Filling the gaps in the evaluation and selection of mobile health technologies in respiratory medicine.

INTRODUCTION: Mobile health (mHealth) technology in respiratory medicine is a fast-growing and promising digital technology that is popular among patients and healthcare providers (HCPs). They provide reminders and step-by-step instructions for the correct inhalation technique, monitor patients' adherence to treatment, and facilitate communication between patients and HCPs. AREAS COVERED: While numerous mHealth apps have been developed over the years, most applications do not have supporting evidence. Selecting the best mHealth app in respiratory medicine is challenging due to limited studies carrying out mHealth app selection. Although mHealth technologies play an important part in the future of respiratory medicine, there is no single guide on the evaluation and selection of mHealth technologies for patients with pulmonary diseases. This paper aims to provide an overview of mHealth technologies, particularly emphasizing digital inhalers and standalone applications used in asthma. Additionally, it offers insights into the evaluation, selection, and pertinent considerations surrounding mHealth applications in respiratory medicine. EXPERT OPINION: Evaluating mHealth apps will take time, resources, and collaboration between stakeholders such as governmental regulatory bodies, subject-matter experts, and industry representatives. Filling the gaps in the evaluation and selection of the mHealth app will improve clinical decision-making, personalized treatments, self-management and disease monitoring in respiratory medicine.

New Generation Nebulizers.

Standard nebulizers are intended for general purpose use and typically are continuously operated jet or ultrasonic nebulizers. Evolutionary developments such as breath-enhanced and breath-triggered devices have improved delivery efficiency and ease of use, yet are still suitable for delivery of nebulized medications approved in this category. However, recent developments of vibrating membrane or mesh nebulizers have given rise to a significant increase in delivery efficiency requiring reformulation of former drug products or development of new formulations to match the enhanced delivery characteristics of these new devices. In addition, the electronic nature of the new devices enables tailoring to specific applications and patient groups, such as guiding or facilitating optimal breathing and improving adherence to the therapeutic regimen. Addressing these patient needs leads to new nebulization technologies being embedded in devices with fundamentally distinct functionality, modes of operation and patient interfaces. Therefore, new generation nebulizers can no longer be regarded as one category with fairly similar performance characteristics but must be clinically tested and approved as drug/device combinations together with the specific drug formulation, similar to the approval of pressurized metered-dose inhalers and dry powder inhalers. From a regulatory viewpoint, it is required that drug and device are associated with each other as combinations by clear, mutually conforming labels or, even more desirably, by distinct container-closure systems (closed system nebulizer).

External Jet Nebulization and Measured Ventilator Performance.

BACKGROUND: During invasive ventilation, external flow jet nebulization results in increases in displayed exhaled tidal volumes (VT). We hypothesized that the magnitude of the increase is inaccurate. An ASL 5000 simulator measured ventilatory parameters over a wide range of adult settings: actual VT, peak inspiratory pressure (PIP), and time to minimum pressure. METHODS: Ventilators with internal and external flow sensors were tested by using a variety of volume and pressure control modes (the target VT was 420 mL). Patient conditions (normal, COPD, ARDS) defined on the ASL 5000 were assessed at baseline and with 3.5 or 8 L/min of added external flow. Patient-triggering was assessed by reducing muscle effort to the level that resulted in backup ventilation and by changing ventilator sensitivity to the point of auto-triggering. RESULTS: Results are reported as percentage change from baseline after addition of 3.5 or 8 L/min external flow. For ventilators with internal flow sensors, changes in displayed exhaled VT ranged from 10% to 118%, however, when using volume control, actual increases in actual VT and PIP were only 4%-21% (P = .063, .031) and 6%-24% (P = .25, .031), respectively. Changes in actual VT correlated closely with changes in PIP (P < .001; R2 = 0.68). For pressure control, actual VT decreased by 3%-5% (P = .031) and 4%-9% (P = .031) with 3.5 and 8 L/min respectively, PIP was unchanged. With external flow sensors at the distal Y-piece junction, volume and pressure changes were statistically insignificant. The time to minimum pressure increased at most by 8% (P = .02) across all modes and ventilators. The effects on muscle pressure were minimal (∼1 cm H2O), and ventilator sensitivity effects were nearly undetectable. CONCLUSIONS: External flow jet nebulization resulted in much smaller changes in volume than indicated by the ventilator display. Statistically significant effects were confined primarily to machines with internal flow sensors. Differences approached the manufacturer-reported variation in ventilator baseline performance. During nebulizer therapy, effects on VT can be estimated at the bedside by monitoring PIP.

Estimating Tiotropium Wasted Doses After Adding Revefenacin to an Inpatient Formulary: A Single-Center Cross-Sectional Study.

Introduction: Revefenacin is a once-daily nebulized long-acting muscarinic antagonist (LAMA). Revefenacin is supplied as single-use nebulized vials, which may be preferable and less costly for hospital and health-system pharmacies to dispense versus multidose tiotropium inhalers. Estimates of LAMA multidose inhaler wasted doses remains unknown. Methods: This was a single-center descriptive cross-sectional study conducted between January 1 2021 and December 31 2021. Adult patients 18 years and older admitted to a 500-bed academic medical center in the southern United States and were ordered multidose tiotropium packages or single-use revefenacin vials during the study period were included. Results: Among 602 inpatients, there were 705 LAMA orders: 541 tiotropium (76.7%) and 164 revefenacin (23.3%). Four hundred ninety-five tiotropium orders (91.5%) wasted between 20% and 90% of multidose packages. Approximately $24,000 tiotropium doses were wasted versus single-use revefenacin vials. Conclusion: Multidose inhalers of tiotropium dispensed to hospitalized patients contributed to wasted doses compared to nebulized single-use revefenacin vials. Opportunities exist to minimize wasted doses of multidose long-acting inhalers dispensed to hospitalized patients.

Comparison of the Application of Vibrating Mesh Nebulizer and Jet Nebulizer in Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-analysis.

Objective: To comparison of the application of Vibrating Mesh Nebulizer and Jet Nebulizer in chronic obstructive pulmonary disease (COPD). Research Methods: This systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statements. The primary outcome measures analyzed included: The amount of inhaler in the urine sample at 30 minutes after inhalation therapy (USAL0.5), The total amount of inhaler in urine sample within 24 hours (USAL24), Aerosol emitted, Forced expiratory volume in 1 second (FEV1), Forced vital capacity (FVC). Results: Ten studies were included with a total of 314 study participants, including 157 subjects in the VMN group and 157 subjects in the JN group. The data analysis results of USAL0.5, MD (1.88 [95% CI, 0.95 to 2.81], P = 0.000), showed a statistically significant difference. USAL24, MD (1.61 [95% CI, 1.14 to 2.09], P = 0.000), showed a statistically significant difference. The results of aerosol emitted showed a statistically significant difference in MD (3.44 [95% CI, 2.84 to 4.04], P = 0.000). The results of FEV1 showed MD (0.05 [95% CI, -0.24 to 0.35], P=0.716), the results were not statistically significant. The results of FVC showed MD (0.11 [95% CI, -0.18 to 0.41], P=0.459), the results were not statistically significant. It suggests that VMN is better than JN and provides higher aerosols, but there is no difference in improving lung function between them. Conclusion: VMN is significantly better than JN in terms of drug delivery and utilization in the treatment of patients with COPD. However, in the future use of nebulizers, it is important to select a matching nebulizer based on a combination of factors such as mechanism of action of the nebulizer, disease type and comorbidities, ventilation strategies and modes, drug formulations, as well as cost-effectiveness, in order to achieve the ideal treatment of COPD.

Pulmonologist Education of the Teach-to-Goal Inhaler Technique for Those With Asthma and COPD.

BACKGROUND: Inhaler education for patients with asthma and patients with COPD is typically provided by non-pulmonologists. We studied inhaler education by pulmonologists to determine changes in clinical outcomes and inhaler use. METHODS: This was a retrospective study of 296 subjects diagnosed with asthma, COPD, or both that evaluated use of inhaler technique education and its impact on (1) inhaler/dosage change consisting of dosage change in the same class of inhaler and/or change in number of inhalers, (2) forced expiratory volume in one second/forced vital capacity (FEV1/FVC%), (3) disease symptom control, (4) out-patient visits, (5) urgent care visits (6) emergency department visits, and (7) hospital admissions. One group received inhaler technique education by a pulmonologist while the other group did not. RESULTS: The pulmonologist inhaler technique-educated group had significantly decreased relative risk for inhaler/dosage increase (relative risk 0.57 [95% CI 0.34-0.96], P = .03) and significantly increased odds for symptom control (odds ratio 2.15 [95% CI 1.24-3.74], P = .01) at 1-y follow-up as compared to the no education group. No differences occurred for FEV1/FVC%, out-patient visits, urgent care visits, emergency department visits, and hospital admissions. CONCLUSIONS: Pulmonologist education of inhaler technique for patients with asthma and patients with COPD was associated with decreased relative risk for inhaler/dosage increase and increased odds for symptom control. We recommend pulmonologists provide education of inhaler technique to patients with asthma and patients with COPD and not rely on non-pulmonologist education alone. Prospective research is needed to confirm the importance of proper inhaler techniques.

Validation of an Inhaled Therapy Beliefs Questionnaire in Patients with Chronic Obstructive Pulmonary Disease.

Background: To carry out a validation questionnaire that assesses beliefs about inhaled treatments in patients with chronic obstructive pulmonary disease (COPD), as knowing patients' beliefs could help to improve medication adherence and health outcomes. Methods: We evaluated data from 260 COPD patients from electronic medical record databases from five primary healthcare centers, in a descriptive, cross-sectional study with a sample size calculated for a 10-item questionnaire, with an estimated Cronbach's alpha of 0.70 and a 95% confidence level. Study participants were selected via systematic random sampling. Variables: Ten-item Inhaled Therapy Beliefs Questionnaire, CCTI-Questionnaire v.2.0, time for completion, age, sex, educational level, spirometry severity (GOLD criteria), exacerbations (previous year), characteristics of inhaled treatment, and smoking habit. A two-year follow-up in a subsample of 77 patients from one health center was utilized. The Morisky-Green test, pharmacy dispensing data, test-retest (kappa coefficient), and an exploratory analysis of the adherence-belief relationship (ji-squared) were measured. Results: The 10-item questionnaire showed good viability (3 min completion time) when performed face-to-face or telephonically; its psychometric properties were acceptable, with an internal consistency (Cronbach's alpha) score of 0.613. Three factors explained 47.58% of the total variance (p < 0.0001): use (factor 1), effects (factor 2), and objectives (factor 3) of inhalers. The two-year follow-up ultimately considered 58 out of the 77 patients (10 deceased, 4 unlocated, 2 mistakes, 2 no inhaled treatment, and 1 withdrawal). Non-adherence was 48.3% in terms of the Morisky-Green test; 31% in terms of pharmacy dispensing data; and 40.4% considering both methods. There was low test-retest reliability, indicated by items 4, 8, and 9 of the CCTI-Questionnaire (Kappa = 0.4, 0.26, and 0.34; p-value < 0.0001, 0.008, and 0.001, respectively). There was mild correlation between beliefs and adherence. Conclusions: The ten-item CCTI-Questionnaire v.2.0 demonstrated acceptable psychometric properties regarding feasibility, reliability, and content validity.

Surfactant therapy using vibrating-mesh nebulizers in adults with COVID-19-induced ARDS: A case series.

Coronavirus adult respiratory distress syndrome, characterized by decreased surfactant due to lysis of type II pneumocytes and hyaline membrane formation, contributes to severe hypoxemia. The administration of surfactant via high-flow nasal cannula (HFNC) may positively affect lung structure and function in this context. In this study, we report on five clinical cases, encompassing patients aged 40-60 years of both sexes, who tested positive for coronavirus disease 2019 via real-time polymerase chain reaction and exhibited significant pulmonary compromise with elevated inflammatory biomarkers. These patients were treated with aerosol therapy using surfactant delivered through vibrating-mesh nebulizers alongside HFNC. Of these patients, four demonstrated positive responses to the treatment, suggesting that aerosol therapy with surfactant through vibrating-mesh nebulizers could be a viable rescue therapy in adults receiving HFNC oxygen therapy for hypoxemic respiratory failure caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Unfortunately, one patient had a negative outcome and succumbed. The findings from these cases indicate that the use of aerosol therapy with vibrating-mesh nebulizers as rescue therapy might offer an alternative approach for managing adults with hypoxemic respiratory failure due to SARS-CoV-2, as evidenced by the positive outcomes in four out of the five cases presented.

Nano-Formulations for Pulmonary Delivery: Past, Present, and Future Perspectives.

With the development of nanotechnology and confronting the problems of traditional pharmaceutical formulations in treating lung diseases, inhalable nano-formulations have attracted interest. Inhalable nano-formulations for treating lung diseases allow for precise pulmonary drug delivery, overcoming physiological barriers, improving aerosol lung deposition rates, and increasing drug bioavailability. They are expected to solve the difficulties faced in treating lung diseases. However, limited success has been recorded in the industrialization translation of inhalable nano-formulations. Only one relevant product has been approved by the FDA to date, suggesting that there are still many issues to be resolved in the clinical application of inhalable nano-formulations. These systems are characterized by a dependence on inhalation devices, while the adaptability of device formulation is still inconclusive, which is the most important issue impeding translational research. In this review, we categorized various inhalable nano-formulations, summarized the advantages of inhalable nano-formulations over conventional inhalation formulations, and listed the inhalable nano-formulations undergoing clinical studies. We focused on the influence of inhalation devices on nano-formulations and analyzed their adaptability. After extensive analysis of the drug delivery mechanisms, technical processes, and limitations of different inhalation devices, we concluded that vibrating mesh nebulizers might be most suitable for delivering inhalable nano-formulations, and related examples were introduced to validate our view. Finally, we presented the challenges and outlook for future development. We anticipate providing an informative reference for the field.

Nebulisation of Paclitaxel, Sotatercept and Iloprost for pulmonary hypertension for lung cancer. From In vitro to In vivo.

Background: Pulmonary hypertension is common symptom among several diseases. The consequences are severe for several organs. Pulmonary hypertension is usually under-diagnosed and the main symptom observed is dyspnea with or without exercise. Currently we have several treatment modalities administered orally, via inhalation, intravenously and subcutaneously. In advanced disease then heart or lung transplantation is considered. The objective of the study was to investigate the optimum method of aerosol production for the drugs: iloprost, paclitaxel and the novel sotatercept. Materials and Methods: In our experiment we used the drugs iloprost, paclitaxel and the novel sotatercept, in an experimental concept of nebulization. We performed nebulization experiments with 3 jet nebulizers and 3 ultrasound nebulizers with different combinations of residual cup designs, and residual cup loadings in order to identify which combination produces droplets of less than 5µm in mass median aerodynamic diameter. Results: We concluded that paclitaxel cannot produce small droplets and is also still very greasy and possible dangerous for alveoli. However; iloprost vs sotatercept had smaller droplet size formation at both inhaled technologies (1.37<2.23 and 1.92<3.11, jet and ultrasound respectively). Moreover; residual cup designs C and G create the smallest droplet size in both iloprost and sotatercept. There was no difference for the droplet formation between the facemask and cone mouthpieces. Discussion: Iloprost and sotatercept can be administered as aerosol in any type of nebulisation system and they are both efficient with the residual cups loaded with small doses of the drug (2.08 and 2.12 accordingly).

Aerosol delivery and spatiotemporal tissue distribution of hydroxychloroquine in rat lung.

Inhalation enables the delivery of drugs directly to the lung, increasing the retention for prolonged exposure and maximizing the therapeutic index. However, the differential regional lung exposure kinetics and systemic pharmacokinetics are not fully known, and their estimation is critical for pulmonary drug delivery. The study evaluates the pharmacokinetics of hydroxychloroquine in different regions of the respiratory tract for multiple routes of administration. We also evaluated the influence of different inhaled formulations on systemic and lung pharmacokinetics by identifying suitable nebulizers followed by early characterization of emitted aerosol physicochemical properties. The salt- and freebase-based formulations required different nebulizers and generated aerosol with different physicochemical properties. An administration of hydroxychloroquine by different routes resulted in varied systemic and lung pharmacokinetics, with oral administration resulting in low tissue concentrations in all regions of the respiratory tract. A nose-only inhalation exposure resulted in higher and sustained lung concentrations of hydroxychloroquine with a lung parenchyma-to-blood ratio of 386 after 1440 min post-exposure. The concentrations of hydroxychloroquine in different regions of the respiratory tract (i.e., nasal epithelium, larynx, trachea, bronchi, and lung parenchyma) varied over time, indicating different retention kinetics. The spatiotemporal distribution of hydroxychloroquine in the lung is different due to the heterogeneity of cell types, varying blood perfusion rate, clearance mechanisms, and deposition of inhaled aerosol along the respiratory tract. In addition to highlighting the varied lung physiology, these results demonstrate the ability of the lung to retain increased levels of inhaled lysosomotropic drugs. Such findings are critical for the development of future inhalation-based therapeutics, aiming to optimize target site exposure, enable precision medicine, and ultimately enhance clinical outcomes.

Individualized aerosol medicine: Integrating device into the patient.

Pulmonary drug delivery is complex due to several challenges including disease-, patient-, and clinicians-related factors. Although many inhaled medications are available in aerosol medicine, delivering aerosolized medications to patients requires effective disease management. There is a large gap in the knowledge of clinicians who select and provide instructions for the correct use of aerosol devices. Since improper device selection, incorrect inhaler technique, and poor patient adherence to prescribed medications may result in inadequate disease control, individualized aerosol medicine is essential for effective disease management and control. The components of individualized aerosol medicine include: (1) Selecting the right device, (2) Selecting the right interface, (3) Educating the patient effectively, and (4) Increasing patient adherence to therapy. This paper reviews each of these components and provides recommendations to integrate the device and interface into the patient for better clinical outcomes.

The Use of an Inspiration-Synchronized Vibrating Mesh Nebulizer for Prolonged Inhalative Iloprost Administration in Mechanically Ventilated Patients-An In Vitro Model.

Mechanically ventilated patients suffering from acute respiratory distress syndrome (ARDS) frequently receive aerosolized iloprost. Because of prostacyclin's short half-life, prolonged inhalative administration might improve its clinical efficacy. But, this is technically challenging. A solution might be the use of inspiration-synchronized vibrating mesh nebulizers (VMNsyn), which achieve high drug deposition rates while showing prolonged nebulization times. However, there are no data comparing prolonged to bolus iloprost nebulization using a continuous vibrating mesh nebulizer (VMNcont) and investigating the effects of different ventilation modes on inspiration-synchronized nebulization. Therefore, in an in vitro model of mechanically ventilated adults, a VMNsyn and a VMNcont were compared in volume-controlled (VC-CMV) and pressure-controlled continuous mandatory ventilation (PC-CMV) regarding iloprost deposition rate and nebulization time. During VC-CMV, the deposition rate of the VMNsyn was comparable to the rate obtained with the VMNcont, but 10.9% lower during PC-CMV. The aerosol output of the VMNsyn during both ventilation modes was significantly lower compared to the VMNcont, leading to a 7.5 times longer nebulization time during VC-CMV and only to a 4.2 times longer nebulization time during PC-CMV. Inspiration-synchronized nebulization during VC-CMV mode therefore seems to be the most suitable for prolonged inhalative iloprost administration in mechanically ventilated patients.

Inhaled nintentanib, pirfenidone and macitentan for pulmonary fibrosis: a laboratory experiment.

Aim: Idiopathic pulmonary fibrosis is a rare disease with few efficient drugs in the market. The consequences of this disease are mainly respiratory failure and pulmonary hypertension. Materials & methods: In our experiment we used the drugs pirfenidone, nintetanib and macitentan. We performed nebulization experiments with three jet nebulizers and three ultrasound nebulizers with different combinations of residual cup designs, and residual cup loadings in order to identify which combination produces droplets of less than 5 µm in mass median aerodynamic diameter. Results: Pirfenidone versus nintetanib had smaller droplet size formation at both inhaled technologies (1.37 < 2.23 and 1.92 < 3.11, jet and ultrasound respectively). Discussion: Pirfenidone and nintetanib can be administered as aerosol in any type of nebulization system.

Influence of Aerosol Mask Design on Fugitive Aerosol Concentrations During Nebulization.

BACKGROUND: Secondhand exposure to fugitive aerosols may cause airway diseases in health providers. We hypothesized that redesigning aerosol masks to be closed-featured would reduce the fugitive aerosol concentrations during nebulization. This study aimed to evaluate the influence of a mask designed for a jet nebulizer on the concentration of fugitive aerosols and delivered doses. METHODS: An adult intubation manikin was attached to a lung simulator to mimic normal and distressed adult breathing patterns. The jet nebulizer delivered salbutamol as an aerosol tracer. The nebulizer was attached to 3 aerosol face masks: an aerosol mask, a modified non-rebreathing mask (NRM, with no vent holes), and an AerosoLess mask. An aerosol particle sizer measured aerosol concentrations at parallel distances of 0.8 m and 2.2 m and a frontal distance of 1.8 m from the manikin. The drug dose delivered distal to the manikin's airway was collected, eluted, and analyzed using a spectrophotometer at a 276 nm wavelength. RESULTS: With a normal breathing pattern, the trends of aerosol concentrations were higher with an NRM followed by an aerosol mask and AerosoLess mask (P < .001) at 0.8 m; however, the concentrations were higher with an aerosol mask followed by NRM and AerosoLess mask at 1.8 m (P < .001) and 2.2 m (P < .001). With a distressed breathing pattern, the aerosol concentrations were higher with an aerosol mask followed by an NRM and AerosoLess mask at 0.8 m, 1.8 m (P < .001), and 2.2 m (P = .005). The delivered drug dose was significantly higher with AerosoLess mask with a normal breathing pattern and with an aerosol mask with a distressed breathing pattern. CONCLUSIONS: Mask design influences fugitive aerosol concentrations in the environment, and a filtered mask reduces the concentration of aerosols at 3 different distances and with 2 breathing patterns.

High-Dose Nebulized Colistin Methanesulfonate and the Role in Hospital-Acquired Pneumonia Caused by Gram-Negative Bacteria with Difficult-to-Treat Resistance: A Review.

Hospital-acquired pneumonia, including ventilator-associated pneumonia (VAP) due to difficult-to-treat-resistant (DTR) Gram-negative bacteria, contributes significantly to morbidity and mortality in ICUs. In the era of COVID-19, the incidences of secondary nosocomial pneumonia and the demand for invasive mechanical ventilation have increased dramatically with extremely high attributable mortality. Treatment options for DTR pathogens are limited. Therefore, an increased interest in high-dose nebulized colistin methanesulfonate (CMS), defined as a nebulized dose above 6 million IU (MIU), has come into sight. Herein, the authors present the available modern knowledge regarding high-dose nebulized CMS and current information on pharmacokinetics, clinical studies, and toxicity issues. A brief report on types of nebulizers is also analyzed. High-dose nebulized CMS was administrated as an adjunctive and substitutive strategy. High-dose nebulized CMS up to 15 MIU was attributed with a clinical outcome of 63%. High-dose nebulized CMS administration offers advantages in terms of efficacy against DTR Gram-negative bacteria, a favorable safety profile, and improved pharmacokinetics in the treatment of VAP. However, due to the heterogeneity of studies and small sample population, the apparent benefit in clinical outcomes must be proven in large-scale trials to lead to the optimal use of high-dose nebulized CMS.

Influence of Mechanical Ventilation Modes on the Efficacy of Nebulized Bronchodilators in the Treatment of Intubated Adult Patients with Obstructive Pulmonary Disease.

BACKGROUND: Little has been reported in terms of clinical outcomes to confirm the benefits of nebulized bronchodilators during mechanical ventilation (MV). Electrical Impedance Tomography (EIT) could be a valuable method to elucidate this gap. OBJECTIVE: The purpose of this study is to evaluate the impact of nebulized bronchodilators during invasive MV with EIT by comparing three ventilation modes on the overall and regional lung ventilation and aeration in critically ill patients with obstructive pulmonary disease. METHOD: A blind clinical trial in which eligible patients underwent nebulization with salbutamol sulfate (5 mg/1 mL) and ipratropium bromide (0.5 mg/2 mL) in the ventilation mode they were receiving. EIT evaluation was performed before and after the intervention. A joint and stratified analysis into ventilation mode groups was performed, with p < 0.05. RESULTS: Five of nineteen procedures occurred in controlled MV mode, seven in assisted mode and seven in spontaneous mode. In the intra-group analysis, the nebulization increased total ventilation in controlled (p = 0.04 and ⅆ = 2) and spontaneous (p = 0.01 and ⅆ = 1.5) MV modes. There was an increase in the dependent pulmonary region in assisted mode (p = 0.01 and ⅆ = 0.3) and in spontaneous mode (p = 0.02 and ⅆ = 1.6). There was no difference in the intergroup analysis. CONCLUSIONS: Nebulized bronchodilators reduce the aeration of non-dependent pulmonary regions and increase overall lung ventilation but there was no difference between the ventilation modes. As a limitation, it is important to note that the muscular effort in PSV and A/C PCV modes influences the impedance variation, and consequently the aeration and ventilation values. Thus, future studies are needed to evaluate this effort as well as the time on ventilator, time in UCI and other variables.

Predicting Inhaled Drug Dose Generated by Mesh Nebulizers.

Background: The lung dose of nebulized drugs for spontaneous breathing is influenced by breathing patterns and nebulizer performance. This study aimed to develop a system for measuring breath patterns and a formula for estimating inhaled drugs, and then to validate the hypothesized prediction formula. Methods: An in vitro model was first used to determine correlations among the delivered dose, breath patterns, and doses deposited on the accessories and reservoirs testing with a breathing simulator to generate 12 adult breathing patterns (n = 5). A pressure sensor was developed to measure breathing parameters and used along with a prediction formula that accounted for the initial charge dose, respiratory pattern, and dose on the accessory and reservoir of a nebulizer. Three brands of nebulizers were tested by placing salbutamol (5.0 mg/2.5 mL) in the drug holding chamber. Ten healthy individuals participated in the ex vivo study to validate the prediction formula. The agreement between the predicted and inhaled doses was analyzed using the Bland-Altman plot. Results: The in vitro model showed that the inspiratory time to total respiratory cycle time (Ti/Ttotal; %) was significantly directly correlated with the delivered dose among the respiratory factors, followed by inspiratory flow, respiratory rate, and tidal volume. The ex vivo model showed that Ti/Ttotal was significantly directly correlated with the delivered dose among the respiratory factors, in addition to the nebulization time and accessory dose. The Bland-Altman plots for the ex vivo model showed similar results between the two methods. Large differences in inhaled dose measured at the mouth were observed among the subjects, ranging from 12.68% to 21.68%; however, the difference between the predicted dose and inhaled dose was lower, at 3.98%-5.02%. Conclusions: The inhaled drug dose could be predicted with the hypothesized estimation formula, which was validated by the agreement between the inhaled and predicted doses of breathing patterns of healthy individuals.

Multidrug Aerosol Delivery During Mechanical Ventilation.

Background: In the critically ill, pulmonary vasodilators are often provided off label to intubated patients using continuous nebulization. If additional aerosol therapies such as bronchodilators or antibiotics are needed, vasodilator therapy may be interrupted. This study assesses aerosol systems designed for simultaneous delivery of two aerosols using continuous nebulization and bolus injection without interruption or circuit disconnection. Methods: One i-AIRE dual-port breath-enhanced jet nebulizer (BEJN) or two Aerogen® Solo vibrating mesh nebulizers (VMNs) were installed on the dry side of the humidifier. VMN were stacked; one for infusion and the second for bolus drug delivery. The BEJN was powered by air at 3.5 L/min, 50 psig. Radiolabeled saline was infused at 5 and 10 mL/h with radiolabeled 3 and 6 mL bolus injections at 30 and 120 minutes, respectively. Two adult breathing patterns (duty cycle 0.13 and 0.34) were tested with an infusion time of 4 hours. Inhaled mass (IM) expressed as % of initial syringe activity (IM%/min) was monitored in real time with a ratemeter. All delivered radioaerosol was collected on a filter at the airway opening. Transients in aerosol delivery were measured by calibrated ratemeter. Results: IM%/h during continuous infusion was linear and predictable, mean ± standard deviation (SD): 2.12 ± 1.45%/h, 2.47 ± 0.863%/h for BEJN and VMN, respectively. BEJN functioned without incident. VMN continuous aerosol delivery stopped spontaneously in 3 of 8 runs (38%); bolus delivery stopped spontaneously in 3 of 16 runs (19%). Tapping restarted VMN function during continuous and bolus delivery runs. Bolus delivery IM% (mean ± SD): 20.90% ± 7.01%, 30.40% ± 11.10% for BEJN and VMN, respectively. Conclusion: Simultaneous continuous and bolus nebulization without circuit disconnection is possible for both jet and mesh technology. Monitoring of VMN devices may be necessary in case of spontaneous interruption of nebulization.

Liposomes or Extracellular Vesicles: A Comprehensive Comparison of Both Lipid Bilayer Vesicles for Pulmonary Drug Delivery.

The rapid and non-invasive pulmonary drug delivery (PDD) has attracted great attention compared to the other routes. However, nanoparticle platforms, like liposomes (LPs) and extracellular vesicles (EVs), require extensive reformulation to suit the requirements of PDD. LPs are artificial vesicles composed of lipid bilayers capable of encapsulating hydrophilic and hydrophobic substances, whereas EVs are natural vesicles secreted by cells. Additionally, novel LPs-EVs hybrid vesicles may confer the best of both. The preparation methods of EVs are distinguished from LPs since they rely mainly on extraction and purification, whereas the LPs are synthesized from their basic ingredients. Similarly, drug loading methods into/onto EVs are distinguished whereby they are cell- or non-cell-based, whereas LPs are loaded via passive or active approaches. This review discusses the progress in LPs and EVs as well as hybrid vesicles with a special focus on PDD. It also provides a perspective comparison between LPs and EVs from various aspects (composition, preparation/extraction, drug loading, and large-scale manufacturing) as well as the future prospects for inhaled therapeutics. In addition, it discusses the challenges that may be encountered in scaling up the production and presents our view regarding the clinical translation of the laboratory findings into commercial products.