Summary Statement

Ischaemic preconditioning protected skeletal myotubes against the effects of ischaemia-reperfusion in vitro. This protection was associated with increased Nrf2 signalling.

Objectives

Ischaemic preconditioning (IPC) is a phenomenon whereby tissues develop an increased tolerance to ischaemia and subsequent reperfusion if first subjected to sublethal periods of ischaemia. Despite extensive investigation of IPC, the molecular mechanism remains largely unknown. Our aim was to show genetic changes that occur in skeletal muscle cells in response to IPC.

Background

The internet has revolutionized the way we live our lives. Over 60% of people nationally now have access to the internet. Healthcare is not immune to this phenomenon. We aimed to assess level of access to the internet within our practice population and gauge the level of internet use by these patients and ascertain what characteristics define these individuals.

Introduction

Matrix metalloproteinases (MMP) play a key role in cartilage degradation in osteoarthritis. Statins are a potential suppressor of MMPs. The aim of this research was to assess the efficacy of Pravastatin in suppressing MMP gene and protein expression in an in vitro model.

Although chondrocytes have been used for autologous implantation in defects of articular cartilage, limited availability and donor-site morbidity have led to the search for alternative cell sources. Mesenchymal stem cells from various sources represent one option. The infrapatellar fat-pad is a promising source. Advantages include low morbidity, ease of harvest and ex-vivo evidence of chondrogenesis. Expansion of MSCs from human fat-pad in FGF-2 has been shown to enhance chondrogenesis. To further elucidate this process, we assessed the role of TGF-?3, FGF-2 and oxygen tension on growth kinetics of these cells during expansion.

Introduction

Local anaesthetic has been reported to have a detrimental effect on human chondrocytes both in vitro and in vivo. Magnesium, an NMDA-receptor antagonist, may be an alternative intra-articular analgesic agent following arthroscopy. We aimed to report the dose response effect of commonly used local anaesthteitc on chondrocyte viability and also report on the effect of adding magnesium to local anaesthetic.

Introduction

Ischaemic preconditioning (IPC) is a phenomenon whereby a tissue is more tolerant to an insult if it is first subjected to short bursts of sublethal ischaemia and reperfusion. The potential of this powerful mechanism has been realised in many branches of medicine where there is an abundance of ongoing research. However, there has been a notable lack of development of the concept in Orthopaedic surgery. The routine use of tourniquet-controlled limb surgery and traumatic soft tissue damage are just two examples of where IPC could be utilised to beneficial effect in Orthopaedic surgery.

Introduction

Local anaesthetic has been reported to have a potentially detrimental effect on human chondrocytes both in vitro and in vivo. Due to chondroproliferative effects, magnesium may be an alternative intra-articular analgesic agent following arthroscopy. We aimed to examine the dose response effect of commonly used local anaesthetics on chondrocyte viability and also to report on the effect of adding magnesium to the local anesthetic agent.

Introduction: Low-molecular-weight heparin is commonly used for thromboprophylactic therapy post orthopaedic surgery. Studies in the past have suggested that it may have a negative effect on osteoblasts and some have implicated its use with the risk of developing osteoporosis. Recently, Rivaroxaban, an oral Factor Xa inhibitor is gaining impetus for antithrombotic therapy over the last year and has been recommended for licensing by the FDA for this purpose. The effect of Rivaroxa-ban on bone and osteoblasts, if any, remains to be seen.

Methods: In a standardized in vitro model, human osteoblasts were cultured and exposed to a range of Enoxaparin and Rivaroxaban concentrations including their therapeutic dose. We evaluated the effects of these drugs on osteoblastic proliferation and activity using CellTiter 96 AQueous non-radioactive cell proliferation (MTS) and alkaline phosphatase assays respectively. Gene expression of Runt-related transcription factor 2 (Runx2), osteocalcin and bone morphogenetic protein 2 (BMP-2) were evaluated using Real time-polymerase chain reaction (RT-PCR) studies. Statistical analyses (t-test) were conducted using Microsoft Excel 2007.

Results: Rivaroxaban and Enoxaparin significantly reduced alkaline phosphatase activity (p< 0.05) however, no negative effects on osteoblastic proliferation was seen at all concentrations of both drugs. Rivaroxaban decreased Osteocalcin and Runx2 mRNA expression levels at 24 hours at therapeutic concentrations (p< 0.05). This effect was similarly found at therapeutic levels of Enoxaparin. Both Rivaroxaban and Enoxaparin significantly reduced BMP-2 mRNA expression both at 24 hours and 7 days at therapeutic concentrations. (p< 0.05).

Conclusion: Our study suggests that Rivaroxaban has similar negative effects on osteoblasts compared to Enoxaparin in the early stages. The increased duration of recommended Rivaroxaban therapy (2 and 5 weeks) post arthroplasty compared to Enoxaparin therapy (around 1 week) may have a more pronounced effect on bone homeostasis.

Introduction: Ischaemic preconditioning (IPC) is a well recognised and powerful phenomenon where a tissue becomes more tolerant to prolonged ischaemia when it is first subjected to short bursts of ischaemia/reperfusion. IPC has been most comprehensively studied in cardiothoracic surgery, to date there has been little use of this powerful phenomenon in orthopaedic surgery. In this study, we report on the first clinical trial of IPC on human skeletal muscle, and show the potential of IPC in orthopaedics using global gene expression analysis.

Methods: After local ethics committee approval and informed consent, patients undergoing primary knee arthroplasty were randomly assigned into an IPC group and a control group. Diabetic patients or patients with an ankle/brachial index of less than 1 were excluded.

The IPC consisted of three five-minute periods of tourniquet insufflation on the operative limb, interrupted by five minute periods of reperfusion. The tourniquet was again insufflated and the operation started. The control group simply had tourniquet insufflation as normal prior to the start of surgery.

Muscle samples were taken from the operative knee of all patients at the immediate onset of surgery (t=0), and again, at one hour into the surgery (t=1). Total RNA was extracted from the muscle samples, and the gene expression profiles were determined using microarray technology.

Results: Comparison of IPC and control samples identified 702 transcripts with differences of ≥1.5-fold in their expression. Of these, 137 were altered at t=0 while 565 were altered at t=1. Amongst these changes was an up-regulation in the expression of a number of heat shock proteins (HSPs) in the IPC group as compared to the control group. Notably, there was up-regulation of the well known cytoprotective/anti-apoptotic gene, HSP72, at one hour post IPC (1.5-fold, p=0.039). There was also up-regulation of important oxidative stress defense genes, such as glutathione-S-transferase (1.6-fold, p = 0.021) and superoxide dismutase 2 (3.6-fold, p= 0.048). Microarray analysis also revealed a down-regulation in the expression of genes involved in metabolism, down-regulation of pro-apoptotic genes and up-regulation of genes necessary for transformation to a hypoxia-tolerant state.

Discussion: We present convincing evidence that IPC is beneficial to human skeletal muscle and for the first time show that IPC of human skeletal muscle works in the clinical setting. In this study, the protective effect of IPC involved a down-regulation in the expression of genes associated with metabolism, and an up-regulation in the expression of genes that provide protection from cell stress, oxidative stress and apoptosis. HSPs, and especially HSP72, have well documented roles in cell stress protection. Their presence has been cited by other studies as an indicator of cell adaptation to stress.

Slipped capital femoral epiphysis (SCFE) is the most common hip disorder in adolescents and its incidence is on the increase. Obesity is purported to be a significant risk factor in the pathogenesis of this condition. Measurements for weight and BMI’s are good techniques in identifying children at risk and those who are obese. In this retrospective review, we provide clear evidence of a relationship between SCFE and obesity based on weight-to-age percentiles. 64 patients with radiologically diagnosed SCFE were compared with 88 controls without histories of hip pathology. In the SCFE group, 45.3% were above the 95th percentile as opposed to 12.1% in the control group (P=< 0.0001). In addition, the obesity risk group (85–95th percentile) numbers were much higher in the SCFE group (15.6%) compared to controls (7.7%) (P=< 0.0001). Obesity is a modifiable risk factor in most cases and thus, identifying children at risk using weight-to-age percentile charts correcting for gender is potentially beneficial in reducing the incidence of SCFE.

Backgroud: Revision total knee arthroplasty (TKA) consumes considerably more resources than primary TKA. Management of infected arthroplasty has been shown to require even more resources in terms of inpatient stay, microbiological investigation, multiple stage procedures and more complex implants than treatment of aseptic failures. We investigated the trends in cost of revision TKA over a 10 year period.

Patients and Methods: Between 1997 and 2006, 189 patients underwent revision total knee arthroplasty in our institution. The perioperative data was available for 181 of these (95.77%). Data collected included age, gender, diagnosis, number of revisions length of stay, operative time, blood loss, number of units of blood transfused and ASA grade. Financial data included cost of implants and instrumentation, cost and number of bed-days, investigations and treatment. In the case of 2 stage revisions involving 2 admissions, the cumulative data was compiled as a single episode.

Results: The study group comprised 123 females (65.07%) and 66 males (34.93%). The mean age for both groups was 68.97 (range of 20 to 91years), with a 6.7% increase in mean age over the ten year period (66.75 to 71.19). The mean ASA score dropped from 2.67 in 1997 to 2.23 in 2006. The number of revision surgeries per year increased over the study period from 8 to 36. The number of TKA revisions for infection over the 10 years was 18(9.5%).

The mean length of stay for revision due to aseptic loosening in 1997 was 14.3 days. The average length of stay for revision for infected arthroplasty was 35 days. In 2006, the length of stay increased to 65 days for infected arthroplasty and 15.03 days for aseptic cases.

The mean total cost of aseptic revision per patient was 12,409.92 (range 8,822.58–13,559.65) euro in 1997 with revisions for infection costing 20,888.66 euro, a difference of 68.32%.

The industry cost of implants increased by 32–35% (€3119–€4371 and €4216–€5800) between 1999 and 2006 depending on implant selection. There was a 20– 42% increase in generic hospital costs (admission, investigation and treatment related costs) in the same period.

Conclusion: With increasing life expectancy and increased indication for primary arthroplasty more patients are coming to revision surgery. The cost of Revision TKR has increased steadily over the last 10 years. Revision TKR for infection remains significantly more expensive than revision for aseptic loosening or other causes and provides a significant financial burden on orthopaedic services. Infected arthroplasty incurs significantly greater cost and every precaution should be taken to avoid infection in total knee arthroplasty.

Introduction: Proximal femur fractures are an important cause of morbidity in the elderly and comprise a significant proportion of acute orthopaedic admissions.

Aim: To study the demographics of and factors responsible for prolonged hospital stay following admission with a fractured neck of femur.

Methods: We reviewed of a consecutive series of hip fractures presenting to our unit over a five-year period between 2000 and 2004. A complete patient cohort was obtained from the casualty register, the OT register and from a Hospital In-Patient Enquiry (HIPE) database. Pathological, high energy and peri-prosthetic fractures were excluded. We reviewed records to obtain demographic and clinical data including age, sex, length of stay, time to operation and comorbidities. Those who remained in-patients for greater than 14 days were analysed for reasons responsible for prolonged stay.

Results: 717 low-energy hip fractures treated in the period 2000–2004. The M:F ratio was 1:3.3. The average age for males and females was 73.6 yrs (SD 11.23) and 79.6 yrs (SD 9.74) respectively. The overall average length of stay was 28 days. 351 patients (49%) stayed in hospital > 14 days. For these, the mean length of stay was 48 days (range 15–443). Reasons for prolonged stay included acute medical and surgical issues (32%), social and placement issues (22%), active chronic disease (17%) and post-operative complications (4%).

Conclusion: Hip fractures in the elderly constitute a significant burden on an acute trauma service. Further strategies are needed to address both medical and social reasons for prolonged stay in and delayed discharge from hospital. A national hip fracture audit is required.

Introduction: The increasing numbers and costs of lower limb arthroplasty procedures has lead to medical and administrative pressures to reduce lengths of stay (LOS) and the hospital costs associated with these procedures. We compared a prospective application of an arthroplasty care pathway in a tertiary referral unit in the United States (US) to a retrospective review of standard practice in an Irish unit to assess reasons for delayed discharge.

Methods: We performed the study in 2 orthopaedic units, one in the US and one in Ireland. In the US an arthroplasty perioperative care pathway was implemented, which among other elements involved a coordinated undertaking by therapists, surgeons and social workers to achieve discharge on the 3rd postoperative day. A consecutive series of primary total knee and hip arthroplasty patients were entered into that limb of the study and had demographic, clinical and LOS data collected. We then collected the same data from a randomly selected consecutive series of primary total knee and hip arthroplasty patients in the Irish unit.

Results: In the US orthopaedic unit 43 patients were included, 24 women and 19 men, of average age 60.5 years (range, 36–82). The average LOS was 3.6 days (range, 2–10), with 27 patients going to a rehabilitation facility and 16 directly home.

In the Irish orthopaedic unit 42 consecutive hip and knee arthroplasty patients from a single consultant were included. There were 26 women and 16 men with average age of 63.9 years (range 36 to 88 years). The average LOS was 6.5 days (range, 3 to 10 days), with 24 patients going to a rehabilitation facility and 18 directly home.

There was no correlation found between LOS and either comorbidities, social factors or complications, in both groups although one patient had a delayed discharge due to haematoma and wound drainage in the US. Prolonged LOS in both groups was correlated with delays in rehabilitation bed and transportation availability, reported short staffing in hospital and weekend stays.

Both groups were well matched for comparison. The average shorter LOS noted in the US unit appears to be almost entirely attributable to an implemented perioperative care pathway and a more proactive coordinated approach to discharge planning.

Discussion and Conclusion: This study demonstrates the effectiveness of multidisciplinary clinical pathways in achieving desired LOS objectives but that substantial impediments still exist from an administrative and logistical viewpoint. Such information is important for clinicians in negotiating and establishing appropriate management of their arthroplasty patients in the current care provision climate.

As the numbers of revision total knee arthroplasty (RTKA) rise, we continually need current information regarding the etiology/modes of failure and functional disability of patients presenting for RTKA. We used a prospective cohort study to assess these fundamental aspects of RTKA.

290 consecutive subjects presenting for RTKA had relevant clinical information, including modes of failure, collected from surgeon-completed documents. Patients themselves also completed quality of life and functional questionnaires, including the SF-36 and WOMAC Osteoarthritis Index.

Mean patient age was 68.6 years (55 to 79 years). Mean SF-36 and WOMAC score at baseline indicated significant functional disability. The mean time from primary procedure to RTKA was 7.9 years (6 months to 27 years). Our series included 31 percent ‘early’ (under 2 years) revisions and 69 percent ‘late’ revisions. Sepsis was the cause of 10.4 percent revisions. The tibia needed revision in 78 percent, femur in 71 percent and patella in 31 percent of cases. The predominant modes of failure (non-exclusive frequency values as patients could have more than one cause) were (in percentages): instability (28.9), malalignment (27.5), tibial osteolysis (27.5), polyethylene wear (24.5), femoral osteolysis (22.5) and tibial loosening (22.2).

These patients are relatively young, and considerably disabled by their failed primary procedure. Many modes of failure are within surgical control and direct us toward improved techniques and approaches. Other modes confirm the need for continued development of implants and materials. Information gained here will allow better formulation of measures and resource allocation that may prevent RTKAs.

Background: Infected total knee arthroplasty causes significant morbidity to patients and also challenges to surgeons to provide a functional mobile knee joint.

Aim: Present a 10-year review (1997 to 2006) of all the revision total knee replacements performed for infection in our centre.

Methods and Materials: Data including the demographics, ASA grade, blood loss, blood transfusions, length of stay, laboratory investigations including culture and sensitivity of the deep swabs. The sensitivity and specificity of pre-operative CRP and ESR were related to culture results. Post operative complication was recorded. The financial implication of the whole treatment was calculated by applying the prescribed cost by the Voluntary health insurance limited.

Results: Revisions for suspected infection constituted 14.8% (28 out of 189 cases) of the total revision knee procedures performed during the period. All the patients underwent 2 staged revision knee Arthroplasty. The mean age was 68.6 (46–83 yrs). The mode for ASA grade was 2. The average blood loss was 2 litres and the mean blood transfusion units per case were 3.8 units. The average length of stay was 42.25 days, a 24.32 days longer than aseptic revisions.

46.4% of the cases had positive cultures from the deep tissues. Staphylococcus species were responsible for 62% of cases, while enterococci, pseudomonas, streptococcus pneumonia, and MRSA have similar occurrences. The mean total cost per case was € 21,895 (13,597 for aseptic revision) a 61% increase in cost for cases revised for non septic reasons.

Conclusion: Revision Total knee replacement for infection remains significantly more expensive than revision for aseptic loosening or other causes and provides a significant financial burden on orthopaedic services. Every precaution should be taken to avoid infection in total knee arthroplasty.

Introduction: Chronic stiffness is an uncommon complication of total knee arthroplasty (TKA) with reports in the literature citing an incidence of 1–5%. Surgical options to manage this debilitating condition include manipulation under anaesthesia (MUA) and arthrolysis; there is concern regarding revision surgery given the potential for stiffness recurrence.

Methods: Patients undergoing revision TKA for stiffness were prospectively identified. Inclusion criteria required a flexion contracture greater than 10 degrees and/or less than 70 degrees arc of motion. WOMAC and SF-36 self-report questionnaires were completed by all patients’ pre and post revision surgery.

Results: Between July 2005 and Dec 2006, 7 consecutive, aseptic, primary TKA’s were revised to address limited range of motion. Five female and 2 male patients (mean age: 57.6 years) underwent revision TKA 17.1 months (range, 7–25 months) after index TKA. All patients had attempted MUA, with additional open arthrolysis unsuccessful in 1 case. A medial parapatellar approach was performed although 3 required additional quadriceps snip for exposure. Five cases were revised with the Scorpio TS system and 2 with posterior stabilised components. Femoral augmentation was required in 2 cases and tibial in 1. Gap imbalance with increased soft tissue tension was noted intra-operatively in 5 cases with arthrofibrosis found in the remainder. At 6 months follow-up, arc of motion increased from a mean of 41.3° preoperatively to 81.4° (p=0.001) while mean flexion contracture decreased from 17.4° to 2.1° (p=0.004). Subjective improvement was also demonstrated: mean WOMAC decreased from 46.5 to 22.5 (p=0.023) and SF-36 scores increased by a mean of 35.8 points (p=0.001).

Conclusion: When conservative, implant preserving measures fail, revision surgery can be considered a viable option in addressing restricted movement following primary TKA. Aggressive physiotherapy and good patient compliance is required to minimise the recurrence of stiffness.

Introduction: A critical technical and economic challenge in total knee arthroplasty revision (TKAR) is bone loss management. Easily applied, valid pre-operative measurements of bone loss are essential to allow accurate planning and meaningful comparisons between series. We compared 2 radiographic measurement ment systems with actual intra-operative bone loss in order to determine their validity.

Methods: A prospective IRB approved cohort study of 290 consecutive TKAR patients was utilized to assess the Anderson Orthopaedic Research Institute (AORI) system and the University of Pennsylvania (UPenn) assessment system. These preoperative measures were performed on standardized antero-posterior and lateral knee radiographs by 31 orthopaedic surgeons trained in their use. The validity and reproducibility of both systems was determined versus the gold standard measure of actual intra-operative bone loss.

Results: 215 patients (74.1 percent) were assessed to have bone loss pre-operatively versus 222 (76.4 percent) intra-operatively. Using the AORI classification system agreement between preoperative and intraoperative classification was moderate for the femur (K = 0.50) and good for the tibia (K = 0.63). The UPenn system gave resultant mean scores of 0.137 for femur and tibia versus intraoperative findings of resultant mean scores of 0.14 and 0.143 for the femur and tibia, respectively. These differences were not statistically significant (p < 0.02).

Discussion: This study demonstrates a high incidence of bone loss among TKAR patients, emphasizing the importance of effective measurement tools. Both the AORI and UPenn systems are valid tools for pre-operative estimation of actual bone loss facilitating planning and clinically successful, cost effective management of bone loss in TKAR.

Total knee arthroplasty revisions (TKAR) are increasing in incidence. These complex and demanding procedures are typically associated with a higher complication rate than primaries. We report on the actual complications encountered in a prospective study of TKAR patients to determine the current nature and incidence of these problems.

230 consecutive patients undergoing TKAR were enrolled to our database and had information on demographics, comorbidities, outcomes (WOMAC and SF-36) and complications recorded. Baseline information and data from 2 month, 6 month and 1 year follow up was collated.

Mean patient age was 68.0 and clinical outcomes scores showed significant improvements for function, stiffness and pain at all points of follow-up. The total number of complications was 131 in 97 (42.2%) patients (48 by 2 months, 46 at 6 months and 32 at 1 year). Systemic complications comprised 41 of these, many being relatively minor. There were no deaths, 4 deep vein thromboses and 3 myocardial infarctions. The majority of complications (90) were local, including 2 patellar dislocations, 3 periprosthetic fractures, 3 peroneal nerve injuries, 2 ‘late’ patellar tendon ruptures and 1 patellar avascular necrosis, 9 wound hematomas, and a substantial rate of 21 superficial or deep wound infections.

Although patients experience significant improvement in function, activity and pain following TKAR, there is a considerable incidence of complications up to 1 year following TKAR. This is important in terms of resources, patient counseling and also in identifying and instituting preventive measures where possible in order to improve outcomes for these patients.

Introduction: Alcohol can induce osteoporosis and osteonecrosis. Studies have demonstrated that alcohol contributed to abnormal lipid metabolism in cells in bone marrow but the mechanisms have not been defined. The purpose of this study was to evaluate the effect of alcohol on the differentiation of pluripotential cells cloned from bone marrow.

Materials and Methods: The cells were maintained in culture and treated with either increasing concentrations of ethanol (0.09, 0.15, and 0.21 mol/L) or without alcohol to serve as controls. Morphologic features of the cells were monitored using a phase-contrast microscope. Alkaline phosphatase activity was determined using a colorimetric assay. Gene expression of adipogenesis [422 (aP2), PPAR y] and osteogenesis (osteocalcin) was evaluated using the Northern blot technique and reverse transcription-polymerase chain reaction (RT-PCR). ANOVA was used for statistical analysis.

Results: The cells treated with ethanol started to accumulate triglyceride vesicles at Day 7; the number of adipocytes and the percentage of the area that contained the cells with fat vesicles increased significantly; and the level of alkaline phosphatase activity diminished with longer durations of exposure and with higher concentrations of ethanol. Analysis of gene expression showed diminished expression of osteocalcin without a significant increase in the expression of the fat cell specific gene, 422 (aP2), and PPAR y, in cells treated with ethanol. This suggested that adipogenesis may occur at a point downstream in the fatty acid metabolism pathway.

Discussion: Alcohol induces bone marrow fatty changes in patients and in animal models contributing to osteoporosis and osteonecrosis. This study demonstrated that alcohol treatment decreased osteogenesis while enhancing adipogenesis by bone marrow stromal cells, which may be one of the mechanisms leading to osteoporosis and osteonecrosis. Inhibition of adipogenesis may lead to the prevention of the disease.

Clinical relevance: This is a novel finding that alcohol induces adipogenesis in a cloned bone marrow stromal cell. The results explain the clinical observation that there is increased adipogenesis in alcohol-induced osteoporosis and osteonecrosis.