Development of Alternative Models to In Vivo Animal Human Experiments for Regional Aerosol Deposition

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Nicotine delivery from the refill liquid to the aerosol via high-power e-cigarette device

International audienceTo offer an enhanced and well-controlled nicotine delivery from the refill liquid to the aerosol is a key point to adequately satisfy nicotine cravings using electronic nicotine delivery systems (ENDS). A recent high-power ENDS, exhibiting higher aerosol nicotine delivery than older technologies, was used. The particle size distribution was measured using a cascade impactor. The effects of the refill liquid composition on the nicotine content of each size-fraction in the submicron range were investigated. Nicotine was quantified by liquid chromatography coupled with tandem mass spectrometry. Particle size distribution of the airborne refill liquid and the aerosol nicotine demonstrated that the nicotine is equally distributed in droplets regardless of their size. Results also proved that the nicotine concentration in aerosol was significantly lower compared to un-puffed refill liquid. A part of the nicotine may be left in the ENDS upon depletion, and consequently a portion of the nicotine may not be transferred to the user. Thus, new generation high-power ENDS associated with propylene glycol/vegetable glycerin (PG/VG) based solvent were very efficient to generate carrier-droplets containing nicotine molecules with a constant concentration. Findings highlighted that a portion of the nicotine in the refill liquid may not be transferred to the user

Impact of power level and refill liquid composition on the aerosol output and particle size distribution generated by a new-generation e-cigarette device

The new high-power Electronic Nicotine Delivery System (ENDS) can generate aerosols with higher nicotine concentrations than older ENDS . Aerosol particle sizes affect deposition patterns and then plasma nicotine levels in vapers. Consequently, understanding the factors influencing particle size distribution of high-power ENDS is relevant to assess their performance in terms of nicotine delivery. The particle size distribution and the aerosol output (aerosol mass) were measured using cascade impactors. The effects of the refill liquid composition (80% PG/20% VG vs. 80% VG/20% PG; PG refers to propylene glycol and VG to vegetable glycerin) and the power level of the battery (from 7 W to 22 W) were investigated. The aerosol output increases significantly with the power level following a logarithmic law. The PG/VG ratio also has an impact on the aerosol output. The higher the VG content in the refill liquid, the higher is the aerosol output. Besides, particle size distribution is positively related to the power level, following linear correlations between the mass median aerodynamic diameter (MMAD) and the power level in the range of 7-22 W. A moderate impact of the PG/VG ratio on size distribution is equally observed. Changes in the power level allow the transition between a dominant mode with MMAD from 613 nm to 949 nm. We demonstrated that the power level can strongly change the aerodynamic properties of high-power ENDS, especially at high voltage. Associated with the aerosol nicotine level assessment, MMAD could be determined as a means for comparing ENDS devices and nicotine delivery

Assessment of new-generation high-power electronic nicotine delivery system as thermal aerosol generation device for inhaled bronchodilators

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Impact of gas humidification and nebulizer position under invasive ventilation: preclinical comparative study of regional aerosol deposition

Abstract Successful aerosol therapy in mechanically ventilated patients depends on multiple factors. Among these, position of nebulizer in ventilator circuit and humidification of inhaled gases can strongly influence the amount of drug deposited in airways. Indeed, the main objective was to preclinically evaluate impact of gas humidification and nebulizer position during invasive mechanical ventilation on whole lung and regional aerosol deposition and losses. Ex vivo porcine respiratory tracts were ventilated in controlled volumetric mode. Two conditions of relative humidity and temperature of inhaled gases were investigated. For each condition, four different positions of vibrating mesh nebulizer were studied: (i) next to the ventilator, (ii) right before humidifier, (iii) 15 cm to the Y-piece adapter and (iv) right after the Y-piece. Aerosol size distribution were calculated using cascade impactor. Nebulized dose, lung regional deposition and losses were assessed by scintigraphy using 99mtechnetium-labeled diethylene-triamine-penta-acetic acid. Mean nebulized dose was 95% ± 6%. For dry conditions, the mean respiratory tract deposited fractions reached 18% (± 4%) next to ventilator and 53% (± 4%) for proximal position. For humidified conditions, it reached 25% (± 3%) prior humidifier, 57% (± 8%) before Y-piece and 43% (± 11%) after this latter. Optimal nebulizer position is proximal before the Y-piece adapter showing a more than two-fold higher lung dose than positions next to the ventilator. Dry conditions are more likely to cause peripheral deposition of aerosols in the lungs. But gas humidification appears hard to interrupt efficiently and safely in clinical use. Considering the impact of optimized positioning, this study argues to maintain humidification

Impact of medical face mask wear on bacterial filtration efficiency and breathability

International audienceWearing a medical mask for longer than the manufacturer's recommended 4 h would reduce the number of masks used and limit their environmental impact. The objective of this study was to determine if a medical mask could be worn for an extended period of time by simulating different wearing conditions. A simulator was developed to reproducibly study various experimental conditions (wearing time, breathing pattern, mask fit, inhaled air humidity) by placing the masks on a 3D replica of the upper airways connected to a respiratory pump. Medical mask performance was determined by assessing normative requirements: bacterial filtration and breathability. No impact on performance was observed for wearing times from 2 h to 8 h. Similarly, when simulating moderate respiratory effort or at rest, various humidity levels in the inhaled air or different fitting conditions, no influence on performance was found. These results imply that none of these experimental conditions appear to have a significant impact on mask performance. In conclusion some medical masks can be used for up to 8 h under different wearing conditions without significant decrease in their bacterial filtration and breathability performance. This recommendation of a possible rise of usage duration would limit mask waste, and thus environmental consequence

Change in cardiac output during Trendelenburg maneuver is a reliable predictor of fluid responsiveness in patients with acute respiratory distress syndrome in the prone position under protective ventilation

Abstract 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

Hemodynamic effects of extended prone position sessions in ARDS

Abstract 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 (R 2 = 0.42, p < 0.001) with a concordance rate amounting to 85%. Cardiac index increased significantly between T1 and T3 in 49 sessions (25% [95% confidence interval (CI95%) 18–32%]), decreased significantly in 46 (23% [CI95% 16–31%]), and remained stable in 102 (52% [CI95% 45–59%]). Global end-diastolic volume index (GEDVI) increased slightly but significantly from 719 ± 193 mL m−2 at T1 to 757 ± 209 mL m−2 at T3 and returned to baseline values at T4. Cardiac index and oxygen delivery decreased slightly but significantly from T3 to T4, without detectable increase in lactate level. Patients who increased their cardiac index during PP had significantly lower CI, GEDVI, global ejection fraction at T1, and received significantly more fluids than patients who did not. Conclusion PP is associated with an increase in cardiac index in 18% to 32% of all PP sessions and a sustained increase in GEDVI reversible after return to supine position. Return from prone to supine position is associated with a slight hemodynamic impairment

Development of an ex vivo preclinical respiratory model of idiopathic pulmonary fibrosis for aerosol regional studies

International audienceIdiopathic pulmonary fibrosis is a progressive disease with unsatisfactory systemic treatments. Aerosol drug delivery to the lungs is expected to be an interesting route of administration. However, due to the alterations of lung compliance caused by fibrosis, local delivery remains challenging. This work aimed to develop a practical, relevant and ethically less restricted ex vivo respiratory model of fibrotic lung for regional aerosol deposition studies. This model is composed of an Ear-Nose-Throat replica connected to a sealed enclosure containing an ex vivo porcine respiratory tract, which was modified to mimic the mechanical properties of fibrotic lung parenchyma-i.e. reduced compliance. Passive respiratory mechanics were measured. 81m Kr scintigraphies were used to assess the homogeneity of gas-ventilation, while regional aerosol deposition was assessed with 99m Tc-DTPA scintigraphies. We validated the procedure to induce modifications of lung parenchyma to obtain aimed variation of compliance. Compared to the healthy model, lung respiratory mechanics were modified to the same extent as IPF-suffering patients. 81m Kr gas-ventilation and 99m tc-DtpA regional aerosol deposition showed results comparable to clinical studies, qualitatively. This ex vivo respiratory model could simulate lung fibrosis for aerosol regional deposition studies giving an interesting alternative to animal experiments, accelerating and facilitating preclinical studies before clinical trials. Idiopathic pulmonary fibrosis (IPF), a progressive fibrotic disease of the lungs without identified etiology, is the most common form of idiopathic interstitial pneumonia 1,2. Estimated incidence is around 2.8/100000 in North America and Europe, while lower incidences are observed in Asia and South America 3. The spontaneous 3-5 years survival is around 50% 4-6. IPF is characterized by progressive fibrotic lesions extending into the lungs from subpleural regions with a heterogeneous distribution throughout the lung. This leads to impairments of lung mechanics with a prominent reduction of lung compliance 7-12-i.e decreased ability of the lung to stretch and expand during the breathing cycle. IPF symptoms include cough, exertional dyspnea 1,7,13-18 , alterations in pulmonary gas exchange 8,17 , physiology of airways 19 and pulmonary hemodynamics 14-16,20,21. Currently, IPF is treated with systemic antifibrotic drugs, such as pirfenidone and nintedatinib, which have been shown to delay the progressive decrease of lung function and to reduce mortality 3,22-24. However, neither pirfenidone nor nintedatinib stops disease progression, while lung transplantation is associated with significant morbidity and mortality 25-28. Thus, new treatments for IPF are strongly needed. Pulmonary delivery of drugs is expected to be an interesting route of administration as an alternative to systemic therapies in IPF. Indeed, work is ongoing to develop inhaled IPF therapies using either repurposed drugs such as interferon gamma 29 or new chemical entities, such as the α v β 6 integrin inhibitor GSK3008348 30. Nevertheless, optimization of nebulization technologies appears necessary to reach this aim. Indeed, due to the alterations of lung compliance in IPF, aerosolized delivery of treatments remains challenging. Heterogeneous reduction of lung compliance is associated with impaired deposition of aerosol in affected pulmonary regions 31