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Background and Purpose Marijuana smoking is widespread in many countries, and the use of smoked synthetic cannabinoids is increasing. Smoking a marijuana joint leads to bronchodilation in both healthy subjects and asthmatics. The effects of Δ9-tetrahydrocannabinol and synthetic cannabinoids on human bronchus reactivity have not previously been investigated. Here, we sought to assess the effects of natural and synthetic cannabinoids on cholinergic bronchial contraction. Experimental Approach Human bronchi isolated from 88 patients were suspended in an organ bath and contracted by electrical field stimulation ( EFS) in the presence of the phytocannabinoid Δ9-tetrahydrocannabinol, the endogenous 2-arachidonoylglycerol, the synthetic dual CB1 and CB2 receptor agonists WIN55,212-2 and CP55,940, the synthetic, CB2-receptor-selective agonist JWH-133 or the selective GPR55 agonist O-1602. The receptors involved in the response were characterized by using selective CB1 and CB2 receptor antagonists ( SR141716 and SR144528 respectively). Key Results Δ9-tetrahydrocannabinol, WIN55,212-2 and CP55,940 induced concentration-dependent inhibition of cholinergic contractions, with maximum inhibitions of 39, 76 and 77% respectively. JWH-133 only had an effect at high concentrations. 2-Arachidonoylglycerol and O-1602 were devoid of any effect. Only CB1 receptors were involved in the response because the effects of cannabinoids were antagonized by SR141716, but not by SR144528. The cannabinoids did not alter basal tone or contractions induced by exogenous Ach. Conclusions and Implications Activation of prejunctional CB1 receptors mediates the inhibition of EFS-evoked cholinergic contraction in human bronchus. This mechanism may explain the acute bronchodilation produced by marijuana smoking. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Use comparison with indirect calorimetry to confirm the ability of our previously described equation to predict resting energy expenditure in mechanically ventilated patients. DESIGN: Prospective, validation study. SETTING: Eighteen-bed, medical intensive care unit at a teaching hospital. PATIENTS: All adult patients intubated >24 hrs were assessed for eligibility. Exclusion criteria were clinical situations that could contribute to erroneous calorimetric measurements. INTERVENTIONS: Resting energy expenditure was calculated using the original Harris-Benedict equations and those corrected for usual stress factors, the Swinamer equation, the Fusco equation, the Ireton-Jones equation, and our equation: resting energy expenditure (kcal/day) = 8 x weight (kg) + 14 x height (cm) + 32 x minute ventilation (L/min) + 94 x temperature (degrees C) - 4834. MEASUREMENTS AND MAIN RESULTS: Resting energy expenditure was measured by indirect calorimetry for the 45 included patients. Resting energy expenditure calculated with our predictive model correlated with the measured resting energy expenditure (r2 = .62, p < .0001), and Bland-Altman analysis showed a mean bias of -192 +/- 277 kcal/day, with limits of agreement ranging from -735 to 351 kcal/day. Resting energy expenditure calculated with the Harris-Benedict equations was more weakly correlated with measured resting energy expenditure (r2 = .41, p < .0001), with Bland-Altman analysis showing a mean bias of 279 +/- 346 kcal/day between them and the limits of agreement ranging from -399 to 957 kcal/day. Applying usual stress-correction factors to the Harris-Benedict equations generated wide variability, and the correlation with measured resting energy expenditure was poorer (r2 = .18, p < .0001), with Bland-Altman analysis showing a mean bias of -357 +/- 750 kcal/day and limits of agreement ranging from -1827 to 1113 kcal/day. The use of the Swinamer, Fusco, or Ireton-Jones predictive methods yielded weaker correlation between calculated and measured resting energy expenditure (r2 = .41, p < .0001; r2 = .38, p < .0001; r2 = .39, p < .0001, respectively) than our equation, and Bland-Altman analysis showed no improvement in agreement and variability between methods. CONCLUSIONS: The Faisy equation, based on static (height), less stable (weight), and dynamic biometric variables (temperature and minute ventilation), provided precise and unbiased resting energy expenditure estimations in mechanically ventilated patients. [ABSTRACT FROM AUTHOR]

Second-generation histamine H(1) receptor antagonists were developed to provide efficacious treatment of allergic rhinitis (AR) and chronic idiopathic urticaria (CIU) while decreasing adverse effects associated with first-generation agents. When comparing the efficacy and safety profiles of the newest second-generation antihistamines - desloratadine, fexofenadine and levocetirizine - many pharmacological and clinical criteria must be considered. Most importantly, these elements should not be evaluated separately but, rather, as parts of a puzzle that create a whole picture. As a class, second-generation antihistamines are highly selective for the H(1) receptor. Some bind to it with high affinity, although there is marked heterogeneity among the various compounds. They have a limited effect on the CNS, and clinical studies have noted almost no significant drug-drug interactions in the agents studied. No major cytochrome P450 inhibition has been reported with desloratadine, fexofenadine and levocetirizine, and the bioavailability of desloratadine is minimally affected by drugs interfering with transporter molecules. Of the second-generation antihistamines, desloratadine has the greatest binding affinity for the H(1) receptor. The use of desloratadine, fexofenadine and levocetirizine is not associated with clinically relevant antimuscarinic effects. Desloratadine and fexofenadine do not impair cognitive or psychomotor functioning and are comparable with placebo in terms of somnolence. Based on these pharmacological characteristics, as well as clinical endpoints such as symptom scores, quality-of-life surveys, inflammatory cell counts and investigators' global evaluations, we conclude that desloratadine, fexofenadine and levocetirizine are all efficacious treatments for AR and CIU. However, differences among the antihistamines in relation to a lack of significant interaction with drug transporter molecules and somnolence in excess of placebo may provide some advantages for the overall profile of desloratadine compared with fexofenadine and levocetirizine. [ABSTRACT FROM AUTHOR]

Introduction: Acetazolamide is commonly given to chronic obstructive pulmonary disease (COPD) patients with metabolic alkalosis. Little is known of the pharmacodynamics of acetazolamide in the critically ill. We undertook the pharmacodynamic modeling of bicarbonate response to acetazolamide in COPD patients under mechanical ventilation.Methods: This observational, 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 nonlinear mixedeffect model. The main covariates of interest were baseline demographic data, Simplified Acute Physiology Score II (SAPS II) at 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 = 0.01), serum chloride (P < 0.001) and concomitant administration of corticosteroids (P = 0.02). Co-administration of furosemide significantly decreased bicarbonate elimination. Acetazolamide induced a decrease in serum bicarbonate with a dose-response relationship. The amount of acetazolamide inducing 50% of the putative maximum effect was 117 ± 21 mg. According to our model, an acetazolamide dosage > 500 mg twice daily is required to reduce serum bicarbonate concentrations > 5 mmol/L in the presence of high serum chloride levels or coadministration 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. [ABSTRACT FROM AUTHOR]

Introduction: Lung inflation may have deleterious effects on the alveoli during mechanical ventilation. However, the consequences of stretch during excessive lung inflation on basal tone and responsiveness of human bronchi are unknown. This study was undertaken to devise an experimental model of acute mechanical stretch in isolated human bronchi and to investigate its effect on airway tone and responsiveness.Methods: Bronchi were removed from 48 thoracic surgery patients. After preparation and equilibration in an organ bath, bronchial rings were stretched for 5 min using a force (2.5 × basal tone) that corresponded to airway-inflation pressure > 30 cm H₂O. The consequences of stretch were examined by using functional experiments, analysis of organ-bath fluid, and ribonucleic acid (RNA) isolation from tissue samples.Results: Following removal of the applied force the airways immediately developed an increase in basal tone (P < 0.0001 vs. paired controls) that was sustained and it did so without significantly increasing responsiveness to acetylcholine. The spontaneous tone was abolished with a Rho-kinase inhibitor and epithelium removal, a leukotriene antagonist or nitric oxide synthase inhibitors reduced it, whereas indomethacin, sensory nerve inhibitors or antagonists for muscarinic, endothelin and histamine receptors had no effect. Stretch enhanced leukotriene-E4 production during the immediate spontaneous contraction of human bronchi (P < 0.05). Moreover, stretch up-regulated the early mRNA expression of genes involved in wingless-type mouse mammary tumor virus integration-site family (WNT)-signaling and Rho-kinase pathways.Conclusions: Stretching human bronchi for only 5 min induces epithelial leukotriene release via nitric oxide synthase activation and provokes a myogenic response dependent on Rho-kinase and WNT-signaling pathways. From a clinical perspective, these findings highlight the response of human airway to acute mechanical stress during excessive pulmonary inflation. [ABSTRACT FROM AUTHOR]

We investigated whether fenoterol was able to enhance contractile responsiveness to neurokinin A (NKA) on the guinea-pig isolated trachea. We then studied the effects of two inhibitors of nuclear factor kappa B (NFκB), gliotoxin and pyrrolidine dithiocarbamate, and of the tachykinin NK1, NK2 and NK3 receptor antagonists, SR 140333, SR 48968 and SR 142801 and determined whether tachykinin receptor gene expression was up-regulated in the trachea after exposure to fenoterol. Fenoterol (0.1 μM, 15 h, 21 °C) induced an increased contractile response to NKA (mean of difference in maximal tension between control and fenoterol ± S.E.M; +0.47 ± 0.14 g, n = 26, P < 0.01). This hyperresponsiveness was strongly reduced by co-incubation with gliotoxin (0.1 μg/ml) or pyrrolidine dithiocarbamate (0.1 mM) and abolished by SR 140333 (0.1 μM) and SR 142801 (0.1 μM). SR 48968 (0.1 μM) diminished the tracheal contractility to NKA but failed to reduce the hyperreactivity induced by fenoterol. Tachykinin NK1 receptor (NK1R), NK2 receptor (NK2R) and NK3 receptor (NK3R) gene expression was analyzed by semiquantitative RT–PCR. Compared to control tissues, NK1R and NK2R mRNA expression was increased by about 1.6-fold and 1.4-fold, respectively, in tissues treated with fenoterol. We were unable to detect the presence of NK3R mRNA in the guinea-pig trachea. In conclusion, fenoterol induces tracheal hyperresponsiveness to NKA and an up-regulation of NK1R and NK2R gene expression. The hyperresponsiveness implicates the NFκB pathway and is abolished by tachykinin NK1 (SR 140333) and NK3 (SR 142801) receptor antagonists. [Copyright &y& Elsevier]

Background: Community-acquired pneumonia (CAP) requires urgent and specific antimicrobial therapy. However, the causal pathogen is typically unknown at the point when anti-infective therapeutics must be initiated. Physicians synthesize information from diverse data streams to make appropriate decisions. Artificial intelligence (AI) excels at finding complex relationships in large volumes of data. We aimed to evaluate the abilities of experienced physicians and AI to answer this question at patient admission: is it a viral or a bacterial pneumonia?, Methods: We included patients hospitalized for CAP and recorded all data available in the first 3-h period of care (clinical, biological and radiological information). For this proof-of-concept investigation, we decided to study only CAP caused by a singular and identified pathogen. We built a machine learning model prediction using all collected data. Finally, an independent validation set of samples was used to test the pathogen prediction performance of: (i) a panel of three experts and (ii) the AI algorithm. Both were blinded regarding the final microbial diagnosis. Positive likelihood ratio (LR) values > 10 and negative LR values < 0.1 were considered clinically relevant., Results: We included 153 patients with CAP (70.6% men; 62 [51-73] years old; mean SAPSII, 37 [27-47]), 37% had viral pneumonia, 24% had bacterial pneumonia, 20% had a co-infection and 19% had no identified respiratory pathogen. We performed the analysis on 93 patients as co-pathogen and no-pathogen cases were excluded. The discriminant abilities of the AI approach were low to moderate (LR+ = 2.12 for viral and 6.29 for bacterial pneumonia), and the discriminant abilities of the experts were very low to low (LR+ = 3.81 for viral and 1.89 for bacterial pneumonia)., Conclusion: Neither experts nor an AI algorithm can predict the microbial etiology of CAP within the first hours of hospitalization when there is an urgent need to define the anti-infective therapeutic strategy.

Background: Bitter-taste receptors (TAS2Rs) are involved in airway relaxation but are also expressed in human blood leukocytes. We studied TAS2R expression and the effects of TAS2R agonists on the lipopolysaccharide (LPS)-induced cytokine release in human lung macrophages (LMs)., Methods: Lung macrophages were isolated from patients undergoing surgery for carcinoma. We used RT-qPCR to measure transcripts of 16 TAS2Rs (TAS2Rs 3/4/5/7/8/9/10/14/19/20/31/38/39/43/45 and 46) in unstimulated and LPS-stimulated (10 ng.mL -1 ) LMs. The macrophages were also incubated with TAS2R agonists for 24 h. Supernatant levels of the cytokines TNF-α, CCL3, CXCL8 and IL-10 were measured using ELISAs., Results: The transcripts of all 16 TAS2Rs were detected in macrophages. The addition of LPS led to an increase in the expression of most TAS2Rs, which was significant for TAS2R7 and 38. Although the promiscuous TAS2R agonists, quinine and denatonium, inhibited the LPS-induced release of TNF-α, CCL3 and CXCL8, diphenidol was inactive. Partially selective agonists (dapsone, colchicine, strychnine, and chloroquine) and selective agonists [erythromycin (TAS2R10), phenanthroline (TAS2R5), ofloxacin (TAS2R9), and carisoprodol (TAS2R14)] also suppressed the LPS-induced cytokine release. In contrast, two other agonists [sodium cromoglycate (TAS2R20) and saccharin (TAS2R31 and 43)] were inactive. TAS2R agonists suppressed IL-10 production - suggesting that this anti-inflammatory cytokine is not involved in the inhibition of cytokine production., Conclusion: Human LMs expressed TAS2Rs. Experiments with TAS2R agonists' suggested the involvement of TAS2Rs 3, 4, 5, 9, 10, 14, 30, 39 and 40 in the inhibition of cytokine production. TAS2Rs may constitute new drug targets in inflammatory obstructive lung disease., (Copyright © 2019 Grassin-Delyle, Salvator, Mantov, Abrial, Brollo, Faisy, Naline, Couderc and Devillier.)

Background: Epinephrine may impair splanchnic blood flow, but the impact of epinephrine dose on the occurrence of clinically significant gastrointestinal bleeding (CSGB) caused by stress ulcer remains unclear. We investigated the effect of epinephrine dose on the occurrence of stress ulcer-related CSGB in intensive care unit (ICU) patients., Methods: In this prospective, observational, cohort study conducted in a French teaching hospital, 40 consecutive ICU patients receiving epinephrine infusion in whom a stress ulcer was diagnosed by an upper gastrointestinal endoscopy were included, from February 2010 to July 2015. The effects of epinephrine dose, and other covariates, on the occurrence of stress ulcer-related CSGB were analyzed using a multiple logistic regression model for repeated measures: At each observation, each patient serves as his own control., Results: A total of 1484 time-dependent epinephrine dose modifications were available for analysis. The median epinephrine dose rate was 0.8 (0-9.5) mg/h, and the median epinephrine cumulative dose was 44.8 (2.6-2343) mg. Epinephrine, expressed as the average dose per day at time t, had a significant protective effect on the occurrence of stress ulcer (odds ratio 0.22; 95% confidence interval (CI), 0.12-0.38; p < 0.0001, for a log10 increase of epinephrine dose). Enteral feeding had also a protective effect (odds ratio 0.55; 95% CI 0.41-0.72; p < 0.0001, for a log10 increase of kcal/day). Only renal replacement therapy increased the occurrence of stress ulcer in the model., Conclusions: An increase in the average dose of epinephrine per day increased the time to occurrence of stress ulcer in critically ill patients.

Background and Purpose: Long-acting muscarinic antagonists (LAMAs) have been recommended for the treatment of chronic obstructive pulmonary disease and (more recently) asthma. However, the in vitro pharmacological profiles of the four LAMAs currently marketed (tiotropium, umeclidinium, aclidinium and glycopyrronium) have not yet been compared (relative to ipratropium) by using the same experimental approach., Experimental Approach: With a total of 560 human bronchial rings, we investigated the antagonists' potency, onset and duration of action for inhibition of the contractile response evoked by electrical field stimulation. We also evaluated the antagonists' potency for inhibiting cumulative concentration-contraction curves for acetylcholine and carbachol., Key Results: The onset and duration of action were concentration-dependent. At submaximal, equipotent concentrations, the antagonists' onsets of action were within the same order of magnitude. However, the durations of action differed markedly. After washout, ipratropium's inhibitory activity decreased rapidly (within 30-90 min) but those of tiotropium and umeclidinium remained stable (at above 70%) for at least 9 h. Aclidinium and glycopyrronium displayed less stable inhibitory effects, with a progressive loss of inhibition at submaximal concentrations. In contrast to ipratropium, all the LAMAs behaved as insurmountable antagonists by decreasing the maximum responses to both acetylcholine and carbachol., Conclusions and Implications: The observed differences in the LAMAs' in vitro pharmacological profiles in the human bronchus provide a compelling pharmacological rationale for the differences in the drugs' respective recommended daily doses and frequencies of administration., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Atrial tachyarrhythmias (AT) are common in intensive care unit (ICU) patients and might contribute to hemodynamic instability if heart rate (HR) is persistently too rapid. We aimed to assess if HR control below 115 or 130bpm with amiodarone improves hemodynamics in ICU patients with AT. This observational study included 73 ICU patients with disabling AT receiving amiodarone for HR control. A total of 525 changes (mainly within 4-8h) in mean arterial pressure (MAP) and 167 changes in plasma lactate in response to HR variations above 115 or 130bpm were analyzed. Epinephrine, sedative drugs, fluid loading, use of diuretics, continuous renal replacement therapy and amiodarone dosing were among covariables assessed. Univariable analysis showed that HR variations above 115bpm were poorly correlated to change in MAP (r=0.11, p<0.01). Multivariable analysis showed that changes in MAP were still positively associated to HR variation (p<0.05) and to initiation or termination of epinephrine (p<0.05) or sedatives infusions (p<0.05). Changes in plasma lactate did not correlate to HR variations above 115bpm. When considering 130 bpm as a threshold, HR variations were not associated to changes in MAP or to changes in plasma lactate. Amiodarone dose was associated to HR decrease but not to MAP or plasma lactate increase. In ICU patients with AT, strict HR control below 115bpm or 130bpm with amiodarone does not improve hemodynamics. A prospective randomized trial assessing strict versus lenient HR control in this setting is needed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: In vivo, the airways are constantly subjected to oscillatory strain (due to tidal breathing during spontaneous respiration) and (in the event of mechanical ventilation) positive pressure. This exposure is especially problematic for the cartilage-free bronchial tree. The effects of cyclic stretching (other than high-force stretching) have not been extensively characterized. Hence, the objective of the present study was to investigate the functional and transcriptional response of human bronchi to repetitive mechanical stress caused by low-frequency, low-force cyclic stretching., Methods: After preparation and equilibration in an organ bath, human bronchial rings from 66 thoracic surgery patients were stretched in 1-min cycles of elongation and relaxation over a 60-min period. For each segment, the maximal tension corresponded to 80% of the reference contraction (the response to 3 mM acetylcholine). The impact of cyclic stretching (relative to non-stretched controls) was examined by performing functional assessments (epithelium removal and incubation with sodium channel agonists/antagonists or inhibitors of intracellular pathways), biochemical assays of the organ bath fluid (for detecting the release of pro-inflammatory cytokines), and RT-PCR assays of RNA isolated from tissue samples., Results: The application of low-force cyclic stretching to human bronchial rings for 60 min resulted in an immediate, significant increase in bronchial basal tone, relative to non-cyclic stretching (4.24 ± 0.16 g vs. 3.28 ± 0.12 g, respectively; p < 0.001). This cyclic stimulus also increased the affinity for acetylcholine (-log EC50: 5.67 ± 0.07 vs. 5.32 ± 0.07, respectively; p p < 0.001). Removal of airway epithelium and pretreatment with the Rho-kinase inhibitor Y27632 and inward-rectifier K+ or L-type Ca 2+ channel inhibitors significantly modified the basal tone response. Exposure to L-NAME had opposing effects in all cases. Pro-inflammatory pathways were not involved in the response; cyclic stretching up-regulated the early mRNA expression of MMP9 only, and was not associated with changes in organ bath levels of pro-inflammatory mediators., Conclusion: Low-frequency, low-force cyclic stretching of whole human bronchi induced a myogenic response rather than activation of the pro-inflammatory signaling pathways mediated by mechanotransduction.

Objective: Our purpose was to identify potential organizational factors that contributed to life-threatening adverse events in adult intensive care unit., Methods: A prospective, observational, dynamic cohort study was carried out from January 2006 to December 2013 in a 20-bed adult medical intensive care unit. All patients admitted to the intensive care unit and who experienced one or more selected life-threatening adverse events (mainly unexpected cardiac arrest, unplanned extubation, reintubation after planned extubation, and readmission within 48h of intensive care unit discharge) were included in the analysis. Negative binomial regression was used to model how human resources, work organization, and intensive care activity influenced the monthly rate of selected severe adverse events. Data were collected from local and national databases., Results: Overall, 638 severe adverse events involving 498 patients were recorded. Adverse events increased seasonally in May, November and December (p<.001 vs other months). The proportion of inexperienced nurses and doctors' working hours could not explain these seasonal peaks of adverse events. Multivariate analysis identified bed-to-nurse ratio and the arrival of inexperienced residents or senior registrars as being independently associated with the rate of adverse events (incidence risk ratio=1.36 (95% confidence interval, 1.05-1.75), and 1.07 (95% confidence interval, 1.01-1.13), respectively; p=.01 in both cases). According to this model, a one-unit increase in the day-night shifts carried out by each nurse per month tended to reduce the rate of adverse events (incidence risk ratio=0.60 (95% confidence interval, 0.36-1.01), p=.05). Severity at intensive care unit admission did not influence the rate of adverse events (incidence risk ratio=1.02 (95% confidence interval, 1.00-1.04), p=.12)., Conclusions: Results identify nurse workload and the arrival of inexperienced residents or senior registrars as risk factors for the occurrence of life-threatening adverse events in the adult medical intensive care unit. Limiting fluctuations in bed-to-nurse ratio and providing inexperienced medical staff members with sufficient supervision may decrease severe adverse events in critically ill patients., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Short-acting β2-agonists (SABA) are widely used in the emergency department (ED) to treat patients with decompensated chronic obstructive pulmonary disease (COPD). We sought to model the effectiveness of nebulized SABA (terbutaline) on clinically relevant parameters associated with a reduction in work of breathing or respiratory muscle fatigue in decompensated COPD patients admitted to the ED.Forty consecutive decompensated COPD patients (having received at least one dose of nebulized terbutaline during their stay in the ED) were included in an observational cohort study. The terbutaline dose received at time t was expressed as cumulative dose and as a rate (mg/day). The associations between the terbutaline dose and time-dependent outcome parameters (respiratory rate, heart rate, arterial blood gases, and, as a marker of terbutaline's systemic effect, serum potassium) were analyzed using a nonlinear, mixed-effects model. The effect of various covariates influencing terbutaline's effectiveness (baseline characteristics and concomitant treatments) was assessed on the model.Among the investigated patients, a total of 377 time-dependent observations were available for analysis. Neither the cumulative dose nor the dose rate at time t significantly influenced the arterial blood gas parameters or heart rate. The cumulative dose of terbutaline was associated with a lower serum potassium level (P < 0.001) and, less significantly, a lower respiratory frequency (P = 0.036). In a tertile analysis, the need for post-ED hospitalization was not associated with the cumulative dose or dose rate of terbutaline.Overall, the results of our modeling study strongly suggest that terbutaline dose did not influence time-dependent outcomes other than serum potassium, and thus call into question the systematic administration of inhaled SABA to patients admitted to the ED for decompensated COPD.

Aims: Amiodarone is the gold-standard medication to control heart rate in critically ill patients with atrial tachyarrhythmias (ATs); however, effective doses and covariates influencing its efficacy remain unknown. We therefore performed pharmacodynamic modeling of heart rate reduction induced by amiodarone in these patients., Methods and Results: This observational study included 80 consecutive severely ill patients receiving amiodarone to treat ATs. A total of 1348 time-heart rate observations with 361 amiodarone dose administrations were analyzed during a period of up to 6 days after hospital treatment initiation using a nonlinear mixed-effect model. Pretreatment with amiodarone before intensive care administration, paroxysmal versus persistent AT, catecholamine infusion, and fluid and magnesium loading were among the covariates assessed in the model. In case of paroxysmal AT in a patient not pretreated with amiodarone, a 300 mg intravenous loading dose combined with an 800 mg oral dose on the first day, followed by 800 mg/day orally for 4 days was effective in achieving a heart rate between 80 and 115 bpm within the first day, and to maintain it during the next 4 days. Corresponding doses were twice as high in patients with persistent AT. Use of intravenous magnesium (p < 0.02) and fluid loading (p < 0.02) was associated with an earlier and greater heart rate decrease, while use of dobutamine had an opposite influence (p < 0.05)., Conclusions: In critically ill patients with AT, the dose of amiodarone required to control heart rate is influenced by the type of AT and by other easily measurable conditions which may allow better individualization of amiodarone dosing.

Importance: Acetazolamide has been used for decades as a respiratory stimulant for patients with chronic obstructive pulmonary disease (COPD) and metabolic alkalosis, but no large randomized placebo-controlled trial is available to confirm this approach., Objective: To determine whether acetazolamide reduces mechanical ventilation duration in critically ill patients with COPD and metabolic alkalosis., Design, Setting, and Participants: The DIABOLO study, a randomized, double-blind, multicenter trial, was conducted from October 2011 through July 2014 in 15 intensive care units (ICUs) in France. A total of 382 patients with COPD who were expected to receive mechanical ventilation for more 24 hours were randomized to the acetazolamide or placebo group and 380 were included in an intention-to treat analysis., Interventions: Acetazolamide (500-1000 mg, twice daily) vs placebo administered intravenously in cases of pure or mixed metabolic alkalosis, initiated within 48 hours of ICU admission and continued during the ICU stay for a maximum of 28 days., Main Outcomes and Measures: The primary outcome was the duration of invasive mechanical ventilation via endotracheal intubation or tracheotomy. Secondary outcomes included changes in arterial blood gas and respiratory parameters, weaning duration, adverse events, use of noninvasive ventilation after extubation, successful weaning, the duration of ICU stay, and in-ICU mortality., Results: Among 382 randomized patients, 380 (mean age, 69 years; 272 men [71.6%]; 379 [99.7%] with endotracheal intubation) completed the study. For the acetazolamide group (n = 187), compared with the placebo group (n = 193), no significant between-group differences were found for median duration of mechanical ventilation (-16.0 hours; 95% CI, -36.5 to 4.0 hours; P = .17), duration of weaning off mechanical ventilation (-0.9 hours; 95% CI, -4.3 to 1.3 hours; P = .36), daily changes of minute-ventilation (-0.0 L/min; 95% CI, -0.2 to 0.2 L/min; P = .72), or partial carbon-dioxide pressure in arterial blood (-0.3 mm Hg; 95% CI, -0.8 to 0.2 mm Hg; P = .25), although daily changes of serum bicarbonate (between-group difference, -0.8 mEq/L; 95% CI, -1.2 to -0.5 mEq/L; P < .001) and number of days with metabolic alkalosis (between-group difference, -1; 95% CI, -2 to -1 days; P < .001) decreased significantly more in the acetazolamide group. Other secondary outcomes also did not differ significantly between groups., Conclusions and Relevance: Among patients with COPD receiving invasive mechanical ventilation, the use of acetazolamide, compared with placebo, did not result in a statistically significant reduction in the duration of invasive mechanical ventilation. However, the magnitude of the difference was clinically important, and it is possible that the study was underpowered to establish statistical significance., Trial Registration: clinicaltrials.gov Identifier: NCT01627639.

Models are mathematical tools used to describe real-world features. Therapeutic interventions in the field of critical care medicine may easily be translated into such models. Indeed, numerous variables influencing drug pharmacokinetics and pharmacodynamics are systematically documented in the intensive care unit over time. Organ failure, fluid shifts, other drug administration, and renal replacement therapy may cause changes in physiological values, such as body weight and composition, temperature, serum protein levels, arterial pH, and renal or hepatic function. Trials assessing the efficacy and safety of novel drugs usually exclude critically ill patients, and guidelines regarding drug dosage rarely apply to such patients. Modeling in the critically ill may allow physicians to inform decisions related to therapeutic interventions, particularly relating to infectious diseases. However, few clinicians are familiar with these methods. Here, we present a current overview of population pharmacokinetic and pharmacodynamic models applicable in critically ill patients aimed at nonspecialists and then emphazize recent potential of modeling for optimizing treatments and care in the intensive care unit., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

Purpose: Caloric insufficiency during the first week of intensive care unit (ICU) stay was reported to be associated with increased infection rates, especially ICU-acquired bloodstream infection (ICU-BSI). However, the predisposition to ICU-BSI by a given pathogen remains not well known. We aimed to determine the impact of early energy-calorie deficit on the pathogens responsible for ICU-BSI., Design: Prospective, observational, cohort study in a 18-bed medical ICU of a tertiary care hospital., Methods: Daily energy balance (energy-calorie intakes minus calculated energy-calorie expenditure) was compared according to the microbiological results of the blood cultures of 92 consecutive prolonged (at least 96 h) acute mechanically ventilated patients who developed a first episode of ICU-BSI., Results: Among the 92 ICU-BSI, nine were due to methicillin-resistant Staphylococcus aureus (MRSA). The cumulated energy deficit of patients with MRSA ICU-BSI was greater than those with ICU-BSI caused by other pathogens (-1,348 ± 260 vs -1,000 ± 401 kcal/day from ICU admission to day of ICU-BSI, p = 0.008). ICU admission, risk factors for nosocomial infections, nutritional status, and conditions potentially limiting feeding did not differ significantly between the two groups. Patients with MRSA ICU-BSI had lower delivered energy and similar energy expenditure, causing higher energy deficits. More severe energy deficit and higher rate of MRSA blood cultures (p = 0.01 comparing quartiles) were observed., Conclusions: Early in-ICU energy deficit was associated with MRSA ICU-BSI in prolonged acute mechanically ventilated patients. Results suggest that limiting the early energy deficit could be a way to optimize MRSA ICU-BSI prevention.

Background: Regular use of β2-agonists may enhance non-specific airway responsiveness. The wingless/integrated (Wnt) signaling pathways are responsible for several cellular processes, including airway inflammation and remodeling while cAMP-PKA cascade can activate the Wnt signaling. We aimed to investigate whether the Wnt signaling pathways are involved in the bronchial hyperresponsiveness induced by prolonged exposure to β2-adrenoceptor agonists in human isolated airways., Methods: Bronchi were surgically removed from 44 thoracic surgery patients. After preparation, bronchial rings and primary cultures of bronchial epithelial cells were incubated with fenoterol (0.1 µM, 15 hours, 37 °C), a β2-agonist with high intrinsic efficacy. The effects of inhibitors/blockers of Wnt signaling on the fenoterol-induced airway sensitization were examined and the impact of fenoterol exposure on the mRNA expression of genes interacting with Wnt signaling or cAMP-PKA cascade was assessed in complete bronchi and in cultured epithelial cells., Results: Compared to paired controls, fenoterol-sensitization was abolished by inhibition/blockage of the Wnt/β-catenin signaling, especially the cell-surface LRP5/6 co-receptors or Fzd receptors (1 µM SFRP1 or 1 µM DKK1) and the nuclear recruitment of TCF/LEF transcriptions factors (0.3 µM FH535). Wnt proteins secretion did not seem to be involved in the fenoterol-induced sensitization since the mRNA expression of Wnt remained low after fenoterol exposure and the inactivator of Wnt secretion (1 µM IWP2) had no effect on the fenoterol-sensitization. Fenoterol exposure did not change the mRNA expression of genes regulating Wnt signaling or cAMP-PKA cascade., Conclusions: Collectively, our pharmacological investigations indicate that fenoterol-sensitization is modulated by the inhibition/blockage of canonical Wnt/β-catenin pathway, suggesting a phenomenon of biased agonism in connection with the β2-adrenoceptor stimulation. Future experiments based on the results of the present study will be needed to determine the impact of prolonged fenoterol exposure on the extra- and intracellular Wnt signaling pathways at the protein expression level.

Background and Objective: Vancomycin is commonly used to treat serious methicillin-resistant staphylococcal infections, especially post-sternotomy mediastinitis (PSM). However, information on pharmacokinetics and pharmacodynamics in intensive care unit (ICU) patients remains scarce. We conducted vancomycin pharmacokinetic-pharmacodynamic modeling for ICU patients with PSM., Methods: This cohort study included 30 consecutive patients who received multiple vancomycin doses during primary closed drainage of PSM with Redon catheters, targeting serum drug trough concentrations of 25-35 mg/L, and generating 359 serum vancomycin concentration-time values for analysis. Population pharmacodynamics served to describe the withdrawal of Redon catheters, i.e., the probability of in-ICU cure., Results: Vancomycin pharmacokinetics corresponded to a two-compartment open model with first-order elimination kinetics. Mean [between-subject variability] population estimates were 1.91 (men)/1.25 (women) [0.28] L/h for vancomycin elimination, with intercompartmental clearance of 5.71 [1.01] L/h, and respective central and peripheral distribution volumes of 21.9 and 68 [0.53] L. Vancomycin clearance increased with body weight and declined with severity at ICU admission and serum creatinine (SCr), thereby allowing the prediction of the vancomycin plateau. Intercompartmental clearance decreased with diabetes mellitus (-70 %). The probability of withdrawing all Redon catheters (patient cured) was dependent only on the area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) exposures ratio in plasma. Neither preoperative factors, antistaphylococcal co-treatments, nor the initial number of Redon catheters significantly influenced this probability. The AUC/MIC exposures ratio had no significant effect on SCr levels., Conclusion: These modeling analysis results identified five clinically relevant covariates that influenced vancomycin pharmacokinetics and might achieve better individualization of vancomycin dosing for methicillin-resistant staphylococcal PSM in ICU patients.