Preliminary bronchodilator dose effect on aerosol-delivery through different nebulizers in noninvasively ventilated COPD patients.

Objectives: This study aimed to evaluate the effect of a preliminary bronchodilator dose on the aerosol-d elivery by different nebulizers in noninvasively ventilated chronic obstructive pulmonary disease (COPD) patients. Method: COPD patients were randomized to receive study doses of 800 µg beclomethasone dipropionate (BPD) nebulized by either a vibrating mesh nebulizer (VMN) or a jet nebulizer (JN) connected to MinimHal spacer device. On a different day, the nebulized dose of beclomethasone was given to each patient by the same aerosol generator with and without preceded two puffs (100 µg each) of salbutamol delivered by a pressurized-metered dose inhaler. Urinary BPD and its metabolites in 30 min post-inhalation samples and pooled up to 24 h post-inhalation were measured. On day 2, ex-vivo studies were performed with BPD collected on filters before reaching patients which were eluted from filters and analyzed to estimate the total emitted dose.Results: The highest urinary excretion amounts of BPD and its metabolites 30 min and 24 h post-inhalation were identified with pMDI + VMN compared with other regimens(p < 0.001). The amounts of BPD and its metabolites excreted 30 min post inhalation had approximately doubled with pMDI + JN compared with JN delivery (p < 0.05). No significant effect was found in the ex-vivo study results except between VMN and JN with a significant superiority of the VMN (p < 0.001).Conclusion: Using a preliminary bronchodilator dose before drug nebulization significantly increased the effective lung dose of the nebulized drug with both VMNs and JNs. However, adding a preliminary bronchodilator dose increased the 24 hr cumulative urinary amount of the drug representing higher systemic delivery of the drug, which in turn could result in higher systemic side effects.

Rationale for COVID-19 Treatment by Nebulized Interferon-ß-1b-Literature Review and Personal Preliminary Experience.

The inflammatory response to COVID-19 is specifically associated with an impaired type I interferon (IFN) response and complete blockade of IFN-ß secretion. Clinically, nebulization of IFN-α-2b has been historically used in China to treat viral pneumonia associated with SARS-CoV. Very recent data show that the use of inhaled type I IFN is associated with decreased mortality in Chinese COVID-19 patients. However, IFN nebulization is currently not standard in Europe and the United States. Therefore, our group has set up a project aimed to evaluate the possibility to nebulize IFN-ß-1b (a drug currently used in Europe to treat multiple sclerosis via subcutaneous injections) and to assess the safety of this new mode of administration in SARS-CoV-2 infected patients. We present here literature data that allowed us to build our hypothesis and to develop collaboration between clinical pharmacists, intensivists and nebulization engineers in order to gain first pre-clinical and clinical experience of IFN-ß-1b nebulization. After validation of the nebulization method and verification of droplet size compatible with nebulization, the method has been applied to four intensive care patients treated at our university hospital, for whom none of the COVID-19 therapies initially used in France led to significant clinical improvement. All patients exhibited negative viral carriage and experienced clinical improvement 7-16 days after having initiated nebulized IFN-ß-1b inhalation therapy. No side effects were observed. All patients were alive within a 90-days follow-up. Although it is not possible to draw firm conclusions on treatment efficacy based on this case report, our study shows that pulmonary IFN-ß-1b administration is feasible, with a good safety profile. This procedure, which presents the advantage of directly targeting the lungs and reducing the risks of systemic side effects, may represent a promising therapeutic strategy for the care of patients with severe COVID-19. However, our preliminary observation requires confirmation by randomized controlled trials.

Real-Time Analysis of the Respiratory Flow Through a Valved Holding Chamber.

Background: The ability of patients to take, correctly and regularly, aerosol treatments is a key for good control of asthma and chronic obstructive pulmonary disease. Devices that help to improve inhalation technique could train the patient to take their medication properly, reducing risk of exacerbations. In this study we evaluate a new device that by recording real-time respiratory flow into the valved holding chamber (VHC) mouthpiece, could be used to improve patient technique. Methods and Results: Using computational fluid dynamics analysis we demonstrated that compared to a mouthpiece with no flow probe, the presence of a probe modifies the flow profile and velocity regardless of the probe shape or position. During flow measurement using a SDP610 pressure sensor (Sensirion, Switzerland), all probes can accurately record adult and child respiratory patterns. Resistance was determined from the back pressure generated by the VHC with or without probes; and resistance was not impacted by the probes. Aerodynamic particle size distribution and drug delivery measurement were assessed using the United States Pharmacopeia throat model (Copley Scientific, UK), next generation impactor (NGI; Copley Scientific), and a breath simulator (BRS200; Copley Scientific). To test different formulations, these experiments were performed with fluticasone propionate (Flixotide®; GSK, UK), salbutamol (Ventolin®; GSK), and beclomethasone dipropionate (BDP) (QvarSpray®; GSK). Depending on the molecule or the probe configuration, we noticed a decrease of the emitted doses, fine particle deposition, mass median aerodynamic diameter, but no significant change in the mass of drug delivered. A decrease in the fine particle fraction (FPF) was observed in most testing conditions. However, a slight increase was noticed for two conformations with BDP (round and close [Rc] and diamond and far [Df]) and salbutamol (Rc and round and far [Rf]). Conclusion: By inserting a flow probe directly into the mouthpiece of a VHC we could perform real-time analysis of respiratory flow during the VHC use without disturbing drug delivery, or increasing resistance.

In vitro performance of spacers for aerosol delivery during adult mechanical ventilation.

BACKGROUND: During mechanical ventilation, different aerosol generators are employed with various interfaces. The objective of this study was to evaluate the performance of a range of spacers, including a new device called Combihaler® designed for connection with both nebulizers and pressurized Metered-Dose Inhalers (pMDIs). METHODS: To assess the spacers, we used a ventilator and the Dual Adult Training and Test Lung (model 5600i, Michigan Instruments). Ventilation parameters were measured with and without spacers in volume-controlled and pressure-controlled mode. A filter was placed at the end of the endotracheal tube to measure aerosol delivery. Amikacin (1 g/8 mL) and salbutamol (5 mg/5 mL) were nebulized with an Aeroneb Solo® connected to its T-adapter or the Combihaler® spacer. Salbutamol (100 µg/actuation with 10 actuations) and beclomethasone (250 µg/actuation with 10 actuations) were delivered with a pMDI connected to a Minispacer®, an ACE® spacer, or a Combihaler® spacer. Drug delivery measurements were performed in volume-controlled mode in dry and humidified conditions. Drug deposits on the filter were assayed. RESULTS: The use of spacers and the T-adapter did not change the ventilation parameters (p>0.9). Aerosol delivery of salbutamol and Amikacin by nebulization increased up to three-fold with the Combihaler® compared with the T-adapter in humidified and nonhumidified conditions (p<0.05). Aerosol delivery of salbutamol and beclometasone by pMDI increased up to three-fold with the Combihaler® and the ACE® spacer compared with the Minispacer® in humidified and nonhumidified conditions (p<0.05). Aerosol delivery by pMDIs and vibrating mesh nebulizers using either a T-adapter or spacers was reduced by up to 62.5% in a humidified circuit compared with a nonhumidified circuit. CONCLUSION: Aerosol delivery via pMDIs and vibrating mesh nebulizers is greater with large spacers (Combihaler® and ACE®) than with smaller spacers (Minispacer®) or a T-adapter, in both humidified and nonhumidified conditions. In humidified conditions, the aerosol delivery decreased with all spacers.