In Vitro Evaluation of Nebulized Pharmaceutical Aerosol Delivery to the Lungs Using a New Heated Dryer System (HDS).

The objective of this study was to develop a new heated dryer system (HDS) for high efficiency lung delivery of nebulized aerosol and demonstrate performance with realistic in vitro testing for trans-nasal aerosol administration simultaneously with high-flow nasal cannula (HFNC) therapy and separately for direct oral inhalation (OI) of the aerosol. With the HDS-HFNC and HDS-OI platforms, new active synchronization control routines were developed to sense subject inhalation and coordinate drug aerosol delivery. In vitro experiments were conducted to predict regional drug loss and lung delivery efficiency in systems that included the HDS with various patient interfaces, realistic airway models, and simulated breathing waveforms. For the HDS-HFNC platform and a repeating breathing waveform, total system loss was < 10%, extrathoracic deposition was approximately 6%, and best-case lung delivery efficiency was 75-78% of nebulized dose. Inclusion of randomized breathing with the HFNC system decreased lung delivery efficiency by ~ 10% and had no impact on nasal depositional loss. For the HDS-OI platform and best-case mouthpiece, total system loss was < 8%, extrathoracic deposition was < 1%, and lung delivery efficiency was > 90% of nebulized dose. Normal vs. deep randomized oral inhalation had little impact on performance of the HDS-OI platform and environmental aerosol loss was negligible. In conclusion, both platforms demonstrated the potential for high efficiency lung delivery of the aerosol with the HDS-OI platform having the added advantages of nearly eliminating extrathoracic deposition, being insensitive to breathing waveform, and preventing environmental aerosol loss.

CFD Guided Optimization of Nose-to-Lung Aerosol Delivery in Adults: Effects of Inhalation Waveforms and Synchronized Aerosol Delivery.

PURPOSE: The objective of this study was to optimize nose-to-lung aerosol delivery in an adult upper airway model using computational fluid dynamics (CFD) simulations in order to guide subsequent human subject aerosol delivery experiments. METHODS: A CFD model was developed that included a new high-flow nasal cannula (HFNC) and pharmaceutical aerosol delivery unit, nasal cannula interface, and adult upper airway geometry. Aerosol deposition predictions in the system were validated with existing and new experimental results. The validated CFD model was then used to explore aerosol delivery parameters related to synchronizing aerosol generation with inhalation and inhalation flow rate. RESULTS: The low volume of the new HFNC unit minimized aerosol transit time (0.2 s) and aerosol bolus spread (0.1 s) enabling effective synchronization of aerosol generation with inhalation. For aerosol delivery correctly synchronized with inhalation, a small particle excipient-enhanced growth delivery strategy reduced nasal cannula and nasal depositional losses each by an order of magnitude and enabled ~80% of the nebulized dose to reach the lungs. Surprisingly, nasal deposition was not sensitive to inhalation flow rate due to use of a nasal cannula interface with co-flow inhaled air and the small initial particle size. CONCLUSIONS: The combination of correct aerosol synchronization and small particle size enabled high efficiency nose-to-lung aerosol delivery in adults, which was not sensitive to inhalation flow rate.

Use of computational fluid dynamics deposition modeling in respiratory drug delivery.

INTRODUCTION: Respiratory drug delivery is a surprisingly complex process with a number of physical and biological challenges. Computational fluid dynamics (CFD) is a scientific simulation technique that is capable of providing spatially and temporally resolved predictions of many aspects related to respiratory drug delivery from initial aerosol formation through respiratory cellular drug absorption. AREAS COVERED: This review article focuses on CFD-based deposition modeling applied to pharmaceutical aerosols. Areas covered include the development of new complete-airway CFD deposition models and the application of these models to develop a next-generation of respiratory drug delivery strategies. EXPERT OPINION: Complete-airway deposition modeling is a valuable research tool that can improve our understanding of pharmaceutical aerosol delivery and is already supporting medical hypotheses, such as the expected under-treatment of the small airways in asthma. These complete-airway models are also being used to advance next-generation aerosol delivery strategies, like controlled condensational growth. We envision future applications of CFD deposition modeling to reduce the need for human subject testing in developing new devices and formulations, to help establish bioequivalence for the accelerated approval of generic inhalers, and to provide valuable new insights related to drug dissolution and clearance leading to microdosimetry maps of drug absorption.

Monitoring Lung Mechanics during Mechanical Ventilation using Machine Learning Algorithms.

Evaluation of lung mechanics is the primary component for designing lung protective optimal ventilation strategies. This paper presents a machine learning approach for bedside assessment of respiratory resistance (R) and compliance (C). We develop machine learning algorithms to track flow rate and airway pressure and estimate R and C continuously and in real-time. An experimental study is conducted, by connecting a pressure control ventilator to a test lung that simulates various R and C values, to gather sensor data for validation of the devised algorithms. We develop supervised learning algorithms based on decision tree, decision table, and Support Vector Machine (SVM) techniques to predict R and C values. Our experimental results demonstrate that the proposed algorithms achieve 90.3%, 93.1%, and 63.9% accuracy in assessing respiratory R and C using decision table, decision tree, and SVM, respectively. These results along with our ability to estimate R and C with 99.4% accuracy using a linear regression model demonstrate the potential of the proposed approach for constructing a new generation of ventilation technologies that leverage novel computational models to control their underlying parameters for personalized healthcare and context-aware interventions.

Comparison of pressure, volume and gas washout characteristics between PCV and HFPV in healthy and formalin fixed ex vivo porcine lungs.

OBJECTIVE: This study employs a recently developed experimental technique for comparison of the flow characteristics and the effectiveness of gas washout between pressure control ventilation (PCV) and high-frequency percussive ventilation (HFPV) in high-compliance and low-compliance ex vivo porcine respiratory tracts. APPROACH: The ex vivo porcine lungs are filled with nitrogen prior to ventilating with atmospheric gas using either PCV or HFPV to investigate the flow characteristics and gas washout characteristics. The study considered freshly removed lungs from porcine carcasses that were humanely harvested for human consumption. Subsequently, the porcine lungs were exposed externally to formalin to simulate low-compliance conditions. The first order models of respiratory mechanics were employed to predict the lung compliance and resistance in normal and formalin exposed lungs. HFPV was operated in two different modes based upon the set pressures, namely HFPV-Low and HFPV-High. The peak pressures of HFPV and PCV were matched in HFPV-Low and the peak pressures are increased to about 20-30% in the HFPV-High mode. MAIN RESULTS: Both HFPV-Low and HFPV-High mode deliver smaller tidal volume (V T) as compared to PCV in high and compliance states (about 70% and 40% for healthy and formalin treated lungs, repsectively). Although the tidal volume delivered by HFPV-High and HFPV-Low are comparable, they reveal a substantial difference in washout time as well as total ventilation volumes. In a high compliant lung (healthy lung), HFPV-High washes out the nitrogen within the lung more rapidly, whereas HFPV-Low washes out the inert gas more slowly as compared to PCV. In a low-compliance lung, HFPV-Low delivers similar washout rates as PCV at a much smaller V T and lower mean airway pressure. SIGNIFICANCE: The ex vivo study supports the hypothesis that in low compliant lungs HFPV provides effective washout with a protective ventilation.

Comparison of flow and gas washout characteristics between pressure control and high-frequency percussive ventilation using a test lung.

OBJECTIVE: A comparison between flow and gas washout data for high-frequency percussive ventilation (HFPV) and pressure control ventilation (PCV) under similar conditions is currently not available. This bench study aims to compare and describe the flow and gas washout behavior of HFPV and PCV in a newly designed experimental setup and establish a framework for future clinical and animal studies. APPROACH: We studied gas washout behavior using a newly designed experimental setup that is motivated by the multi-breath nitrogen washout measurements. In this procedure, a test lung was filled with nitrogen gas before it was connected to a ventilator. Pressure, volume, and oxygen concentrations were recorded under different compliance and resistance conditions. PCV was compared with two settings of HFPV, namely, HFPV-High and HFPV-Low, to simulate the different variations in its clinical application. In the HFPV-Low mode, the peak pressures and drive pressures of HFPV and PCV are matched, whereas in the HFPV-High mode, the mean airway pressures (MAP) are matched. MAIN RESULTS: HFPV-Low mode delivers smaller tidal volume (V T) as compared to PCV under all lung conditions, whereas HFPV-High delivers a larger V T. HFPV-High provides rapid washout as compared to PCV under all lung conditions. HFPV-Low takes a longer time to wash out nitrogen except at a low compliance, where it expedites washout at a smaller V T and MAP compared to PCV washout. SIGNIFICANCE: Various flow parameters for HFPV and PCV are mathematically defined. A shorter washout time at a small V T in low compliant test lungs for HFPV could be regarded as a hypothesis for lung protective ventilation for animal or human lungs.