Mark S. Vrahas

Pressure-volume characteristics of the intact and disrupted pelvic retroperitoneum.

Hemorrhage is a major cause of mortality in pelvic fractures. Bleeding can be controlled in hypotensive patients by direct ligation, angiographic embolization, pelvic packing, and acute external fixation. Acute application of an external fixator can reduce pelvic volume and reduce bleeding fractures to effect tamponade. This therapy assumes that the pelvis represents a closed space, which clearly is not true anatomically. However, the premise may hold functionally. This study explored the relationship between pressure and volume in the intact and disrupted pelvic retroperitoneum. In cadaveric specimens, the external iliac vein was dissected, ruptured, and cannulated. This method allowed controlled flow of fluid, with simultaneous measurement of pressure, into the intact retroperitoneum. Open book pelvic fractures were created by applying external rotation to the pelvis through the femoral heads. The pressure-volume measurements, without and with external fixation applied, were repeated after the fracture, as well as after a laparotomy. In the intact retroperitoneum, pressures rapidly rose to an average of 30 mm Hg after infusion of 5 liters of fluid. After fracture, up to 20 liters of fluid could be infused at pressures not exceeding 35 mm Hg. External fixation increased pressures approximately 3 mm Hg at low fluid volumes, and approximately 11 mm Hg at the highest fluid volumes. Laparotomy decreased retroperitoneal pressure from approximately 35 mm Hg to approximately 15 mm Hg. The results of the study suggest that low-pressure venous hemorrhage may be tamponaded by an external fixator, given that enough fluid volume is present in the pelvic retroperitoneum. However, external fixation may not generate sufficient pressure to stop arterial bleeding. In any case, it seems that a large volume of fluid must be lost into the pelvis before an external fixator can have much effect on retroperitoneal pressures.

Direct Percutaneous Gene Delivery to Enhance Healing of Segmental Bone Defects

BACKGROUND Healing of segmental bone defects can be induced experimentally with genetically modified osteoprogenitor cells, an ex vivo strategy that requires two operative interventions and substantial cost. Direct transfer of osteogenic genes offers an alternative, clinically expeditious, cost-effective approach. We evaluated its potential in a well-established, critical-size, rat femoral defect model. METHODS A critical-size defect was created in the right femur of forty-eight skeletally mature Sprague-Dawley rats. After twenty-four hours, each defect received a single, intralesional, percutaneous injection of adenovirus carrying bone morphogenetic protein-2 (Ad.BMP-2) or luciferase cDNA (Ad.luc) or it remained untreated. Healing was monitored with weekly radiographs. At eight weeks, the rats were killed and the femora were evaluated with dual-energy x-ray absorptiometry, micro-computed tomography, histological analysis, histomorphometry, and torsional mechanical testing. RESULTS Radiographically, 75% of the Ad.BMP-2-treated femora showed osseous union. Bone mineral content was similar between the Ad.BMP-2-treated femora (0.045 +/- 0.020 g) and the contralateral, intact femora (0.047 +/- 0.003 g). Histologically, 50% of the Ad.BMP-2-treated defects were bridged by lamellar, trabecular bone; the other 50% contained islands of cartilage. The control (Ad.luc-treated) defects were filled with fibrous tissue. Histomorphometry demonstrated a large difference in osteogenesis between the Ad.BMP-2 group (mean bone area, 3.25 +/- 0.67 mm(2)) and the controls (mean bone area, 0.65 +/- 0.67 mm(2)). By eight weeks, the Ad.BMP-2-treated femora had approximately one-fourth of the strength (mean, 0.07 +/- 0.04 Nm) and stiffness (mean, 0.5 +/- 0.4 Nm/rad) of the contralateral femora (0.3 +/- 0.08 Nm and 2.0 +/- 0.5 Nm/rad, respectively). CONCLUSIONS A single, percutaneous, intralesional injection of Ad.BMP-2 induces healing of critical-size femoral bone defects in rats within eight weeks. At this time, the repair tissue is predominantly trabecular bone, has normal bone mineral content, and has gained mechanical strength.

Blue light for infectious diseases: Propionibacterium acnes, Helicobacter pylori, and beyond?

Blue light, particularly in the wavelength range of 405-470 nm, has attracted increasing attention due to its intrinsic antimicrobial effect without the addition of exogenous photosensitizers. In addition, it is commonly accepted that blue light is much less detrimental to mammalian cells than ultraviolet irradiation, which is another light-based antimicrobial approach being investigated. In this review, we discussed the blue light sensing systems in microbial cells, antimicrobial efficacy of blue light, the mechanism of antimicrobial effect of blue light, the effects of blue light on mammalian cells, and the effects of blue light on wound healing. It has been reported that blue light can regulate multi-cellular behavior involving cell-to-cell communication via blue light receptors in bacteria, and inhibit biofilm formation and subsequently potentiate light inactivation. At higher radiant exposures, blue light exhibits a broad-spectrum antimicrobial effect against both Gram-positive and Gram-negative bacteria. Blue light therapy is a clinically accepted approach for Propionibacterium acnes infections. Clinical trials have also been conducted to investigate the use of blue light for Helicobacter pylori stomach infections and have shown promising results. Studies on blue light inactivation of important wound pathogenic bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa have also been reported. The mechanism of blue light inactivation of P. acnes, H. pylori, and some oral bacteria is proved to be the photo-excitation of intracellular porphyrins and the subsequent production of cytotoxic reactive oxygen species. Although it may be the case that the mechanism of blue light inactivation of wound pathogens (e.g., S. aureus, P. aeruginosa) is the same as that of P. acnes, this hypothesis has not been rigorously tested. Limited and discordant results have been reported regarding the effects of blue light on mammalian cells and wound healing. Under certain wavelengths and radiant exposures, blue light may cause cell dysfunction by the photo-excitation of blue light sensitizing chromophores, including flavins and cytochromes, within mitochondria or/and peroxisomes. Further studies should be performed to optimize the optical parameters (e.g., wavelength, radiant exposure) to ensure effective and safe blue light therapies for infectious disease. In addition, studies are also needed to verify the lack of development of microbial resistance to blue light.

Osteogenic Potential of Reamer Irrigator Aspirator (RIA) Aspirate Collected from Patients Undergoing Hip Arthroplasty

Intramedullary nailing preceded by canal reaming is the current standard of treatment for long‐bone fractures requiring stabilization. However, conventional reaming methods can elevate intramedullary temperature and pressure, potentially resulting in necrotic bone, systemic embolism, and pulmonary complications. To address this problem, a reamer irrigator aspirator (RIA) has been developed that combines irrigation and suction for reduced‐pressure reaming with temperature modulation. Osseous particles aspirated by the RIA can be recovered by filtration for use as an autograft, but the flow‐through is typically discarded. The purpose of this study was to assess whether this discarded filtrate has osteogenic properties that could be used to enhance the total repair potential of aspirate. RIA aspirate was collected from five patients (ages 71–78) undergoing hip hemiarthroplasty. Osseous particles were removed using an open‐pore filter, and the resulting filtrate (230 ± 200 mL) was processed by Ficoll‐gradient centrifugation to isolate mononuclear cells (6.2 ± 5.2 × 106 cells/mL). The aqueous supernatant contained FGF‐2, IGF‐I, and latent TGF‐β1, but BMP‐2 was below the limit of detection. The cell fraction included culture plastic‐adherent, fibroblastic cells that displayed a surface marker profile indicative of mesenchymal stem cells and that could be induced along the osteogenic, adipogenic, and chondrogenic lineages in vitro. When compared to outgrowth cells from the culture of osseous particles, filtrate cells were more sensitive to seeding density during osteogenic culture but had similar capacity for chondrogenesis. These results suggest using RIA aspirate to develop improved, clinically expeditious, cost‐effective technologies for accelerating the healing of bone and other musculoskeletal tissues.

The medical-legal aspects of compartment syndrome.

BACKGROUND Management of compartment syndrome in the modern era involves not only avoiding the sequelae of a missed diagnosis but also minimizing the risk of a malpractice claim. Little information is available on the legal aspects of compartment syndrome. METHODS Twenty-three years of records on closed malpractice claims involving compartment syndrome were reviewed. The data were abstracted from medical records and were analyzed to determine the factors associated with a successful defense. RESULTS Nineteen closed claims, involving sixteen patients and encompassing a total liability of 3.8 million USD, were found in the data for malpractice claims closed between 1980 and 2003. Ten claims were resolved in favor of the physician. The average time to closure was 5.5 years. All three claims that went to trial resulted in a verdict for the physician. Evidence of poor physician-patient communication was found in six cases, all of which resulted in an indemnity payment (p < 0.01). Increasing time from the onset of symptoms to the fasciotomy was linearly associated with an increased indemnity payment (p < 0.05). A fasciotomy performed within eight hours after the first presentation of symptoms was uniformly associated with a successful defense. CONCLUSIONS While malpractice claims involving compartment syndrome were uncommon, they resulted in a high rate and amount of indemnity payments. Early fasciotomy not only improves patient outcome but is also associated with decreased indemnity risk.

Delayed administration of adenoviral BMP-2 vector improves the formation of bone in osseous defects

The direct, local, administration of adenovirus carrying human BMP-2 cDNA (Ad.BMP-2) heals critical-sized femoral bone defects in rabbit and rat models. However, the outcome is suboptimal and the technology needs to provide a more reliable and uniform outcome. To this end, we investigated whether the timing of Ad.BMP-2 administration influenced the formation of mineralized tissue within the defect. Critical-sized defects were created in the femora of 28 Sprague–Dawley rats. Animals were injected intralesionally with a single, percutaneous injection of Ad.BMP-2 (4 × 108 plaque-forming units) either intraoperatively (day 0) or 24 h (day 1), 5 days or 10 days after surgery. The femora were evaluated 8 weeks after surgery by X-ray, microcomputed tomography, dual-energy X-ray absorptiometry and biomechanical testing. The incidence of radiological union was markedly increased when administration of Ad.BMP-2 was delayed until days 5 and 10, at which point 86% of the defects healed. These time points also provided greater bone mineral content within the defect site and improved the average mechanical strength of the healed bone. Thus, delaying the injection of Ad.BMP-2 until 5 or 10 days after surgery enables a greater percentage of critical-sized, segmental defects to achieve radiological union, producing a repair tissue with enhanced mineralization and greater mechanical strength.

Psychological Factors Predict Disability and Pain Intensity After Skeletal Trauma

BACKGROUND The aims of this study were to (1) estimate the prevalence of clinical depression and posttraumatic stress disorder (PTSD) one to two months (Time 1) and five to eight months (Time 2) after musculoskeletal trauma and (2) determine the cross-sectional and longitudinal relationship of psychological variables (depression, PTSD, catastrophic thinking, and pain anxiety) at Time 1 to musculoskeletal disability and pain intensity at Time 1 and Time 2, after accounting for injury characteristics and demographic variables. METHODS Patients with one or more fractures that had been treated operatively completed measures of depression, PTSD, pain anxiety, catastrophic thinking, musculoskeletal disability (the Short Musculoskeletal Function Assessment [SMFA]), and pain (the Numerical Rating Scale) at rest and during activity at Time 1 (152 patients) and at Time 2 (136 patients). Additional explanatory variables included injury severity, use of opioid pain medication at Time 1, and multiple or single injuries. RESULTS The screening criteria for an estimated diagnosis of clinical depression were met by thirty-five of the 152 patients at Time 1, and twenty-nine of the 136 patients at Time 2. Screening criteria for an estimated diagnosis of PTSD were met by forty-three of the 152 patients at Time 1 and twenty-five of the 136 patients at Time 2. Cross-sectional hierarchical linear regression models that included multiple injuries, scores of the Abbreviated Injury Scale, and self-reported opioid use explained between 24% and 29% of the variance in pain and disability, respectively, at Time 1. After the addition of psychological variables, the model explained between 49% and 55% of the variance. Catastrophic thinking (as measured with use of the Pain Catastrophizing Scale) at Time 1 was the sole significant predictor of pain at rest, pain during activity, and disability (as measured with use of the SMFA) at Time 2. CONCLUSIONS We found that psychological factors that are responsive to cognitive behavioral therapy--catastrophic thinking, in particular--are strongly associated with pain intensity and disability in patients recovering from musculoskeletal trauma.

Perioperative Lower Urinary Tract Infections and Deep Sepsis in Patients Undergoing Total Joint Arthroplasty

&NA; Deep sepsis in the involved joint after hip or knee arthroplasty may be the result of hematogenous seeding from a remote infectious source. This mechanism has been used to explain the well‐documented association between postoperative urinary tract infections and subsequent joint infection after hip or knee arthroplasty. However, it is unclear whether there is an association between preoperative bacteriuria and deep prosthetic infection. The purpose of this review is to identify perioperative risk factors associated with bacteriuria that have a positive correlation with deep joint sepsis following total hip or knee arthroplasty. The classic symptoms of dysuria, urgency, and frequency seen with urinary tract infections are often absent in the elderly despite the presence of urine coliforms; in these patients, pyuria (as indicated by the presence of more than 1×104 white blood cells per milliliter of noncentrifuged urine) may be used as a preliminary screening criterion. If there are irritative symptoms, the presence of more than 1×103 bacteria per milliliter of urine should be regarded as indicative of a urinary tract infection. If there is bacteriuria without symptoms of urinary irritation or obstruction, the current literature supports proceeding with total joint arthroplasty and treating those patients with urine colony counts greater than 1×103/mL with an 8‐ to 10‐day postoperative course of an appropriate oral antibiotic. Postponement of total joint surgery should be considered if preoperative evaluation reveals symptoms related to obstruction of the urinary pathway. Irritative symptoms in combination with a bacterial count greater than 1 × 103/mL should also serve as an indication to postpone surgery. To diminish postoperative urinary tract infection, a bladder catheter should be inserted immediately preoperatively and removed within 24 hours of surgery to diminish the risk of urinary retention, which has been shown to increase the likelihood of a postoperative urinary tract infection.

Blue Light Rescues Mice from Potentially Fatal Pseudomonas aeruginosa Burn Infection: Efficacy, Safety, and Mechanism of Action

ABSTRACT Blue light has attracted increasing attention due to its intrinsic antimicrobial effect without the addition of exogenous photosensitizers. However, the use of blue light for wound infections has not been established yet. In this study, we demonstrated the efficacy of blue light at 415 nm for the treatment of acute, potentially lethal Pseudomonas aeruginosa burn infections in mice. Our in vitro studies demonstrated that the inactivation rate of P. aeruginosa cells by blue light was approximately 35-fold higher than that of keratinocytes (P = 0.0014). Transmission electron microscopy revealed blue light-mediated intracellular damage to P. aeruginosa cells. Fluorescence spectroscopy suggested that coproporphyrin III and/or uroporphyrin III are possibly the intracellular photosensitive chromophores associated with the blue light inactivation of P. aeruginosa. In vivo studies using an in vivo bioluminescence imaging technique and an area-under-the-bioluminescence-time-curve (AUBC) analysis showed that a single exposure of blue light at 55.8 J/cm2, applied 30 min after bacterial inoculation to the infected mouse burns, reduced the AUBC by approximately 100-fold in comparison with untreated and infected mouse burns (P < 0.0001). Histological analyses and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assays indicated no significant damage in the mouse skin exposed to blue light at the effective antimicrobial dose. Survival analyses revealed that blue light increased the survival rate of the infected mice from 18.2% to 100% (P < 0.0001). In conclusion, blue light therapy might offer an effective and safe alternative to conventional antimicrobial therapy for P. aeruginosa burn infections.

Depression in orthopaedic trauma patients. Prevalence and severity.

BACKGROUND There is a known connection between physical injury and disability and emotional distress. Several investigators have shown a relationship between trauma, depression, and poor outcomes. The literature on trauma and depression is limited with regard to clarifying the relationship between the degree of injury and depression and the relationship between physical function of patients with less severe injuries and depression. METHODS One hundred and sixty-one patients who presented to our orthopaedic trauma services were enrolled in the study and interviewed. We obtained information about patient demographics and administered several self-reported outcome measures: the Beck Depression Inventory (BDI), the Short Musculoskeletal Function Assessment (SMFA), and the Physical Function-10 (PF-10) subset of the Short Form-36 (SF-36). We documented the nature and severity of the injury or injuries and calculated correlations between the outcome measures and the BDI. Injury-specific factors such as the AO Fracture Classification, the Abbreviated Injury Scale (AIS), the Injury Severity Score (ISS), and the Gustilo and Anderson grade of open fractures were also examined. RESULTS Fifty-five percent of the patients had minimal depression, as measured with the BDI; 28% had moderate depression; 13% had moderate-to-severe depression; and 3.7% had severe depression. When the somatic elements of the BDI were removed, the prevalence of moderate, moderate-to-severe, or severe depression was 26%. The SMFA scores had a strong negative correlation with the BDI (-0.75; p < 0.001). Of the injury-specific factors, only open factures were found to have an impact on the presence of depression, with an odds ratio of 4.58 (95% confidence ratio, 1.57 to 12.35). CONCLUSIONS The prevalence of clinically relevant depression approached 45% in a diverse cohort of orthopaedic trauma patients. Global disability is strongly correlated with depression. The presence of an open fracture may also increase the risk of depression. LEVEL OF EVIDENCE Prognostic Level II.