Intra-operative protective mechanical ventilation in lung transplantation: a randomised, controlled trial.

Primary graft dysfunction occurs in up to 25% of patients after lung transplantation. Contributing factors include ventilator-induced lung injury, cardiopulmonary bypass, ischaemia-reperfusion injury and excessive fluid administration. We evaluated the feasibility, safety and efficacy of an open-lung protective ventilation strategy aimed at reducing ventilator-induced lung injury. We enrolled adult patients scheduled to undergo bilateral sequential lung transplantation, and randomly assigned them to either a control group (volume-controlled ventilation with 5 cmH2 O, positive end-expiratory pressure, low tidal volumes (two-lung ventilation 6 ml.kg-1 , one-lung ventilation 4 ml.kg-1 )) or an alveolar recruitment group (regular step-wise positive end-expiratory pressure-based alveolar recruitment manoeuvres, pressure-controlled ventilation set at 16 cmH2 O with 10 cmH2 O positive end-expiratory pressure). Ventilation strategies were commenced from reperfusion of the first lung allograft and continued for the duration of surgery. Regular PaO2 /FI O2 ratios were calculated and venous blood samples collected for inflammatory marker evaluation during the procedure and for the first 24 h of intensive care stay. The primary end-point was the PaO2 /FI O2 ratio at 24 h after first lung reperfusion. Thirty adult patients were studied. The primary outcome was not different between groups (mean (SD) PaO2 /FI O2 ratio control group 340 (111) vs. alveolar recruitment group 404 (153); adjusted p = 0.26). Patients in the control group had poorer mean (SD) PaO2 /FI O2 ratios at the end of the surgical procedure and a longer median (IQR [range]) time to tracheal extubation compared with the alveolar recruitment group (308 (144) vs. 402 (154) (p = 0.03) and 18 (10-27 [5-468]) h vs. 15 (11-36 [5-115]) h (p = 0.01), respectively). An open-lung protective ventilation strategy during surgery for lung transplantation is feasible, safe and achieves favourable ventilation parameters.

The International Collaboration of Orthopaedic Nursing: advancing nursing through technology.

AIM: To report on the International Collaboration of Orthopaedic Nursing, a mostly virtual network of orthopaedic nursing organizations across four continents. BACKGROUND: Formed by leaders of three national associations, the collaboration is based on recognition of patient problems and challenges shared by orthopaedic nurses globally. METHODS/INITIATIVES: The Collaboration provides a range of services including education, mentoring, and organizational development. Low cost internet-based technologies, such as email and Skype, support global networking in real time. DISCUSSION/IMPLICATIONS FOR NURSING AND HEALTH POLICY: The Collaboration is a cost effective example of how nurses can collaborate internationally to promote the highest standards of orthopaedic nursing.

Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and pioglitazone on glycemic control and measures of ß-cell function in patients with type 2 diabetes.

AIM/HYPOTHESIS: To assess the safety and efficacy of initial combination therapy with sitagliptin and pioglitazone compared with pioglitazone monotherapy in drug-naïve patients with type 2 diabetes. METHODS: A total of 520 patients were randomised to initial combination therapy with sitagliptin 100 mg q.d. and pioglitazone 30 mg q.d. or pioglitazone 30 mg q.d. monotherapy for 24 weeks. RESULTS: Initial combination therapy with sitagliptin and pioglitazone led to a mean reduction from baseline in A1C of -2.4% compared with -1.5% for pioglitazone monotherapy (p<0.001). Mean reductions from baseline were greater in patients with a baseline A1C≥10% (-3.0% with combination therapy vs. -2.1% with pioglitazone monotherapy) compared with patients with a baseline A1C<10% (-2.0% with combination therapy vs. -1.1% with pioglitazone monotherapy). Sixty percent of patients in the combination therapy group vs. 28% in the pioglitazone monotherapy group had an A1C of <7% at week 24 (p<0.001). Fasting plasma glucose decreased by -63.0 mg/dl (-3.5 mmol/l) in the combination therapy group compared with -40.2 mg/dl (-2.2 mmol/l) for pioglitazone monotherapy (p<0.001), and 2-h post meal glucose decreased by -113.6 mg/dl (-6.3 mmol/l) with combination therapy compared with -68.9 mg/dl (-3.8 mmol/l) for pioglitazone monotherapy (p<0.001). Measures related to ß-cell function also improved significantly with combination therapy compared with pioglitazone monotherapy. Combination therapy was generally well-tolerated compared with pioglitazone monotherapy, with similar incidences of hypoglycemia (1.1% and 0.8%, respectively), gastrointestinal adverse events (5.7% and 6.9%, respectively), and oedema (2.7% and 3.5%, respectively). CONCLUSION/INTERPRETATION: Initial combination therapy with sitagliptin and pioglitazone substantially improved glycemic control and was generally well-tolerated compared with pioglitazone monotherapy.

A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: a high-dose study.

OBJECTIVE: To evaluate the efficacy, safety and tolerability of taranabant in obese and overweight patients. DESIGN: Double-blind, randomized, placebo-controlled study. SUBJECTS: Patients were >or=18 years old, with body mass index of 27-43 kg m(-2), and 51% with metabolic syndrome (MS) randomized to placebo (N=417) or taranabant 2 mg (N=414), 4 mg (N=415) or 6 mg (N=1256) for 104 weeks. MEASUREMENTS: Key efficacy measurements included body weight, waist circumference (WC), lipid and glycemic end points. RESULTS: On the basis of risk/benefit assessments, the 6-mg dose was discontinued during year 1 (patients on 6 mg were down-dosed to 2 mg or placebo) and the 4-mg dose was discontinued during year 2 (patients on 4 mg were down-dosed to 2 mg). Changes from baseline in body weight at week 52 (all-patients-treated population, last observation carried forward analysis) were -2.6, -6.6 and -8.1 kg, respectively, for placebo and taranabant 2 and 4 mg (both doses P<0.001 vs placebo). For patients who completed year 1, changes from baseline in body weight at week 104 were -1.4, -6.4 and -7.6 kg for placebo and taranabant 2 and 4 mg, respectively (both doses P<0.001 vs placebo). The proportions of patients at weeks 52 and 104 who lost at least 5 and 10% of their baseline body weight were significantly higher and the proportions of patients who met criteria for MS were significantly lower for taranabant 2 and 4 mg vs placebo. The incidence of adverse experiences classified in the gastrointestinal, nervous, psychiatric, cutaneous and vascular organ systems were generally observed to be dose related with taranabant vs placebo. CONCLUSION: Taranabant at the 2- and 4-mg dose was effective in achieving clinically significant weight loss over 2 years and was associated with dose-related increases in adverse experiences. On the basis of these and other data, an assessment was made that the overall safety and efficacy profile of taranabant did not support its further development for the treatment of obesity.

Long-term results of surgery for lithium-associated hyperparathyroidism.

BACKGROUND: Lithium therapy for affective bipolar disease is frequently associated with hyperparathyroidism (HPT), but the results of surgical treatment are virtually unknown. The aim of this retrospective review was to analyse the long-term outcome after surgery for lithium-induced HPT in a large series of patients. METHODS: Seventy-one patients on chronic lithium therapy who underwent surgery in three university and three district hospitals in Sweden were followed for a median of 6.3 years. Histopathology, complications of surgery and normocalcaemia at 6 months after surgery and last follow-up were analysed. RESULTS: The primary histopathological diagnoses were adenoma (45 per cent), double adenomas (3 per cent) and hyperplasia (52 per cent). No permanent paresis of the recurrent laryngeal nerve was recorded but 13 per cent of the patients suffered from permanent hypoparathyroidism. At follow-up, the rate of persistent and recurrent HPT was 42 per cent regardless of the histopathological diagnosis. CONCLUSION: The results of conventional surgery for lithium-associated HPT are poor. The surgical approach should be adjusted for the multiglandular disease that is usually the cause of HPT in patients on chronic lithium therapy.

Do patients with heart failure appropriately undergo invasive procedures post-myocardial infarction? Results from a prospective multicentre study.

BACKGROUND: The degree of adherence to guideline recommendations that patients following myocardial infarction (MI) with congestive heart failure (CHF) undergo early angiography, and angioplasty if indicated, is unknown. METHODS: We prospectively evaluated the use of invasive procedures in patients with segment-elevation myocardial infarction (STEMI), non-STEMI and CHF, admitted in 1 month to 16 Australian hospitals. RESULTS: Of 475 post-MI patients (248 (52.2%) with STEMI), 112 (23.6%) had CHF, (57 (23.0%) with STEMI). Patients with CHF, compared with those without CHF, were older (67.8 vs 63.2 years; P = 0.002) and were more often women (34 vs 24%, P = 0.03), but had similar rates of other risk factors. Compared with post-MI patients without CHF, patients with CHF had fewer invasive procedures: angiography 72.3% versus 85.1% (P = 0.002) and angioplasty 33.9% versus 52.9% (P < 0.001) (12 (2.5%) patients underwent coronary surgery in-hospital); and among STEMI patients (angiography 72.3% CHF vs 89.5% no CHF [P < 0.001]; angioplasty 50.9% CHF vs 69.1% no CHF [P = 0.011]); these differences remained significant after adjustment for clinical covariates. Of the 121 (25.5%) post-MI patients aged > or =75 years, compared with those <75 years, the frequencies of angiography and angioplasty procedures were 66.1% versus 87.6% (P < 0.001) and 33.9% versus 53.4% (P < 0.001), respectively; 66% of the elderly with, and without, CHF had angiography. CONCLUSION: The presence of CHF post-MI resulted in lower rates of use of angiography and angioplasty, which was not explained by lower procedure rates in the elderly. As these guideline-recommended procedures may improve survival in patients with CHF post-MI, future strategies should aim to enhance their use.

A new model to evaluate the long-term cost effectiveness of orphan and highly specialised drugs following listing on the Australian Pharmaceutical Benefits Scheme: the Bosentan Patient Registry.

BACKGROUND: Pharmaceutical subsidy schemes are under increasing pressure to evaluate the cost effectiveness of new highly specialised and orphan drugs for universal subsidy. In the absence of longer-term outcome data, drug sponsors often present modelled data, which can carry a significant level of uncertainty over longer-term projections. Risk-sharing schemes between drug sponsor and government may provide an acceptable method of balancing the uncertainty of longer-term cost effectiveness with the public demand for equitable and timely access to new drugs. METHODS: The Bosentan Patient Registry (BPR) is an example of a unique risk-sharing model utilised in Australia aiming to provide clinical evidence to support the modelled predictions, with the registry survival outcomes linked to future price. Concomitant medication, health and vital status data was collected from clinicians, government health departments and death registries. RESULTS: The BPR has identified a number of issues surrounding registry governance, ethics and patient privacy, and the collection of timely and accurate data, which need to be addressed for the development of a generic registry model for systematic evaluation. CONCLUSION: The success of a generic drug registry model based on the BPR will be enhanced by addressing a number of operational issues identified during the implementation of this project.

Effect of treatment with biological agents for arthritis in Australia: the Australian Rheumatology Association Database.

BACKGROUND: The Australian Rheumatology Association Database (ARAD), a voluntary national registry, has been established to collect health information from Australian patients with inflammatory arthritis for the purpose of monitoring the benefits and safety of new treatments, in particular the biological disease-modifying anti-rheumatic drugs (bDMARDs). These drugs are proving to be very effective, yet little is known of their long-term effectiveness or safety. Patient registries that systematically gather data on large cohorts of unselected patients are increasingly believed to be an essential means of answering questions of the long-term effectiveness and safety of new drugs. The aim of this report is to describe the role, development and structure of ARAD and provide some preliminary data. METHODS: As of 1 August 2006, 563 patients with rheumatoid arthritis prescribed a bDMARD have been enrolled in ARAD, involving 105 rheumatologists from across Australia. RESULTS: The data collected will enable examination of multiple domains of patient responses to bDMARDs, including quality of life, health-care utilization, incidence of adverse events and the effects of therapy switching. CONCLUSION: Evidence-based information about the long-term outcome of bDMARD therapy is essential for clinicians, consumers, policy-makers, drug development companies and approval agencies, to enable better care and improved outcomes for patients with inflammatory arthritis.

Outcome of penicillin-susceptible streptococcal prosthetic joint infection treated with debridement and retention of the prosthesis.

Debridement with retention of the prosthesis was the initial treatment modality for 19 cases of penicillin-susceptible streptococcal prosthetic joint infection that occurred in 18 patients who presented to the Mayo Clinic (Rochester, Minnesota) during 1969-1998. All of the cases of prosthetic joint infection occurred >30 days after implantation of the prosthesis, which was well fixed at the time of debridement. The median duration of symptoms before debridement was 4 days (range, 1-10 days). Treatment failure (defined as relapse of infection with the original microorganism) occurred in 2 cases (10.5%) during a median follow-up period of 3.9 years (range, 0.3-21.7 years). The 1-year cumulative risk of relapse was 11% (95% confidence interval, 0%-26%). Relapse of prosthetic joint infection due to penicillin-susceptible streptococci after debridement and retention of the prosthesis is uncommon. For patients who present with a well-fixed prosthesis and a short duration of symptoms, debridement with retention appears to be an effective treatment modality.

Influence of the endothelium on the amplification by serotonin of vasoconstrictor responses to noradrenaline and sympathetic nerve stimulation in rabbit isolated ear artery.

The influence of the vascular endothelium on the amplifying effect of serotonin on steady-state responses to noradrenaline (NA) and sympathetic nerve stimulation (SNS) has been studied in the rabbit isolated ear artery. Removal of the endothelium abolished the dilator effect of acetylcholine (ACh, 1 microM) obtained in the presence of NA (0.3 microM). Responses to NA were increased after endothelium removal; however, responses to SNS were unaffected. Serotonin in a concentration which did not itself produce vasoconstriction (100 nM) increased responses of endothelium-intact preparations to NA and SNS and of endothelium-denuded preparations to SNS but had no effect on NA responses of endothelium-denuded preparations. If neuronal uptake was inhibited with cocaine (1 microM), serotonin markedly amplified responses to NA and SNS in both endothelium-intact and endothelium-denuded preparations. These results suggest that the endothelium influences the amplifying effect of serotonin on responses of rabbit ear artery to NA but not to SNS. Inhibition of removal of serotonin and NA by neuronal uptake may extend the facilitatory interaction between NA and serotonin to smooth muscle cells which are not subject to the inhibitory influence of an endothelium derived relaxing factor.

CCKA receptors mediate slow depolarizations in cultured mammalian sympathetic neurons.

The effect of cholecystokinin octapeptide (CCK-8) was examined in guinea-pig celiac ganglion (CG) neurons in primary culture using standard intracellular recording techniques. Sulfated CCK-8 (CCK-8S; 1 microM) evoked slow depolarizing responses in 94% of CG neurons tested. In contrast, membrane potential was not affected by nonsulfated CCK-8 (CCK-8NS; 1 microM), CCK tetrapeptide (CCK-4; 1 microM), or gastrin (1 microM). The selective CCKA receptor antagonist L 364,718 potently inhibited CCK-8S-induced slow depolarizations (IC50 2.9 pM). In contrast, the selective CCKB receptor antagonist L 365,260 was a weak inhibitor of CCK-8S-induced slow depolarizations (IC50 1.3 microM). The depolarizing responses to CCK-8S were associated with an average increase in cell input resistance of 61%. Single electrode voltage clamp experiments indicated that CCK-8S-induced depolarizations were associated with a slow inward shift in holding current. Thus, the present findings indicate that guinea-pig cultured CG neurons are endowed with excitatory CCKA receptors the activation of which elicits a decrease in membrane conductance, thereby resulting in slow depolarizations.

Variable influence of heparin and contrast agents on platelet function as assessed by the in vitro bleeding time.

Both heparin and contrast agents have anticoagulant effects which are well-documented but their effects on platelets are not well-characterized. The purpose of the present study was to evaluate the sequential effects of heparin and then a contrast agent on platelet function during an angiographic procedure. Blood samples from 54 patients were obtained at baseline, after a 5000 unit bolus of heparin and after administration of a contrast agent (iohexol, n = 30: diatrizoate, n = 24) during angiography. The in vitro bleeding time (IVBT) was determined on nonanticoagulated whole blood using a hollow fiber device under physiological flow conditions. Mean IVBT at baseline was 3.6 +/- 2.7 minutes and increased to 17.0 +/- 12.3 minutes after heparin (p < 0.01). After heparin, 44.5% of the patients still had a normal IVBT (< 9.0 minutes), 11% of the patients had a moderately increased IVBT and the remaining patients had a large increase in their IVBT. When contrast was given (167 +/- 52 mls) following heparin, mean IVBT was higher in those who received diatrizoate (23.3 +/- 9.4 minutes) compared with iohexol (15.0 +/- 10.9 minutes, p < 0.05). However, 15 patients (28%) continued to have a normal IVBT after contrast and of these 80% had received iohexol.

Involvement of Ca2+ mobilization in the amplifying effect of serotonin on responses of rabbit isolated ear artery to exogenous noradrenaline.

The present study examined the involvement of Ca2+ mobilization in the amplifying effect of serotonin on steady-state responses of rabbit isolated perfused ear artery to exogenous noradrenaline (NA; 0.001-3 mumol/l). In contrast to its marked amplifying effect on responses to NA, serotonin in the subconstrictor concentration of 100 nmol/l had no effect on responses to KCl. The Ca2+-entry blocking drug diltiazem (10 mumol/l) decreased responses to NA; in addition, the amplifying effect of serotonin on responses to NA was reduced by diltiazem. Lowering the concentration of Ca2+ in the Krebs-Henseleit perfusion solution from 2.5 to 0.25 mmol/l also reduced both responses to NA and the amplifying effect of serotonin. Using the method of Manzini et al. (1982), separate intra- and extracellular Ca2+-dependent responses to NA were obtained. Serotonin had no effect on intracellular Ca2+-dependent responses to NA but enhanced extracellular Ca2+-dependent NA responses. These results suggest that the amplifying effect of serotonin on responses of rabbit ear artery to exogenous NA involves a selective enhancement of the component of the NA response which is dependent on extracellular Ca2+; serotonin may increase NA-evoked entry of Ca2+ into the vascular smooth muscle cells through receptor-operated Ca2+ channels.

A clinical pathway for the secondary diagnosis of alcohol misuse: implications for the orthopaedic patient.

This article presents the process of developing a method of routine identification, assessment, intervention, and follow-up for the trauma patient with a concomitant diagnosis of alcohol misuse. A clinical pathway approach to addressing the needs of the alcohol misuser is outlined, and an alternative method that adapts this approach to other settings is also presented. Ever mindful of decreasing lengths of stay and reimbursement predicated on diagnosis-related groups, this pathway is tailored to overlay onto an existing clinical path of care so as not to increase length of stay nor duplicate services.

The foundation and launch of the Melbourne Interventional Group: a collaborative interventional cardiology project.

The Melbourne Interventional Group (MIG) is a voluntary collaborative venture of interventional cardiologists practicing at 12 major public and private hospitals in Victoria, designed to record data pertaining to percutaneous coronary interventions (PCI) and perform long-term follow-up. The potential advantages of collaboration involve large-scale analysis of current interventional strategies (e.g. drug-eluting stents, evaluation of new technologies and cost-effective analysis), provide a basis for multi-centred clinical trials and allow comparison of clinical outcomes with cardiac surgery. The established registry documents demographic, clinical and procedural characteristics of consecutive patients undergoing PCI and permits analysis of those characteristics at 30 days and 12 months. The registry is co-ordinated by the Centre of Clinical Research Excellence (CCRE), a research body within the Department of Epidemiology and Preventive Medicine (Monash University, Melbourne). The eventual goal of MIG is to provide a contemporary appraisal of Australian interventional cardiology practice, with opportunities to improve in-hospital and long-term outcomes of patients with coronary artery disease.