Population pharmacokinetic model of cefazolin in total hip arthroplasty.

Cefazolin is an antibiotic recommended for infection prevention in total hip arthroplasty (THA). However, the dosing regimen necessary to achieve therapeutic concentrations in obese patients remains unclear. The aim of this study was to conduct a population analysis of cefazolin pharmacokinetics (PK) and assess whether cefazolin administration should be weight adapted in THA. Adult patients undergoing THA surgery received an injection of 2000 mg of cefazolin, doubled in the case of BMI > 35 kg/m2 and total body weight > 100 kg. A population PK study was conducted to quantify cefazolin exposure over time compared to the therapeutic concentration threshold. A total of 484 cefazolin measurements were acquired in 100 patients, of whom 29% were obese. A 2-compartment model best fitted the data, and creatinine clearance determined interpatient variability in elimination clearance. Our PK simulations using a 2000 mg cefazolin bolus showed that cefazolin concentrations remained above the threshold throughout surgery, regardless of weight or renal function. A 2000 mg cefazolin single injection without adaptation to weight or renal function and without intraoperative reinjection was efficient in maintaining therapeutic concentrations throughout surgery. The optimal target concentration and necessary duration of its maintenance remain unclear.

Pharmacokinetic Model for Cefuroxime Dosing during Cardiac Surgery under Cardiopulmonary Bypass.

Cefuroxime (CXM) is an antibiotic recommended for surgical site infection prevention in cardiac surgery. However, the dosing regimens commonly used do not sustain therapeutic concentrations throughout surgery. The aim of this study was to conduct a population analysis of CXM pharmacokinetics (PK), and to propose an optimized dosing regimen. Adult patients undergoing cardiac surgery under cardiopulmonary bypass (CPB) received a 1,500 mg CXM intravenous bolus followed by a 750 mg bolus at CPB priming, then every 2 h thereafter. Model-based PK simulations were used to develop an optimized dosing regimen and evaluate its efficacy in attaining various concentration thresholds, including those recommended in US and European guidelines. In total, 447 CXM measurements were acquired in 50 patients. A two-compartment model best fit the data, with total body weight and creatinine clearance determining interpatient variability in the central and peripheral volumes of distribution, and in elimination clearance, respectively. Using our optimized dosing regimen, different dosing schemes adapted to body weight and renal function were calculated to attain total concentration thresholds ranging from 12 to 96 mg/liter. Our simulations showed that the dosing regimens recommended in US and European guidelines failed to maintain concentrations above 48 mg/liter. Our individualized dosing strategy was capable of ensuring therapeutic CXM concentrations conforming to each target threshold. Our model yielded an optimized CXM dosing regimen adapted to body weight and renal function, and sustaining therapeutic concentrations consistent with each desired threshold. The optimal target concentration and necessary duration of its maintenance in cardiac surgery still remain unclear.

Comparative effectiveness of antitumour necrosis factor agents, biologics with an alternative mode of action and tofacitinib in an observational cohort of patients with rheumatoid arthritis in Switzerland.

BACKGROUND: Multiple biologic and targeted synthetic disease-modifying rheumatic drugs (b/tsDMARDs) are approved for the management of rheumatoid arthritis (RA), including TNF inhibitors (TNFi), bDMARDs with other modes of action (bDMARD-OMA) and Janus kinase inhibitors (JAKi). Combination of b/tsDMARDs with conventional synthetic DMARDs (csDMARDs) is recommended, yet monotherapy is common in practice. OBJECTIVE: To compare drug maintenance and clinical effectiveness of three alternative treatment options for RA management. METHODS: This observational cohort study was nested within the Swiss RA Registry. TNFi, bDMARD-OMA (abatacept or anti-IL6 agents) or the JAKi tofacitinib (Tofa) initiated in adult RA patients were included. The primary outcome was overall drug retention. We further analysed secondary effectiveness outcomes and whether concomitant csDMARDs modified effectiveness, adjusting for potential confounding factors. RESULTS: 4023 treatment courses of 2600 patients were included, 1862 on TNFi, 1355 on bDMARD-OMA and 806 on Tofa. TNFi was more frequently used as a first b/tsDMARDs, at a younger age and with shorter disease duration. Overall drug maintenance was significantly lower with TNFi compared with Tofa [HR 1.29 (95% CI 1.14 to 1.47)], but similar between bDMARD-OMA and Tofa [HR 1.09 (95% CI 0.96 to 1.24)]. TNFi maintenance was decreased when prescribed without concomitant csDMARDs [HR: 1.27 (95% CI 1.08 to 1.49)], while no difference was observed for bDMARD-OMA or Tofa maintenance with respect to concomitant csDMARDs. CONCLUSION: Tofa drug maintenance was comparable with bDMARDs-OMA and somewhat higher than TNFi. Concomitant csDMARDs appear to be required for optimal effectiveness of TNFi, but not for bDMARD-OMA or Tofa.

Incidence and risk factors of major bleeding following major orthopaedic surgery with fondaparinux thromboprophylaxis. A time-to-event analysis.

AIMS: Increased exposure to fondaparinux, as observed in patients with renal impairment, may increase bleeding risk. This study aims to determine the time course of major bleeding after major orthopaedic surgery, identify predictors of bleeding and simulate the effect of a reduced dose of fondaparinux on bleeding for patients with moderate renal impairment (creatinine clearance = 20-50 ml min-1 ). METHODS: Data including fondaparinux anti-Xa activities from two multicentre prospective cohorts were used. In the first cohort, patients (n = 957) received fondaparinux 2.5 mg once a day. In the second, patients with moderate renal impairment (n = 436) received 1.5 mg once per day. The time-to-major bleeding after the end of surgery was modelled using a parametric survival analysis in NONMEM. RESULTS: The observed rate of major bleeding up to day 11 was 5.2%. The time-to-event analysis indicated that the hazard of bleeding was highest in the first days following surgery and then remained low thereafter. Independent significant predictors of an increased hazard of major bleeding were male sex, lower body weight and increased drug exposure. Simulated rates of major bleeding up to day 11 in patients with moderate renal impairment were 6.5% with fondaparinux 2.5 mg once daily and 3.8% with fondaparinux 1.5 mg once daily. CONCLUSION: The hazard of major bleeding is highest in the first postoperative days and increases with fondaparinux exposure. To reduce the risk of bleeding in patients with moderate renal impairment, this study supports the use of a lower dose of fondaparinux 1.5 mg once daily.

Assessment of clinically relevant bleeding as a surrogate outcome for major bleeding: validation by meta-analysis of randomized controlled trials.

Essentials Surrogacy of clinically relevant bleeding (CRB) for major bleeding has never been validated. Our meta-analysis evaluated CRB surrogacy in trials of new versus traditional anticoagulants. Surrogacy was not validated in orthopedic surgery, venous thromboembolism or atrial fibrillation The difficulty in demonstrating the surrogacy may reflect a lack of homogeneity in its definition SUMMARY: Background Clinically relevant bleeding (CRB), comprising major bleeding and clinically relevant non-major bleeding, has been used as a surrogate for major bleeding in most anticoagulant trials. The validity of this surrogate to estimate trade-off between thrombotic and bleeding events in clinical trials was never assessed. Methods We systematically reviewed randomized phase III trials comparing new anticoagulants with the standard of care for venous thromboembolism prevention following major orthopedic surgery, venous thromboembolism (VTE) treatment, or stroke and systemic embolism prevention in atrial fibrillation (AF), and reporting both major bleeding and CRB rates. The validity of CRB as a surrogate for major bleeding was assessed according to the strength of the association between the relative risks of major bleeding and CRB, measured by the use of R2trial and its 95% confidence interval (CI). Results In the postoperative prophylactic setting (13 studies), major bleeding and CRB rates were 1.12% and 3.56%, respectively, and R2trial was 0.69 (95% CI 0.34-0.93). For acute VTE studies (n = 12), major bleeding and CRB rates were 1.87% and 9.07%; the corresponding R2trial values were 0.28 (95% CI 0.01-0.80) and 0.68 (95% CI 0.09-1.00) when only double-blind studies were considered (n = 7). For AF studies (n = 7; 22 strata), major bleeding and CRB rates were 4.82% and 15.3%, and R2trial was 0.59 (95% CI 0.15-0.82). Conclusion Despite an apparent correlation between CRB and major bleeding in major orthopedic surgery, AF, and double-blind acute VTE studies, the wide CIs suggest that CRB might not be an acceptable surrogate outcome in any of these settings.

Necrotising Scleritis and Peripheral Ulcerative Keratitis Associated with Rheumatoid Arthritis Treated with Rituximab.

Background Rheumatoid arthritis is a chronic and common inflammatory autoimmune disease. This primarily involves the synovia of the joints, but can cause many extra-articular manifestations as well, including peripheral ulcerative keratitis (PUK) and necrotising scleritis. These are often a threat to vision; they significantly compromise not only the eye's structural integrity but are also important for prognosis and need urgent management. History and signs Three cases of peripheral ulcerative keratitis associated with rheumatoid arthritis were recorded in the electronic databank of the Jules Gonin Uveitis Clinic, two with necrotising scleritis and peripheral ulcerative keratitis and one with only peripheral ulcerative keratitis. They were all followed at Jules Gonin Eye Hospital (Lausanne, Switzerland), conjointly with the Department of Rheumatology at the Centre Hospitalier Universitaire Vaudois (Lausanne, Switzerland). Therapy and Outcome Good initial therapeutic response was observed in the two patients who received rituximab therapy. The patient who received only high dose corticosteroid developed massive colon perforation as well as acute renal insufficiency a few days after her ocular event. Conclusion From our limited number of patients, we found that the two patients who received the induction therapy with rituximab were stabilised from an ocular standpoint; however, rituximab had to be switched to other molecules, either due to other systemic symptoms from the disease itself or due to adverse effect of this treatment. This contributes to the increasing number of reports that rituximab can be an effective treatment for refractory ocular complications of rheumatoid arthritis (RA), at least as an induction therapy.

[Whipple's disease, when to think about it?]. / Maladie de Whipple: quand y penser?

Whipple's disease is a chronic, systemic, bacterial infection caused by Tropheryma whipplei. Its cardinal symptoms include intermittent and recurrent arthralgia or arthritis together with chronic diarrhoea, abdominal pain and weight loss. It may mimick many chronic inflammatory diseases, and the diagnosis remains a challenge. Salivary and faecal quantitative PCR for T. whipplei should be ensued, if positive, by an upper endoscopy for duodenal biopsies. The treatment consists of a combination of oral doxycycline and hydroxychloroquine for 12 months followed by life-long doxycycline. Whipple's disease, although rare, is an entity that should be considered regularly, as its progression may be fatal if left untreated.

[Elbow tendinopathy]. / Tendinopathies du coude.

The lateral and medial epicondylitis is often manifested in a professional or in a sport context leading to repetitive wrist movements. The diagnosis is primarily clinical. Additional tests are indicated in chronic evolution and in searching for differential diagnoses. Elbow X-ray can be completed with ultrasound or MRI, the most efficient but expensive diagnostic procedure. There is no consensus on treatment. After a period of rest, stretching then strengthening exercises are recommended. Corticosteroid injections may provide a short-term beneficial effect. Platelet-Rich Plasma injections have recently gained notoriety. In case of failure of treatment, surgery is possible, but only in a minority of patients.

[Tendinitis in athletes: etiology, diagnosis and treatment]. / Tendinopathies du sportif: étiologie, diagnostic et traitement.

Tendinopathy is one of the most common diagnosis in sports. Knowledges about their etiology, the repair process to their diagnosis and their treatment have improved thanks to the development of imaging, especially ultra- sound. The disorder whose etiology could be mechanical or degenerative can cause long- term disability and sometimes the end of the sport carreer. The risk of reccurence is com- mon; this may lead to tendon rupture whose functional effects can be significative. The management should be early: it must respect the deadlines for tendon healing and pro- pose a gradual recovery efforts after elimina tion of the contributing factors involved.

[Achilles tendinopathy]. / Tendinopathie d'Achille.

Achilles tendinopathy (AT) is the most common cause of posterior heel pain. It is most often due to mechanical stress related to overload or overuse of muscle-tendon unit. It also may be associated in a minority of cases with inflammatory arthritis. Pain secondary to AT is generally located in the corporeal part of the tendon or its attachment to the bone and is worsened by exercise. Examination can reveal a painful swelling or thickening on palpation. Additional tests are not routinely recommended but may be useful. Treatment should be tailored to the stage of tendinopathy and to functional disability, and should include an assessment of predisposing factors, analgesia and physiotherapy. Other treatments (shock waves, ultrasound) are less well documented. The indications and effectiveness of infiltrations are controversial and are reserved for chronic AT. The risk benefit ratio should be well discussed with the patient.

Indirect comparison meta-analysis of two enoxaparin regimens in patients undergoing major orthopaedic surgery. Impact on the interpretation of thromboprophylactic effects of new anticoagulant drugs.

Two enoxaparin dosage regimens are used as comparators to evaluate new anticoagulants for thromboprophylaxis in patients undergoing major orthopaedic surgery, but so far no satisfactory direct comparison between them has been published. Our objective was to compare the efficacy and safety of enoxaparin 3,000 anti-Xa IU twice daily and enoxaparin 4,000 anti-Xa IU once daily in this clinical setting by indirect comparison meta-analysis, using Bucher's method. We selected randomised controlled trials comparing another anticoagulant, placebo (or no treatment) with either enoxaparin regimen for venous thromboembolism prophylaxis after hip or knee replacement or hip fracture surgery, provided that the second regimen was assessed elsewhere versus the same comparator. Two authors independently evaluated study eligibility, extracted the data, and assessed the risk of bias. The primary efficacy outcome was the incidence of venous thomboembolism. The main safety outcome was the incidence of major bleeding. Overall, 44 randomised comparisons in 56,423 patients were selected, 35 being double-blind (54,117 patients). Compared with enoxaparin 4,000 anti-Xa IU once daily, enoxaparin 3,000 anti-Xa IU twice daily was associated with a reduced risk of venous thromboembolism (relative risk [RR]: 0.53, 95% confidence interval [CI]: 0.40 to 0.69), but an increased risk of major bleeding (RR: 2.01, 95% CI: 1.23 to 3.29). In conclusion, when interpreting the benefit-risk ratio of new anticoagulant drugs versus enoxaparin for thromboprophylaxis after major orthopaedic surgery, the apparently greater efficacy but higher bleeding risk of the twice-daily 3,000 anti-Xa IU enoxaparin regimen compared to the once-daily 4,000 anti-Xa IU regimen should be taken into account.

[Role of imaging in the diagnosis and follow-up of rheumatoid arthritis]. / Rôle de l'imagerie dans le diagnostic et le suivi de la polyarthrite rhumatoïde.

Cross-sectional imaging techniques such as magnetic resonance imaging and ultrasound are becoming essential tools not only for making an early diagnosis of rheumatoid arthritis, but also to help clarify the prognosis of the disease and better assess the response to various therapies. This article summarises the recommendations established in 2013 by the European League Against Rheumatism on the role of imaging in the diagnosis and follow-up of rheumatoid arthritis, while adding comments and emphasising on our Swiss experience with the use of ultrasound.

[Family physician and connective tissue disorders]. / Rôle du médecin interniste ou du généraliste dans le diagnostic et le suivi d'une collagénose.

The exact place of the family physician in the diagnosis and management of connective tissue disease is poorly studied moreover will essentially depend on the health system and the organization of medical network of each country. Connective tissue diseases are rare and complex diseases that require in all cases referral to specialists for their diagnosis as well as monitoring. All patients must still keep a family doctor whose importance increases more and more as our specialized treatments prolong survival of patients who become chronically ill with multi-organic sequelae. A closely interaction between the various specialists and family physicians is necessary to ensure a good long-term follow-up.

Severe stroke: patient profile and predictors of favorable outcome.

BACKGROUND: Severe stroke carries high rates of mortality and morbidity. The aims of this study were to determine the characteristics of patients who initially presented with severe ischemic stroke, and to identify acute and subacute predictors of favorable clinical outcome in these patients. METHODS: An observational cohort study, Acute Stroke Registry and Analysis of Lausanne (ASTRAL), was analyzed, and all patients presenting with severe stroke - defined as a National Institute of Health Stroke Scale score of ≥ 20 on admission - were compared with all other patients. In a multivariate analysis, associations with demographic, clinical, pathophysiologic, metabolic and neuroimaging factors were determined. Furthermore, we analyzed predictors of favorable outcome (modified Rankin scale score of ≤ 3 at 3 months) in the subgroup of severe stroke patients. RESULTS: Of 1915 consecutive patients, 243 (12.7%) presented with severe stroke. This was significantly associated with cardio-embolic stroke mechanism (odds ratio [OR] 1.74, 95% confidence interval [CI] 1.19-2.54), unknown stroke onset (OR 2.35, 95% CI 1.14-4.83), more neuroimaging signs of early ischemia (mostly computed tomography; OR 2.65, 95% CI 1.79-3.92), arterial occlusions on acute imaging (OR 27.01, 95% CI 11.5-62.9), fewer chronic radiologic infarcts (OR 0.43, 95% CI 0.26-0.72), lower hemoglobin concentration (OR 0.97, 95% CI 0.96-0.99), and higher white cell count (OR 1.05, 95% CI 1.00-1.11). In the 68 (28%) patients with favorable outcomes despite presenting with severe stroke, this was predicted by lower age (OR 0.94, 95% CI 0.92-0.97), preceding cerebrovascular events (OR 3.00, 95% CI 1.01-8.97), hypolipemic pretreatment (OR 3.82, 95% CI 1.34-10.90), lower acute temperature (OR 0.43, 95% CI 0.23-0.78), lower subacute glucose concentration (OR 0.74, 95% CI 0.56-0.97), and spontaneous or treatment-induced recanalization (OR 4.51, 95% CI 1.96-10.41). CONCLUSIONS: Severe stroke presentation is predicted by multiple clinical, radiologic and metabolic variables, several of which are modifiable. Predictors in the 28% of patients with favorable outcome despite presenting with severe stroke include hypolipemic pretreatment, lower acute temperature, lower glucose levels at 24 h, and arterial recanalization.

Stages of change, barriers, benefits, and preferences for exercise in RA patients: a cross-sectional study.

OBJECTIVES: To determine the distribution of exercise stages of change in a rheumatoid arthritis (RA) cohort, and to examine patients' perceptions of exercise benefits, barriers, and their preferences for exercise. METHODS: One hundred and twenty RA patients who attended the Rheumatology Unit of a University Hospital were asked to participate in the study. Those who agreed were administered a questionnaire to determine their exercise stage of change, their perceived benefits and barriers to exercise, and their preferences for various features of exercise. RESULTS: Eighty-nine (74%) patients were finally included in the analyses. Their mean age was 58.4 years, mean RA duration 10.1 years, and mean disease activity score 2.8. The distribution of exercise stages of change was as follows: precontemplation (n = 30, 34%), contemplation (n = 11, 13%), preparation (n = 5, 6%), action (n = 2, 2%), and maintenance (n = 39, 45%). Compared to patients in the maintenance stage of change, precontemplators exhibited different demographic and functional characteristics and reported less exercise benefits and more barriers to exercise. Most participants preferred exercising alone (40%), at home (29%), at a moderate intensity (64%), with advice provided by a rheumatologist (34%) or a specialist in exercise and RA (34%). Walking was by far the preferred type of exercise, in both the summer (86%) and the winter (51%). CONCLUSIONS: Our cohort of patients with RA was essentially distributed across the precontemplation and maintenance exercise stages of change. These subgroups of patients exhibit psychological and functional differences that make their needs different in terms of exercise counselling.

[Imaging in osteoarthritis]. / Imagerie et arthrose.

Plain radiography remains useful for the diagnosis of osteoarthritis, even if it is not always essential. It is moreover poorly correlated with symptoms, as it reflects rather the accumulation of damage then active processes. Similarly, it is a poor indicator of the progression of osteoarthritis. Modem imaging, particularly MRI, has allowed us to understand better the evolving processes, demonstrating a good correlation with symptoms and a better predictive value of clinical course. It has gradually replaced standard radiography in the study because it directly demonstrates sequelae and the active processes in all the structures of the joint. It remains clinically indicated only to exclude an alternative diagnosis or to determine a possible complication of osteoarthritis.

Adalimumab in acute sciatica reduces the long-term need for surgery: a 3-year follow-up of a randomised double-blind placebo-controlled trial.

INTRODUCTION: Two subcutaneous injections of adalimumab in severe acute sciatica significantly reduced the number of back operations in a short-term randomised controlled clinical trial. OBJECTIVE: To determine in a 3-year follow-up study whether the short-term benefit of adalimumab in sciatica is sustained over a longer period of time. METHODS: The primary outcome of this analysis was incident discectomy. Three years after randomisation, information on surgery could be retrieved in 56/61 patients (92%).A multivariate Cox proportional hazard models, adjusted for potential confounders, was used to determine factors predisposing to surgery. RESULTS: Twenty-three (41%) patients had back surgery within 3 years, 8/29 (28%) in the adalimumab group and 15/27 (56%) in the placebo group, p=0.04. Adalimumab injections reduced the need for back surgery by 61% (HR)=0.39 (95% CI 0.17 to 0.92). In a multivariate model, treatment with a tumour necrosis factor-α antagonist remained the strongest protective factor (HR=0.17, p=0.002). Other significant predictors of surgery were a good correlation between symptoms and MRI findings (HR=11.6, p=0.04), baseline intensity of leg pain (HR=1.3, p=0.06), intensity of back pain (HR=1.4, p=0.03) and duration of sickness leave (HR=1.01 per day, p=0.03). CONCLUSION: A short course of adalimumab in patients with severe acute sciatica significantly reduces the need for back surgery.

Tranexamic acid in hip fracture surgery: a randomized controlled trial.

BACKGROUND: Hip fracture surgery may be associated with substantial blood loss. This study was designed to assess the efficacy and safety of the use of tranexamic acid in hip fracture surgery for the reduction of erythrocyte transfusion. METHODS: The study pertains to a randomized double-blind study with blinded adjudication of outcomes. Patients requiring surgery for an isolated hip fracture of less than 48 h received saline or tranexamic acid 15 mg kg(-1) given at skin incision and 3 h later. Primary efficacy outcome was erythrocyte transfusion from surgery up to day 8. Transfusion was administered according to a standardized protocol (Hb<9 g dl(-1)). Safety criterion was a composite of symptomatic and asymptomatic vascular events up to 6 weeks. RESULTS: Fifty-seven patients were randomized to tranexamic acid and 53 to placebo. The rate of erythrocyte transfusion was 42% with tranexamic acid and 60% with placebo (P=0.06). Preoperative haemoglobin value, age, and type of surgery were risk factors for erythrocyte transfusion independent of treatment group. The probability of vascular events at 6 weeks was 16% in the tranexamic acid group and 6% in the placebo group (P=0.10). A meta-analysis combining this study with previous trials showed that tranexamic acid significantly reduced erythrocyte transfusion in hip fracture surgery although efficacy was lower than that observed in hip or knee arthroplasty. CONCLUSIONS: In hip fracture surgery, tranexamic acid reduces erythrocyte transfusion but may promote a hypercoagulable state. Thus, further evaluation of safety is required before recommending the off-label use of tranexamic acid.