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In this article, we present a case of apixaban elimination prolonged by 450% in a patient with coronavirus disease 2019 because of multiple conditions, including drug–drug interaction, severe inflammation, and acute kidney injury. Therapeutic drug monitoring was used to explain unusual routine coagulation assays. This grand round highlights the importance of dialog between the clinician and a therapeutic drug monitoring consultant for optimal patient care.

In intensive care units, nebulization is a usual route for drug administration to patients under mechanical ventilation (MV). The effectiveness of inhalation devices as well as depositions sites of aerosols for ventilated patients remain poorly documented. In vivo human inhalation studies are scarce due to ethical restrictions because imaging techniques require radioaerosols to assess regional aerosol deposition. Thus, we developed an ex vivo respiratory model under invasive MV for preclinical aerosol deposition studies. The model was composed of ex vivo porcine respiratory tracts. MV was achieved thanks to a tracheal intubation and a medical ventilator under controlled conditions. Respiratory features were studied using analogical sensors. Then regional homogeneity of gas-ventilation was assessed with 81mKrypton scintigraphies. Finally, a proof of concept study for aerosol deposition was performed. Obtained respiratory features as well as gamma-imaging techniques, which demonstrated a homogenous regional ventilation and about 18% ± 4% of the nebulized dose deposited the respiratory tract, were in good agreement with human data available in the literature. This original ex vivo respiratory model provides a feasible, reproducible and cost-effective preclinical tool to achieve aerosol deposition studies under MV.

Background Hemodynamic response to prone position (PP) has never been studied in a large series of patients with acute respiratory distress syndrome (ARDS). The primary aim of this study was to estimate the rate of PP sessions associated with cardiac index improvement. Secondary objective was to describe hemodynamic response to PP and during the shift from PP to supine position. Methods The study was a single-center retrospective observational study, performed on ARDS patients, undergoing at least one PP session under monitoring by transpulmonary thermodilution. PP sessions performed more than 10 days after ARDS onset, or with any missing cardiac index measurements before (T1), at the end (T3), and after the PP session (T4) were excluded. Changes in hemodynamic parameters during PP were tested after statistical adjustment for volume of fluid challenges, vasopressor and dobutamine dose at each time point to take into account therapeutic changes during PP sessions. Results In total, 107 patients fulfilled the inclusion criteria, totalizing 197 PP sessions. Changes in cardiac index between T1 and T2 (early response to PP) and between T1 and T3 (late response to PP) were significantly correlated (R2 = 0.42, p

Background Predicting fluid responsiveness may help to avoid unnecessary fluid administration during acute respiratory distress syndrome (ARDS). The aim of this study was to evaluate the diagnostic performance of the following methods to predict fluid responsiveness in ARDS patients under protective ventilation in the prone position: cardiac index variation during a Trendelenburg maneuver, cardiac index variation during an end-expiratory occlusion test, and both pulse pressure variation and change in pulse pressure variation from baseline during a tidal volume challenge by increasing tidal volume (VT) to 8 ml.kg-1. Methods This study is a prospective single-center study, performed in a medical intensive care unit, on ARDS patients with acute circulatory failure in the prone position. Patients were studied at baseline, during a 1-min shift to the Trendelenburg position, during a 15-s end-expiratory occlusion, during a 1-min increase in VT to 8 ml.kg-1, and after fluid administration. Fluid responsiveness was deemed present if cardiac index assessed by transpulmonary thermodilution increased by at least 15% after fluid administration. Results There were 33 patients included, among whom 14 (42%) exhibited cardiac arrhythmia at baseline and 15 (45%) were deemed fluid-responsive. The area under the receiver operating characteristic (ROC) curve of the pulse contour-derived cardiac index change during the Trendelenburg maneuver and the end-expiratory occlusion test were 0.90 (95% CI, 0.80–1.00) and 0.65 (95% CI, 0.46–0.84), respectively. An increase in cardiac index ≥ 8% during the Trendelenburg maneuver enabled diagnosis of fluid responsiveness with sensitivity of 87% (95% CI, 67–100), and specificity of 89% (95% CI, 72–100). The area under the ROC curve of pulse pressure variation and change in pulse pressure variation during the tidal volume challenge were 0.52 (95% CI, 0.24–0.80) and 0.59 (95% CI, 0.31–0.88), respectively. Conclusions Change in cardiac index during a Trendelenburg maneuver is a reliable test to predict fluid responsiveness in ARDS patients in the prone position, while neither change in cardiac index during end-expiratory occlusion, nor pulse pressure variation during a VT challenge reached acceptable predictive performance to predict fluid responsiveness in this setting. Trial registration ClinicalTrials.gov, NCT01965574. Registered on 16 October 2013. The trial was registered 6 days after inclusion of the first patient. Electronic supplementary material The online version of this article (doi:10.1186/s13054-017-1881-0) contains supplementary material, which is available to authorized users.

Limiting tidal volume (TV) in ARDS patients may not be achieved once assisted modes are used. We systematically investigated on the bench effect of assisted modes on size and variability of TV at different breathing frequencies (BF), patient effort and ARDS severity. We used V500 Infinity ICU ventilator connected to ASL 5000 lung model mimicking mild, moderate and severe ARDS. Thirteen assisted modes were tested falling into three categories, namely volume controlled ventilation with mandatory minute ventilation (VCV-MMV), pressure-controlled ventilation (PCV) including airway pressure release ventilation (APRV) and pressure support ventilation (PSV). Two levels of BF and effort were tested for each ARDS severity in each mode. Median (first-third quartiles) TV was compared across modes using non parametric tests. Probability of TV > 6 ml/kg ideal body weight was assessed by binomial regression and expressed as odds ratio (OR) with 95% confidence intervals. TV variability was measured from coefficient of variation. TV distribution over all BF, effort and ARDS categories significantly differed across modes (P 6ml/kg was significantly increased with spontaneous breaths assisted by PSV (OR 19.36 [12.37-30.65]) and significantly reduced in APRV (OR 0.44 [0.26-0.72]) and PSV with guaranteed volume mode. Coefficient of variation of TV was greater for low BF and VCV-MMV and PCV modes. Risk of TV > 6ml/kg was significantly reduced in APRV and PSV with guaranteed volume mode. APRV had the highest variability.

Legionella are bacteria responsible for severe lung pathologies but how they are aerosolized and enter the respiratory tract remains poorly documented. Previous data using animal experimentations (especially through intratracheal instillations) led to the establishment of mathematical models allowing the estimation of aerosol dispersion risks. But direct extrapolation to humans is questionable and a model more representative of a physiological route (for example inhalation of aerosols) should be developed. The aim of this study was to determine the deposition pattern of aerosolized Legionella in a model as close as possible to the human anatomy and to the physiological respiratory function while limiting in vivo experiments. To that purpose, we used a human-porcine respiratory tract model previously published. This chimeric model consists of a replica of the upper respiratory airways made by additive manufacturing connected to ex vivo porcine lungs ventilated by passive expansion, as for humans in physiological conditions. In 6 independent experiments, fluorescent Legionella were aerosolized in the model and visualized using the Cellvizio Lab technology (probe-based confocal fluorescence microscope). Legionella were found in the whole respiratory tract. Broncho-alveolar lavages were also performed and the amount of Legionella reaching the thoracic region was quantified by culture and quantitative PCR. 0.3 to 21% of aerosolized Legionella reached the left upper lobe while only 0.003 to 0.06% the right lower lobe. To the best of our knowledge, it is the first time that experiments mimicking a real human physiological exposure are performed while limiting animal experiments.

BACKGROUND: Limiting tidal volume (VT) in patients with ARDS may not be achieved once patient-triggered breaths occur. Furthermore, ICU ventilators offer numerous patient-triggered modes that work differently across brands. We systematically investigated, using a bench model, the effect of patient-triggered modes on the size and variability of VT at different breathing frequencies (f), patient effort, and ARDS severity. METHODS: We used a V500 Infinity ICU ventilator connected to an ASL 5000 lung model whose compliance was mimicking mild, moderate, and severe ARDS. Thirteen patient-triggered modes were tested, falling into 3 categories, namely volume control ventilation with mandatory minute ventilation; pressure control ventilation, including airway pressure release ventilation (APRV); and pressure support ventilation. Two levels of f and effort were tested for each ARDS severity in each mode. Median (first-third quartiles) VT was compared across modes using non-parametric tests. The probability of VT > 6 mL/kg ideal body weight was assessed by binomial regression and expressed as the odds ratio (OR) with 95% CI. VT variability was measured from the coefficient of variation. RESULTS: VT distribution over all f, effort, and ARDS categories significantly differed across modes (P 6 mL/kg was significantly increased with spontaneous breaths patient-triggered by pressure support (OR 19.36, 95% CI 12.37–30.65) and significantly reduced in APRV (OR 0.44, 95% CI 0.26–0.72) and pressure support with guaranteed volume mode. The risk increased with increasing effort and decreasing f. Coefficient of variation of VT was greater for low f and volume control-mandatory minute ventilation and pressure control modes. APRV had the greatest within-mode variability. CONCLUSIONS: Risk of VT > 6 mL/kg was significantly reduced in APRV and pressure support with guaranteed volume mode. APRV had the highest variability. Pressure support with guaranteed volume could be tested in patients with ARDS.

Introduction: Respiratory models to assess aerosol regional deposition on human are often irrelevant or difficult to use. On the other hand, in vivo human experimentations have ethical restrictions. Objectives: This study aims to develop an ex vivo human-like respiratory tract model relevant to compare to human in vivo data, cheaper and easy to use. The main objective of this work is the validation of this model. Methods: This model includes a human plastinated head connected to an ex vivo porcine pulmonary tract ventilating artificially by passive expansion. First, a physiological study measures “pleural” depressions, tidal volumes and minute ventilation for the three respiratory rates chosen (10, 15 and 20 per minute) with three inspiratory / exiratory ratios (1/1, 1/2 and 1/3). Finally, a scintigraphy with 81m Krypton assesses the homogenous of the ventilation. Results: 36 different experiments were set for validation. At a respiratory rate of 15/minute with Inspiratory / Expiratory ratio of 1/2, the tidal volume average was 824mL (standard deviation 207mL). The scintigraphy performed on 16 ex vivo models (44.4%), showed homogenous ventilation with great similarity with human physiologic studies. Conclusion: This new model provides a realistic approach of human inhalation. Moreover, it allows variations of ventilation parameters permitting comparison to different human in vivo data. Consequently, it will likely become an indispensable work tool in aerosol deposition studies by combining research feasibility and human physiology likeness.