Population pharmacodynamic model of bicarbonate response to acetazolamide in mechanically ventilated chronic obstructive pulmonary disease patients

International audienceABSTRACT: INTRODUCTION: Acetazolamide is commonly used in chronic obstructive pulmonary disease (COPD) patients with metabolic alkalosis. Little is known of the pharmacodynamics of acetazolamide in the critically ill. We undertook a pharmacodynamic modeling of bicarbonate response to acetazolamide in COPD patients under mechanical ventilation. METHODS: This observationnal, retrospective study included 68 invasively ventilated COPD patients who received one or multiple doses of 250 or 500 mg of acetazolamide during the weaning period. Among the 68 investigated patients, 207 time-serum bicarbonate observations were available for analysis. Population pharmacodynamics was modeled using a non linear mixed effect model. The main covariates of interest were baseline demographic data, simplified acute physiology score II (SAPS II) at intensive care unit (ICU) admission, cause of respiratory failure, co-prescription of drugs interfering with the acid-base equilibrium, and serum concentrations of protein, creatinin, potassium and chloride. The effect of acetazolamide on serum bicarbonate levels at different doses and in different clinical conditions was subsequently simulated in silico. RESULTS: The main covariates interacting with acetazolamide pharmacodynamics were SAPS II at ICU-admission (P = .01), serum chloride (P 500 mg twice daily is required to reduce serum bicarbonate concentration > 5 mmol/L in presence of high serum chloride levels or co- administration of systemic corticosteroids or furosemide. CONCLUSIONS: This study identified several covariates that influenced acetazolamide pharmacodynamics and could allow a better individualization of acetazolamide dosing when treating COPD patients with metabolic alkalosis

French academic physicians had a poor knowledge of terms used in clinical epidemiology

Objectives: To assess academic physicians' understanding and usage of basic epidemiological terms commonly used in medical journals. Study Design and Setting: Observational study. A total of 274 physicians, working in a teaching hospital in Paris, France were asked to answer a questionnaire including four vignettes presenting the results of a therapeutic, a diagnostic, a prognostic study and a meta-analysis of clinical trials. Results: A total of 130 (47%) questionnaires were returned. We observed the highest proportion of good answers for questions about absolute risk reduction (87.7%), sensitivity (84.6%), and specificity (80%); and the lowest for the calculation and use of the likelihood ratio (16.9% and 9.2%, respectively). The global mean score was 5.0/10 (95% confidence interval54.6e5.4, range 0e9.4). Physicians got higher scores for questions related to treatment than for questions related to diagnosis: mean scores 7.1 (6.6e7.6) vs. 4.2 (3.8e4.6). Regression analysis did not reveal any significant relationship between global performance and physicians' age (r250.002, not significant [NS]). Conclusion: Physicians demonstrated only moderate knowledge and usage of clinical epidemiology terms used in major medical journals. Their capacity to interpret quantitative data from medical scientific literature may be limited. [Authors]]]> Epidemiology ; Health Knowledge, Attitudes, Practice ; Medical Staff, Hospital ; Physicians oai:serval.unil.ch:BIB_470C9DE8C422 2022-05-07T01:17:02Z openaire documents urnserval <oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd"> https://serval.unil.ch/notice/serval:BIB_470C9DE8C422 A neuron-specific deletion of the microRNA-processing enzyme DICER induces severe but transient obesity in mice. info:doi:10.1371/journal.pone.0116760 info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0116760 info:eu-repo/semantics/altIdentifier/pmid/25629159 Mang, G.M. Pradervand, S. Du, N.H. Arpat, A.B. Preitner, F. Wigger, L. Gatfield, D. Franken, P. info:eu-repo/semantics/article article 2015 PLoS One, vol. 10, no. 1, pp. e0116760 info:eu-repo/semantics/altIdentifier/eissn/1932-6203 urn:issn:1932-6203 <![CDATA[MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression post-transcriptionally. MiRNAs are implicated in various biological processes associated with obesity, including adipocyte differentiation and lipid metabolism. We used a neuronal-specific inhibition of miRNA maturation in adult mice to study the consequences of miRNA loss on obesity development. Camk2a-CreERT2 (Cre+) and floxed Dicer (Dicerlox/lox) mice were crossed to generate tamoxifen-inducible conditional Dicer knockouts (cKO). Vehicle- and/or tamoxifen-injected Cre+;Dicerlox/lox and Cre+;Dicer+/+ served as controls. Four cohorts were used to a) measure body composition, b) follow food intake and body weight dynamics, c) evaluate basal metabolism and effects of food deprivation, and d) assess the brain transcriptome consequences of miRNA loss. cKO mice developed severe obesity and gained 18 g extra weight over the 5 weeks following tamoxifen injection, mainly due to increased fat mass. This phenotype was highly reproducible and observed in all 38 cKO mice recorded and in none of the controls, excluding possible effects of tamoxifen or the non-induced transgene. Development of obesity was concomitant with hyperphagia, increased food efficiency, and decreased activity. Surprisingly, after reaching maximum body weight, obese cKO mice spontaneously started losing weight as rapidly as it was gained. Weight loss was accompanied by lowered O2-consumption and respiratory-exchange ratio. Brain transcriptome analyses in obese mice identified several obesity-related pathways (e.g. leptin, somatostatin, and nemo-like kinase signaling), as well as genes involved in feeding and appetite (e.g. Pmch, Neurotensin) and in metabolism (e.g. Bmp4, Bmp7, Ptger1, Cox7a1). A gene cluster with anti-correlated expression in the cerebral cortex of post-obese compared to obese mice was enriched for synaptic plasticity pathways. While other studies have identified a role for miRNAs in obesity, we here present a unique model that allows for the study of processes involved in reversing obesity. Moreover, our study identified the cortex as a brain area important for body weight homeostasis

Early-onset ventilator-associated pneumonia in adults randomized clinical trial: comparison of 8 versus 15 days of antibiotic treatment

International audiencePurposeThe optimal treatment duration for ventilator-associated pneumonia is based on one study dealing with late-onset of the condition. Shortening the length of antibiotic treatment remains a major prevention factor for the emergence of multiresistant bacteria.ObjectiveTo demonstrate that 2 different antibiotic treatment durations (8 versus 15 days) are equivalent in terms of clinical cure for early-onset ventilator-associated pneumonia.MethodsRandomized, prospective, open, multicenter trial carried out from 1998 to 2002.MeasurementsThe primary endpoint was the clinical cure rate at day 21. The mortality rate was evaluated on days 21 and 90.Results225 patients were included in 13 centers. 191 (84.9%) patients were cured: 92 out of 109 (84.4%) in the 15 day cohort and 99 out of 116 (85.3%) in the 8 day cohort (difference = 0.9%, odds ratio = 0.929). 95% two-sided confidence intervals for difference and odds ratio were [−8.4% to 10.3%] and [0.448 to 1.928] respectively. Taking into account the limits of equivalence (10% for difference and 2.25 for odds ratio), the objective of demonstrative equivalence between the 2 treatment durations was fulfilled. Although the rate of secondary infection was greater in the 8 day than the 15 day cohort, the number of days of antibiotic treatment remained lower in the 8 day cohort. There was no difference in mortality rate between the 2 groups on days 21 and 90.ConclusionOur results suggest that an 8-day course of antibiotic therapy is safe for early-onset ventilator-associated pneumonia in intubated patients

Hyperréactivité bronchique provoquée par les b2-agonistes (mécanismes de signalisation intracellulaire)

PARIS5-BU Saints-Pères (751062109) / SudocSudocFranceF

Effectiveness of a load-imposing device for cyclic stretching of isolated human bronchi: a validation study.

Mechanical ventilation may induce harmful effects in the airways of critically ill patients. Nevertheless, the effects of cyclic stretching caused by repetitive inflation-deflation of the bronchial compartment have not been well characterized in humans. The objective of the present study was to assess the effectiveness of a load-imposing device for the cyclic stretching of human bronchi.Intact bronchial segments were removed from 128 thoracic surgery patients. After preparation and equilibration in an organ bath, bronchi were stretched repetitively and cyclically with a motorized transducer. The peak force imposed on the bronchi was set to 80% of each individual maximum contraction in response to acetylcholine and the minimal force corresponded to the initial basal tone before stretching. A 1-min cycle (stretching for 15 sec, relaxing for 15 sec and resting for 30 sec) was applied over a time period ranging from 5 to 60 min. The device's performance level was assessed and the properties of the stretched bronchi were compared with those of paired, non-stretched bronchi.Despite the intrinsic capacities of the device, the targets of the tension adjustments remained variable for minimal tension (156-178%) while the peak force set point was unchanged (87-115%). In the stretched bronchi, a time-dependent rise in basal tone (P < .05 vs. non-stretched) was apparent after as little as 5 min of cyclic stretching. The stretch-induced rise in basal tone continued to increase (P < .01) after the stretching had ended. Only 60 min of cyclic stretching was associated with a significant (P < .05) increase in responsiveness to acetylcholine, relative to non-stretched bronchi.Low-frequency, low-force, cyclic loading of human bronchi is associated with elevated basal tone and acetylcholine responsiveness. The present experimental model is likely to be a useful tool for future investigations of the bronchial response to repetitive stress during mechanical ventilation

Population pharmacodynamic modeling and simulation of the respiratory effect of acetazolamide in decompensated COPD patients.

Chronic obstructive pulmonary disease (COPD) patients may develop metabolic alkalosis during weaning from mechanical ventilation. Acetazolamide is one of the treatments used to reverse metabolic alkalosis.619 time-respiratory (minute ventilation, tidal volume and respiratory rate) and 207 time-PaCO2 observations were obtained from 68 invasively ventilated COPD patients. We modeled respiratory responses to acetazolamide in mechanically ventilated COPD patients and then simulated the effect of increased amounts of the drug.The effect of acetazolamide on minute ventilation and PaCO2 levels was analyzed using a nonlinear mixed effect model. The effect of different ventilatory modes was assessed on the model. Only slightly increased minute ventilation without decreased PaCO2 levels were observed in response to 250 to 500 mg of acetazolamide administered twice daily. Simulations indicated that higher acetazolamide dosage (>1000 mg daily) was required to significantly increase minute ventilation (P<.001 vs pre-acetazolamide administration). Based on our model, 1000 mg per day of acetazolamide would increase minute ventilation by >0.75 L min(-1) in 60% of the population. The model also predicts that 45% of patients would have a decrease of PaCO2>5 mmHg with doses of 1000 mg per day.Simulations suggest that COPD patients might benefit from the respiratory stimulant effect after the administration of higher doses of acetazolamide

Comparison of the in vitro pharmacological profiles of long-acting muscarinic antagonists in human bronchus

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