Cytotoxicity of novel hybrid composite materials for making bone fracture plates.

Bone fracture plates are usually made from steel or titanium, which are much stiffer than cortical bone. This may cause bone 'stress shielding' (i.e. bone resorption leading to plate loosening) and delayed fracture healing (i.e. fracture motion is less than needed to stimulate callus formation at the fracture). Thus, the authors previously designed, fabricated, and mechanically tested novel 'hybrid' composites made from inorganic and organic materials as potential bone fracture plates that are more flexible to reduce these negative effects. This is the first study to measure the cytotoxicity of these composites via the survival of rat cells. Cubes of carbon fiber/flax fiber/epoxy and glass fiber/flax fiber/epoxy had better cell survival vs. Kevlar fiber/flax fiber/epoxy (57% and 58% vs. 50%). Layers and powders made of carbon fiber/epoxy and glass fiber/epoxy had higher cell survival than Kevlar fiber/epoxy (96%-100% and 100% vs. 39%-90%). The presence of flax fibers usually decreased cell survival. Thus, carbon and glass fiber composites (with or without flax fibers), but not Kevlar fiber composites (with or without flax fibers), may potentially be used for bone fracture plates.

Fasciotomy and rate of amputation after tibial fracture in adults: a population-based cohort study.

Objectives: Limb amputation is a possible outcome of acute compartment syndrome. We undertook this study to investigate the occurrence of fasciotomy and amputation in patients with tibial fractures in the Ontario adult population, aiming to evaluate variables that may be associated with each of these outcomes. Design: Retrospective, population-based cohort study (April 1, 2003-March 31, 2016). Setting: Canadian province of Ontario. Participants: Patients with tibial fracture, aged 14 years and older. Interventions: Fasciotomy after tibial fracture. Main Outcomes and Measures: The primary outcomes were fasciotomy and amputation within 1 year of fasciotomy. Secondary outcomes included repeat surgery, new-onset renal failure, and mortality, all within 30 days of fasciotomy. Results: We identified 76,299 patients with tibial fracture; the mean (SD) age was 47 (21) years. Fasciotomy was performed in 1303 patients (1.7%); of these, 76% were male and 24% female. Patients who were younger, male, or experienced polytrauma were significantly more likely to undergo fasciotomy. Limb amputation occurred in 4.3% of patients undergoing fasciotomy, as compared with 0.5% in those without fasciotomy; older age, male sex, presence of polytrauma, and fasciotomy were associated with an increased risk of amputation (age odds ratio [OR] of 1.03 [95% CI, 1.02-1.03], P < 0.0001; sex OR of 2.04 [95% CI, 1.63-2.55], P < 0.0001; polytrauma OR of 9.37 [95% CI, 7.64-11.50], P < 0.0001; fasciotomy OR of 4.35 [95% CI, 3.21-5.90], P < 0.0001), as well as repeat surgery within 30 days (sex OR of 1.54 [95% CI, 1.14-2.07], P = 0.0053; polytrauma OR of 4.24 [95% CI, 3.33-5.38], P < 0.0001). Conclusions: Among tibial fracture patients, those who were male and who experienced polytrauma were at significantly higher risk of undergoing fasciotomy and subsequent amputation. Fasciotomy was also significantly associated with risk of amputation, a finding that is likely reflective of the severity of the initial injury.

Postfasciotomy Classification System for Acute Compartment Syndrome of the Leg.

OBJECTIVE: Acute compartment syndrome (ACS) is a true emergency. Even with urgent fasciotomy, there is often muscle damage and need for further surgery. Although ACS is not uncommon, no validated classification system exists to aid in efficient and clear communication. The aim of this study was to establish and validate a classification system for the consequences of ACS treated with fasciotomy. METHODS: Using a modified Delphi method, an international panel of ACS experts was assembled to establish a grading scheme for the disease and then validate the classification system. The goal was to articulate discrete grades of ACS related to fasciotomy findings and associated costs. A pilot analysis was used to determine questions that were clear to the respondents. Discussion of this analysis resulted in another round of cases used for 24 other raters. The 24 individuals implemented the classification system 2 separate times to compare outcomes for 32 clinical cases. The accuracy and reproducibility of the classification system were subsequently calculated based on the providers' responses. RESULTS: The Fleiss Kappa of all raters was at 0.711, showing a strong agreement between the 24 raters. Secondary validation was performed for paired 276 raters and correlation was tested using the Kendall coefficient. The median correlation coefficient was 0.855. All 276 pairs had statistically significant correlation. Correlation coefficient between the first and second rating sessions was strong with the median pair scoring at 0.867. All surgeons had statistically significant internal consistency. CONCLUSION: This new ACS classification system may be applied to better understand the impact of ACS on patient outcomes and economic costs for leg ACS.

Compartment Syndrome: The Issues and Solutions You Need to Know About.

The diagnosis and management of compartment syndrome remains challenging and controversial. There continues to be a significant burden of disease and substantial resource implications associated with fractures complicated by compartment syndrome. Achieving consensus opinions regarding the diagnosis and treatment of this problem has important implications given the profound effect on patient outcomes.

Evaluation of a tiered operating room strategy at an academic centre: comparing high-efficiency and conventional operating rooms.

BACKGROUND: Wait times for many elective orthopedic surgical procedures in Ontario have become unacceptably long and substantially exceed the recommended guidelines. As a consequence, many patients experience chronic pain, disability and other poor health outcomes. The purpose of this study was to test a novel, resource-saving redesign of outpatient operating room (OR) services, based on tiered grouping of surgical cases, to maximize health benefits for patients while improving efficiency and decreasing wait times. METHODS: This prospective cohort study enrolled adult patients scheduled to undergo unilateral lower limb procedures that had a low requirement for surgical resources and did not require admission to the hospital (ambulatory surgical services) at an academic hospital. Patients were randomly assigned to a conventional OR group or a high-efficiency (tiered) OR group, in which the intensity of surgical, anesthesia and nursing resources was matched to the procedure and the patient's health status. The tiered OR made use of local anesthesia and a block room rather than general anesthesia. Primary outcomes were costs of surgical services provided and patient health outcomes; secondary outcomes were patient and staff satisfaction with each OR setup. RESULTS: The costs associated with the high-efficiency OR were 60% lower than those associated with the conventional OR (this was primarily due to the streamlining of OR care and elimination of the need to use a postanesthetic care unit), with the same or equivalent patient health outcomes. No differences in patient and staff satisfaction were found between the 2 setups. CONCLUSION: The use of tiered, ambulatory services for elective orthopedic surgery does not compromise health outcomes and patient satisfaction, and it is associated with substantial cost savings.

Cost and safety of inpatient versus outpatient open reduction internal fixation of isolated ankle fractures.

BACKGROUND: As health care shifts to value-based models, one strategy within orthopedics has been to transition appropriate cases to outpatient or ambulatory settings to reduce costs; however, there are limited data on the efficacy and safety of this practice for isolated ankle fractures. The purpose of this study was to compare the cost and safety associated with inpatient versus outpatient ankle open reduction internal fixation (ORIF). METHODS: All patients who underwent ORIF of isolated closed ankle fractures at 2 affiliated hospitals between April 2016 and March 2017 were identified retrospectively. Demographic characteristics, including age, gender, comorbidities and injuryspecific variables, were collected. We grouped patients based on whether they underwent ankle ORIF as an inpatient or outpatient. We determined case costing for all patients and analyzed it using multivariate regression analysis. RESULTS: A total of 196 patients (125 inpatient, 71 outpatient) were included for analysis. Inpatients had a significantly longer mean length of stay than outpatients (54.3 h [standard deviation (SD) 36.3 h] v. 7.5 h [SD 1.7 h], p < 0.001). The average cost was significantly higher for the inpatient cohort than the outpatient cohort ($4137 [SD $2285] v. $1834 [SD $421], p < 0.001). There were more unimalleolar ankle fractures in the outpatient group than in the inpatient group (42 [59.2%] v. 41 [32.8%], p < 0.001). Outpatients waited longer for surgery than inpatients (9.6 d [SD 5.6 d] v. 2.0 d [SD 3.3 d], p < 0.001). Fourteen patients (11.2%) in the inpatient group presented to the emergency department or were readmitted to hospital within 30 days of discharge, compared to 5 (7.0%) in the outpatient group (p = 0.3). CONCLUSION: In the treatment of isolated closed ankle fractures, outpatient surgery was associated with a significant reduction in length of hospital stay and overall case cost compared to inpatient surgery, with no significant difference in readmission or reoperation rates. In medically appropriate patients, isolated ankle ORIF can be performed safely in an ambulatory setting and is associated with significant cost savings.

Early radiographic outcomes following deltoid ligament repair in bimalleolar equivalent ankle fractures.

BACKGROUND: Indications for deltoid ligament repair in bimalleolar equivalent ankle fractures are unclear. This study compared radiographic outcomes in bimalleolar equivalent ankle fractures undergoing open reduction internal fixation (ORIF) +/- deltoid ligament repair. METHODS: A retrospective review of 1024 ankle fractures was performed. Bimalleolar equivalent injuries treated with ORIF +/- deltoid ligament repair were included. Radiographic assessment was performed preoperatively, and at three months postoperatively. RESULTS: One hundred and forty-seven ankle fractures met inclusion criteria with 46 undergoing deltoid ligament repairs. There was a significant decrease in medial clear space (1.93 ± 0.65 mm vs. 2.26 ± 0.64 mm, p = 0.01), and tibiofibular clear space (3.89 ± 1.20 mm vs. 4.87 ± 1.37 mm, p = 0.0001) at 3 months postoperative in the deltoid repair group compared to the no repair group. When syndesmotic fixation was performed, there were no differences between groups. CONCLUSION: Deltoid ligament repair in bimalleolar equivalent ankle fractures resulted in reduced medial clear space, and tibiofibular clear space in the early postoperative period. These differences were small and remained within established normal limits. LEVEL OF CLINICAL EVIDENCE: Level III, retrospective cohort study.

Anatomic Repair vs Closed Reduction of the Syndesmosis.

BACKGROUND: The goal of the study was to compare radiographic and functional outcomes between conventional closed syndesmotic reduction and screw fixation with open reduction, direct repair of the anterior inferior tibiofibular ligament (AiTFL) and screw fixation. We hypothesized that open reduction with restoration of the AiTFL would provide an improved reduction with better radiographic and functional outcomes. METHODS: Fifty consecutive patients with OTA 44-C ankle fractures were enrolled. Treatment was nonrandomized and based on surgeon preference. Patients were treated with either open reduction, suture-anchor AiTFL repair, and screw fixation (ART group), or conventional closed reduction of the syndesmosis followed by screw fixation (CR group). The primary outcome measure was anteroposterior (AP) displacement of the fibula on CT scan at 3 months postoperatively. Secondary outcome measures included the Maryland Foot Score, the American Orthopaedic Foot & Ankle Society (AOFAS) Ankle Hindfoot Score, and the Foot and Ankle Outcome Score (FAOS). RESULTS: Mean AP difference between injured and noninjured ankles was decreased in the ART group compared with the CR group (0.7 ± 0.3 mm vs 1.5 ± 0.3 mm, P = .008). No differences were observed between groups in overall scores for secondary outcome measures. The ART group displayed a significant difference in Maryland Foot Shoe subscore at 12 months (ART = 9.5 vs CR = 8.3, P = .03) and FAOS Quality of Life subscore at 12 months (64.1 compared to 38.3, P = .04). CONCLUSION: Open anatomic syndesmotic repair resulted in improved radiographic outcomes compared with closed reduction. Cosmesis was worse at 6 weeks compared to the CR group; however, quality of life and shoewear were improved in the ART group at 1 year postoperatively. LEVEL OF EVIDENCE: Level II, prospective comparative study.

Improved Reduction of the Tibiofibular Syndesmosis With TightRope Compared With Screw Fixation: Results of a Randomized Controlled Study.

OBJECTIVE: To compare the rate of malreduction after high fibular fractures associated with syndesmosis injury treated with open reduction and internal fixation, with either 2 screws or 1 knotless TightRope device. DESIGN: Prospective randomized controlled multicenter trial. SETTING: Eleven academic and community hospitals including Level 1 and Level 2 trauma centers across Canada. PATIENTS/PARTICIPANTS: One hundred three patients with OTA/AO 44-C injuries with demonstrated radiographic syndesmosis diastasis or instability after malleolar bony fixation were followed for 12 months after treatment. METHODS: Open reduction of the syndesmosis was performed in all cases. Fixation was randomized to either TightRope (1 knotless TightRope, group T) or screw fixation (two 3.5-mm cortical positional screws placed across 3 cortices, group S). Surgical techniques and rehabilitation were standardized. All surgeons were trained or experienced in the use of the TightRope device. Follow-up was performed at 2 and 6 weeks, 3, 6, and 12 months. MAIN OUTCOME MEASURE: Rate of malreduction based on bilateral ankle computed tomography scan results at 3 months after fixation. Secondary outcome measures included adverse events, reoperation, and validated functional outcomes including the EQ-5D, the Olerud-Molander Ankle Score, the Foot and Ankle Disability Index, and the Work Productivity Activity Impairment Questionnaire. The estimated sample size required to detect a difference in reduction rate was 72 patients, but the estimated sample size required to detect a difference in functional outcome scores was 240 patients, suggesting the study was adequately powered for radiographic results only. RESULTS: Overall, the rate of malreduction using screw fixation was 39% compared with 15% using TightRope fixation (P = 0.028, χ). Analysis of computed tomography results was performed using a 2-mm translation or 10-degree rotation threshold for malreduction and included fibular translation (anterior, posterior); syndesmosis distance (anterior, posterior, and mid); medial compression; and rotation (fibular and articular). Patients in group T had greater anterior translation (5.4 ± 1.8 mm) compared with the contralateral limb (4.3 ± 1.3 mm, P < 0.01) or group S (4.6 ± 1.5 mm, P = 0.05). Group T syndesmoses also had greater diastasis compared with control limb (4.1 ± 1.3 vs. 3.3 ± 1.4 mm, P < 0.01) and less fibular medialization compared with group S (1.04 ± 1.8 vs. 0.3 ± 1.8 mm, P = 0.05). Functional outcome measures demonstrated significant improvements over time, but no differences between fixation groups. Foot and Ankle Disability Index scores at each time interval were 44 ± 22 (T) versus 45 ± 24 (S) (6 weeks), 76 ± 14 versus 73 ± 17 (3 months), 89 ± 10 versus 86 ± 13 (6 months), and 93 ± 9 versus 90 ± 14 (12 months) (all P > 0.2). The reoperation rate was higher in the screw group compared with TightRope (30% vs. 4%, P = 0.02) with the difference driven by the rate of implant removal. CONCLUSIONS: Based on our results, the TightRope device seems to compare favorably with two, 3.5-mm, 3-cortex screw fixation for syndesmosis injuries. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Effects of accelerated versus standard care surgery on the risk of acute kidney injury in patients with a hip fracture: a substudy protocol of the hip fracture Accelerated surgical TreaTment And Care tracK (HIP ATTACK) international randomised controlled trial.

INTRODUCTION: Inflammation, dehydration, hypotension and bleeding may all contribute to the development of acute kidney injury (AKI). Accelerated surgery after a hip fracture can decrease the exposure time to such contributors and may reduce the risk of AKI. METHODS AND ANALYSIS: Hip fracture Accelerated surgical TreaTment And Care tracK (HIP ATTACK) is a multicentre, international, parallel-group randomised controlled trial (RCT). Patients who suffer a hip fracture are randomly allocated to either accelerated medical assessment and surgical repair with a goal of surgery within 6 hours of diagnosis or standard care where a repair typically occurs 24 to 48 hours after diagnosis. The primary outcome of this substudy is the development of AKI within 7 days of randomisation. We anticipate at least 1998 patients will participate in this substudy. ETHICS AND DISSEMINATION: We obtained ethics approval for additional serum creatinine recordings in consecutive patients enrolled at 70 participating centres. All patients provide consent before randomisation. We anticipate reporting substudy results by 2021. TRIAL REGISTRATION NUMBER: NCT02027896; Pre-results.

Carbon monoxide-releasing molecule-3 (CORM-3) offers protection in an in vitro model of compartment syndrome.

OBJECTIVE: Limb compartment syndrome (CS), a complication of trauma, results in muscle necrosis and cell death; ischemia and inflammation contribute to microvascular dysfunction and parenchymal injury. Carbon monoxide-releasing molecule-3 (CORM-3) has been shown to protect microvascular perfusion and reduce inflammation in animal models of CS. The purpose of the study was to test the effect of CORM-3 in human in vitro CS model, allowing exploration of the mechanism(s) of CO protection and potential development of pharmacologic treatment. METHODS: Confluent human vascular endothelial cells (HUVECs) were stimulated for 6 h with serum isolated from patients with CS. Intracellular oxidative stress (production of reactive oxygen species (ROS)) apoptosis, transendothelial resistance (TEER), polymorphonuclear leukocyte (PMN) activation and transmigration across the monolayer in response to the CS stimulus were assessed. All experiments were performed in the presence of CORM-3 (100 µM) or its inactive form, iCORM-3. RESULTS: CS serum induced a significant increase in ROS, apoptosis and endothelial monolayer breakdown; it also increased PMN superoxide production, leukocyte rolling and adhesion/transmigration. CORM-3 completely prevented CS-induced ROS production, apoptosis, PMN adhesion, rolling and transmigration, while improving monolayer integrity. CONCLUSION: CORM-3 offers potent anti-oxidant and anti-inflammatory effects, and may have a potential application to patients at risk of developing CS.

Early post-operative outcomes of plate versus nail fixation for humeral shaft fractures.

INTRODUCTION: This study was designed to measure early postoperative outcomes of plate vs. nail fixation for humeral shaft fractures. PATIENTS AND METHODS: Patients ≥18 years who underwent plate or nail fixation for low-energy humeral shaft fractures between 2005-2016 were identified from the National Surgical Quality Improvement Program (NSQIP). Multivariable regression was used to compare postoperative outcomes using propensity score adjustment to account for differences between fixation groups. Variables included in the propensity score were age, American Society of Anesthesiologists (ASA) class, hypertension, steroid use, cancer, functional status, chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), and sex. RESULTS: Plate fixation was used in 1418 patients (70.6%), while nail fixation was used in 591 (29.4%). Patients undergoing nail fixation were more likely to be older, have a higher American Society of Anesthesiologists (ASA) class, and have comorbidities. Mean operative time was statistically longer in the plate fixation group (130 +/-62 min vs. 102 +/-54 min). After propensity score adjustment, type of fixation was not a significant predictor of major or minor complications, length of stay, or readmission. However, nail fixation was a significant predictor of mortality following propensity score adjustment (OR 3.15, 95% Confidence interval 1.26-7.85). CONCLUSION: Patients undergoing intramedullary nail fixation tended to be older patients with more comorbidities, suggesting that surgeons are selecting nail fixation in patients who may not be ideal surgical candidates. Although LOS, complications, and readmission rates were higher in the nail group, this difference was not statistically significant following propensity score adjustment. However, nail fixation remained an independent predictor of 30-day mortality following adjustment. This suggests that nail fixation may not be a safer surgical option in patients with multiple medical co-morbidities and low-energy humeral shaft fractures.

Rationale and design of the HIP fracture Accelerated surgical TreaTment And Care tracK (HIP ATTACK) Trial: a protocol for an international randomised controlled trial evaluating early surgery for hip fracture patients.

INTRODUCTION: Annually, millions of adults suffer hip fractures. The mortality rate post a hip fracture is 7%-10% at 30 days and 10%-20% at 90 days. Observational data suggest that early surgery can improve these outcomes in hip fracture patients. We designed a clinical trial-HIP fracture Accelerated surgical TreaTment And Care tracK (HIP ATTACK) to determine the effect of accelerated surgery compared with standard care on the 90-day risk of all-cause mortality and major perioperative complications. METHODS AND ANALYSIS: HIP ATTACK is a multicentre, international, parallel group randomised controlled trial (RCT) that will include patients ≥45 years of age and diagnosed with a hip fracture from a low-energy mechanism requiring surgery. Patients are randomised to accelerated medical assessment and surgical repair (goal within 6 h) or standard care. The co-primary outcomes are (1) all-cause mortality and (2) a composite of major perioperative complications (ie, mortality and non-fatal myocardial infarction, pulmonary embolism, pneumonia, sepsis, stroke, and life-threatening and major bleeding) at 90 days after randomisation. All patients will be followed up for a period of 1 year. We will enrol 3000 patients. ETHICS AND DISSEMINATION: All centres had ethics approval before randomising patients. Written informed consent is required for all patients before randomisation. HIP ATTACK is the first large international trial designed to examine whether accelerated surgery can improve outcomes in patients with a hip fracture. The dissemination plan includes publishing the results in a policy-influencing journal, conference presentations, engagement of influential medical organisations, and providing public awareness through multimedia resources. TRIAL REGISTRATION NUMBER: NCT02027896; Pre-results.

Avoiding and Managing Complications After Hip Fracture Fixation.

There is an enormous burden of disease associated with the management of a failed hip fracture fixation. The goal of surgical management is to facilitate an early return to mobilization with the retention of as much independence as possible. Despite numerous studies that are focused on the care of patients with proximal femur fractures, complication rates remain high. Surgeons should review current strategies to avoid and manage complications after hip fracture fixation. This will have important implications given the detrimental consequences of failed management of hip fractures, including permanent disability, life-threatening medical complications, and an increased risk of death.

Systemic Administration of Carbon Monoxide-Releasing Molecule-3 Protects the Skeletal Muscle in Porcine Model of Compartment Syndrome.

OBJECTIVES: Acute limb compartment syndrome, a complication of musculoskeletal trauma, results in muscle necrosis and cell death. Carbon monoxide, liberated from the carbon monoxide-releasing molecule-3, has been shown protective in a rat model of compartment syndrome. The purpose of this study was to test the effect of carbon monoxide-releasing molecule-3 in a preclinical large animal model of compartment syndrome, with the ultimate goal of developing a pharmacologic adjunct treatment for compartment syndrome. DESIGN: Animal research study. SETTING: Basic research laboratory in a hospital setting. SUBJECTS: Male Yorkshire-Landrace pigs (50-60 kg). INTERVENTIONS: Pigs underwent 6 hours of intracompartmental pressure elevation by infusing fluid into the anterior compartment of the right hind limb. Carbon monoxide-releasing molecule-3 was administered systemically (2 mg/kg, IV) at fasciotomy, followed by 3-hour reperfusion. MEASUREMENTS AND MAIN RESULTS: Muscle perfusion, inflammation, injury, and apoptosis were assessed in the skeletal muscle. Systemic leukocyte activation was assessed during compartment syndrome and reperfusion. Elevation of hind limb intracompartmental pressure resulted in significant microvascular perfusion deficits (44% ± 1% continuously perfused capillaries in compartment syndrome vs 76% ± 4% in sham; p < 0.001), increased tissue injury (ethidium bromide/bisbenzimide of 0.31 ± 0.07 in compartment syndrome vs 0.17 ± 0.03 in sham; p < 0.05), apoptosis (fluorescence in vivo/bisbenzimide of 0.26 ± 0.06 in compartment syndrome vs 0.13 ± 0.03 in sham; p < 0.05), and systemic leukocyte activation (14.7 relative luminescence units/10 polymorphonuclear leukocytes in compartment syndrome vs 1.0 ± 0.1 in baseline; p < 0.001). Systemic application of carbon monoxide-releasing molecule-3 at fasciotomy increased the number of continuously perfused capillaries (68% ± 3%; p < 0.001), diminished tissue injury (ethidium bromide/bisbenzimide of 0.13 ± 0.04; p < 0.05), apoptosis (fluorescence in vivo/bisbenzimide of 0.12 ± 0.03; p < 0.05), and blocked systemic leukocyte activation (3.9 ± 0.3 relative luminescence unit/10 polymorphonuclear leukocytes; p < 0.001). CONCLUSIONS: Administration of carbon monoxide-releasing molecule-3 at fasciotomy offered protection against compartment syndrome-induced microvascular perfusion deficit, tissue injury, and systemic leukocyte activation. The data suggest the potential therapeutic application of carbon monoxide-releasing molecule-3 to patients at risk of developing compartment syndrome.

Compartment syndrome-induced muscle injury is diminished by the neutralization of pro-inflammatory cytokines.

OBJECTIVES: Compartment syndrome (CS) is one of the most devastating consequences of musculoskeletal trauma. The pathophysiology of CS includes elevation of intracompartmental pressure (ICP), causing damage to the microcirculation, decreased oxygen delivery, tissue anoxia, and cell death. CS is a combined ischemic and inflammatory condition that induces the systemic inflammatory cascade. In complete ischemia, within the first hour of reperfusion, a peak in the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α) has been previously reported. The purpose of this study was to examine the suspected systemic inflammatory cytokine/chemokine release in response to CS, and to evaluate the microvascular dysfunction, tissue injury, and inflammatory response following the neutralization of pro-inflammatory cytokines TNF-α and/or interleukin-1 beta (IL-1ß). METHODS: Twenty-eight male Wistar rats were randomly assigned into 5 groups: Sham (no CS), CS (with isotype control), CS+TNF-α neutralizing antibody (NA), CS+IL-1ß NA, CS+Combo (both TNF-α and IL-1ß NA). CS was induced by elevation of ICP above 30 mm Hg through an infusion of isotonic saline into the anterior compartment of the hind limb for 2 hours; NA were administered just prior to fasciotomy. Microvascular perfusion, cellular tissue injury, and inflammatory response within the extensor digitorum longus muscle were assessed using intravital video microscopy for 45 minutes after fasciotomy. Systemic levels of 24 different cytokines/chemokines were also measured, using the xMAP Luminex technology. RESULTS: Of the 24 cytokines/chemokines sampled, 6 were significantly elevated from their baseline levels, and included the pro-inflammatory cytokines TNF-α, IL-1ß, growth-related oncogene/keratinocyte chemoattractant (GRO/KC), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1 alpha (MIP-1α), and the anti-inflammatory cytokine IL-10. CS resulted in a significant decrease in microvascular perfusion, from 75 ±â€Š2% continuously perfused capillaries in the sham to 31 ±â€Š4% in CS (P < .001), a significant increase in tissue injury (0.33 ±â€Š0.4 versus 0.04 ±â€Š0.01 in sham) and leukocyte activation (14 ±â€Š2 adherent leukocytes/1000 µm2 versus 2 ±â€Š1 adherent leukocytes/100 µm2 in sham, P < .001). CS-associated tissue injury was significantly decreased with TNF-α neutralization (P < .05), both when administered alone or in combination with IL-1ß (P < .05). Additionally, TNF-α neutralization blocked CS-associated leukocyte activation (P < .05); IL-1ß neutralization also diminished leukocyte adhesion (P < .05). Perfusion remained virtually unchanged in CS animals treated with NA (36 ±â€Š4%, 32 ±â€Š3% and 30 ±â€Š2% in CS+TNF-α, CS+IL-1ß and CS+Combo groups, respectively). CONCLUSION: The results of this study indicate that CS induces a systemic inflammation, as evidenced by upregulation of inflammatory cytokines/chemokines in circulation. Neutralization of TNF-α led to a significant reduction in tissue injury; however, it had no effect on the CS-induced microvascular dysfunction. This suggests a distinct role of TNF-α in the pathophysiology of muscle injury in CS.

Carbon monoxide and hydrogen sulphide reduce reperfusion injury in abdominal compartment syndrome.

BACKGROUND: Carbon monoxide (CO)- and hydrogen sulphide-releasing molecules (CORM-3 and GYY4137, respectively) have been shown to be potent antioxidant and antiinflammatory agents at the tissue and systemic level. We hypothesized that both CORM-3 and GYY4137 would reduce the significant organ dysfunction associated with abdominal compartment syndrome (ACS). MATERIAL AND METHODS: Randomized trial was conducted where ACS was maintained for 2 hours in 27 rats using an abdominal plaster cast and intraperitoneal CO2 insufflation at 20 mmHg. Three experimental groups underwent ACS and received an experimental molecule at the time of decompression: inactive CORM-3, active CORM-3, and GYY4137, whereas three groups underwent no ACS to serve as a sham. Sinusoidal perfusion, inflammatory response and cell death were quantified in exteriorized livers. Respiratory, liver, and renal dysfunction was assessed biochemically. RESULTS: Hepatocellular death and the number of activated leukocytes within postsinusoidal venules were significantly increased in rats with ACS (16-fold increase, 17-fold leukocyte activation, respectively, P < 0.05). Administration of CORM-3 or GYY4137 resulted in a significant decrease of both parameters (P = 0.03 and P = 0.009). ACS resulted in an increase in markers of renal and liver injury; CORM-3 or GYY4137 partially restored levels to those seen in sham animals. Myeloperoxidase was significantly elevated in the ACS group in lung, liver, and small intestine (P = 0.0002, P = 0.01, and P = 0.08, respectively). CORM-3 treatment, but not GYY4137, was able to completely block the response (65 ± 11 U/ml and 92 ± 18 U/ml, respectively versus 110 ± 10U/ml in the ACS group, lung tissue). CONCLUSIONS: We have demonstrated the effect of two molecules, CO and hydrogen sulphide, on tempering the reperfusion-associated metabolic and organ derangements in ACS. CORM-3 demonstrated a greater effect than GYY4137 and was able to restore most of the measured parameters to levels comparable to sham.

Systemic application of carbon monoxide-releasing molecule 3 protects skeletal muscle from ischemia-reperfusion injury.

OBJECTIVE: Ischemia-reperfusion (IR) is a limb- and life-threatening complication of acute limb ischemia and musculoskeletal trauma. Carbon monoxide-releasing molecules (CORMs) have recently been shown to protect microvascular perfusion and to reduce inflammation and injury in various ischemic animal models. The purpose of this study was to examine the effects of water-soluble CORM-3 on the extent of IR-induced muscle injury. METHODS: Wistar rats were randomized into three groups: sham (no ischemia), IR + CORM-3 (10 mg/kg intraperitoneally), and IR + inactive CORM-3 (iCORM-3; 10 mg/kg intraperitoneally). No-flow ischemia was induced by the application of a tourniquet to the hind limb for 2 hours; tourniquet release commenced the reperfusion phase. Both CORM-3 and iCORM-3 were injected immediately after tourniquet release. Temporal changes in microvascular perfusion, cellular tissue injury (ethidium bromide and bisbenzimide staining), and inflammatory response (leukocyte recruitment) within the extensor digitorum longus muscle were assessed using intravital video microscopy every 15 minutes for a total of 90 minutes after initiation of reperfusion. Systemic levels of tumor necrosis factor-α were also measured. RESULTS: Hind limb IR resulted in (1) a significant no-reflow phenomenon followed by progressive increase in microvascular perfusion deficit (21% ± 2% continuously perfused capillaries in IR vs 76% ± 4% in sham [P < .001]; 52% ± 8% nonperfused capillaries in IR vs 13% ± 2% in sham at 90 minutes of reperfusion [P < .001]), (2) tissue injury (ethidium bromide and bisbenzimide staining of 0.52 ± 0.07 in IR vs 0.05 ± 0.03 in sham at 90 minutes of reperfusion [P < .001]), (3) leukocyte recruitment (13.7 ± 0.9 adherent leukocytes/30 seconds/1000 µm2 in IR vs 1.8 ± 0.5 adherent leukocytes/30 seconds/1000 µm2 in sham at 90 minutes of reperfusion [P < .001]), and (4) an increase in circulating tumor necrosis factor-α levels. Systemic administration of CORM-3 (but not of iCORM-3) effectively reduced the IR-associated skeletal muscle perfusion deficits, tissue injury, and inflammatory activation. CONCLUSIONS: CORM-3 displays potent protective and anti-inflammatory effects in an experimental model of hind limb IR, suggesting a potential therapeutic application of CORMs in treatment of ischemic conditions.

A Multicenter Randomized Control Trial Comparing a Novel Intramedullary Device (InterTAN) Versus Conventional Treatment (Sliding Hip Screw) of Geriatric Hip Fractures.

OBJECTIVES: To compare outcomes in elderly patients with intertrochanteric hip fractures treated with either the sliding hip screw (SHS) or InterTAN intramedullary device (IT). DESIGN: Prospective, randomized, multicenter clinical trial. SETTING: Five level 1 trauma centers. PATIENTS: Two hundred forty-nine patients 55 years of age or older with AO/OTA 31A1 (43) and OA/OTA 31A2 (206) fractures were prospectively enrolled and followed for 12 months. INTERVENTION: Computer generated randomization to either IT (n = 123) or SHS (n = 126). MAIN OUTCOME MEASUREMENTS: The Functional Independence Measure (FIM) and the Timed Up and Go test (TUG) were used to measure function and motor performance. Secondary outcome measures included femoral shortening, complications, and mortality. RESULTS: Demographics, comorbidities, preinjury FIM scores and TUG scores were similar between groups. Patients (17.2%) who received an IT had limb shortening greater than 2 cm compared with 42.9% who received an SHS (P < 0.001). To determine the importance of preinjury function and fracture stability, we analyzed the subgroup of patients with the ability to walk 150 m independently preinjury and an OA/OTA 31A-2 fracture (n = 70). In this subgroup, patients treated with SHS had greater shortening and demonstrated poorer FIM and TUG scores compared with patients treated with an IT. CONCLUSIONS: Overall, most patients with intertrochanteric femur fractures can expect similar functional results whether treated with an intramedullary or extramedullary device. However, active, functional patients have an improved outcome when the InterTAN is used to treat their unstable intertrochanteric fracture. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.