Inhaled drug delivery: a randomized study in intubated patients with healthy lungs.

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.

Influence of mesh nebulizer characteristics on aerosol delivery in non-human primates.

Non-Human Primates (NHPs) are particularly relevant for preclinical studies during the development of inhaled biologics. However, aerosol inhalation in NHPs is difficult to evaluate due to a low lung deposition fraction and high variability. The objective of this study was to evaluate the influence of mesh nebulizer parameters to improve lung deposition in macaques. We developed a humidified heated and ventilated anatomical 3D printed macaque model of the upper respiratory tract to reduce experiments with animals. The model was compared to in vivo deposition using 2D planar scintigraphy imaging in NHPs and demonstrated good predictivity. Next, the anatomical model was used to evaluate the position of the nebulizer on the mask, the aerosol particle size and the aerosol flow rate on the lung deposition. We showed that placing the mesh-nebulizer in the upper part of the mask and in proximal position to the NHP improved lung delivery prediction. The lower the aerosol size and the lower the aerosol flow rate, the better the predicted aerosol deposition. In particular, for 4.3 ± 0.1 µm in terms of volume mean diameter, we obtained 5.6 % ± 0.2 % % vs 19.2 % ± 2.5 % deposition in the lung model for an aerosol flow rate of 0.4 mL/min vs 0.03 mL/min and achieved 16 % of the nebulizer charge deposited in the lungs of macaques. Despite the improvement of lung deposition efficiency in macaques, its variability remained high (6-21 %).

Inhalable Nanofitin demonstrates high neutralization of SARS-CoV-2 virus via direct application in respiratory tract.

Nanofitins are small and hyperthermostable alternative protein scaffolds that display physicochemical properties making them suitable for the development of topical therapeutics, notably for the treatment of pulmonary infectious diseases. Local administration of biologics to the lungs involves a particularly stressful step of nebulization that is poorly tolerated by most antibodies, which limits their application by this delivery route. During the COVID-19 pandemic, we generated anti-SARS-CoV-2 monomeric Nanofitins of high specificity for the spike protein. Hit Nanofitin candidates were identified based on their binding properties with punctual spike mutants and assembled into a linear multimeric construction constituting of four different Nanofitins, allowing the generation of a highly potent anti-SARS-CoV-2 molecule. The therapeutic efficacy of the multimeric assembly was demonstrated both in in vitro and in vivo models. Interestingly, the neutralization mechanism of the multimeric construction seems to involve a particular conformation switch of the spike trimer. In addition, we reported the stability and the conserved activity of the tetrameric construction after nebulization. This advantageous developability feature for pulmonary administration associated with the ease of assembly, as well as the fast generation process position the Nanofitin technology as a potential therapeutic solution for emerging infectious diseases.

Nebulized fusion inhibitory peptide protects cynomolgus macaques from measles virus infection.

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.

Nebulized fusion inhibitory peptide protects cynomolgus macaques from measles virus infection.

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 inhibitors, derived from heptad-repeat regions of the measles virus (MeV) fusion protein, block respiratory MeV infection in a non-human primate model, the cynomolgus macaque. We used a custom-designed mesh nebulizer to ensure efficient aerosol delivery of peptides to the respiratory tract and demonstrated the absence of adverse effects and lung pathology in macaques. The nebulized peptide efficiently prevented 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 shield which complements vaccination to fight against respiratory infection, presenting 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, that can be readily translated to human trials.

Inhaled amikacin versus placebo to prevent ventilator-associated pneumonia: the AMIKINHAL double-blind multicentre randomised controlled trial protocol.

INTRODUCTION: Pre-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 ANALYSIS: Academic, 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 DISSEMINATION: The 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 NUMBERS: EudraCT 2016-001054-17 and NCT03149640.

Cystic fibrosis in the modern therapeutic era: Give the shower a thought!

Fifty-two meshes of e-flow rapid® were characterized for tobramycin delivery with a laser diffractometer after 6 months of home use by cystic fibrosis patients treated with various nebulized drugs. Three meshes were out of order and 30 considered to be defective for tobramycin delivery. The use of the specific mesh cleaning shower system permitted 14 defective meshes to be in the expected range of nebulized volume.

Salbutamol Nebulization During Noninvasive Ventilation in Exacerbated Chronic Obstructive Pulmonary Disease Patients: A Randomized Controlled Trial.

Background: Although nebulizing beta 2-agonists during noninvasive ventilation (NIV) could prove helpful, this administration route has to date never been studied in unstable chronic obstructive pulmonary disease (COPD) patients. We sought to demonstrate that salbutamol could be nebulized through an NIV circuit in COPD exacerbation and improve forced expiratory volume in 1 second (FEV1) as compared with placebo. Patient and Methods: This is a bench study to determine the optimal pattern of nebulization followed by a randomized double-blind parallel-group trial comparing salbutamol and placebo aerosols delivered during NIV to 43 intensive care unit patients. Aerosols were generated by a vibrating mesh nebulizer positioned just after the Y-piece. Spirometry was performed immediately before and at several predetermined time points after nebulization. Clinical and biological safety parameters were recorded. Results: We failed to demonstrate a difference between salbutamol and placebo when changes in FEV1 were assessed immediately after nebulization (-20 vs. -35 mL, p = 0.66). However, FEV1 increased significantly from baseline to 40 minutes after the end of salbutamol nebulization, as compared with placebo (+30 vs. -50 mL, p = 0.04). Nebulization was well tolerated. Conclusion: When assessing FEV1 changes 40 minutes after the end of 5 mg salbutamol nebulization in patients undergoing NIV, we observed a slight improvement that was statistically significant compared with the changes observed with an equivalent saline volume.

Nasal high-flow bronchodilator nebulization: a randomized cross-over study.

BACKGROUND: There is an absence of controlled clinical data showing bronchodilation effectiveness after nebulization via nasal high-flow therapy circuits. RESULTS: Twenty-five patients with reversible airflow obstruction received, in a randomized order: (1) 2.5 mg albuterol delivered via a jet nebulizer with a facial mask; (2) 2.5 mg albuterol delivered via a vibrating mesh nebulizer placed downstream of a nasal high-flow humidification chamber (30 L/min and 37 °C); and (3) nasal high-flow therapy without nebulization. All three conditions induced significant individual increases in forced expiratory volume in one second (FEV1) compared to baseline. The median change was similar after facial mask nebulization [+ 350 mL (+ 180; + 550); + 18% (+ 8; + 30)] and nasal high flow with nebulization [+ 330 mL (+ 140; + 390); + 16% (+ 5; + 24)], p = 0.11. However, it was significantly lower after nasal high-flow therapy without nebulization [+ 50 mL (- 10; + 220); + 3% (- 1; + 8)], p = 0.0009. FEV1 increases after facial mask and nasal high-flow nebulization as well as residual volume decreases were well correlated (p < 0.0001 and p = 0.01). Both techniques showed good agreement in terms of airflow obstruction reversibility (kappa 0.60). CONCLUSION: Albuterol vibrating mesh nebulization within a nasal high-flow circuit induces similar bronchodilation to standard facial mask jet nebulization. Beyond pharmacological bronchodilation, nasal high flow by itself may induce small but significant bronchodilation.

Nasal high flow nebulization in infants and toddlers: An in vitro and in vivo scintigraphic study.

Aerosol therapy in infants and toddlers is challenging. Nebulization within a nasal high flow (NHF) circuit is attractive. The aim of this study was to quantify aerosol lung deposition when combined with NHF as compared with standard practice. Lung doses were measured scintigraphically after nebulization with jet and mesh nebulizer placed within a NHF circuit in a spontaneously breathing non-human primate model (macaque) and in the anatomical bench SAINT model, respectively representing a full-term newborn and a 9-month-old toddler. In the SAINT model, lung depositions observed with the mesh nebulizer placed in the NHF circuit set at 2 and 4 L/min were 3.3% and 4.2% of the nebulizer charge, respectively, and similar to the 1.70% observed with the control standard facemask jet nebulization (6 L/min flow). In the macaque model, the depositions observed with the mesh nebulizer in the NHF circuit set at 2 and 4 L/min were 0.49% and 0.85%, respectively, also similar to the control measurement (0.71%). Mesh nebulization within a NHF circuit set at 8 L/min and jet nebulization either within a NHF circuit or placed on top of the cannula (NHF set at 2 L/min; total flow of 8 L/min), resulted in a significantly lower lung depositions. Mesh nebulization within a NHF circuit delivering up to 4 L/min gas is likely to be at least as effective than jet nebulization with a facemask in infants and toddlers. Aerosol facemask placement on top of cannulas or jet nebulization within the NHF circuit may be less effective. Pediatr Pulmonol. 2017;52:337-344. © 2016 Wiley Periodicals, Inc.

In Vitro Comparison of a Vibrating Mesh Nebulizer Operating in Inspiratory Synchronized and Continuous Nebulization Modes During Noninvasive Ventilation.

UNLABELLED: Backround: Coupling nebulization with noninvasive ventilation (NIV) has been shown to be effective in patients with respiratory diseases. However, a breath-synchronized nebulization option that could potentially improve drug delivery by limiting drug loss during exhalation is currently not available on bilevel ventilators. The aim of this in vitro study was to compare aerosol delivery of amikacin with a vibrating mesh nebulizer coupled to a single-limb circuit bilevel ventilator, using conventional continuous (Conti-Neb) and experimental inspiratory synchronized (Inspi-Neb) nebulization modes. METHODS: Using an adult lung bench model of NIV, we tested a vibrating mesh device coupled with a bilevel ventilator in both nebulization modes. Inspi-Neb delivered aerosol only during the whole inspiratory phase, whereas Conti-Neb delivered aerosol continuously. The nebulizer was charged with amikacin solution (250 mg/3 mL) and placed at two different positions: between the lung and exhalation port and between the ventilator and exhalation port. Inhaled, expiratory wasted and circuit lost doses were assessed by residual gravimetric method. Particle size distribution of aerosol delivered at the outlet of the ventilator circuit during both nebulization modes was measured by laser diffraction method. RESULTS: Regardless of the nebulizer position, Inspi-Neb produced higher inhaled dose (p < 0.01; +6.3% to +16.8% of the nominal dose), lower expiratory wasted dose (p < 0.05; -2.7% to -42.6% of the nominal dose), and greater respirable dose (p < 0.01; +8.4% to +15.2% of the nominal dose) than Conti-Neb. The highest respirable dose was found with the nebulizer placed between the lung and exhalation port (48.7% ± 0.3% of the nominal dose). CONCLUSIONS: During simulated NIV with a single-limb circuit bilevel ventilator, the use of inspiratory synchronized vibrating mesh nebulization improves respirable dose and reduces drug loss of amikacin compared with continuous vibrating mesh nebulization.

Ventilator-integrated jet nebulization systems: tidal volume control and efficiency of synchronization.

BACKGROUND: Jet nebulizers constitute the aerosolization devices most frequently used during mechanical ventilation. Continuous nebulization can influence the delivered tidal volume (V(T)) and lead to significant medication loss during expiration. Ventilators thus provide integrated jet nebulization systems that are synchronized during inspiration and ostensibly keep VT constant. METHODS: This was a bench study of systems integrated in the Evita XL, Avea, Galileo, and G5 ventilators. The VT delivered with and without nebulization, the inspiratory synchronization of nebulization, and the aerosol deposition were measured with 2 locations of the nebulizer. RESULTS: Changes in V(T) with the nebulizer were below 20 mL and below 10% of set V(T) for all ventilators. Synchronization was good at the beginning of insufflation, but prolonged nebulization was observed with all ventilators at the end of insufflation, until up to 1 s during expiration: 5-80% of nebulization occurred during expiration with significant aerosol loss in the expiratory limb. Synchrony could be improved by (1) reducing gas compression/decompression phenomena proximal to the jet nebulizer and (2) increasing inspiratory time, which reduced the amount of nebulization occurring during expiration. Placing the nebulizer upstream in the inspiratory limb did not affect inspiratory synchrony but allowed reduction of the amount of aerosol lost in the expiratory limb. CONCLUSIONS: Jet nebulizer systems integrated in the tested ventilators are reliable in terms of V(T) control. Gas compression in tubing driving gas to the nebulizer delays synchronization and reduces nebulization yield if the nebulizer is placed close to the Y-piece. Increasing inspiratory time with no end-inspiratory pause reduces the expiratory loss of medication if placement of the nebulizer upstream in the inspiratory limb is not feasible.

Particle deposition in a child respiratory tract model: in vivo regional deposition of fine and ultrafine aerosols in baboons.

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.

Validation of anatomical models to study aerosol deposition in human nasal cavities.

PURPOSE: Intranasal deposition of aerosols is often studied using in vitro nasal cavity models. However, the relevance of these models to predict in vivo human deposition has not been validated. This study compared in vivo nasal aerosol deposition and in vitro deposition in a human plastinated head model (NC1) and its replica constructed from CT-scan (NC2). METHODS: Two nebulizers (Atomisor Sonique® and Easynose®) were used to administer a 5.6 µm aerosol of (99m)Tc-DTPA to seven healthy volunteers and to the nasal models. Aerosol deposition was quantified by γ-scintigraphy in the nasal, upper nasal cavity and maxillary sinus (MS) regions. The distribution of aerosol deposition was determined along three nasal cavity axes (x, y and z). RESULTS: There was no significant difference regarding aerosol deposition between the volunteers and NC1. Aerosol deposition was significantly lower in NC2 than in volunteers regarding nasal region (p < 0.05) but was similar for the upper nasal cavity and MS regions. Mean aerosol distribution for NC1 came within the standard deviation (SD) of in vivo distribution, whereas that of NC2 was outside the in vivo SD for x and y axes. CONCLUSIONS: In conclusion, nasal models can be used to predict aerosol deposition produced by nebulizers, but their performance depends on their design.

Deposition of aerosols delivered by nasal route with jet and mesh nebulizers.

PURPOSE: To quantify the amount of aerosol deposited in different parts of the airways with a commercially available nasal sonic jet nebulizer (NJN) using a sound effect, and to compare its performance with a new nasal mesh nebulizer (NMN). METHODS: Seven healthy non-smoking male volunteers aged 21-36 years with a mean weight of 77±10 kg were included in this single-center study. Both nebulizer systems were loaded with (99m)Tc-DTPA and scintigraphies were performed with a gamma camera. Particle size distribution of the aerosols produced by the two nebulizer systems was measured. RESULTS: There was no statistical difference between the two nebulizers in terms of fraction of particles smaller than 5 µm (44±4% vs 45±2%) (p>0.9). Aerosol deposition in the nasal region was 73±10% (% of aerosol deposited in airways) with the NJN, and 99±3% with the NMN (p=0.01). Total nasal deposition was 9.6±1.9% of the nebulizer charge with the NJN and 28.4±8.9% with the NMN (p=0.01). 0.5±0.3% of the nebulizer charge was deposited in the maxillary sinuses with the NJN, compared to 2.2±1.6% with the NMN (p=0.01). CONCLUSION: Although the two nebulizers had the same particle size, NMN significantly improved aerosol deposition in nasal cavity and prevents deposition into the lungs.