Measles is the most contagious airborne viral infection and the leading cause of child death among vaccine-preventable diseases. We show here that aerosolized lipopeptide fusion inhibitor, derived ...from heptad-repeat regions of the measles virus (MeV) fusion protein, blocks respiratory MeV infection in a non-human primate model, the cynomolgus macaque. We use a custom-designed mesh nebulizer to ensure efficient aerosol delivery of peptide to the respiratory tract and demonstrate the absence of adverse effects and lung pathology in macaques. The nebulized peptide efficiently prevents MeV infection, resulting in the complete absence of MeV RNA, MeV-infected cells, and MeV-specific humoral responses in treated animals. This strategy provides an additional means to fight against respiratory infection in non-vaccinated people, that can be readily translated to human trials. It presents a proof-of-concept for the aerosol delivery of fusion inhibitory peptides to protect against measles and other airborne viruses, including SARS-CoV-2, in case of high-risk exposure.
To relate exposure to adverse health effects, it is necessary to know where particles in the submicron range deposit in the respiratory tract. The possibly higher vulnerability of children requires ...specific inhalation studies. However, radio-aerosol deposition experiments involving children are rare because of ethical restrictions related to radiation exposure. Thus, an in vivo study was conducted using three baboons as a child respiratory tract model to assess regional deposition patterns (thoracic region vs. extrathoracic region) of radioactive polydisperse aerosols (d16-d84, equal to 0.15 µm-0.5 µm, 0.25 µm-1 µm, or 1 µm-9 µm). Results clearly demonstrated that aerosol deposition within the thoracic region and the extrathoraic region varied substantially according to particle size. High deposition in the extrathoracic region was observed for the 1 µm-9 µm aerosol (72% ± 17%). The 0.15 µm-0.5 µm aerosol was associated almost exclusively with thoracic region deposition (84% ± 4%). Airborne particles in the range of 0.25 µm-1 µm showed an intermediate deposition pattern, with 49% ± 8% in the extrathoracic region and 51% ± 8% in the thoracic region. Finally, comparison of baboon and human inhalation experiments for the 1 µm-9 µm aerosol showed similar regional deposition, leading to the conclusion that regional deposition is species-independent for this airborne particle sizes.
Bacteriophages have been identified as a potential treatment option to treat lung infection in the context of antibiotic resistance. We performed a preclinical study to predict the efficacy of ...delivery of bacteriophages against
(PA) when administered via nebulization during mechanical ventilation (MV). We selected a mix of four anti-PA phages containing two
and two
with a coverage of 87.8% (36/41) on an international PA reference panel. When administered via nebulization, a loss of 0.30-0.65 log of infective phage titers was measured. No difference between jet, ultrasonic and mesh nebulizers was observed in terms of loss of phage viability, but a higher output was measured with the mesh nebulizer. Interestingly,
are significantly more sensitive to nebulization than
since their long tail is much more prone to damage. Phage nebulization has been measured as compatible with humidified ventilation. Based on in vitro measurement, the lung deposition prediction of viable phage particles ranges from 6% to 26% of the phages loaded in the nebulizer. Further, 8% to 15% of lung deposition was measured by scintigraphy in three macaques. A phage dose of 1 × 10
PFU/mL nebulized by the mesh nebulizer during MV predicts an efficient dose in the lung against PA, comparable with the dose chosen to define the susceptibility of the strain.
Background
Clinical practice of aerosol delivery in conjunction with respiratory support devices for critically ill adult patients remains a topic of controversy due to the complexity of the clinical ...scenarios and limited clinical evidence.
Objectives
To reach a consensus for guiding the clinical practice of aerosol delivery in patients receiving respiratory support (invasive and noninvasive) and identifying areas for future research.
Methods
A modified Delphi method was adopted to achieve a consensus on technical aspects of aerosol delivery for adult critically ill patients receiving various forms of respiratory support, including mechanical ventilation, noninvasive ventilation, and high-flow nasal cannula. A thorough search and review of the literature were conducted, and 17 international participants with considerable research involvement and publications on aerosol therapy, comprised a multi-professional panel that evaluated the evidence, reviewed, revised, and voted on recommendations to establish this consensus.
Results
We present a comprehensive document with 20 statements, reviewing the evidence, efficacy, and safety of delivering inhaled agents to adults needing respiratory support, and providing guidance for healthcare workers. Most recommendations were based on in-vitro or experimental studies (low-level evidence), emphasizing the need for randomized clinical trials. The panel reached a consensus after 3 rounds anonymous questionnaires and 2 online meetings.
Conclusions
We offer a multinational expert consensus that provides guidance on the optimal aerosol delivery techniques for patients receiving respiratory support in various real-world clinical scenarios.
Background
The administration technique for inhaled drug delivery during invasive ventilation remains debated. This study aimed to compare in vivo and in vitro the deposition of a radiolabeled ...aerosol generated through four configurations during invasive ventilation, including setups optimizing drug delivery.
Methods
Thirty-one intubated postoperative neurosurgery patients with healthy lungs were randomly assigned to four configurations of aerosol delivery using a vibrating-mesh nebulizer and specific ventilator settings: (1) a specific circuit for aerosol therapy (SCAT) with the nebulizer placed at 30 cm of the wye, (2) a heated-humidified circuit switched off 30 min before the nebulization or (3) left on with the nebulizer at the inlet of the heated-humidifier, (4) a conventional circuit with the nebulizer placed between the heat and moisture exchanger filter and the endotracheal tube. Aerosol deposition was analyzed using planar scintigraphy.
Results
A two to three times greater lung delivery was measured in the SCAT group, reaching 19.7% (14.0–24.5) of the nominal dose in comparison to the three other groups (
p
< 0.01). Around 50 to 60% of lung doses reached the outer region of both lungs in all groups. Drug doses in inner and outer lung regions were significantly increased in the SCAT group (
p
< 0.01), except for the outer right lung region in the fourth group due to preferential drug trickling from the endotracheal tube and the trachea to the right bronchi. Similar lung delivery was observed whether the heated humidifier was switched off or left on. Inhaled doses measured in vitro correlated with lung doses (
R
= 0.768,
p
< 0.001).
Conclusion
Optimizing the administration technique enables a significant increase in inhaled drug delivery to the lungs, including peripheral airways. Before adapting mechanical ventilation, studies are required to continue this optimization and to assess its impact on drug delivery and patient outcome in comparison to more usual settings.
Aerosol sizing is generally measured at ambient air but human airways have different temperature (37°C) and relative humidity (100%) which can affect particle size in airways and consequently ...deposition prediction. This work aimed to develop and evaluate a new method using cascade impactor to measure particle size at human physiological temperature and humidity (HPTH) taking into account ambient air conditions. A heated and humidified trachea was built and a cascade impactor was heated to 37°C and humidified inside. Four medical aerosols jet nebulizer, mesh nebulizer, Presurized Metered Dose Inhaler (pMDI), and Dry Powder Inhaler (DPI) under ambient conditions and at HPTH were tested. MMAD was lower at HPTH for the two nebulizers; it was similar at ambient conditions and HPTH for pMDI, and the mass of particles smaller than 5 μm decreased for DPI at HPTH (51.9 vs. 82.8 μg/puff). In conclusion, we developed a new method to measure particle size at HPTH affecting deposition prediction with relevance. In vivo studies are required to evaluate the interest of this new model to improve the precision of deposition prediction.Aerosol sizing is generally measured at ambient air but human airways have different temperature (37°C) and relative humidity (100%) which can affect particle size in airways and consequently deposition prediction. This work aimed to develop and evaluate a new method using cascade impactor to measure particle size at human physiological temperature and humidity (HPTH) taking into account ambient air conditions. A heated and humidified trachea was built and a cascade impactor was heated to 37°C and humidified inside. Four medical aerosols jet nebulizer, mesh nebulizer, Presurized Metered Dose Inhaler (pMDI), and Dry Powder Inhaler (DPI) under ambient conditions and at HPTH were tested. MMAD was lower at HPTH for the two nebulizers; it was similar at ambient conditions and HPTH for pMDI, and the mass of particles smaller than 5 μm decreased for DPI at HPTH (51.9 vs. 82.8 μg/puff). In conclusion, we developed a new method to measure particle size at HPTH affecting deposition prediction with relevance. In vivo studies are required to evaluate the interest of this new model to improve the precision of deposition prediction.
IntroductionPre-emptive inhaled antibiotics may be effective to reduce the occurrence of ventilator-associated pneumonia among critically ill patients. Meta-analysis of small sample size trials ...showed a favourable signal. Inhaled antibiotics are associated with a reduced emergence of antibiotic resistant bacteria. The aim of this trial is to evaluate the benefit of a 3-day course of inhaled antibiotics among patients undergoing invasive mechanical ventilation for more than 3 days on the occurrence of ventilator-associated pneumonia.Methods and analysisAcademic, investigator-initiated, parallel two group arms, double-blind, multicentre superiority randomised controlled trial. Patients invasively ventilated more than 3 days will be randomised to receive 20 mg/kg inhaled amikacin daily for 3 days or inhaled placebo (0.9% Sodium Chloride). Occurrence of ventilator-associated pneumonia will be recorded based on a standardised diagnostic framework from randomisation to day 28 and adjudicated by a centralised blinded committee.Ethics and disseminationThe protocol and amendments have been approved by the regional ethics review board and French competent authorities (Comité de protection des personnes Ouest I, No.2016-R29). All patients will be included after informed consent according to French law. Results will be disseminated in international scientific journals.Trial registration numbersEudraCT 2016-001054-17 and NCT03149640.
The development of jet nebulizers for medical purposes is an important challenge of aerosol therapy. The performance of a nebulizer is characterized by its output rate of droplets with a diameter ...under 5 µm. However the optimization of this parameter through experiments has reached a plateau. The purpose of this study is to design a numerical model simulating the nebulization process and to compare it with experimental data. Such a model could provide a better understanding of the atomization process and the parameters influencing the nebulizer output. A model based on the Updraft nebulizer (Hudson) was designed with ANSYS Workbench. Boundary conditions were set with experimental data then transient 3D calculations were run on a 4 µm mesh with ANSYS Fluent. Two air flow rate (2 L/min and 8 L/min, limits of the operating range) were considered to account for different turbulence regimes. Numerical and experimental results were compared according to phenomenology and droplet size. The behavior of the liquid was compared to images acquired through shadowgraphy with a CCD Camera. Three experimental methods, laser diffractometry, phase Doppler anemometry (PDA) and shadowgraphy were used to characterize the droplet size distributions. Camera images showed similar patterns as numerical results. Droplet sizes obtained numerically are overestimated in relation to PDA and diffractometry, which only consider spherical droplets. However, at both flow rates, size distributions extracted from numerical image processing were similar to distributions obtained from shadowgraphy image processing. The simulation then provides a good understanding and prediction of the phenomena involved in the fragmentation of droplets over 10 µm. The laws of dynamics apply to droplets down to 1 µm, so we can assume the continuity of the distribution and extrapolate the results for droplets between 1 and 10 µm. So, this model could help predicting nebulizer output with defined geometrical and physical parameters.
In patients with fibrotic pulmonary disease such as idiopathic pulmonary fibrosis (IPF), inhaled aerosols deposit mostly in the less affected region of the lungs, resulting in suboptimal ...pharmacokinetics of airway-delivered treatments. Refinement of aerosol delivery technique requires new models to simulate the major alterations of lung physiology associated with IPF, i.e., heterogeneously reduced lung compliance and increased airway caliber. A novel physical model of the respiratory system was constructed to simulate aerosol drug delivery in spontaneously breathing (negative pressure ventilation) IPF patients. The model comprises upper (Alberta ideal throat) and lower airway (plastic tubing) models and branches into two compartments (Michigan lung models) which differ in compliance and caliber of conducting airway. The model was able to reproduce the heterogeneous, compliance-dependent reduction in ventilation and aerosol penetration (using NaF as a model aerosol) seen in fibrotic lung regions in IPF. Of note, intrapulmonary percussive ventilation induced a 2-3-fold increase in aerosol penetration in the low-compliance/high airway caliber compartment of the model, demonstrating the responsiveness of the model to therapeutic intervention.
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