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BACKGROUND Previous formulations of alfaxalone have shown it to be a fast-acting intravenous anesthetic with high therapeutic index. Alfaxalone has been reformulated for human use as Phaxan, an aqueous solution of 10 mg/mL of alfaxalone and 13% betadex. This study assessed the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of alfaxalone given as a bolus intravenous injection of this formulation to human male volunteers. METHODS A dose of 0.5 mg/kg (0.42-0.55 mg/kg) of alfaxalone [mean (range)] was given by single intravenous bolus injection to 12 healthy subjects. Plasma alfaxalone concentrations and bispectral index (BIS) values were analyzed using an integrated pharmacokinetic-pharmacodynamic (PKPD) model using nonlinear mixed-effects models. Effect (BIS) was described using a sigmoidal fractional maximum effect (EMAX) model. All parameters were scaled using allometry and standardized to a 70-kg person using exponents of 0.75 for clearance parameters (CL, Q2, and Q3), 1.0 for volumes (V1, V2, and V3), and 0.25 for time-related parameters half-time keo (t1/2keo). RESULTS A 3-compartment model used to fit PK data with an additional compartment, linked by t1/2keo to describe the effect compartment, yielded alfaxalone PK parameter estimates: CL: 1.08 L/min; 0.87-1.34 L/min (median; 95% confidence interval [CI]); central volume of distribution (V1): 0.99 L; 0.53-2.05 L (median; 95% CI); intercompartment CLs (Q2): 0.87 L/min; 0.32-1.71 L/min (median; 95% CI) and Q3: 0.46 L/min; 0.19-1.03 L/min (median; 95% CI); and peripheral volumes of distribution (V2): 6.36 L; 2.79-10.7 L (median; 95% CI) and V3: 19.1 L; 8.61-37.4 L (median; 95% CI). PD interrogation assumed a baseline BIS of 96, with an estimated EMAX: 0.94; 0.71-0.99 (median; 95% CI), a plasma concentration (Cp) for 50% effect (C50): 0.98 mg/L; 0.83-1.09 mg/L (median; 95% CI), and a Hill coefficient (γ): 12.1; 6.7-15 (median; 95% CI). The t1/2keo was 8 minutes; 4.70-12.8 minutes (median; 95% CI). The mean time to a BIS 50 was 0.94 minutes (standard deviation [SD] = 0.2 minutes). CONCLUSIONS After a single bolus intravenous injection, alfaxalone has a high plasma CL equal to hepatic blood flow as reported for earlier studies of bolus injections of a previous formulation of alfaxalone. The plasma levels associated with BIS values of

Purpose of review The current review examines the success and failures of the development of new hypnotic compounds for the human market. One of the important aspects is that one of the key present agents, propofol, is considered by many anaesthesiologists as 'the ideal'. However, all drugs have adverse or side-effects. Recent findings The last 30 years since the introduction of propofol has seen many new compounds evaluated; but as at the present time, only three agents may achieve a pivotal position in the market - fospropofol (a sedative agent which may have a role in endoscopic surgery); remimazolam (a short-acting benzodiazepine) whose development is also being focused on the sedation rather than anaesthesia market; and the pregnane steroid, alfaxalone (an anaesthetic agent first introduced in 1972, but withdrawn in 1984 because of adverse allergic reactions to the solvent, Cremophor EL) now solvented in a cyclodextrin. Summary Studies of these three agents thus far have shown that none of them has any major adverse side-effects; all have properties which warrant further clinical evaluation.

Hypertension is a prevalent chronic disease associated with significant morbidity; early treatment is indicated to reduce end-organ damage and associated morbidity and mortality. First line treatments include diuretics, calcium channel blockers, and antagonists of the adrenergic system; other important classes of antihypertensive drugs include antagonists of the renin-angiotensin system and vasodilators. These drugs have distinct mechanisms of action, and are frequently used in combination. All have side effects, largely cardiovascular, and important drug interactions that must be considered in the perioperative period.

Background The association between preinduction blood pressure (BP) and postoperative outcomes after noncardiac surgery is poorly understood. Whether this association depends on the presence of risk factors for poor cardiovascular outcomes remains unclear. Accordingly, we evaluated the association between preinduction BP and its different components; isolated systolic hypertension (ISH) and wide pulse pressure (WPP), and postoperative complications in patients with and without revised cardiac risk index (RCRI) components. Methods We analysed consecutive patients undergoing elective noncardiac surgery at Cleveland Clinic. Separate analyses were undertaken for patients with and without any RCRI components. Preinduction BP was assessed both continuously and according to hypertension stages. Logistic regression was used to assess the association between the BP values and composite of in-hospital mortality as well as cardiovascular, renal, and neurologic morbidity. We considered the following potential confounding factors in our analysis; year of surgery, age, sex, race, BMI, and American College of Cardiology/American Heart Association surgical procedure risk classification. Results Of 58 276 patients, 10 512 had one or more RCRI components. For those with no RCRI, no significant relationship was found between preinduction BP and outcome after adjustment for confounders. For patients with RCRI, the adjusted incidence was the greatest among those with normal preinduction SBP and DBP of less than 70 mmHg. Among patients with preinduction DBP greater than 75 mmHg, risk rose slightly with increasing SBP. However, we found no association between preinduction hypertension stages, ISH, or WPP and the composite outcome in patients with and without RCRI. Conclusion Preinduction low DBP less than 70 mmHg or SBP greater than 160 mmHg and not ISH, nor WPP were associated with an increased risk of postoperative complications in noncardiac surgery patients with one or more RCRI components.

Objectives To evaluate the potential benefits of high-dose buprenorphine formulations for analgesia in cats, serial and crossover studies were undertaken to investigate their pharmacokinetics and thermal antinociceptive effects. Methods Twelve healthy adult domestic shorthair cats (6.0 ± 1.1 kg body weight) were studied. Aqueous solutions of buprenorphine hydrochloride at 0, 0.02, 0.06, 0.12 and 0.24 mg/kg body weight and formulations containing 0, 0.3, 0.6 and 1.2 mg/ml with and without preservatives were given subcutaneously. Blood samples were taken and thermal threshold (TT) measured prior to and at regular time points up to 72 h after dosing. Descriptive statistics and analyses of variance were applied as appropriate. Results Baseline TT was 47.6 ± 4.1°C, which increased in all groups treated with all buprenorphine dosages and formulations. After doses of 0.12 mg/kg and above, TT was significantly higher than baseline at most time points from 1–30 h post-treatment. The time to maximum effect (Tmax) ranged between 0.25 and 2.00 h; and plasma concentrations associated with maximum antinociceptive effect (Cmax) were 1.01–1.72 ng/ml after the 0.02 mg/kg dose, 1.4–4.9 ng/ml after the 0.06 mg/kg dose, 4.6–51.4 ng/ml after the 0.12 mg/kg dose and 5.3–22.3 ng/ml after the 0.24 mg/kg dose. The range of estimates for the buprenorphine elimination half-life were as follows: 0.02 mg/kg = 1.35–5.33 h; 0.06 mg/kg = 16.1–31.2 h; 0.12 mg/kg = 10.1–34.0 h; and 0.24 = mg/kg 16.1–31.6 h. The mean ‘plasma concentration for the offset of analgesia’ was 2.3 ± 2.0 ng/ml. No adverse effects were seen. The addition of preservatives to a high-concentration buprenorphine formulation had no impact on antinociception nor any side effects. Conclusions and relevance Aqueous high-concentration buprenorphine formulations administered at 0.12 or 0.24 mg/kg have potential for clinical use in cats, providing prolonged antinociception in a single subcutaneous injection of minimal dose volume.

Administration of drugs to cats can be challenging and simple but effective techniques would be attractive to the owners. The purpose of this study was to compare the pharmacokinetics of buprenorphine (B) after buccal administration, and compare these to data previously collected from the same colony of cats after IV and IM injection. Twenty-four hours before each study, jugular catheters were inserted under isoflurane anesthesia into six adult female cats weighing between 2.9 and 4.5 kg. The buprenorphine-injectable formulation (0.01 mg kg−1 = 0.033 mL kg−1) was administered into the side of the cat's mouth. Blood was withdrawn before, at 1, 2, 4, 6, 10, 15, 30, 45, 60 minutes and at 2, 4, 6, 8, 12, and 24 hours after the drug administration. The volume of blood withdrawn was adjusted, so that

Among the first reports of the intravenous injection of drugs are those describing the studies of Wren and Major (Philos Trans R Soc Lond 1:128–30, 1665; Cirurgia infusoria placidis CL: vivorium dubiis impugnata, cun modesta, ad eadem. Responsione. Kiloni, 1667). They injected opium dissolved in water into the venous system of a dog, which caused it to be stupefied but did not kill it! Despite this observation made more than 350 years ago, the history of clinical intravenous anesthesia does not really become significant before the late nineteenth century.

The first of the modern generation of intravenous agents for the induction (and maintenance) of anesthesia dates back to the introduction and evaluation of thiopental in 1934 (Lundy and others). Since then, there have been a large number of intravenous agents introduced and in parallel a number which have undergone clinical usage and then withdrawn when found wanting.

Methods. A total of 8351 non-cardiac surgical patients at high risk of cardiovascular complications were randomized to b-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; P¼0.03] and MI [230 (5.9%) vs 177 (4.4%); OR, 1.32; 95% CI, 1.07–1.64; P¼0.009] but not stroke [23 (0.6%) vs 32 (0.8%); OR, 0.76; 95% CI, 0.44 –1.33; P¼0.34], death [96 (2.5%) vs 111 (2.8%); OR, 0.87; 95% CI, 0.65 –1.17; P¼0.37] or clinically significant hypotension [522 (13.4%) vs 484 (12.1%); OR, 1.13; 95% CI, 0.99 –1.30; P¼0.08]. 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].

To describe simultaneous pharmacokinetics (PK) and thermal antinociception after intravenous (i.v.), intramuscular (i.m.) and subcutaneous (SC) buprenorphine in cats.Randomized, prospective, blinded, three period crossover experiment.Six healthy adult cats weighing 4.1±0.5 kg.Buprenorphine (0.02 mg kg(-1)) was administered i.v., i.m. or s.c.. Thermal threshold (TT) testing and blood collection were conducted simultaneously at baseline and at predetermined time points up to 24 hours after administration. Buprenorphine plasma concentrations were determined by liquid chromatography tandem mass spectrometry. TT was analyzed using anova (p0.05). A pharmacokinetic-pharmacodynamic (PK-PD) model of the i.v. data was described using a model combining biophase equilibration and receptor association-dissociation kinetics.TT increased above baseline from 15 to 480 minutes and at 30 and 60 minutes after i.v. and i.m. administration, respectively (p0.05). Maximum increase in TT (mean±SD) was 9.3±4.9°C at 60 minutes (i.v.), 4.6±2.8°C at 45 minutes (i.m.) and 1.9±1.9°C at 60 minutes (s.c.). TT was significantly higher at 15, 60, 120 and 180 minutes, and at 15, 30, 45, 60 and 120 minutes after i.v. administration compared to i.m. and s.c., respectively. I.v. and i.m. buprenorphine concentration-time data decreased curvilinearly. S.c. PK could not be modeled due to erratic absorption and disposition. I.v. buprenorphine disposition was similar to published data. The PK-PD model showed an onset delay mainly attributable to slow biophase equilibration (t(1/2) k(e0)=47.4 minutes) and receptor binding (k(on)=0.011 mL ng(-1) minute(-1)). Persistence of thermal antinociception was due to slow receptor dissociation (t(1/2) k(off)=18.2 minutes).I.v. and i.m. data followed classical disposition and elimination in most cats. Plasma concentrations after i.v. administration were associated with antinociceptive effect in a PK-PD model including negative hysteresis. At the doses administered, the i.v. route should be preferred over the i.m. and s.c. routes when buprenorphine is administered to cats.

We read the editorial on ‘Preoperative blood pressure measurement: what should GPs be doing?’ with great interest.1 In support of the lack of evidence that reducing blood pressure helps, the authors quote the POISE study,2 stating that beta-blockers were used to reduce blood pressure preoperatively and the data suggested that it did more …

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 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.

Background There is uncertainty regarding the prognostic value of troponin and creatine kinase muscle and brain isoenzyme measurements after noncardiac surgery. Methods The current study undertook a systematic review and meta-analysis. The study used six search strategies and included noncardiac surgery studies that provided data from a multivariable analysis assessing whether a postoperative troponin or creatine kinase muscle and brain isoenzyme measurement was an independent predictor of mortality or a major cardiovascular event. Independent investigators determined study eligibility and abstracted data in duplicate. Results Fourteen studies, enrolling 3,318 patients and 459 deaths, demonstrated that an increased troponin measurement after surgery was an independent predictor of mortality (odds ratio [OR] 3.4, 95% confidence interval [CI] 2.2-5.2), but there was substantial heterogeneity (I(2) = 56%). The independent prognostic capabilities of an increased troponin value after surgery in the 10 studies that assessed intermediate-term (≤ 12 months) mortality was an OR = 6.7 (95% CI 4.1-10.9, I(2) = 0%) and in the 4 studies that assessed long-term (more than 12 months) mortality was an OR = 1.8 (95% CI 1.4-2.3, I(2) = 0%; P < 0.001 for test of interaction). Four studies, including 1,165 patients and 202 deaths, demonstrated an independent association between an increased creatine kinase muscle and brain isoenzyme measurement after surgery and mortality (OR 2.5, 95% CI 1.5-4.0, I(2) = 4%). Conclusions An increased troponin measurement after surgery is an independent predictor of mortality, particularly within the first year; limited data suggest an increased creatine kinase muscle and brain isoenzyme measurement also predicts subsequent mortality. Monitoring troponin measurements after noncardiac surgery may allow physicians to better risk stratify and manage their patients.

Bonding, binding and isomerism influence the activity and elimination of many drugs. The bonding of drugs by tissues is dependent on their attraction and combination with cellular groups. Four main types of chemical bonds are involved (ionic bonds, dipole–dipole interactions, hydrogen bonds and covalent bonds). Ionic or electrostatic bonds are reversible bonds between ionized compounds and proteins. Hydrogen bonds are a rapidly reversible type of dipole–dipole interaction, and are particularly important in biological reactions. Covalent bonds are stable chemical bonds produced by electron sharing between atoms. The action of most drugs depends on their initial binding by effector proteins (e.g. enzymes, receptors or ion channels). This results in secondary effects (e.g. enzyme activation or inhibition, or the accumulation of intermediate metabolites). In contrast, plasma-protein binding plays an essential role in drug distribution, and varies widely (even among closely related drugs). It may be modified in pathological conditions and surgery, and sometimes restricts the hepatic elimination of drugs. Some extensively bound drugs may be displaced from plasma proteins by other agents. Isomers are drugs with the same chemical composition and molecular formula. Structural isomers have different chemical structures because of the different arrangement of their atoms (e.g. enflurane and isoflurane). In contrast, stereoisomers have identical structures, but different configurations. Enantiomers are pairs of stereoisomers that are mirror images, because of the presence of a chiral centre. A racemic mixture is an equal mixture of two enantiomers, which may have different pharmacodynamic activities and pharmacokinetic properties.

ambulatory surgery. Eighty-one percent of the patients had been taking at least 1 medication (prescribed drug; over the counter medication; vitamins or minerals; herbals or natural substances) in the week before anesthesia and surgery, and 50% had been taking at least 1 “prescription drug.” Further scrutiny shows that 7% of the patients were taking at least 5 prescription drugs, with the highest prevalence in women patients aged over 65 years. Qato et al. 2 suggest that 1 in 25 patients are potentially at risk of a major drug–drug interaction. One such interaction for perioperative patients may be with our anesthetics themselves. The high incidence of comedication has fostered debate about the potential for interactions between general anesthetic agents and preoperative cardiovascular drugs. One issue far from settled is whether cardiovascular drugs should be maintained throughout the perioperative period. Logic dictates that if an individual needs a medication to control a disease or a pattern of symptoms during daily life (in the absence of the stresses of anesthesia and surgery), then the same drugs are probably needed during the perioperative period. Obvious exceptions include anticoagulants and antihyperglycemic agents. But the maintenance of any drug during the surgical period is subject to the premise that there is low potential for adverse interaction between that drug and the components of general anesthesia. This is why we maintain preoperative β blockers and statins in the perioperative period, because we know that preoperative withdrawal may lead to increased perioperative morbidity and mortality associated with myocardial ischemia and infarction. Such interactions are certainly possible between anesthesia and cardiovascular drugs. Wolf and McGoldrick 3 reviewed the available literature for such adverse effects

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.

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.

Much has been published about the impact of treatment on adverse outcomes in patients with cardiovascular diseases. Hypertension is an extremely common condition affecting a significant percentage of the world population. Although care guidelines exist for the medical patient with raised blood pressure, there are no accepted guidelines for the preoperative evaluation and perioperative care of the patient with hypertension who undergoes noncardiac surgery. Of particular importance are defining at-risk groups of patients, and the indications for cancellation to treat and hence reduce this risk. This review examines the interactions between hypertension, drug therapies, anesthesia, and adverse outcomes in these patients. Recommendations for identifying patients at greatest risk of adverse cardiovascular events and cardiac mortality have been developed through evaluation of available data. Based on these findings, the only patients in whom cancellation may be justified and the level of hypertension treated prior to surgery are those with stage 2 hypertension and accompanying target-organ damage, or stage 3 hypertension (blood pressure > 180/> 110 mm Hg).

The number of percutaneous coronary interventions (PCI) performed annually has increased rapidly over the last two decades. Coronary angioplasties are now commonly complemented with the insertion of coronary artery stents. Initially bare metal stents (BMS) were developed with drug-eluting stents (DES) subsequently being introduced. Drug-eluting stents reduce in-stent restenosis at the cost of prolonged anti-platelet therapy. While observational studies suggest that coronary artery bypass graft surgery protects against perioperative cardiac events in non-cardiac surgery, no such evidence exists for PCI. In order to prevent stent thrombosis, patients need to receive dual anti-platelet therapy (generally aspirin and clopidogrel) for four to six weeks with BMS, and at least one year with DES. Patients on dual anti-platelet therapy are at risk of severe bleeding during surgery. However, withdrawal of dual anti-platelet therapy is associated with the risk of stent thrombosis. The risk of cardiac complications seems to exceed the risk of bleeding, and maintenance of dual anti-platelet therapy is advocated whenever possible. Surgery in closed cavities (neurosurgery, intraocular surgery) necessitates the withdrawal of dual anti-platelet therapy. There is a significant risk of perioperative complications in patients who have DES, or recently inserted BMS, and consequently surgery should not be performed without a discussion involving the surgeon, cardiologist, anaesthetist, and the patient.

Diabetes mellitus (DM) is the most common non-communicable disease worldwide. Presently there are about 150 million diabetics; it affects between 1 and 2% of the population in the United Kingdom (UK), and about 10% of the population in the United States of America (USA). There may also be an equal number of undiagnosed patients. Diabetes affects about 1 in 6 patients over the age of 65 years, and 1 in 4 over the age of 85 years; over 90% of patients are non-insulin dependent (type 2) diabetics.

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.

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.

Summary Opioid drugs in high doses can obtund the stress response to major surgery but only at the expense of marked cardiorespiratory depression. The postoperative hormonal response to surgical stress was measured in 20 patients undergoing hysterectomy who were given either meptazinol 100 mg or morphine 15 mg intramuscularly at the end of the surgery. Both drugs at the doses used failed to diminish the stress response. Those patients who received meptazinol showed elevated prolactin levels: this may be an indicator of agonist activity at the μ1, opioid receptor.

Objectives The aim of the study was to assess simultaneous pharmacokinetics and thermal and mechanical antinociception after intramuscular methadone (0.6 mg/kg) in 10 cats. Methods Thermal and mechanical threshold (TT and MT, respectively) testing and blood collection were conducted at baseline and up to 24 h after administration. Methadone plasma concentrations were determined by liquid chromatography–tandem mass spectrometry and pharmacokinetic parameters were estimated by a non-compartmental method. TT and MT were analysed using ANOVA ( P max), time of onset of antinociception and time of reaching cut-out threshold (TT 55°C; MT 30 Newtons [N]) were determined. Results TT and MT increased above baseline from 20–240 mins and 5–40 mins, respectively, after intramuscular (IM) administration ( P max at 20 mins (range 5–360 mins). Conclusions and relevance IM data followed classical disposition and elimination in all cats. Plasma concentrations after IM administration were associated with an antinociceptive effect, including negative hysteresis. These data can be used for devising dosing schedules for methadone in clinical feline practice.

Atherosclerosis is a common condition in both the developed and developing world and is now recognised to be an inflammatory condition leading to the development of ischaemic heart disease, cerebrovascular disease and peripheral vascular disease. Ischaemic heart disease is a major risk factor in the pathogenesis of perioperative adverse cardiovascular events which lead to significant morbidity and mortality within the high risk surgical patient population. Current methods of evaluating the likelihood of postoperative cardiovascular complications depend largely on risk scoring systems, and the preoperative assessment of the functional status of the cardiovascular system. However, the possible role of inflammation in the generation of atherosclerosis has led to the identification of several biochemical markers such as acute phase proteins, cellular adhesion molecules and cytokines. An alternative approach therefore is the measurement of preoperative levels of these biomarkers with the aim of assessing pre-existing disease activity. This review summarises the pathophysiology of atherosclerosis and perioperative myocardial infarction, and discusses the possible future role of biomarkers in the risk stratification of patients undergoing non-cardiac surgery.

Atenolol has been proposed as a peri-operative cardioprotective agent in patients with coronary disease. However, recent reports have cast doubt over the cardioprotective efficacy of atenolol in patients with hypertension and coronary artery disease. There is therefore doubt whether atenolol is the correct cardioprotective drug in the surgical setting. It is possible that some of the physiochemical properties of atenolol (hydrophilic and cardioselective) may decrease it's efficacy in comparison to its more lipophilic congeners (such as propranolol, metoprolol, bisoprolol and carvedilol). The issue of prevention of perioperative cardiac events is complicated by many confounders. As a result, the role of the physicochemical properties of beta-blockers can only be determined in the simpler setting of myocardial infarction. Therefore, we conducted a restricted systematic review to evaluate the effect of initiating atenolol and metoprolol on the prevention of ventricular fibrillation following acute my...

It is widely recommended that beta-blockade be used peri-operatively as it may reduce the incidence of postoperative cardiovascular complications including death. However, there are few data concerning the cost-effectiveness of such strategies. We have analysed the pharmacoeconomics of acute beta-blockade using data from eight prospective peri-operative studies in which patients underwent elective non-cardiac surgery, and in which the incidence of adverse side-effects of treatment, as well as clinical outcomes, have been reported. The costs of treatment were based on the NHS reference costs for 2004. From these data, the number-needed-to-treat (NNT) to prevent a major cardiovascular complication (including cardiovascular death) in high-risk patients was 18.5. This is comparable to the NNT for peri-operative statin therapy. The incremental cost of peri-operative beta-blockade (costs of drug acquisition and of treating associated adverse drug events) was 67.80 pounds sterling per patient. This results in a total cost of 1254.30 pounds sterling per peri-operative cardiovascular complication prevented. However, there is evidence that in patients at lower cardiovascular risk, beta-blockers may be potentially harmful, since their adverse effects (hypotension, bradycardia) may outweigh their potential cardioprotective effects.

Summary Statin cardiovascular protection is mediated by lipid lowering and pleiotropic effects. The efficacy of statins has been established in non-surgical patients with cardiovascular disease and also more recently in non-surgical patients who sustain an acute coronary event. Peri-operative statin administration has been shown to improve both short-term and long-term cardiac outcome following non-cardiac and coronary bypass graft surgery. This cardioprotection may be independent of peri-operative haemodynamics due to a positive effect on plaque stability. Recommendations for the peri-operative statin administration are suggested. These include indications for peri-operative statin therapy, timing of administration, therapeutic targets, duration of administration, the adverse implications of peri-operative statin withdrawal, safety and cost-effectiveness.

We analysed the pharmaco-economics of the prospective peri-operative studies of statin administration for major elective vascular surgery, using the NHS reference costs for 2004. This analysis suggests that peri-operative statin therapy for patients undergoing vascular surgery may present the most cost-effective use of statin therapy yet described, with a number-needed-to-treat of 15 and almost 60% of the total cost of atorvastatin therapy recovered through a reduction in peri-operative adverse events.

The pharmacokinetics and thermal antinociceptive effects of buprenorphine after intravenous (i.v.) or oral transmucosal (OTM) administration were studied in six adult cats. Plasma buprenorphine concentrations were measured using radioimmunoassay in a crossover study after a dose of 20 microg/kg given by the i.v. or OTM route. Oral pH was measured. Blood for drug analyses was collected before, and at 1, 2, 4, 6, 10, 15, 30, and 60 min and at 2, 4, 6, 8, 12, and 24 h after treatment. Thermal thresholds were measured before treatment, then following treatment every 30 min to 6 h, every 1 hour to 12 h and at 24 hours postadministration. Plasma buprenorphine concentration effect relationships were analyzed using a log-linear effect model. Oral pH was 9 in each cat. Peak plasma buprenorphine concentration was lower and occurred later in the OTM group but median bioavailability was 116.3%. Thermal thresholds increased significantly between 30 and 360 min in both groups. Peak effect was at 90 min and there was no difference at any time between the two groups. There was distinct hysteresis between plasma drug concentration and effect in both groups. Overall, OTM administration of buprenorphine is as effective as i.v. treatment and offers a simple, noninvasive method of administration which produces thermal antinociception for up to 6 h in cats.

Background Knowledge about UK doctors' career intentions and pathways is essential for understanding future workforce requirements. The aim of this study was to report career choices for and career progression in anaesthesia in the UK. Methods Postal questionnaire surveys were undertaken of qualifiers from all UK medical schools in nine qualification years since 1974. Results 74% (24623/33417) and 73% (20709/28468) of doctors responded at 1 and 3 yr after qualification. At 1 and 3 yr after qualification, on average, 8% of doctors chose anaesthesia. Between 1974 and 2002 the percentage of doctors choosing anaesthesia, 1 yr after qualification, increased from 5 to 12%. A majority of doctors who chose anaesthesia 1 and 3 yr after qualification were working in anaesthesia 10 yr after qualification. In addition to doctors' enthusiasm for the specialty, career choices for anaesthesia were positively influenced by their perception of working hours, conditions of work, and career and promotion prospects. Conclusions Anaesthesia has become increasingly popular as a career choice in the UK. Training numbers could be increased in the short term to speed up the process of providing a consultant-delivered service.

Data allowing rational use of analgesics in cats are limited. Pharmacokinetics and pharmacodynamics of fentanyl were studied in cats. Plasma fentanyl concentrations were measured using radioimmunoassay in a crossover study in six cats after 10 microg/kg (i.v.) or by application of fentanyl in pluronic lecithin organogel (PLO) to the inner ear pinna. On a separate occasion thermal thresholds were measured after i.v. fentanyl (10 microg/kg) or saline. Plasma fentanyl concentrations reached 4.7-8.31 ng/mL 2 min after i.v. administration and were undetectable after 95 min. Fentanyl was not detected in plasma at any time after PLO use. Thermal thresholds did not change following saline administration but were increased above baseline from 5 to 110 min after i.v. fentanyl. In this model a plasma concentration of >1.07 ng/mL was required to provide analgesia. Plasma concentrations were measured in additional cats after intranasal or oral dosing (2 microg/kg) and after 30 microg/kg in PLO gel. After oral and nasal dosing, Cmax values were 0.96 and 1.48 ng/mL at 5 and 2 min, respectively. Plasma fentanyl was not detected after application of the higher dose of fentanyl in PLO.

To assess the incidence of major cardiac events in critically ill patients with a high risk of cardiac complications presenting with an elevated heart rate.Observational, retrospective study in a 15-bed medical/surgical Intensive Care Unit (ICU) at a university hospital for a period of 12 months.We studied patients with a high risk of cardiac complications, according to the revised Goldman index, who were treated for at least 36 hrs in the ICU. Patients presenting with prolonged elevated heart rate, defined as a heart rate95 beats/min for12 hrs in at least one 24-hr period of their ICU stay, were investigated. Cardiac high-risk patients not developing this criterion served as controls. Major cardiac events, defined as nonfatal myocardial infarction, nonfatal cardiac arrest, and cardiac related death, were the primary outcome measures.From a total of 791 patients, 69 patients were assessed as cardiac high-risk patients. Of 39 patients with prolonged elevated heart rates, 19 (49%) sustained major cardiac events, whereas in the control group of 30 patients, only four patients (13%) had a major cardiac event (p = .002; odds ratio, 6.2). Patients with elevated heart rate had to be treated 4.5 days longer in the ICU (p = .01), whereas the ICU and 30-day post-ICU discharge survival rates did not differ significantly.In this study, we provide evidence for an increased incidence of major cardiac events in critically ill, cardiac high-risk patients with a prolonged elevated heart rate during their ICU stay. In addition, elevated heart rate was associated with a significantly longer ICU stay.

It is generally understood that patients who have cardiovascular disease are at risk of cardiac complications after surgery. In patients undergoing major or vascular surgery, the risk of such complications can be signi®cant. Eagle and colleagues studied patients enrolled on the CASS (Coronary Artery Surgery Study) registry who subsequently underwent non-cardiac surgery. They reported a perioperative myocardial infarction rate of 8.5% in patients with medically managed coronary artery disease who underwent vascular surgery. The authors de®ned high-risk surgery as surgery associated with a risk of perioperative death or myocardial infarction of greater than 4%. Abdominal surgery, thoracic surgery, and head and neck surgery fell into this category. For patients undergoing these types of surgery who had medically treated coronary artery disease, the overall perioperative myocardial infarction rate was 2.7% and the overall death rate 3.3%. This compared with rates of 0.8 and 1% respectively in patients undergoing similar surgery who did not have coronary artery disease. Data such as these are often considered with information on the prevalence of coronary artery disease to obtain some indication of the population burden of disease. For example, in 1990 Mangano stated that 25 million patients undergo major surgery in the USA each year and suggested that perhaps 6±7 million of these people are at risk of perioperative cardiac complications. Such estimates suggest that perioperative cardiac complications are both a major issue in the care of individual surgical patients and a major public health issue. This review will examine in more detail the population impact of perioperative cardiac morbidity and the implications of this for the individual patient.

Objective : To determine if increased QT interval dispersion (corrected and not corrected for heart rate) is associated with perioperative silent myocardial ischemia or postoperative adverse cardiovascular events. Design : Blinded retrospective observational study. Setting : University hospital. Participants : One hundred eighty-one perioperative patients receiving general anesthesia for elective major vascular or orthopedic surgery. Interventions : None. Measurements and main results : QT dispersion, corrected and uncorrected for heart rate, was prolonged in patients suffering significant myocardial ischemia up to 48 hours assessed by Holter ECG monitoring, for early cardiac morbidity and all early cardiac events (including mortality) up to 1 month postoperatively. There were no significant changes in patients showing early cardiovascular mortality or late cardiac morbidity or mortality between 1 and 12 months postoperatively. Morbidity and mortality were determined from clinical notes, laboratory investigations, and autopsy when available. QT dispersion performed poorly as a screening test to identify those who subsequently developed early adverse cardiovascular outcomes. Conclusions : QT dispersion is prolonged in those at risk of early adverse cardiovascular events but is a poor screening tool.

Little is known about the effect of chronic beta-adrenoceptor antagonist therapy during the peri-operative period in patients undergoing non-cardiac surgery. We conducted a literature review to identify studies examining the relationship between chronic therapy and adverse peri-operative outcome. Eighteen studies were identified in which it was possible to ascertain the incidence of adverse cardiac outcomes in those patients who were and were not receiving chronic beta-blocker therapy. None of the studies demonstrated a protective effect of chronic beta-blockade. The results of these studies were then combined and a cumulative odds ratio calculated for the likelihood of myocardial infarction, cardiac death and major cardiac complications. Patients receiving chronic beta-blocker therapy were more likely to suffer a myocardial infarction (p < 0.05). These findings differ from the published effects of acute beta-blockade. Reasons for this discrepancy are considered.

Background. The molecular basis of i.v. general anaesthetic activity was investigated using comparative molecular field analysis (CoMFA). Methods. The free plasma concentrations that abolish movement to a noxious stimulus for 14 structurally diverse i.v. anaesthetics were obtained from the literature. The compounds were randomly divided into a training set (n=10) to derive the activity model, and a separate test set (n=4) used to assess its predictive capability. The anaesthetic structures were aligned so as to maximize their similarities in molecular shape and electrostatic potential to conformers of the most active agent in the group, eltanolone. The conformers and alignments that showed the maximum similarity (calculated using combined Carbo indices) were retained, and used to derive the CoMFA models. Results. The final model explained 94.0% of the variance in the observed activities of the training set (n=10, P Conclusions. A single activity model can be formulated for i.v. general anaesthetics and preliminary pharmacophoric maps derived, which describe the molecular basis of their in vivo potency.

PURPOSE OF REVIEW The elderly population is increasing in number each year, and more patients are presenting for anesthesia and surgery. One of the key areas for improving the care of the elderly is a better understanding of the influence of aging on drug pharmacokinetics and dynamics. RECENT FINDINGS We now know more about the effects of risk factors on the occurrence of postoperative complications, and strategies to improve outcome after anesthesia and surgery. Two such strategies include the role of perioperative beta-adrenoceptor blockade in obtunding cardiovascular responses and myocardial ischaemia, and the provision of effective perioperative analgesia. Both topics have featured in key publications during the past year. Cognitive dysfunction following surgery occurs in about 10% of elderly patients; possible etiologies include a decline in central nervous system cholinergic function. One major disease of the elderly is Parkinson's disease, which offers challenges to the anesthesiologist both with regard to alterations of physiology and in choice of anesthetic drugs and techniques. SUMMARY The effects of comorbidity and intercurrent medications may alter the normal anesthetic practice of the clinician's care of the elderly patient. Further studies in these key areas may lead to improved outcomes.