Length of stay and mortality associated with healthcare-associated urinary tract infections: a multi-state model.

BACKGROUND: The emergence of antimicrobial resistance is of particular concern with respect to urinary tract infections, since the majority of causative agents are Gram-negative bacteria. Healthcare-associated urinary tract infections (HAUTIs) are frequently associated with instrumentation of the urinary tract, specifically with indwelling catheters. AIM: To evaluate the current incidence, mortality, and length of hospital stay associated with HAUTIs. METHODS: A non-concurrent cohort study design was used, conducted between January 1st, 2010 and June 30th, 2014. All patients admitted to one of the eight participating Australian hospitals and who were hospitalized for more than two days were included. The primary outcome measures were the incidence, mortality, and excess length of stay associated with HAUTIs. FINDINGS: From 162,503 patient admissions, 1.73% [95% confidence interval (CI): 1.67-1.80] of admitted patients acquired a HAUTI. Using a multi-state model, the expected extra length of stay due to HAUTI was four days (95% CI: 3.1-5.0 days). Using a Cox regression model, infection significantly reduced the rate of discharge (hazard ratio: 0.78; 95% CI: 0.73-0.83). Women were less likely to die (0.71; 0.66-0.75), whereas older patients were more likely to die (1.40; 1.38-1.43). Death was rarer in a tertiary referral hospital compared to other hospitals, after adjusting for age and sex (0.74; 0.69-0.78). CONCLUSION: This study is the first to explore the burden of HAUTIs in hospitals using appropriate statistical methods in a developed country. Our study indicates that the incidence of HAUTI, in addition to its associated extra length of stay in hospital, presents a burden to the hospital system. With increasing incidence of UTI due to antimicrobial-resistant organisms, surveillance and interventions to reduce the incidence of HAUTI are required.

Comparison of tiletamine and zolazepam pharmacokinetics in tigers (Panthera tigris) and leopards (Panthera pardus): do species differences account for adverse effects in tigers?

Serious post-operative neurological complications of unknown aetiology are reported in tigers after immobilisation using tiletamine and zolazepam. These complications may arise from the persistent effects of tiletamine or active metabolites of tiletamine or zolazepam. Concentrations of tiletamine, zolazepam and some metabolites were measured using high performance liquid chromatography-mass spectrometry in plasma from captive tigers (n = 8) and leopards (n = 9; an unaffected species, for comparison) during anaesthesia for routine clinical procedures. The zolazepam:tiletamine (Z:T) ratio was calculated. Peak concentrations occurred at 9-33 min and ranged from 83.5 to 379.2 ng/mL for tiletamine and 301.1 to 1239.3 ng/mL for zolazepam after correction for dose by weight. There were no significant differences between tigers and leopards. The Z:T ratio was generally <5 and did not differ between species. In both tigers and leopards, zolazepam metabolism appeared to be primarily via demethylation. There was evidence for hydroxylation in leopards, but much less in tigers than leopards. No major differences between the species in parent pharmacokinetics were identified. The metabolism of tiletamine could not be defined with any degree of certainty for either species.

Neuraxial block, death and serious cardiovascular morbidity in the POISE trial.

BACKGROUND: This post hoc analysis aimed to determine whether neuraxial block was associated with a composite of cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal cardiac arrest within 30 days of randomization in POISE trial patients. METHODS: A total of 8351 non-cardiac surgical patients at high risk of cardiovascular complications were randomized to ß-blocker or placebo. Neuraxial block was defined as spinal, lumbar or thoracic epidural anaesthesia. Logistic regression, with weighting using estimated propensity scores, was used to determine the association between neuraxial block and primary and secondary outcomes. RESULTS: Neuraxial block was associated with an increased risk of the primary outcome [287 (7.3%) vs 229 (5.7%); odds ratio (OR), 1.24; 95% confidence interval (CI), 1.02-1.49; P=0.03] and MI [230 (5.9%) vs 177 (4.4%); OR, 1.32; 95% CI, 1.07-1.64; P=0.009] but not stroke [23 (0.6%) vs 32 (0.8%); OR, 0.76; 95% CI, 0.44-1.33; P=0.34], death [96 (2.5%) vs 111 (2.8%); OR, 0.87; 95% CI, 0.65-1.17; P=0.37] or clinically significant hypotension [522 (13.4%) vs 484 (12.1%); OR, 1.13; 95% CI, 0.99-1.30; P=0.08]. Thoracic epidural with general anaesthesia was associated with a worse primary outcome than general anaesthesia alone [86 (12.1%) vs 119 (5.4%); OR, 2.95; 95% CI, 2.00-4.35; P<0.001]. CONCLUSIONS: In patients at high risk of cardiovascular morbidity, neuraxial block was associated with an increased risk of adverse cardiovascular outcomes, which could be causal or because of residual confounding.

Real time monitoring of propofol blood concentration in ponies anaesthetized with propofol and ketamine.

This study examined the pharmacokinetics of propofol by infusion in ponies using an analyser for the rapid measurement of propofol concentrations. The analyser (Pelorus 1000; Sphere Medical Ltd., Cambridge, UK) has a measurement cycle of approximately five minutes. Ten Welsh-cross ponies (weighing 135-300 kg) undergoing minor procedures were studied after premedication with acepromazine 0.03 mg/kg and detomidine 0.015 mg/kg. Anaesthesia was induced with ketamine 2 mg/kg and diazepam 0.03 mg/kg, and maintained with an infusion of propofol at an initial rate of 0.16 mg/kg/min for the first thirty minutes, after a bolus of 0.3 mg/kg; and ketamine by infusion (20-40 µg/kg/min). Blood samples (<2 mL) were collected prior to, during and after the infusion, and on assuming standing position. Anaesthesia was uneventful; with the duration of infusion 31-89 min. Blood propofol concentrations during the infusion ranged between 1.52 and 7.65 µg/mL; pseudo-steady state concentrations 3.64-6.78 µg/mL, and concentrations on assuming standing position 0.75-1.40 µg/mL. Propofol clearance and volume of distribution were 31.4 (SD 6.1) mL/min/kg and 220.7 (132.0) mL/kg, respectively. The propofol analyser allows titration of propofol to a given concentration; and may be useful for anaesthesia in animals where kinetics are unknown; in disease states; and where intercurrent therapies affect propofol disposition.

Comparative molecular field analysis to derive pharmacophore maps for disposition parameters of intravenous anaesthetic agents.

BACKGROUND: The present study examines the molecular basis of the disposition kinetics for i.v. hypnotic agents using comparative molecular field analysis (CoMFA). METHODS: The systemic clearance (Cl(s) litre min(-1)) and apparent volume of distribution at steady state (Vd(ss) litres) for 14 i.v. anaesthetics in human subjects were obtained from the literature, or from unpublished data, and used to form CoMFA models for the two aspects of drug disposition. Molecular alignment was achieved by field-fit minimization with the lead structure for all models eltanolone. The resulting pharmacophore maps were also compared with the pharmacophores for cardiovascular depression (expressed in terms of the drug concentration in 50% patients, associated with a 20% decrease in mean arterial pressure during infusion anaesthesia in the absence of other adjuvant drugs or noxious stimulation), which were taken from the literature. RESULTS: The CoMFA model for Cl was based on two latent variables, explained 95.2% of the variance in observed activities, and showed good intrinsic predictability (cross-validated q(2) 0.663). The model for Vd(ss) was also based on two latent variables: r(2) 0.986 and q(2) 0.718. Comparison of the pharmacophores for the two disposition parameters showed poor correlation for both electrostatic and steric regions (r=-0.220 and 0.018; both NS). The relative contributions of electrostatic and steric interactions differed between the models (Cl(s) 1.9:1; Vd(ss) 2.5:1). Comparison with the cardiovascular pharmacophores depression models gave r values of 0.551 (P<0.05) and 0.407 (ns) for Cl(s) (for electrostatic and steric models) and -0.225 and -0.448 for Vd(ss) (both ns). CONCLUSIONS: Comparison of CoMFA models for drug disposition show only small elements of commonality, suggesting different molecular features may be responsible are two properties. There was better similarity for both disposition pharmacophores with the pharmacophores for cardiovascular depression.

Comparative molecular field analysis to derive pharmacophore maps for induction doses of intravenous anaesthetic agents.

BACKGROUND: The present study examines the molecular basis of induction of anaesthesia by i.v. hypnotic agents using comparative molecular field analysis (CoMFA). METHODS: ED(50) induction doses for 14 i.v. anaesthetics in human subjects (expressed as molar dose per kilogram body weight) were obtained from the literature. Immobilizing potency data for the same 14 agents (expressed as the EC(50) plasma free drug concentrations that abolish movement in response to a noxious stimulus in 50% patients) were taken from our previous publication. These data were used to form CoMFA models for the two aspects of anaesthetic activity. Molecular alignment was achieved by field-fit minimization techniques. The lead structure for both models was eltanolone. RESULTS: The final CoMFA model for the ED(50) induction dose was based on two latent variables, and explained 99.3% of the variance in observed activities. It showed good intrinsic predictability (cross-validated q(2)=0.849). The equivalent model for immobilizing activity was also based on two latent variables, with r(2)=0.988 and q(2)=0.852. Although there was a correlation between -log ED(50) and -log EC(50) (r(2)=0.779), comparison of the pharmacophore maps showed poor correlation for both electrostatic and steric regions when isocontours were constructed by linking lattice grid points, making the greatest 40% contributions; the relative contributions of electrostatic and steric interactions differing between the models (induction dose: 2.5:1; immobilizing activity 1.8:1). CONCLUSIONS: Comparison of two CoMFA activity models shows only small elements of commonality, suggesting that different molecular features may be responsible for these two properties of i.v. anaesthetics.

Development of pharmacophoric maps for cardiovascular depression by intravenous anaesthetic agents: comparison with maps for immobilizing activity.

BACKGROUND: The molecular basis of the cardiovascular effects of i.v. anaesthetics was investigated using comparative molecular field analysis (CoMFA). METHODS: The cardiovascular effects, measured as changes in mean arterial pressure (MAP), compared with awake values of continuous infusions of 13 structurally diverse i.v. anaesthetics were compared at EC(50) plasma concentrations, and by determination of plasma-free drug concentrations associated with a 20% decrease in MAP (dMAP(20)). Data were obtained both from the literature and from unpublished data of the author. The results were fitted to a CoMFA activity model using field-fit minimization techniques to maximize similarities in molecular bulk and electrostatic potential to the lead compound, eltanolone. RESULTS: The final model for cardiovascular depression based on free drug concentrations associated with dMAP(20) explained 95.8% of the variance in observed activities, with a cross-validated q(2) of 0.824 (n=12). A second model based on change in MAP at EC(50) plasma concentrations explained 98.3% of the variance in arterial pressure, but performed poorly at cross-validation (q(2) 0.526). The comparative model for immobilizing potency had an r(2) value of 0.987 and q(2) 0.823. Comparison of pharmacophoric maps showed several key electrostatic and steric regions common to both models when isocontours were constructed linking lattice grid points, making the greatest 40% contributions (87.57% for electrostatic fields and 86.16% for steric fields). CONCLUSIONS: Comparison of activity models for cardiovascular depression and immobilizing potency for i.v. anaesthetics shows significant commonality, suggesting that it may not be possible to separate those molecular features associated with each of these effects.

What makes a molecule an anaesthetic? Studies on the mechanisms of anaesthesia using a physicochemical approach.

Recent studies of mechanisms of anaesthesia have been mainly 'target orientated', investigating the activity of both volatile and i.v. agents at putative sites of action. An alternative approach is one that is 'ligand orientated', focusing on the properties of molecules that define their immobilizing ability and secondly define their potency. The use of conventional descriptors (such as non-polar solubility or the octanol-water partition coefficient [Log P]) are limited in their utility as predictors of potency as they represent three-dimensional molecular properties as a one-dimensional parameter. Using different computer-based molecular modelling methods (molecular similarity studies and comparative molecular field analysis [CoMFA]), we have identified the molecular bases of the activity of structurally diverse anaesthetics, such that they can be described as a single model based on the spatial distribution of molecular bulk and electrostatic potential. The same approach can also be used to model other properties of anaesthetic agents, such as cardiovascular depression. The present data suggest that, for the i.v. agents, it may be difficult to separate immobilizing (anaesthetic) activity and cardiovascular depression within a single molecule.

Meta-analysis of the effect of heart rate achieved by perioperative beta-adrenergic blockade on cardiovascular outcomes.

BACKGROUND: Acute perioperative beta-adrenergic blockade may be cardioprotective in the high-risk cardiac patient for major non-cardiac surgery. We have investigated the association between the heart rate achieved with perioperative beta-blockade and the incidence of perioperative cardiac complications. METHODS: We identified eight randomized studies (1931 patients) reporting acute perioperative beta-blockade and major perioperative cardiovascular outcomes after non-cardiac surgery. The mean heart rates within the first 72 h after operation were analysed. A meta-analysis of means was conducted using a random effects model. A bivariate correlation analysis was conducted using Spearman's correlation coefficient to assess for an association between the mean postoperative heart rate and the 30 day cardiac outcomes. RESULTS: Acute perioperative beta-blockade did not significantly reduce 30 day cardiac death [odds ratio (OR) 0.35, 95% confidence interval (CI) 0.08-1.52] or non-fatal myocardial infarction (OR 0.90, 95% CI 0.52-1.56) in the studies with adequate methodology. The mean (95% CI) heart rate was 73 (71-74) beats min(-1) in the beta-blockade group, which was significantly lower than the placebo group (mean heart rate 82, P=0.0001). There was no correlation between heart rate and 30 day cardiac complications (P=0.848). The reduction in heart rate was associated with increased drug-associated adverse events (OR 2.53, 95% CI 2.05-3.13, P<0.0001). A major limitation of this analysis may be that postoperative heart rate was not a primary outcome in any of the studies identified and the mean postoperative heart rate achieved may be too high to realize optimal cardioprotection. CONCLUSION: This meta-analysis cannot confirm that heart rate control with beta-adrenergic blockade is cardioprotective. A randomized controlled trial examining the effect of tight perioperative heart rate control with beta-adrenergic blockade on clinically important outcomes and adverse events is warranted.

Use of a transdermal matrix patch of buprenorphine in cats: preliminary pharmacokinetic and pharmacodynamic data.

Six domestic shorthair cats, aged three to four years and weighing 5.1 to 7.4 kg, were used to assess the thermal antinociceptive effect of a transdermal buprenorphine patch, designed to supply 35 mug buprenorphine/hour, which was applied to the shaved thorax. The cats' thermal thresholds were tested before the patch was applied and two, four, six, eight, 10, 12, 14 and 16 hours after it had been applied, and then every six hours until it was removed after 72 hours, and for a further 24 hours afterwards. Blood was collected at each time to measure the plasma concentration of buprenorphine. The patches did not produce a significant change in the thermal thresholds of the cats throughout the testing period. The mean (sd) peak plasma buprenorphine concentration was 10 (0.81) ng/ml.

Coronary artery stents and non-cardiac surgery.

The utility of interventional cardiology has developed significantly over the last two decades with the introduction of coronary angioplasty and stenting, with the associated antiplatelet medications. Acute coronary stent occlusion carries a high morbidity and mortality, and the adoption of therapeutic strategies for prophylaxis against stent thrombosis has major implications for surgeons and anaesthetists involved in the management of these patients in the perioperative period. Currently, there is limited published information to guide the clinician in the optimal care of patients who have had coronary stents inserted when they present for non-cardiac surgery. This review examines the available literature on the perioperative management of these patients. A number of key issues are identified: the role of surgery vs percutaneous coronary intervention for coronary revascularization in the preoperative period; the different types of coronary stents currently available; the emerging issues related to drug-eluting stents; the pathophysiology of coronary stent occlusion; and the recommended antiplatelet regimes that the patient with a coronary stent will be receiving. The role of preoperative platelet function testing is also discussed, and the various available tests are listed. Appropriate management by all the clinicians involved with patients with coronary stents undergoing a variety of non-cardiac surgical procedures is essential to avoid a high incidence of postoperative cardiac mortality and morbidity. The review examines the evidence available for the perioperative strategies aimed at reducing adverse outcomes in a number of different clinical scenarios.

The pharmaco-economics of peri-operative beta-blocker and statin therapy in South Africa.

We conducted a pharmaco-economic analysis of the prospective peri-operative studies of beta-blocker and statin administration for major elective non-cardiac surgery, using the Discovery Health claims costs for 2004. This analysis shows that acute peri-operative beta-blockade and statin therapy could result in a cost saving through a reduction in major perioperative cardiovascular complications in patients with an expected peri-operative major cardiovascular complication rate exceeding 10% following elective major non-cardiac surgery. The validity of these findings is dependent on whether the incidence of cardiovascular complications following major noncardiac surgery reported in the international literature is found to be similar in South Africa.