal tissue samples obtained by reaming were collected at the time of surgical repair for femur fracture nonunion (n = 5) or from native bone controls when harvesting autologous bone graft (n = 4). Cells within the samples were isolated and analyzed using the Chromium Single-Cell System (10x Genomics Inc.) and Illumina sequencers. Twenty-three distinct cell clusters were identified, with higher cell proportions in the nonunion samples for monocytes and CD14 + dendritic cells (DCs), and lower proportions of T cells, myelocytes, and promyelocytes in nonunion samples. Gene expression differences were identified in each of the cell clusters from cell types associated with osteoimmunology, including CD14 + DC, monocytes, T cells, promyelocytes, and myelocytes. These results provide human-derived gene profiles that can further our understanding of pathways that may be a cause or a consequence of nonunion, providing the clinical rationale to focus on specific components of osteoimmunology. Clinical significance: The novel single-cell approach may lead to clinically relevant diagnostic biomarkers during earlier stages of nonunion development and/or investigation into therapeutic options.

Bone Morphogenetic Protein-2 Rapidly Heals Two Distinct Critical Sized Segmental Diaphyseal Bone Defects in a Porcine Model.

INTRODUCTION: Segmental bone defects (SBDs) are devastating injuries sustained by warfighters and are difficult to heal. Preclinical models that accurately simulate human conditions are necessary to investigate therapies to treat SBDs. We have developed two novel porcine SBD models that take advantage of similarities in bone healing and immunologic response to injury between pigs and humans. The purpose of this study was to investigate the efficacy of Bone Morphogenetic Protein-2 (BMP-2) to heal a critical sized defect (CSD) in two novel porcine SBD models. MATERIALS AND METHODS: Two CSDs were performed in Yucatan Minipigs including a 25.0-mm SBD treated with intramedullary nailing (IMN) and a 40.0-mm SBD treated with dual plating (ORIF). In control animals, the defect was filled with a custom spacer and a bovine collagen sponge impregnated with saline (IMN25 Cont, n = 8; ORIF40 Cont, n = 4). In experimental animals, the SBD was filled with a custom spacer and a bovine collage sponge impregnated with human recombinant BMP-2 (IMN25 BMP, n = 8; ORIF40 BMP, n = 4). Healing was quantified using monthly modified Radiographic Union Score for Tibia Fractures (mRUST) scores, postmortem CT scanning, and torsion testing. RESULTS: BMP-2 restored bone healing in all eight IMN25 BMP specimens and three of four ORIF40 BMP specimens. None of the IMN25 Cont or ORIF40 Cont specimens healed. mRUST scores at the time of sacrifice increased from 9.2 (±2.4) in IMN25 Cont to 15.1 (±1.0) in IMN25 BMP specimens (P < .0001). mRUST scores increased from 8.2 (±1.1) in ORIF40 Cont to 14.3 (±1.0) in ORIF40 BMP specimens (P < .01). CT scans confirmed all BMP-2 specimens had healed and none of the control specimens had healed in both IMN and ORIF groups. BMP-2 restored 114% and 93% of intact torsional stiffness in IMN25 BMP and ORIF40 BMP specimens. CONCLUSIONS: We have developed two porcine CSD models, including fixation with IMN and with dual-plate fixation. Porcine models are particularly relevant for SBD research as the porcine immunologic response to injury closely mimics the human response. BMP-2 restored healing in both CSD models, and the effects were evident within the first month after injury. These findings support the use of both porcine CSD models to investigate new therapies to heal SBDs.

Risk factors for complications within 30 days of operatively fixed periprosthetic femur fractures.

Background: With a rising number of periprosthetic femur fractures (PPFFs) each year, the primary objective of our study was to quantify risk factors that predict complications following operative treatment of PPFFs. Methods: A retrospective cohort study of 231 patients with a periprosthetic femur fracture was conducted at an Academic, Level 1 Trauma Center. The main outcome measurement of interest was complications, as defined by the ACS-NSQIP, within 30 days of surgery. Results: 56 patients had 96 complications. Bivariate analyses revealed ASA score, preoperative ambulatory status, length of stay, discharge disposition, time from admission to surgery, length of surgery, perioperative change in hemoglobin, Charlson comorbidity index, cerebral vascular accident/transient ischemic attack, chronic obstructive pulmonary disease, diabetes mellitus, and receipt of a blood transfusion were associated with development of a complication (p < 0.1). Multivariate logistic regression showed length of stay (OR 1.11, 95% CI 1.03-1.19; p = 0.006), receipt of a blood transfusion (OR 2.48, 95% CI 1.14-5.42; p = 0.02), and diabetes mellitus (OR 2.17, 95% CI 1.03-4.56; p = 0.04) remained independently predictive of complication. Conclusions: Length of stay, receipt of a blood transfusion, and diabetes were associated with increased perioperative risk for developing a complication following operative treatment of periprosthetic femur fractures. Methods to decrease length of stay or transfusion rates may mitigate complication risk in these patients. Level of Evidence: Prognostic, Level III.

Risk Factors for Composite Failure of Hip Dysplasia Treated With Periacetabular Osteotomy: A Minimum 10-Year Follow-up.

INTRODUCTION: Periacetabular osteotomy (PAO) is a common surgical treatment of prearthritic hip dysplasia in young adults, but there are few long-term studies of clinical outcomes. The purpose of this investigation was to report a minimum 10-year clinical follow-up of hip dysplasia treated with PAO and identify risk factors for composite failure. METHODS: We identified 151 patients (198 hips) who underwent PAO to treat hip dysplasia at a single institution. Enrolled subjects completed a series of six patient-reported outcome instruments and provided information about subsequent surgeries. We defined composite failure as conversion to total hip arthroplasty or modified Harris Hip Score ≤70. Logistic regression with generalized estimating equations was used to evaluate the relationships between odds of failure and potential predictor variables in univariate and multivariate analyses. RESULTS: A total of 124 subjects (167 hips) with a minimum 10-year follow-up were enrolled. The median time from PAO to the final follow-up was 13 years (range 10-18 years). There were 71 hips that met criteria for failure: 32 with total hip arthroplasty and 39 with modified Harris Hip Score ≤70. Univariate logistic regression analyses revealed multiple preoperative factors that predicted composite failure: increased age and body mass index, osteoarthritis (OA), and more severe acetabular dysplasia. Postoperative factors that predicted failure included lateral undercoverage and formation of heterotopic ossification (HO). The final multivariate model identified body mass index ≥30 kg/m2 (odds ratio [OR], 3.84 [95% confidence interval (CI), 1.68-8.78], P = 0.001), higher preoperative Tönnis grade OA (OR, 2.65 [95% CI, 1.50-4.66], P < 0.001), and HO formation (OR, 16.52 [95% CI, 2.08-135.96], P = 0.009) as independent predictors of failure. CONCLUSIONS: This study corroborates current hip dysplasia literature, identifying increasing age and presence of preoperative OA as risk factors for composite failure in univariate analyses. In addition, we found that obesity and HO formation were independent predictors of persistent hip dysfunction. LEVEL OF EVIDENCE: Therapeutic Level IV.

Patient-Specific Precision Injury Signatures to Optimize Orthopaedic Interventions in Multiply Injured Patients (PRECISE STUDY).

SUMMARY: Optimal timing and procedure selection that define staged treatment strategies can affect outcomes dramatically and remain an area of major debate in the treatment of multiply injured orthopaedic trauma patients. Decisions regarding timing and choice of orthopaedic procedure(s) are currently based on the physiologic condition of the patient, resource availability, and the expected magnitude of the intervention. Surgical decision-making algorithms rarely rely on precision-type data that account for demographics, magnitude of injury, and the physiologic/immunologic response to injury on a patient-specific basis. This study is a multicenter prospective investigation that will work toward developing a precision medicine approach to managing multiply injured patients by incorporating patient-specific indices that quantify (1) mechanical tissue damage volume; (2) cumulative hypoperfusion; (3) immunologic response; and (4) demographics. These indices will formulate a precision injury signature, unique to each patient, which will be explored for correspondence to outcomes and response to surgical interventions. The impact of the timing and magnitude of initial and staged surgical interventions on patient-specific physiologic and immunologic responses will be evaluated and described. The primary goal of the study will be the development of data-driven models that will inform clinical decision-making tools that can be used to predict outcomes and guide intervention decisions.

Long-Term Consequences of Major Extremity Trauma: A Pilot Study.

SUMMARY: Limited data are available on the longer-term physical and psychosocial consequences after major extremity trauma apart from literature on the consequences after major limb amputation. The existing literature suggests that although variations in outcome exist, a significant proportion of service members and civilians sustaining major limb trauma will have less than optimal outcomes or health and rehabilitation needs over their life course. The proposed pilot study will address this gap in current research by locating and consenting METRC participants with the period of 5-7 years postinjury, identifying potential participation barriers and appropriate use of incentives, and conducting the follow-up examination at several data collection sites. The resulting data will inform the primary objective of refining and developing specific hypotheses to determine the design, scope, and feasibility of the main long-term consequences of major extremity trauma. Three METRC enrollment centers will contact past participants to achieve the goal of completing an interview, select patient-reported outcomes, perform a medical record review, and conduct an in-person clinic visit that will consist of a physical examination, blood draw, and x-ray of the study injury area. If successful, it will be possible to design studies to further examine these effects and develop future therapeutic interventions.

Cognitive-Behavioral-Based Physical Therapy for Improving Recovery After Traumatic Orthopaedic Lower Extremity Injury (CBPT-Trauma).

SUMMARY: Physical and psychological impairment resulting from traumatic injuries is often significant and affects employment and functional independence. Extremity trauma has been shown to negatively affect long-term self-reported physical function, the ability to work, and participation in recreational activities and contributes to increased rates of anxiety and/or depression. High pain levels early in the recovery process and psychosocial factors play a prominent role in recovery after traumatic lower extremity injury. Cognitive-behavioral therapy pain programs have been shown to mitigate these effects. However, patient access issues related to financial and transportation constraints and the competing demands of treatment focused on the physical sequelae of traumatic injury limit patient participation in this treatment modality. This article describes a telephone-delivered cognitive-behavioral-based physical therapy (CBPT-Trauma) program and design of a multicenter trial to determine its effectiveness after lower extremity trauma. Three hundred twenty-five patients from 7 Level 1 trauma centers were randomized to CBPT-Trauma or an education program after hospital discharge. The primary hypothesis is that compared with patients who receive an education program, patients who receive the CBPT-Trauma program will have improved physical function, pain, and physical and mental health at 12 months after hospital discharge.

Single-cell RNA sequencing of intramedullary canal tissue to improve methods for studying fracture repair biology.

The ability to study the bone microenvironment of failed fracture healing may lead to biomarkers for fracture nonunion. Herein the authors describe a technique for isolating individual cells suitable for single-cell RNA sequencing analyses from intramedullary canal tissue collected by reaming during surgery. The purpose was to detail challenges and solutions inherent to the collection and processing of intramedullary canal tissue samples. The authors then examined single-cell RNA sequencing data from fresh and reanimated samples to demonstrate the feasibility of this approach for prospective studies.

Polytraumatized patient lower extremity nonunion development: Raw data.

In this article we report data collected to evaluate the pathomechanistic effect of acute anaerobic metabolism in the polytraumatized patient and its subsequent effect on fracture nonunion; see "Base Deficit ≥6 within 24 Hours of Injury is a Risk Factor for Fracture Nonunion in the Polytraumatized Patient" (Sardesai et al., 2021) [1]. Data was collected on patients age ≥16 with an Injury Severity Score (ISS) >16 that presented between 2013-2018 who sustained a fracture of the tibia or femur distal to the femoral neck. Patients presenting to our institution greater than 24 hours post-injury and those with less than three months follow-up were excluded. Medical charts were reviewed to collect patient demographic information and known nonunion risk-factors, including smoking, alcohol use, and diabetes. In addition, detailed injury characteristics to quantify injury magnitude including ISS, Glasgow Coma Scale (GCS) at admission, and ICU length of stay were recorded. ISS values were obtained from our institutional trauma database where they are entered by individuals trained in ISS calculations. Associated fracture-related features including fracture location, soft-tissue injury (open vs. closed fracture), vascular injury, and compartment syndrome were recorded. Finally, vital signs, base deficit (BD), and blood transfusions over 24 hours from admission were recorded. We routinely measure BD and less consistently measure serum lactate in trauma patients at the time of presentation or during resuscitation. BD values are automatically produced by our laboratory with any arterial blood gas order, and we recorded BD values from the medical record. Clinical notes and radiographs were reviewed to confirm fracture union versus nonunion and assess for deep infection at the fracture site. Patients were categorized as having a deep infection if they were treated operatively for the infection prior to fracture healing or classification as a nonunion. Nonunion was defined by failure of progressive healing on sequential radiographs and/or surgical treatment for nonunion repair at least six months post-injury.

Base Deficit ≥ 6 within 24 h of Injury is a risk factor for fracture nonunion in the polytraumatized patient.

BACKGROUND: Polytrauma patients are at risk for fracture nonunion, but the reasons are poorly understood. Increased base deficit (BD) is associated with hypovolemic shock. Although shock delays bone healing in animal models, there have been no clinical studies evaluating the impact of BD on nonunion risk. MATERIALS AND METHODS: Patients age ≥ 16 with injury severity score > 16 that presented to an academic Level One trauma center with an operative femur or tibia fracture were reviewed. Clinical notes and radiographs were assessed to determine fracture healing status. Patient demographics, injury characteristics, BD, and number of packed red blood cell transfusions were recorded. Bivariate and multivariate analyses of multiple risk factors associated with nonunion were conducted to investigate the association of BD with nonunion. RESULTS: The union group was comprised of 243 fractures; there were 36 fractures in the nonunion group. The following predictors were associated with nonunion: smoking (p = 0.009), alcohol use (p < 0.001), open fracture (p < 0.001), and treatment for deep infection at fracture site (p = 0.016). Additionally, worst BD over 24 h ≥ 6 (p = 0.031) was significant for nonunion development. A multivariate logistic regression analysis revealed worst BD ≥6 over 24 h remained significantly associated with the development of nonunion (odds ratio 3.02, p = 0.011) when adjusting for other risk factors. CONCLUSIONS: A BD ≥ 6 within 24 h of admission was associated with a significantly increased risk of developing lower extremity fracture nonunion in polytrauma patients, even after adjusting for multiple other risk factors. Acute post-traumatic acidosis may have effects on long-term fracture healing.

Early dynamic orchestration of immunologic mediators identifies multiply injured patients who are tolerant or sensitive to hemorrhage.

BACKGROUND: Multiply injured patients (MIPs) are at risk of complications including infections, and acute and prolonged organ dysfunction. The immunologic response to injury has been shown to affect outcomes. Recent advances in computational capabilities have shown that early dynamic coordination of the immunologic response is associated with improved outcomes after trauma. We hypothesized that patients who were sensitive or tolerant of hemorrhage would demonstrate differences in dynamic immunologic orchestration within hours of injury. METHODS: We identified two groups of MIPs who demonstrated distinct clinical tolerance to hemorrhage (n = 10) or distinct clinical sensitivity to hemorrhage (n = 9) from a consecutive cohort of 100 MIPs. Hemorrhage was quantified by integrating elevated shock index values for 24 hours after injury (shock volume). Clinical outcomes were quantified by average Marshall Organ Dysfunction Scores from days 2 to 5 after injury. Shock-sensitive patients had high cumulative organ dysfunction after lower magnitude hemorrhage. Shock-tolerant (ST) patients had low cumulative organ dysfunction after higher magnitude hemorrhage. Computational methods were used to analyze a panel of 20 immunologic mediators collected serially over the initial 72 hours after injury. RESULTS: Dynamic network analysis demonstrated the ST patients had increased orchestration of cytokines that are reparative and protective including interleukins 9, 17E/25, 21, 22, 23, and 33 during the initial 0- to 8-hour and 8- to 24-hour intervals after injury. Shock-sensitive patients had delayed immunologic orchestration of a network of largely proinflammatory and anti-inflammatory mediators. Elastic net linear regression demonstrated that a group of five mediators could discriminate between shock-sensitive and ST patients. CONCLUSIONS: Preliminary evidence from this study suggests that early immunologic orchestration discriminates between patients who are notably tolerant or sensitive to hemorrhage. Early orchestration of a group of reparative/protective mediators was amplified in shock-tolerant patients. LEVEL OF EVIDENCE: Prospective clinical outcomes study, level III.

Internal Fixation Construct and Defect Size Affect Healing of a Translational Porcine Diaphyseal Tibial Segmental Bone Defect.

BACKGROUND AND OBJECTIVE: Porcine translational models have become the gold-standard translational tool to study the effects of major injury and hemorrhagic shock because of their similarity to the human immunologic response to trauma. Segmental bone defects (SBDs) typically occur in warfighters with associated severe limb trauma. The purpose of this study was to develop a translational porcine diaphyseal SBD model in Yucatan minipigs (YMPs), which could be used in bone healing investigations that simulate injury-relevant conditions. We were specifically working toward developing a critical sized defect (CSD). METHODS: We used an adaptive experimental design in which both 25.0 mm and 40.0 mm SBDs were created in the tibial mid-diaphysis in skeletally mature YMPs. Initially, eight YMPs were subjected to a 25.0 mm SBD and treated with intramedullary nailing (intramedullary nail [IMN] 25mm). Due to unanticipated wound problems, we subsequently treated four specimens with identical 25.0 mm defect with dual plating (open reduction with internal fixation [ORIF] 25mm). Finally, a third group of four YMPs with 40.0 mm defects were treated with dual plating (ORIF 40mm). Monthly radiographs were made until sacrifice. Modified Radiographic Union Score for Tibia fractures (mRUST) measurements were made by three trauma-trained orthopedic surgeons. CT scans of the tibias were used to verify the union results. RESULTS: At 4 months post-surgery, mean mRUST scores were 11.7 (SD ± 1.8) in the ORIF 25mm YMPs vs. 8.5 (SD ± 1.4) in the IMN 25mm YMPs (P < .0001). All four ORIF 25mm YMPs were clinically healed. In contrast, none of the IMN 25mm YMPs were clinically healed and seven of eight IMN 25mm YMPs developed delayed wound breakdown. All four of the ORIF 40mm YMPs had flail nonunions with complete hardware failure by 3 months after surgery and were sacrificed early. CT scanning confirmed that none of the IMN 25mm YMPs, none of the ORIF 40mm YMPs, and two of four ORIF 25mm YMPs were healed. A third ORIF 25mm specimen was nearly healed on CT scanning. Inter-rater and intra-rater reliability interclass coefficients using the mRUST scale were 0.81 and 0.80, respectively. CONCLUSIONS: YMPs that had a 40 mm segment of bone removed from their tibia and were treated with dual plating did not heal and could be used to investigate interventions that accelerate bone healing. In contrast, a 25 mm SBD treated with dual plating demonstrated delayed but successful healing, indicating it can potentially be used to investigate bone healing adjuncts or conversely how concomitant injuries may impair bone healing. Pigs treated with IMN failed to heal and developed consistent delayed wound breakdown presumably secondary to chronic limb instability. The porcine YMP SBD model has the potential to be an effective translational tool to investigate bone healing under physiologically relevant injury conditions.