Early treatment with GLP-1 after severe trauma preserves renal function in obese Zucker rats.

Early posttrauma hyperglycemia (EPTH) is correlated with later adverse outcomes, including acute kidney injury (AKI). Controlling EPTH in the prehospital setting is difficult because of the variability in the ideal insulin dosage and the potential risk of hypoglycemia, especially in those with confounding medical comorbidities of obesity and insulin resistance. Glucagon-like peptide-1 (GLP-1) controls glucose levels in a glucose-dependent manner and is a current target in antidiabetic therapy. We have shown that after orthopedic trauma, obese Zucker rats exhibit EPTH and a later development of AKI (within 24 h). We hypothesized that GLP-1 treatment after trauma decreases EPTH and protects renal function in obese Zucker rats. Obese Zucker rats (~12 wk old) were fasted for 4 h before trauma. Soft tissue injury, fibula fracture, and homogenized bone component injection were then performed in both hind limbs to induce severe extremity trauma. Plasma glucose levels were measured before and 15, 30, 60, 120, 180, 240, and 300 min after trauma. GLP-1 (3 µg·kg-1·h-1, 1.5 ml/kg total) or saline was continuously infused from 30 min to 5 h after trauma. Afterwards, rats were placed in metabolic cages overnight for urine collection. The following day, plasma interleukin (IL)-6 levels, renal blood flow (RBF), glomerular filtration rate (GFR), and renal oxygen delivery (Do2) and consumption (V̇o2) were measured. EPTH was evident within 15 min after trauma but was significantly ameliorated during the 5 h of GLP-1 infusion. One day after trauma, plasma IL-6 was markedly increased in the trauma group and decreased in GLP-1-treated animals. RBF, GFR, and Do2 all significantly decreased with trauma, but renal V̇o2 was unchanged. GLP-1 treatment normalized RBF, GFR, and Do2 without affecting V̇o2. These results suggest that GLP-1 decreases EPTH and protects against a later development of AKI. Early treatment with GLP-1 (or its analogs) to rapidly, effectively, and safely control EPTH may be beneficial in the prehospital care of obese patients after trauma.

Hyperglycemia-Mediated Oxidative Stress Increases Pulmonary Vascular Permeability.

OBJECTIVE: Hyperglycemia in diabetes mellitus is associated with endothelial dysfunction as evidenced by increased oxidative stress and vascular permeability. Whether impaired glucose control in metabolic syndrome impacts pulmonary vascular permeability is unknown. We hypothesized that in metabolic syndrome, hyperglycemia increases lung vascular permeability through superoxide. METHODS: Lung capillary Kf and vascular superoxide were measured in the isolated lungs of LZ and OZ rats. OZ were subjected to 4 weeks of metformin treatment (300 mg/kg/day orally) to improve insulin sensitivity. In a separate experiment, lung vascular permeability and vascular superoxide were measured in LZ exposed to acute hyperglycemia (30 mM). RESULTS: As compared to LZ, OZ had impaired glucose and insulin tolerance and elevated vascular superoxide which was associated with an elevated lung Kf. Chronic metformin treatment in OZ improved glucose control and insulin sensitivity which was associated with decreased vascular oxidative stress and lung Kf. Acute hyperglycemia in isolated lungs from LZ increased lung Kf, which was blocked with the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin (3 mM). Apocynin also decreased baseline Kf in OZ. CONCLUSIONS: These data suggest that hyperglycemia in metabolic syndrome exacerbates lung vascular permeability through increases in vascular superoxide, possibly through NADPH oxidase.

Oxidative stress contributes to orthopedic trauma-induced acute kidney injury in obese rats.

After trauma, obese patients have an increased risk of developing acute kidney injury (AKI). We have demonstrated that obese Zucker (OZ) rats, but not lean Zucker (LZ) rats, develop AKI 24 h after orthopedic trauma. ROS have been implicated in the pathophysiology of AKI in models of critical illness. However, the contribution of ROS to trauma-induced AKI in the setting of obesity has not been determined. We hypothesized that AKI in OZ rats after trauma is mediated by increased oxidative stress. Male LZ and OZ rats were divided into control and trauma groups, with a subset receiving treatment after trauma with the antioxidant apocynin (50 mg/kg ip, 2 mM in drinking water). The day after trauma, glomerular filtration rate, plasma creatinine, urine kidney injury molecule-1, and albumin excretion as well as renal oxidant and antioxidant activity were measured. After trauma, compared with LZ rats, OZ rats exhibited a significant decrease in glomerular filtration rate along with significant increases in plasma creatinine and urine kidney injury molecule-1 and albumin excretion. Additionally, oxidative stress was significantly increased in OZ rats, as evidenced by increased renal NADPH oxidase activity and urine lipid peroxidation products (thiobarbituric acid-reactive substances), and OZ rats also had suppressed renal superoxide dismutase activity. Apocynin treatment significantly decreased oxidative stress and AKI in OZ rats but had minimal effects in LZ rats. These results suggest that ROS play an important role in AKI in OZ rats after traumatic injury and that ROS may be a potential future therapeutic target in the obese after trauma.

Inhibition of NADPH oxidase prevents acute lung injury in obese rats following severe trauma.

Lung capillary filtration coefficient (Kf) and impacts of oxidative stress have not been determined in the setting of severe trauma, especially in obese patients who exhibit increased lung injury. We hypothesized that severe trauma leads to a greater increase in lung Kf in obesity due to exacerbated production of and/or vulnerability to oxidative stress. Severe trauma was induced in lean and obese Zucker rats by muscle injury, fibula fracture, and bone component injection to both hindlimbs, with or without 24-h treatments of apocynin, a NADPH oxidase (NOX) inhibitor. Lung wet/dry weight ratios, lung vascular Kf, lung neutrophil counts, lung NOX and myeloperoxidase (MPO) activity, and plasma IL-6 levels were measured 24 h after trauma. In an additional study, lungs were isolated from nontrauma lean and obese rats to determine the acute effect of phenazime methosulfate, a superoxide donor, on pulmonary vascular Kf. After trauma, compared with lean rats, obese rats exhibited greater increases in lung capillary Kf, neutrophil accumulation, NOX and MPO activity, and plasma IL-6. The lung wet/dry weight ratio was increased in obese rats but not in lean rats. Apocynin treatment decreased lung Kf, neutrophil counts, NOX and MPO activities, wet/dry weight ratio, and plasma IL-6 in obese rats. Phenazime methosulfate treatment resulted in a greater increase in lung Kf in nontrauma obese rats compared with nontrauma lean rats. These results suggest that obese rats are susceptible to lung injury following severe trauma due to increased production of and responsiveness to pulmonary oxidative stress.

ß(2)-Adrenoreceptor blockade improves early posttrauma hyperglycemia and pulmonary injury in obese rats.

Early hyperglycemia after trauma increases morbidity and mortality. Insulin is widely used to control posttrauma glucose, but this treatment increases the risk of hypoglycemia. We tested a novel method for early posttrauma hyperglycemia control by suppressing hepatic glycogenolysis via ß2-adrenoreceptor blockade [ICI-118551 (ICI)]. We have shown that, after severe trauma, obese Zucker (OZ) rats, similar to obese patients, exhibit increased acute lung injury compared with lean Zucker (LZ) rats. We hypothesized that OZ rats exhibit a greater increase in early posttrauma glucose compared with LZ rats, with the increased posttrauma hyperglycemia suppressed by ICI treatment. Orthopedic trauma was applied to both hindlimbs in LZ and OZ rats. Fasting plasma glucose was then monitored for 6 h with or without ICI (0.2 mg·kg(-1)·h(-1) iv.) treatment. One day after trauma, plasma IL-6 levels, lung neutrophil numbers, myeloperoxidase (MPO) activity, and wet-to-dry weight ratios were measured. Trauma induced rapid hepatic glycogenolysis, as evidenced by decreased liver glycogen levels, and this was inhibited by ICI treatment. Compared with LZ rats, OZ rats exhibited higher posttrauma glucose, IL-6, lung neutrophil infiltration, and MPO activity. Lung wet-to-dry weight ratios were increased in OZ rats but not in LZ rats. ICI treatment reduced the early hyperglycemia, lung neutrophil retention, MPO activity, and wet-to-dry weight ratio in OZ rats to levels comparable with those seen in LZ rats, with no effect on blood pressure or heart rate. These results demonstrate that ß2-adrenoreceptor blockade effectively reduces the early posttrauma hyperglycemia, which is associated with decreased lung injury in OZ rats.

Oxidative stress increases pulmonary vascular permeability in diabetic rats through activation of transient receptor potential melastatin 2 channels.

OBJECTIVE: In vitro superoxide activates pulmonary endothelial TRPM2 channels and increases Kf . We hypothesized that pulmonary capillary Kf is increased in a model of type I diabetes due to elevated vascular superoxide and resultant TRPM2 channel activation. METHODS: Type I diabetes was induced in Zucker rats using STZ. Half of the STZ animals were treated with apocynin, a NOX inhibitor. After four weeks, lung Kf was measured in the isolated lung in the presence or absence of TRPM2 inhibitors (2-APB and FA). In an additional set of experiments, Kf was measured in nondiabetic Zucker rats after applying the superoxide donor (PMS). RESULTS: As compared to control rats, hyperglycemic rats exhibited increased vascular superoxide and Kf , along with decreased lung vascular TRPM2-L expression. Apocynin treatment reduced superoxide and Kf in hyperglycemic rats with no effect in control rats. TRPM2 channel inhibition decreased Kf in hyperglycemic rats with no effect in control rats. PMS increased the lung Kf in control rats, with TRPM2 inhibition attenuating this response. CONCLUSION: Diabetic rats exhibit a TRPM2-mediated increase in lung Kf , which is associated with increased TRPM2 activation and increased vascular superoxide levels.

Impaired vascular KATP function attenuates exercise capacity in obese zucker rats.

OBJECTIVE: Obese subjects exhibit decreased exercise capacity (VO2max ). We have shown that vascular KATP channel mediates arteriolar dilation to muscle contraction. We hypothesize that exercise capacity is decreased in obesity due to impaired vascular KATP function. METHODS: The VO2max was measured in LZR and OZR by treadmill running before and following treatment with the KATP blocker glibenclamide i.p. One week later, the spinotrapezius muscle was prepared for in vivo microscopy. Arcade arteriolar diameters were measured following muscle contraction or application of the KATP opener cromakalim before and after glibenclamide application. In additional animals, LZR and OZR were treated with apocynin for five weeks. VO2max and arteriolar dilation experiments were repeated. RESULTS: The OZR exhibited decreased VO2max , functional and cromakalim-induced vasodilation as compared with LZR. Glibenclamide had no effect on VO2max and functional vasodilation in OZR, but significantly inhibited responses in LZR. Vascular superoxide levels and NADPH oxidase activity were increased in OZR, but reduced in apocynin-treated OZR. Apocynin increased the VO2max , functional and cromakalim-induced vasodilation in OZR with no effect in LZR. CONCLUSIONS: Exercise capacity is dependent on vascular KATP channel function. The reduced exercise capacity in OZR appears to be due in part to superoxide-mediated impairment in vascular KATP function.

Management of High-Energy Tibial Pilon Fractures.

➤ Pilon fractures in the younger patient population are frequently high-energy, intra-articular injuries and are associated with devastating, long-term impacts on patient-reported outcomes and health-related quality of life, as well as high rates of persistent disability.➤ Judicious management of associated soft-tissue injury, including open fractures, is essential to minimizing complications. Optimizing medical comorbidities and negative social behaviors (e.g., smoking) should be addressed perioperatively.➤ Delayed internal fixation with interval temporizing external fixation represents the preferred technique for managing most high-energy pilon fractures presenting with characteristically substantial soft-tissue trauma. In some cases, surgeons elect to utilize circular fixation for these scenarios.➤ Although there have been treatment advances, the results have been generally poor, with high rates of posttraumatic arthritis, despite expert care.➤ Primary arthrodesis may be indicated in cases with severe articular cartilage injury that, in the opinion of the treating surgeon, is likely unsalvageable at the time of the index management.➤ The addition of intrawound vancomycin powder at the time of definitive fixation represents a low-cost prophylactic measure that appears to be effective in reducing gram-positive deep surgical site infections.

Dual Mini-Fragment Plate Fixation of Midshaft Clavicle Fractures Reduces Risk of Reoperation Compared With Single-Plate Fixation Techniques.

BACKGROUND: Recent studies have highlighted dual plating as a method of reducing high rates of postoperative complication after operative management of displaced midshaft clavicular fractures. However, few studies have reliably characterized reoperation rates and magnitude of risk reduction achieved when using dual versus anterior and superior single-plate techniques. HYPOTHESIS: There would be lower rates of reoperation among patients who underwent open reduction and internal fixation (ORIF) of displaced midshaft clavicular fractures via dual plating. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This was a retrospective analysis of patients who underwent ORIF for a displaced midshaft clavicular fracture between 2010 and 2021 at a level 1 trauma center with a minimum 12-month follow-up. Patients were separated into 3 cohorts based on fixation type: (1) orthogonal dual mini-fragment plate fixation, (2) superior plate fixation, and (3) anterior plate fixation. Data on patient characteristics, fracture pattern, and reoperations were documented. All-cause reoperation rates and hazard ratio (HR) estimates of dual, superior, and anterior plating were calculated using a multivariate multilevel mixed-effects parametric survival model. Significant confounders including high-risk fracture morphology and smoking status were controlled for in the final model. RESULTS: A final cohort of 256 patients was identified with mean follow-up of 4.9 ± 3.8 years. In total, 101 patients underwent superior plating, 92 underwent anterior plating, and 63 underwent dual plating. Overall, 31 reoperations took place (18 in superior, 12 in anterior, 1 in dual plating) among 22 patients. Major contributors to reoperation included symptomatic hardware (n = 11), nonunion (n = 8), deep infection (n = 7), and wound dehiscence (n = 2). Superior plating revealed the highest reoperation rate of 0.031 per person-years, followed by anterior plating with 0.026 per person-years and dual plating with 0.005 per person-years. Overall, single plating (either anterior or superior placement) had a nearly 8-fold greater risk of reoperation than dual plating (HR, 7.62; 95% CI, 1.02-56.82; P = .048). Further broken down by technique, superior plating had an 8-fold greater risk of reoperation than dual plating (HR, 8.36; 95% CI, 1.10-63.86; P = .041), but anterior plating did not demonstrate a statistically significant difference compared with dual plating (HR, 6.79; 95% CI, 0.87-52.90; P = .068). CONCLUSION: Dual-plate fixation represents an excellent treatment for displaced midshaft clavicular fractures, with low rates of nonunion and reoperation. When compared with single locked superior or anterior plate fixation, dual mini-fragment plate fixation has a nearly 8-fold lower risk of reoperation.

Temporizing Care of Acute Traumatic Foot and Ankle Injuries.

Temporizing care has become a critical part of the treatment armamentarium for select foot and ankle injuries. Indications for performing temporizing care are based on the specific injury pattern, the host, associated injuries, as well as surgeon resources. Foot and ankle injuries are often associated with severe adjacent injury to the soft tissue sleeve. An acute procedure performed through a traumatized soft tissue envelope will often lead to the failure of wound healing and/or infectious complications. Thus, delayed reconstruction of acute foot and ankle injuries is often advisable in these cases.

Research During Orthopaedic Training.

By the end of their training, all orthopaedic residents should be competent in understanding musculoskeletal research enough to navigate the literature and base clinical decisions on it. To accomplish this, the Accreditation Council for Graduate Medical Education requires involvement in scholarly activity. For those interested in academics and having additional involvement in research, there can be many benefits including professional achievement and intellectual /personal satisfaction. A number of potential career models exist for those interested in being engaged in musculoskeletal research, so trainees should seek the training and level of involvement in research that will help them achieve their individual academic goals. To that end, trainees should become involved with research early and identify research mentors in their field of interest (at home or from afar). Training programs and faculty members should create a milieu conducive to research productivity and support and equip trainees who have such aspirations.

Inflammatory cytokines associated with outcomes in orthopedic trauma patients independent of New Injury Severity score: A pilot prospective cohort study.

Traumatic injury is the leading cause of mortality in patients under 50. It is associated with a complex inflammatory response involving hormonal, immunologic, and metabolic mediators. The marked elevation of cytokines and inflammatory mediators subsequently correlates with the development of posttraumatic complications. The aim was to determine whether elevated cytokine levels provide a predictive value for orthopedic trauma patients. A prospective cohort study of patients with New Injury Severity Score (NISS) > 5 was undertaken. IL-6, IL-8, IL-10, and migration inhibitory factor levels were measured within 24-h of presentation. Demographic covariates and clinical outcomes were obtained from the medical records. Fifty-eight patients (83% male, 40 years) were included. Addition of IL-6 to baseline models significantly improved prediction of pulmonary complication (LR = 6.21, p = 0.01), ICU (change in R2 = 0.31, p < 0.01), and hospital length of stay (change in R2 = 0.16, p < 0.01). The addition of IL-8 significantly improved the prediction of acute kidney injury (LR = 9.15, p < 0.01). The addition of postinjury IL-6 level to baseline New Injury Severity Score model is better able to predict the occurrence of pulmonary complications as well as prolonged ICU and hospital length of stay.

Is Obesity Associated With an Increased Risk of Complications After Surgical Management of Acetabulum and Pelvis Fractures? A Systematic Review.

BACKGROUND: When considering surgical fixation of acetabulum and pelvis fractures in patients with obesity, a thorough understanding of the risks of potential complications is important. We performed a systematic review to evaluate whether obesity is associated with an increased risk of complications after surgical management of acetabulum and pelvis fractures. METHODS: We searched PubMed/MEDLINE, EMBASE, and the Cochrane Library for studies published through December 2020 that reported the effect of increased body mass index (BMI) or obesity on the risk of complications after surgical treatment of acetabulum and pelvis fractures. RESULTS: Fifteen studies were included. Eight of the 11 studies that included infection or wound complication as end points found that increased BMI or some degree of obesity was a significant risk factor for these complications. Two studies found that obesity was significantly associated with loss of reduction. Other complications that were assessed in a few studies each included venous thromboembolism, nerve palsy, heterotopic ossification, general systemic complications, and revision surgery, but obesity was not clearly associated with those outcomes. CONCLUSIONS: Obesity (or elevated BMI) was associated with an increased risk of complications-infection being the most commonly reported-after surgical management of acetabulum and pelvis fractures, which suggests the need for increased perioperative vigilance.

Development of a large animal rabbit model for chronic periprosthetic joint infection.

AIMS: Periprosthetic joint infections (PJIs) and osteomyelitis are clinical challenges that are difficult to eradicate. Well-characterized large animal models necessary for testing and validating new treatment strategies for these conditions are lacking. The purpose of this study was to develop a rabbit model of chronic PJI in the distal femur. METHODS: Fresh suspensions of Staphylococcus aureus (ATCC 25923) were prepared in phosphate-buffered saline (PBS) (1 × 109 colony-forming units (CFUs)/ml). Periprosthetic osteomyelitis in female New Zealand white rabbits was induced by intraosseous injection of planktonic bacterial suspension into a predrilled bone tunnel prior to implant screw placement, examined at five and 28 days (n = 5/group) after surgery, and compared to a control aseptic screw group. Radiographs were obtained weekly, and blood was collected to measure ESR, CRP, and white blood cell (WBC) counts. Bone samples and implanted screws were harvested on day 28, and processed for histological analysis and viability assay of bacteria, respectively. RESULTS: Intraosseous periprosthetic introduction of planktonic bacteria induced an acute rise in ESR and CRP that subsided by day 14, and resulted in radiologically evident periprosthetic osteolysis by day 28 accompanied by elevated WBC counts and histological evidence of bacteria in the bone tunnels after screw removal. The aseptic screw group induced no increase in ESR, and no lysis developed around the implants. Bacterial viability was confirmed by implant sonication fluid culture. CONCLUSION: Intraosseous periprosthetic introduction of planktonic bacteria reliably induces survivable chronic PJI in rabbits. Cite this article: Bone Joint Res 2021;10(3):156-165.

Orthopedic trauma-induced pulmonary injury in the obese Zucker rat.

OBJECTIVE: Obese subjects with orthopedic trauma exhibit increased inflammation and an increased risk of pulmonary edema. Prostaglandin E(2) (PGE(2) ) production is elevated during inflammation and associated with increased vascular permeability. We hypothesize that pulmonary edema in obesity following orthopedic trauma is due to elevated PGE(2) and resultant increases in pulmonary permeability. METHODS: Orthopedic trauma was induced in both hindlimbs in lean (LZ) and obese Zucker rats (OZ). On the following day, plasma interleukin-6 (IL-6) and PGE(2) levels, pulmonary edema, and pulmonary gas exchange capability were compared between groups: LZ, OZ, LZ with trauma (LZT), and OZ with trauma (OZT). Vascular permeability in isolated lungs was measured in LZ and OZ before and after application of PGE(2) . RESULTS: As compared with the other groups, the OZT exhibited elevated plasma IL-6 and PGE(2) levels, increased lung wet/dry weight ratio and bronchoalveolar protein concentration, and an impaired pulmonary gas exchange. Indomethacin treatment normalized plasma PGE(2) levels and pulmonary edema. Basal pulmonary permeability in isolated lungs was higher in OZ than LZ, with a further increase in permeability following treatment with PGE(2) . CONCLUSIONS: These results suggest that pulmonary edema in OZ following orthopedic trauma is due to an elevated PGE(2) and resultant increases in pulmonary permeability.