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BackgroundParkinson’s disease has been identified as a risk factor for severe Coronavirus disease 2019 (COVID-19) outcomes. However, whether the significant high risk of death from COVID-19 in people with Parkinson’s disease is specific to the disease itself or driven by other concomitant and known risk factors such as comorbidities, age, and frailty remains unclear.ObjectiveTo investigate clinical profiles and outcomes of people with Parkinson’s disease and atypical parkinsonian syndromes who tested positive for COVID-19 in the hospital setting in a multicentre UK-based study.MethodsA retrospective cohort study of Parkinson’s disease patients with a positive COVID-19 test admitted to hospital between February 2020 and July 2021. An online survey was used to collect data from clinical care records, recording patient, Parkinson’s disease and COVID-19 characteristics. Associations with time-to-mortality and severe outcomes were analysed using either the Cox proportional hazards model or logistic regression models, as appropriate.ResultsData from 552 admissions were collected: 365 (66%) male; median (inter-quartile range) age 80 (74-85) years. The 34-day mortality rate was 38.4%; male sex, increased age and frailty, Parkinson’s dementia syndrome, requirement for respiratory support and no vaccination were associated with increased mortality risk. Community-acquired COVID-19 and co-morbid chronic neurological disorder were associated with increased odds of requiring respiratory support. Hospital-acquired COVID-19 and delirium were associated with requiring an increase in care level post-discharge.ConclusionsThis first, multicentre, UK-based study on people with Parkinson’s disease or atypical parkinsonian syndromes, hospitalised with COVID-19, adds and expands previous findings on clinical profiles and outcomes in this population.

Intraoperative and postoperative hypotension occur commonly and are associated with organ injury and poor outcomes. Changes in arterial blood pressure (BP) during procedural sedation are not well described.Individual patient data from five trials of propofol sedation for colonoscopy and a clinical database were pooled and explored with logistic and linear regression. A literature search and focused meta-analysis compared the incidence of hypotension with propofol and alternative forms of procedural sedation. Hypotensive episodes were characterised by the original authors' definitions (typically systolic BP90 mm Hg).In pooled individual patient data (n=939), 36% of procedures were associated with episodes of hypotension. Longer periods of propofol sedation and larger propofol doses were associated with longer-lasting and more-profound hypotension. Amongst 380 patients for whom individual BP measurements were available, 107 (28%) experienced systolic BP90 mm Hg for5 min, and in 89 (23%) the episodes exceeded 10 min. Meta-analysis of 18 RCTs identified an increased risk ratio for the development of hypotension in procedures where propofol was used compared with the use of etomidate (two studies; n=260; risk ratio [RR] 2.0 [95% confidence interval: 1.37-2.92]; P=0.0003), remimazolam (one study; n=384; RR 2.15 [1.61-2.87]; P=0.0001), midazolam (14 studies; n=2218; RR 1.46 [1.18-1.79]; P=0.0004), or all benzodiazepines (15 studies; n=2602; 1.67 [1.41-1.98]; P0.00001). Hypotension was less likely with propofol than with dexmedetomidine (one study; n=60; RR 0.24 [0.09-0.62]; P=0.003).Hypotension is common during propofol sedation for colonoscopy and of a magnitude and duration associated with harm in surgical patients.

Rapid elimination of remifentanil facilitates application of intense opioid effect during general anaesthesia whilst maintaining prompt emergence. Interruptions in remifentanil supply mean clinicians must relearn titration of pharmacokinetically longer-acting opioids to achieve appropriate levels of opioid effect whilst maintaining acceptable recovery times. Opioid-free anaesthesia is achievable for many minor and intermediate surgical procedures for which remifentanil might have been used previously.

Summary Anaesthesiologists and non-anaesthesiologist sedationists have a limited set of available i.v. hypnotics, further reduced by the withdrawal of thiopental in the USA and its near disappearance in Europe. Meanwhile, demand for sedation increases and new clinical groups are using what traditionally are anaesthesiologists' drugs. Improved understanding of the determinants of perioperative morbidity and mortality has spotlighted hypotension as a potent cause of patient harm, and practice must be adjusted to respect this. High-dose propofol sedation may be harmful, and a critical reappraisal of drug choices and doses is needed. The development of remimazolam, initially for procedural sedation, allows reconsideration of benzodiazepines as the hypnotic component of a general anaesthetic even if their characterisation as i.v. anaesthetics is questionable. Early data suggest that a combination of remimazolam and remifentanil can induce and maintain anaesthesia. Further work is needed to define use cases for this technique and to determine the impact on patient outcomes.

Purpose of review Anaesthesia and sedation are ubiquitous in contemporary medical practice. Developments in anaesthetic pharmacology are targeted on reducing physiological disturbance whilst maintaining or improving titrateability, recovery profile and patient experience. Remimazolam is a new short-acting benzodiazepine in the final stages of clinical development. Recent findings Clinical experience with remimazolam comprises volunteer studies and a limited number of clinical investigations. In addition, laboratory investigations explore the implications of its 'soft drug' pharmacology. Summary Remimazolam provides effective procedural sedation with superior success rates and recovery profile when compared to midazolam. Comparisons with propofol are required. Preliminary studies suggest potential for using remimazolam as the hypnotic component of general anaesthesia. Definitive studies are awaited. As a benzodiazepine, remimazolam could be evaluated as an anticonvulsant and for intensive care sedation.

Molecular mechanisms linking autonomic dysfunction with poorer clinical outcomes in critical illness remain unclear. We hypothesized that baroreflex dysfunction alone is sufficient to cause cardiac impairment through neurohormonal activation of (nicotinamide adenine dinucleotide phosphate oxidase dependent) oxidative stress resulting in increased expression of G-protein-coupled receptor kinase 2, a key negative regulator of cardiac function.Laboratory/clinical investigations.University laboratory/medical centers.Adult rats; wild-type/nicotinamide adenine dinucleotide phosphate oxidase subunit-2-deficient mice; elective surgical patients.Cardiac performance was assessed by transthoracic echocardiography following experimental baroreflex dysfunction (sino-aortic denervation) in rats and mice. Immunoblots assessed G-protein-coupled receptor recycling proteins expression in rodent cardiomyocytes and patient mononuclear leukocytes. In surgical patients, heart rate recovery after cardiopulmonary exercise testing, time/frequency measures of parasympathetic variables were related to the presence/absence of baroreflex dysfunction (defined by spontaneous baroreflex sensitivity of6 ms mm Hg). The associations of baroreflex dysfunction with intraoperative cardiac function and outcomes were assessed.Experimental baroreflex dysfunction in rats and mice resulted in impaired cardiac contractility and upregulation of G-protein-coupled receptor kinase 2 expression. In mice, genetic deficiency of gp91 nicotinamide adenine dinucleotide phosphate oxidase subunit-2 prevented upregulation of G-protein-coupled receptor kinase 2 expression in conditions of baroreflex dysfunction and preserved cardiac function. Baroreflex dysfunction was present in 81 of 249 patients (32.5%) and was characterized by lower parasympathetic tone and increased G-protein-coupled receptor kinase 2 expression in mononuclear leukocytes. Baroreflex dysfunction in patients was also associated with impaired intraoperative cardiac contractility. Critical illness and mortality were more frequent in surgical patients with baroreflex dysfunction (relative risk, 1.66 [95% CI, 1.16-2.39]; p = 0.006).Reduced baroreflex sensitivity is associated with nicotinamide adenine dinucleotide phosphate oxidase subunit-2-mediated upregulation of G-protein-coupled receptor kinase 2 expression in cardiomyocytes and impaired cardiac contractility. Autonomic dysfunction predisposes patients to the development of critical illness and increases mortality.

BackgroundThe Evaluation of Nitrous oxide in the Gas Mixture for Anesthesia II trial randomly assigned 7,112 noncardiac surgery patients to a nitrous oxide or nitrous oxide–free anesthetic; severe postoperative nausea and vomiting (PONV) was a prespecified secondary end point. Thus, the authors evaluated the association between nitrous oxide, severe PONV, and effectiveness of PONV prophylaxis in this setting.MethodsUnivariate and multivariate analyses of patient, surgical, and other perioperative characteristics were used to identify the risk factors for severe PONV and to measure the impact of severe PONV on patient outcomes.ResultsAvoiding nitrous oxide reduced the risk of severe PONV (11 vs. 15%; risk ratio [RR], 0.74 [95% CI, 0.63 to 0.84]; P < 0.001), with a stronger effect in Asian patients (RR, 0.55 [95% CI, 0.43 to 0.69]; interaction P = 0.004) but lower effect in those who received PONV prophylaxis (RR, 0.89 [95% CI, 0.76 to 1.05]; P = 0.18). Gastrointestinal surgery was associated with an increased risk of severe PONV when compared with most other types of surgery (P < 0.001). Patients with severe PONV had lower quality of recovery scores (10.4 [95% CI, 10.2 to 10.7] vs. 13.1 [95% CI, 13.0 to 13.2], P < 0.0005); severe PONV was associated with postoperative fever (15 vs. 20%, P = 0.001). Patients with severe PONV had a longer hospital stay (adjusted hazard ratio, 1.14 [95% CI, 1.05 to 1.23], P = 0.002).ConclusionsThe increased risk of PONV with nitrous oxide is near eliminated by antiemetic prophylaxis. Severe PONV, which is seen in more than 10% of patients, is associated with postoperative fever, poor quality of recovery, and prolonged hospitalization.

Anaesthesia education is uniquely placed to allow safe and supervised workplace teaching and training delivered in a personalized, contextual one-to-one basis. Trainers and trainees need to manage their expectations in training, enabling flexible and opportunistic capturing of these learning episodes, as well as structured learning. Structured planning of individualized training is imperative to facilitate learning in trainees with different learning styles. Role modelling of trainers in the workplace is an essential component of both clinical and professional teaching. Critical reflection and high-quality trainee feedback enhances this experiential learning. A robust framework of education governance is fundamental in maintaining a high standard of training; this includes trainer accreditation, recognizing the importance of trainer development, and an appropriate infrastructure to support training and education in the clinical workplace.

Clinicians need critical appraisal skills to weigh up the quality of the literature and to decide whether it has implications for their practice. Every belief in medicine is a construct created from the limited information available and carries a degree of uncertainty. A centralized approach to research identifies the highest priority areas of uncertainty so as to bring about the most improvement for the largest number of patients. This patient-centred model classifies studies into basic science, translational, and clinical research. Adequately powered mega-trials are required to bridge the translational gap between efficacy (does a treatment work?) and effectiveness (does a treatment work when applied in ordinary clinical practice?). There is a paucity of these in perioperative medicine.

Explanatory mechanisms for the association between poor exercise capacity and infections following surgery are underexplored. We hypothesized that aerobic fitness—assessed by cardiopulmonary exercise testing (CPET)—would be associated with circulating inflammatory markers, as quantified by the neutrophil-lymphocyte ratio (NLR) and monocyte subsets. The association between cardiopulmonary reserve and inflammation was tested by multivariable regression analysis with covariates including anaerobic threshold (AT) and malignancy. In a first cohort of 240 colorectal patients, AT was identified as the sole factor associated with higher NLR(P=0.03)and absolute and relative lymphopenia(P=0.01). Preoperative leukocyte subsets and monocyte CD14+expression (downregulated by endotoxin and indicative of chronic inflammation) were also assessed in two further cohorts of age-matched elective gastrointestinal and orthopaedic surgical patients. Monocyte CD14+expression was lower in gastrointestinal patients(n=43)compared to age-matched orthopaedic patients(n=31). The circulating CD14+CD16−monocyte subset was reduced in patients with low cardiopulmonary reserve. Poor exercise capacity in patients without a diagnosis of heart failure is independently associated with markers of inflammation. These observations suggest that preoperative inflammation associated with impaired cardiorespiratory performance may contribute to the pathophysiology of postoperative outcome.

After finding out about a distant forebear’s execution, J Robert Sneyd acted as an expert witness in a US court to try to prevent the use of a new drug for lethal injection, appalled that untrained government workers were using lifesaving drugs to kill

Although elevated oxygen fraction is used in intensive care units around the world, pathological changes in pulmonary tissue have been shown to occur with prolonged exposure to hyperoxia. In this work a bovine bronchus culture model has been successfully used to evaluate the effects of hyperoxia on ciliated epithelium in vitro. Samples were cultured using an air interface method and exposed to normoxia, 21% O(2) or hyperoxia, 95% O(2). Cilial coverage was assessed using scanning electron microscopy (SEM). Tissue damage (lactate dehydrogenase, LDH, in the medium), lipid peroxidation (thiobarbituric acid reactive substances, TBARS), DNA damage (comet assay), protein oxidation (OxyBlot kit) and antioxidant status (total glutathione) were used to assess whether the hyperoxia caused significant oxidative stress. Hyperoxia caused a time-dependent decline (t(½)=3.4d compared to 37.1d under normoxia) in cilial coverage (P

Etomidate is a well established intravenous anaesthetic agent which has been widely used. Recognised limitations of the agent include adrenocortical suppression, myoclonus and post-operative nausea and vomiting, PONV. MOC-etomidate, carboetomidate and MOC-carboetomidate are novel etomidate derivatives. Their preclinical data and their potential for human administration are critically reviewed. 'Soft' pharmacology (rapid ester hydrolysis) limits the duration of action of MOC-etomidate and MOC-carboetomidate giving them rapid offset after administration is discontinued. Adrenocortical depression is minimised either by ester hydrolysis or by structural change to the etomidate molecule. Potential limitations include the yet to be determined incidence of myoclonus and PONV if these new agents are administered to humans.

The pharmacokinetics of propofol are relatively well described in the pediatric population. Recent work has confirmed the validity of allometric scaling for predicting propofol disposition across different species and for describing pediatric ontogenesis. In the first year of life, allometric models require adjustment to reflect ontogeny of maturation. Pharmacodynamic data for propofol in children are scarcer, because of practical difficulties in data collection and the limitations of currently available depth of anesthesia monitors for pediatric use. Hence, questions relating to the comparative sensitivity of children to propofol, and differences in time to peak effect relative to adults, remain unanswered. K(eo) half-lives have been determined for pediatric kinetic models using time to peak effect techniques but are not currently incorporated into commercially available target-controlled infusion pumps.

Propofol is a water-insoluble intravenous anesthetic agent that is actually formulated as a water-in-oil emulsion with known drawbacks such as pain on injection, microorganism growth support and stability. We report on the properties of formulations of propofol in poly (N-vinyl-2-pyrrolidone)-block-poly(d,l-lactide), PVP–PLA, polymeric micelles (Propofol-PM). Microbial growth in these formulations was evaluated with Pseudomonas aeruginosa (ATCC 9027), Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 25922) and Candida albicans (ATCC 10231). Sleep-recovery studies in female Sprague–Dawley rats, at a dose of 10mg/kg were performed to compare pharmacodynamic profiles of the new Propofol-PM formulations with those of Diprivan®, a commercially available lipid based propofol formulation. Growth of microorganisms was not supported in the Propofol-PM formulations tested. No significant differences in times to unconsciousness, awakening, recovery of righting reflex and full recovery were observed between Propofol-PM formulations and Diprivan®. Propofol loaded in PVP–PLA micelles (Propofol-PM) is not significantly different in terms of pharmacodynamic but demonstrates no microorganism growth support and improved stability that opens up the door to pain on injection reduction strategy.

The effect of hyperoxia on ciliary abundance in cultured explants of adult human bronchus was investigated. Bronchus samples were removed during surgery from patients receiving pneumonectomy or lobectomy for malignancy. Part or all of each of these samples was used for measurement of cilial abundance by scanning electron microscopy (SEM); in many cases the remainder was subdivided and cultured at 37 degrees C in DMEM medium, maintaining an air interface at the ciliated surface of each segment. Cultured segments were exposed to normoxia or hyperoxia (95% O(2)), and a segment was removed every other day for quantification of cilial abundance by SEM. There was a significant inverse relationship between smoking history and abundance (p = .017; ANOVA); mean values for nonsmokers, ex-smokers, and smokers were 98.2% (n = 6), 97.0% (n = 17), and 84.02% (n = 9), respectively. There was some loss of cilia on explant segments cultured under normoxia, but the rate of loss from segments cultured under hyperoxia was significantly greater (W test, p = .00011); rate constants (means +/- SE) for cilial loss of 0.0208 +/- 0.0044 day(-1) and 0.0880 +/- 0.0179 day(-1) were found for explant segments exposed to 21 and 95% O2, respectively (n = 20).

Safe sedation is fundamental to many modern cardiological procedures, and following the publication of the report on safe sedation by the Academy of Medical Royal Colleges, this report discusses sedation specifically in cardiological practice. The major areas within cardiology that use sedation are cardioversion, catheter ablation particularly of atrial fibrillation, transoesophageal echocardiography, implantable device (cardiovascular implantable electronic device) procedures and other procedures such as transcatheter aortic valve replacement. There is increasing demand for cardiological sedation but there is wide geographical variation in its use and there are also growing data to support non-anaesthetists giving sedation. The use of benzodiazepines, particularly for short procedures, is common, but even here good record-keeping and audit together with an understanding of the continuum of sedation and having appropriately trained staff and the necessary facilities are vital. Nurse administration of propofol may be appropriate for some procedures in cardiology that require at least moderate sedation. Appropriate training is essential and the use of capnography and target controlled infusion pumps for propofol administration is recommended.

OBJECTIVES: The aim of the study was to investigate whether a single hyperbaric oxygen exposure causes oxidative stress in isolated platelets. DESIGN AND METHODS: Isolated horse platelets were exposed to 100% oxygen at 2.2 atmospheres, or 100% oxygen under normobaric conditions, or air under normobaric conditions for 90 min. RESULTS: There were no differences in platelet SOD activity between conditions, but there was a rise in SOD in all cases after 24 h (in control platelets at 24 h, SOD was 11.9 +/- 1.9 nmol/min/mg protein compared to initial background levels of 8.2 +/- 1.9 nmol/min/mg protein) (P < 0.05). Neither platelet catalase activity nor platelet GSH concentration changed over time, nor between conditions (catalase activity remained at around 12 units/mg protein, and GSH at around 1.58 nmol/mg protein). CONCLUSIONS: These data suggest that a single HBO exposure has no detrimental effect on platelet biochemistry, and does not cause overt oxidative stress in vitro.

Rat hearts were perfused for 15 min with buffer equilibrated with 0.01% or 0.05% CO. The buffer was equilibrated with 21% O2 throughout. The ventricular glutathione content decreased by 76% and 84%, 90 min post-exposure to 0.01% and 0.05% CO, respectively, compared with 0% CO controls ( 0.45±0.01 μ mol/g wet tissue; ±SEM, n=3). Both reduced and oxidised glutathione contributed to this decline. When ascorbate and Trolox C were included during exposure to 0.05% CO the glutathione pool was partly protected; here the glutathione decrease was 46%. In most hearts additional creatine kinase activity in the perfusate indicated minor tissue injury occurring immediately after the start and/or about 10 min after the end of exposure to 0.01% CO or 0.05% CO. Ventricle lactate levels were unaffected by exposure to 0.01% CO. This evidence supports a role for oxidative stress in CO cardiotoxicity.

Background Propofol is a commonly used anesthetic induction agent in pediatric anesthesia that, until recently, was used with caution as an intravenous infusion agent for sedation in pediatric intensive care. Few data have described propofol kinetics in critically ill children. Methods Twenty-one critically ill ventilated children aged 1 week to 12 yr were sedated with 4-6 mg. kg(-1).h(-1) of 2% propofol for up to 28 h, combined with a constant morphine infusion. Whole blood concentration of propofol was measured at steady state and for 24 h after infusion using high-performance liquid chromatography. Results A propofol infusion rate of 4 mg. kg(-1).h(-1) achieved adequate sedation scores in 17 of 20 patients. In 2 patients the dose was reduced because of hypotension, and 1 patient was withdrawn from the study because of a increasing metabolic acidosis. Mixed-effects population models were fitted to the blood propofol concentration data. The pharmacokinetics were best described by a three-compartment model. Weight was a significant covariate for all structural model parameters; Cl, Q2, Q3, V1, and V2 were proportional to weight. Estimates for these parameters were 30.2, 16.0, and 13.3 ml. kg(-1).min(-1) and 0.584 and 1.36 l/kg, respectively. The volume of the remaining peripheral compartment, V3, had a constant component (103 l) plus an additional weight-related component (5.67 l/kg). Values for Cl were reduced (typically by 26%) in children who had undergone cardiac surgery. Conclusions Propofol kinetics are altered in very small babies and in children recovering from cardiac surgery. Increased peripheral distribution volume and reduced metabolic clearance following surgery causes prolonged elimination.

The authors are developing a closed-loop system for intravenous anesthesia in humans. Using published pharmacokinetic data for the intravenous anesthetic agent, propofol, they have generated a population of “virtual patients” and simulated their response to induction and maintenance of intravenous anesthesia using a feedback system based on an electroencephalogram derivative. Their simulations suggested that the proposed system would accommodate patients with widely varying pharmacokinetic characteristics. The system was subsequently tested in humans, and successfully induced and maintained anesthesia in 7 volunteers.

The use of hyperoxia for critically ill patients is associated with adverse impacts resulting in lung injury accompanied by inflammation. The aim of this study was to evaluate aspects of mechanisms that contribute to hyperoxia-induced disruption of the epithelial permeability barrier, and also the protective effects of the antioxidants α-tocopherol and ascorbate. 16HBE14o- cells were cultured as monolayers at an air-liquid interface for 6 days, after which transepithelial electrical resistance reached 251.2 ± 4.1 Ω.cm(2) (mean ± standard error of the mean). They were then exposed for 24 h to normoxia (21% O2, 5% CO2), hyperoxia (95% O2, 5% CO2), hyperoxia with 10(-7) M α-tocopherol, hyperoxia with 10(-7) M ascorbate, hyperoxia with 10(-6) M ascorbate, and hyperoxia with a combination of α-tocopherol and ascorbate (10(-7) M and 10(-6) M, respectively). Significant reductions (P < 0.05) in transepithelial electrical resistance seen after hyperoxia (with or without antioxidants) were associated with reductions in the levels of zona occludens-1 (ZO-1) observed by immunohistochemistry, and downregulation of ZO-1 expression (P < 0.01) as compared with normoxia. In contrast, the expression levels of interleukin (IL)-8, IL-6 and tumour necrosis factor-α (TNF-α) were increased after hyperoxia (P < 0.01), and marked increases in the levels of these cytokines (ELISA) were seen in the medium (P < 0.001) as compared with normoxia. The antioxidant vitamins E and C had a partial protective effect against the hyperoxia-induced reduction in ZO-1 levels and the increase in levels of the proinflammatory cytokines IL-8, IL-6, and TNF-α. In conclusion, hyperoxia-induced epithelial disruption is associated with tight junction weakening, and induction of a proinflammatory environment.

This study compared the ability of forty anaesthetists to judge absolute levels of oxygen saturation, direction of change, and size of change in saturation using auditory pitch and pitch difference in two laboratory-based studies that compared a linear pitch scale with a logarithmic scale. In the former the differences in saturation become perceptually closer as the oxygenation level becomes higher whereas in the latter the pitch differences are perceptually equivalent across the whole range of values. The results show that anaesthetist participants produce significantly more accurate judgements of both absolute oxygenation values and size of oxygenation level difference when a logarithmic, rather than a linear, scale is used. The line of best fit for the logarithmic function was also closer to x = y than for the linear function. The results of these studies can inform the development and standardisation of pulse oximetry tones in order to improve patient safety.

JM-1232(-), (-)-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-phenyl-3,5,6,7-tetrahydrocyclopenta [f]isoindol-1(2H)-one, molecular formula, C(24)H(27)N(3)O(2); molecular weight, 389.49, is a novel isoindoline water-soluble benzodiazepine receptor agonist with favorable anesthetic/sedative properties in animals. MR04A3 is a 1% aqueous presentation of JM-1232(-).In Step 1, healthy male volunteers received 10-min infusions of MR04A3, 0.05, 0.1, 0.2, 0.4, and 0.8 mg/kg, with three MR04A3 subjects and one placebo subject per dose concentration. In Step 2, doses were 0.025, 0.05, 0.075, 0.1, 0.2, 0.3, and 0.4 mg/kg over 1 min with six MR04A3 subjects and one placebo subject per dose concentration.Hypnotic effects of MR04A3 were seen at all dose concentrations in Step 1 and at doses of 0.075 mg/kg or more in Step 2. Central nervous system effect was seen at all dose concentrations with larger doses of MR04A3 producing a deeper and longer reduction in bispectral index. Ramsay sedation scores were increased with higher doses causing sedation and then unresponsiveness. The adverse event profile of subjects receiving MR04A3 was similar to that of subjects given placebo except that some subjects receiving MR04A3 developed upper airway obstruction while sedated. This responded to simple maneuvers (i.e., chin lift). Changes in systolic arterial blood pressure and heart rate were minimal.MR04A3 is hypnotic in man with a satisfactory hemodynamic and safety profile.

The pharmacokinetics of propofol are relatively well described in the pediatric population. Recent work has confirmed the validity of allometric scaling for predicting propofol disposition across different species and for describing pediatric ontogenesis. In the first year of life, allometric models require adjustment to reflect ontogeny of maturation. Pharmacodynamic data for propofol in children are scarcer, because of practical difficulties in data collection and the limitations of currently available depth of anesthesia monitors for pediatric use. Hence, questions relating to the comparative sensitivity of children to propofol, and differences in time to peak effect relative to adults, remain unanswered. K(eo) half-lives have been determined for pediatric kinetic models using time to peak effect techniques but are not currently incorporated into commercially available target-controlled infusion pumps.

BackgroundOrg 25435 is a new water-soluble alpha-amino acid ester intravenous anaesthetic which proved satisfactory in animal studies. This study aimed to assess the safety, tolerability and efficacy of Org 25435 and to obtain preliminary pharmacodynamic and pharmacokinetic data.MethodsIn the Short Infusion study 8 healthy male volunteers received a 1 minute infusion of 0.25, 0.5, 1.0, or 2.0 mg/kg (n = 2 per group); a further 10 received 3.0 mg/kg (n = 5) or 4.0 mg/kg (n = 5). Following preliminary pharmacokinetic modelling 7 subjects received a titrated 30 minute Target Controlled Infusion (TCI), total dose 5.8-20 mg/kg.ResultsWithin the Short Infusion study, all subjects were successfully anaesthetised at 3 and 4 mg/kg. Within the TCI study 5 subjects were anaesthetised and 2 showed signs of sedation. Org 25435 caused hypotension and tachycardia at doses over 2 mg/kg. Recovery from anaesthesia after a 30 min administration of Org 25435 was slow (13.7 min). Pharmacokinetic modelling suggests that the context sensitive half-time of Org 25435 is slightly shorter than that of propofol in infusions up to 20 minutes but progressively longer thereafter.ConclusionsOrg 25435 is an effective intravenous anaesthetic in man at doses of 3 and 4 mg/kg given over 1 minute. Longer infusions can maintain anaesthesia but recovery is slow. Hypotension and tachycardia during anaesthesia and slow recovery of consciousness after cessation of drug administration suggest this compound has no advantages over currently available intravenous anaesthetics.

Retired GP leader Pereira Gray snipes at medical schools in general and his local universities in particular.1 2 He might better direct his attention to those who have driven primary care into chaos and made it a less popular choice for trainees. Had he asked before firing his broadsides we could have told him that …

Rat hearts were perfused for 30 min with buffer equilibrated with CO. Mean data for hearts exposed to 0.01% CO show a 15% decrease in heart rate (HR) during exposure followed by recovery, with a further 17% decrease post exposure. Examination of time courses from individual perfusions shows that in 10 hearts exposed to 0.01% CO HR responded in different ways: no response (5 hearts); decrease during exposure followed by recovery (3 hearts); and decrease post exposure (2 hearts). There was a strong association between CO-induced HR decrease and release of creatine kinase into the perfusate, both of which were not prevented by the antioxidants, ascorbate, and Trolox C. Perfusate flow rate declined post exposure (4.9% and 8.9% with 0.01% and 0.05% CO, respectively) and this was prevented by antioxidants. CO may have two, independent, cardiotoxic effects; these may be mediated by CO-induced elevation of oxidant production, H2O2 in one case and peroxynitrite in the other.

Monitored Anaesthesia Care (MAC) refers to the provision of sedation and/or analgesia during diagnostic and therapeutic procedures in the presence or absence of regional anaesthesia. Monitored anaesthesia care has developed as a key component of modern ambulatory surgery and offers patients the benefits of regional anaesthesia with sufficient sedation to permit the patient to tolerate the procedure. Sedation is not the exclusive province of the anaesthetist. Sedative techniques are practised by other clinicians using a wide variety of agents. Used appropriately, monitored anaesthesia care extends the repertoire of surgical procedures that can be considered for ambulatory patients and may also permit day surgery in patient groups who would traditionally be considered unsuitable for outpatient general anaesthesia. Monitored anaesthesia care spans the continuum between conscious sedation and general anaesthesia. It is recognised that in such cases, the level of sedation may vary widely during a single case and the potential jeopardy to the cardiovascular and respiratory systems justifies the continuous presence of an anaesthetist and the deployment of additional monitoring techniques.

Intrathecal diamorphine (heroin, diacetyl morphine) 2.5 mg in isotonic saline 2.5 ml was given to 13 patients in labour through a 26 gauge Quincke needle. Three patients were given epidural bupivacaine at a mean of 295 min after injection of diamorphine and a further 2 used 50% nitrous oxide during the second stage of labour. Eight patients needed no additional analgesia for labour although 1 received a pudendal nerve block for forceps delivery. No neonatal complications attributable to diamorphine were observed. There was a high incidence of post partum headache (6/13 cases). The use of a Sprotte needle and a fine spinal catheter might overcome the limitations of spinal headache and limited duration of action respectively.