Hany Bedair

Angiotensin II Receptor Blockade Administered After Injury Improves Muscle Regeneration and Decreases Fibrosis in Normal Skeletal Muscle

Background Several therapeutic agents have been shown to inhibit fibrosis and improve regeneration after injury in skeletal muscle by antagonizing transforming growth factor-β1. Angiotensin receptor blockers have been shown to have a similar effect on transforming growth factor-β1 in a variety of tissues. Hypothesis Systemic treatment of animals after injury of skeletal muscle with an angiotensin receptor blocker may decrease fibrosis and improve regeneration, mainly through transforming growth factor-β1 blockade, and can be used to improve skeletal muscle healing after injury. Study Design Controlled laboratory study. Methods Forty mice underwent bilateral partial gastrocnemius lacerations. Mice were assigned randomly to a control group (tap water), a low-dose angiotensin receptor blocker group (losartan, 0.05 mg/mL), or a high-dose angiotensin receptor blocker group (0.5 mg/mL). The medication was dissolved in tap water and administered enterally. Mice were sacrificed 3 or 5 weeks after injury, and the lacerated muscles were examined histologically for muscle regeneration and fibrosis. Results Compared with control mice at 3 and 5 weeks, angiotensin receptor blocker-treated mice exhibited a histologic dose-dependent improvement in muscle regeneration and a measurable reduction in fibrous tissue formation within the area of injury. Conclusion By modulating the response to local and systemic angiotensin II, angiotensin receptor blocker therapy significantly reduced fibrosis and led to an increase in the number of regenerating myofibers in acutely injured skeletal muscle. The clinical implications for this application of angiotensin receptor blockers are potentially far-reaching and include not only sports- and military-related injuries, but also diseases such as the muscular dystrophies and trauma- and surgery-related injury. Clinical Relevance Angiotensin receptor blockers may provide a safe, clinically available treatment for improving healing after skeletal muscle injury.

Economic benefit to society at large of total knee arthroplasty in younger patients: a Markov analysis.

BACKGROUND To our knowledge, the economic implications of total knee arthroplasty to society at large have not been assessed with specific consideration of the young working population with osteoarthritis of the knee. The goal of the present study was to use a Markov analysis to estimate the overall average cost to society--in terms of medical expenses and lost wages--of delaying early total knee arthroplasty in favor of nonoperative treatment for end-stage knee osteoarthritis in a hypothetical fifty-year-old patient. METHODS A Markov state-transition decision model was constructed to compare the overall average cost over thirty years of total knee arthroplasty with the average thirty-year cost of nonoperative treatment for a fifty-year-old patient with end-stage osteoarthritis. Earned income, lost wages, and direct medical costs related to nonoperative treatment and to total knee arthroplasty, including revisions and complications, were considered. A sensitivity analysis was performed to assess the effect that variation of key model parameters had on the overall outcome of the model. RESULTS This Markov model favored early total knee arthroplasty over nonoperative treatment across all plausible values for most input parameters assessed during one-way sensitivity analysis. Total knee arthroplasty was more expensive during the first 3.5 years because of higher initial costs, but over thirty years the cost benefit of total knee arthroplasty was

Are prosthetic spacers safe to use in 2-stage treatment for infected total knee arthroplasty?

69,800 (2012 U.S. dollars). Only when lost wages were <17.7 equivalent work days per year for patients treated nonoperatively or when the rate of returning to work after total knee arthroplasty was <81% did the model favor nonoperative treatment. CONCLUSIONS The results of the current study demonstrated that the total economic cost to society for treatment of severe knee osteoarthritis in a relatively young working person is markedly lower with total knee arthroplasty than it is with nonoperative treatment. The increasing financial restrictions on health-care providers in the U.S. necessitate careful consideration of the economic impact of different treatment options from the societal perspective. CLINICAL RELEVANCE The results of this model illustrate the need to account for the implications of treatment choices, not only at the individual patient level, but also for society at large. When deciding among available treatment options, patients, physicians, payers, and policymakers must consider individual treatment cost and effectiveness but also should account for future potential earnings generated when a treatment may restore a patients ability to contribute to society.

The natural progression of synovial fluid white blood-cell counts and the percentage of polymorphonuclear cells after primary total knee arthroplasty: a multicenter study.

This retrospective study compares treatment results of infected total knee arthroplasty with 2-stage exchange technique using 14 articulating spacers using metallic and polyethylene components (prosthetic group) and 33 static all-cement spacer (static group). For the prosthetic and static groups, treatment success rate was 71% and 67% at 58 months of follow-up, respectively, and not significantly different. The prosthetic group required less frequent extensile surgical approaches at the second-stage reimplantation. Range of motion was significantly improved in both groups, but there was no difference at latest follow-up between the groups. Of 14 in the prosthetic group, 4 (28%) did not undergo second-stage procedure. Antibiotic spacers consisting of prosthetic components can be a safe and effective treatment option for 2-stage revision total knee arthroplasty with equivalent infection control rates.

Mortality After Septic Versus Aseptic Revision Total Hip Arthroplasty: A Matched-Cohort Study

BACKGROUND Assessments of the synovial fluid white blood-cell (WBC) count and percentage of polymorphonuclear cells (PMNs) have been reported to be useful in the diagnosis of periprosthetic joint infection. The purpose of this multicenter retrospective study was to evaluate the natural progression of the synovial fluid WBC count, PMN percentage, and total neutrophil count in patients who underwent knee aspiration during the first two years after primary total knee arthroplasty and had no evidence of periprosthetic joint infection. METHODS From April 1999 to March 2012, 571 patients who presented within the first two years after primary total knee arthroplasty underwent knee aspiration as part of an evaluation for periprosthetic joint infection. Patients were categorized into four groups on the basis of the number of days between surgery and arthrocentesis. The synovial fluid WBC count, PMN percentage, and total neutrophil count were compared among the four time periods with use of separate one-way analyses of variance and Tamhane post-hoc analyses. RESULTS Four hundred and fifty-two samples not associated with a periprosthetic joint infection were adequate for analysis. The synovial fluid WBC count, PMN percentage, and total neutrophil count all decreased after the first ninety postoperative days. The synovial fluid WBC count showed an earlier return to a level similar to the two-year time point than the PMN percentage did. The mean total neutrophil count decreased from 2533.2 cells/μL during the first forty-five days to 649.0 cells/μL from forty-six to ninety days, 269.5 cells/μL from three months to one year, and 240.8 cells/μL from one to two years. CONCLUSIONS The synovial fluid WBC count and PMN percentage changed at different rates over the first two years after total knee arthroplasty, with the WBC count exhibiting an initially more rapid decrease and the PMN percentage demonstrating a more linear decrease. Hence, the total neutrophil count, which combines these two parameters, may provide a better method to identify patients with a periprosthetic joint infection. Values for the synovial fluid WBC count, PMN percentage, and total neutrophil count were all significantly elevated in the early postoperative period, and the use of standard cutoff values for the diagnosis of periprosthetic joint infection can lead to false-positive results.

Treatment of early postoperative infections after THA: a decision analysis.

Mortality rates after revision total hip arthroplasty (THA) for periprosthetic sepsis were investigated in 93 patients and compared to 93 patients, matched for age, gender, year of surgery, who underwent revision for aseptic failures. The mortality rate was 33% (31/93) in the septic group and 22% (20/93) in the aseptic group at 5 and 6 year follow-up, respectively (P=0.10). Patients in the septic group died on average 6 years earlier (74 versus 80 yrs; P<0.05) than those in the aseptic group. Charlson Comorbidity Index (CCI) was an independent predictor of mortality among the both groups (P<0.05), while age (P<0.01) was a predictor of mortality only in the aseptic group. While revision THA for sepsis alone did not predict increased mortality, a 33% mortality rate at five years in patients with an average age of 66 years and earlier death by 6 years compared to aseptic revisions is alarming.

Conventional diagnostic challenges in periprosthetic joint infection.

BackgroundThe treatment for an early postoperative periprosthetic infection after cementless THA that results in the highest quality of life after the control of infection is unknown. Although common treatments include irrigation and débridement with component retention, a one-stage exchange, or a two-stage exchange, it is unclear whether any of these provides a higher quality of life after the control of infection.Questions/purposesWe projected, through decision-analysis modeling, the possible estimated final health states defined as health-related quality of life based on quality-of-life studies of an early postoperative periprosthetic infection after cementless THA treated by irrigation and débridement, one-stage exchange, or two-stage exchange.MethodsPublications addressing early postoperative infections after THA were analyzed for the estimated rate of infection control and quality-of-life measures after a specific treatment. Decision analysis was used to model the different treatments and describe which, if any, treatment results in the greatest quality of life after early THA infection.ResultsIn the model, a one-stage exchange was the treatment for early THA infection that maximized quality-of-life outcomes if the probability of controlling the infection exceeded 66% with this procedure. If the probability of infection control of a one-stage exchange was less than 66% or that of irrigation and débridement was greater than 60%, then irrigation and débridement appeared to result in the greatest quality-of-life outcome.ConclusionsA decision analysis using estimates of infection control rate and quality-of-life outcomes after different treatments for an early postoperative infection after THA showed possible outcomes for each treatment.Level of Evidence Level II, economic and decision analyses. See Guidelines for Authors for a complete description of levels of evidence.

Mortality Following Revision Total Knee Arthroplasty: A Matched Cohort Study of Septic versus Aseptic Revisions

Periprosthetic joint infection remains a clinical challenge with no benchmark for diagnosis. The diagnosis is based on many different clinical variables that may be difficult to interpret, especially in the setting of chronic systemic disease. Synovial fluid aspiration, diagnostic imaging, traditional culture, peripheral serum inflammatory markers, and intraoperative frozen sections each have their limitations but continue to be the mainstay for diagnosis of periprosthetic joint infection. As molecular- and biomarker-based technologies improve, the way we interpret and diagnose periprosthetic joint infection will ultimately change and may even improve diagnostic accuracy and turnaround time. Future research on this topic should be focused on improving diagnostic criteria for low-virulence organisms, improving interpretation of intraoperative frozen sections, and establishing improved synovial fluid and peripheral serum biomarker profiles for periprosthetic joint infection.

What is the Long-term Economic Societal Effect of Periprosthetic Infections After THA? A Markov Analysis

We report the medium-term mortality after septic versus aseptic revision total knee arthroplasty (TKA) and factors that can contribute to mortality in revision TKA. Mortality rates of 88 patients undergoing septic revision (septic group) were compared with age- and year of surgery-matched 88 patients of aseptic revision (aseptic group). The overall mortality after revision TKA was 10.7% at a median of 4 years of follow-up (range, 2-7 years). However, the mortality after septic revision (18%, 16/88) was six times higher than that of aseptic revision (3%, 3/88) (P = 0.003). Infections with Staphylococcus aureus and/or methicillin resistance was not associated with higher mortality rates. Multivariate analysis indicated that increased age (P < 0.001), higher ASA class (P = 0.002), and septic revision (P < 0.001) were identified as independent predictors of increased mortality after revision TKA.

Is There a Benefit to Modularity in ‘Simpler’ Femoral Revisions?

BackgroundCurrent estimates for the direct costs of a single episode of care for periprosthetic joint infection (PJI) after THA are approximately USD 100,000. These estimates do not account for the costs of failed treatments and do not include indirect costs such as lost wages.Questions/purposesThe goal of this study was to estimate the long-term economic effect to society (direct and indirect costs) of a PJI after THA treated with contemporary standards of care in a hypothetical patient of working age (three scenarios, age 55, 60, and 65 years).MethodsWe created a state-transition Markov model with health states defined by surgical treatment options including irrigation and débridement with modular exchange, single-stage revision, and two-stage revision. Reoperation rates attributable to septic and aseptic failure modes and indirect and direct costs were calculated estimates garnered via multiple systematic reviews of peer-reviewed orthopaedic and infectious disease journals and Medicare reimbursement data. We conducted an analysis over a hypothetical patient’s lifetime from the societal perspective with costs discounted by 3% annually. We conducted sensitivity analysis to delineate the effects of uncertainty attributable to input variables.ResultsThe model found a base case cost of USD 390,806 per 65-year-old patient with an infected THA. One-way sensitivity analysis gives a range of USD 389,307 (65-year-old with a 3% reinfection rate) and USD 474,004 (55-year-old with a 12% reinfection rate). Indirect costs such as lost wages make up a considerable portion of the costs and increase considerably as age at the time of infection decreases.ConclusionsThe results of this study show that the overall treatment of a periprosthetic infection after a THA is markedly more expensive to society than previously estimated when accounting for the considerable failure rates of current treatment options and including indirect costs. These overall costs, combined with a large projected increase in THAs and a steady state of septic failures, should be taken into account when considering the total cost of THA. Further research is needed to adequately compare the clinical and economic effectiveness of alternative treatment pathways.Level of EvidenceLevel II, economic and decision analysis.