A hybrid in vitro in silico framework for albuterol delivery through an adult ventilator circuit to a patient-specific lung airway model
Graphical abstract
Introduction
Adult patients on invasive mechanical ventilation often receive inhaled medications such as albuterol (Berlinski & Willis, 2013; Kleinstreuer et al., 2008). These medications are administered inline on the ventilator circuit to avoid disconnecting the patient from ventilator support. The disconnection of the circuit could potentially increase the risk of ventilator-associated pneumonia and lead to lung de-recruitment.
The delivery of inhaled medications during invasive mechanical ventilation is a complex task. Several factors are responsible for drug delivery during mechanical ventilation: type and placement of aerosol generator, breathing pattern, ventilation modalities, bias flow, drug dosage, and endotracheal tube (ETT) size (Kleinstreuer et al., 2008). Jet nebulizers (JN) and vibrating mesh nebulizers (VMN) are the most commonly used devices. The JN uses an air source to convert fluid into a mist, while the VMN uses vibration to push liquid through a laser-drilled fine mesh (Ari, 2014). The VMN has higher drug output and lower residual volume than the JN (Ehrmann, 2018). The two most common placement sites for these devices in the ventilator circuit are before the humidifier and between the inspiratory limb and the Y-connector (Fig. 1).
Particle transport and deposition modeling in the oral, nasal and pulmonary airways using computational fluid dynamics (CFD) coupled with Lagrangian particle tracking has been a topic of interest over the last decade (Alzahrany & Banerjee, 2015a; Feng et al., 2021; Kleinstreuer & Zhang, 2010; Zhang et al., 2008). Targeted drug delivery primarily depends on the particle size, breathing pattern, and geometry of the airways (Alzahrany et al., 2016; Kleinstreuer et al., 2008). Aerosol particle size is a vital determinant in drug therapy as the dose deposited, and the drug distribution in the lung depends on it. Larger particles (>5 μm) deliver a higher dose per unit surface area, but they deposit on the central airways and do not reach the lower respiratory tract. In contrast, finer particles (<5 μm) are distributed throughout the airways. However, they deliver much lower doses of drug per unit surface area. In addition to the aerosol size, the breathing conditions (flow rate and oscillatory flow parameters) affect the trajectory of the particles. The transport of particles and their deposition on the airway walls are governed by inertial impaction (3–6 μm), gravitational sedimentation (1–3 μm), and Brownian diffusion (<1 μm) (Kleinstreuer & Zhang, 2010). Thus, effective deposition of aerosol in the lungs could be achieved by manipulating aerosol characteristics, which in turn could be modified by controlling the ventilator design and circuit (Kleinstreuer et al., 2008). The fraction of particles in the diameter range of 1–5 μm is considered the fine particle fraction (FPF) in the current study.
Data regarding the characteristics of aerosols generated by medical nebulizers are largely reported with the device not connected to a ventilator circuit. However, aerosol experiences impaction and condensation when traveling through the ventilator circuit and ETT. Therefore, the aerosol characteristics of the aerosol captured at the tip of the ETT are expected to be different from those measured from the device alone. In addition, the site of placement and type of nebulizer have been reported to affect the aerosol characteristics (Ari, Areabi, & Fink, 2010; Berlinski & Willis, 2013). The drug delivered past the ETT was reported to increase from 2.5% to 30% of the emitted dosage by optimal selection of the type, location, humidification, and bias flow (Ari, 2014). A literature review of the experimental studies investigating the placement site of nebulizers in a ventilator circuit is presented in Table 1.
Experimental particle deposition studies in idealized single and double bifurcation airways indicated that the deposition efficiency is a function of the inlet Stokes number (DeHaan & Finlay, 2004; Grgic et al., 2004; Kim & Fisher, 1999). However, due to secondary flow effects, particle deposition efficiencies also depend on geometric factors and local Stokes and Reynolds numbers (Comer et al., 2001; Luo & Liu, 2009; Zhang et al., 2002). The development of computational capability and computerized tomography (CT) has facilitated the development of a realistic, anatomically accurate lung airway models. Computational fluid dynamics (CFD) provides a valuable research tool to characterize the fluid flow and particle deposition in the human airway geometry that could be used for developing respiratory drug delivery strategies (Feng et al., 2021; Kleinstreuer & Zhang, 2010). CFD simulations can characterize particle deposition while reducing the cost and time of experiments. van Ertbruggen et al. (2005) studied the laminar flow and particle deposition in a three-dimensional (3D) model of the bronchial tree, extending from the trachea to the segmental bronchi (till generation G7 of the airway tree), and concluded that the turbulent effect should be appropriately accounted for as the deposition fraction could be twice that of the laminar model.
In our investigation, turbulence induced by the jet from the ETT as well as the laryngeal jet was modeled using the low Reynolds number (LRN) k-ω turbulence model. Particle deposition patterns, deposition efficiency, deposition fraction, and penetration fractions were studied in detail for the anatomically accurate tracheobronchial airways. The main objective of this study is to experimentally evaluate the aerosol size distribution in an adult ventilator circuit by changing the type and location of the nebulizer employed, as well as to measure the aerosol characteristics of the nebulizers alone. Coupled in silico computations were also performed to estimate the drug delivered to various regions of a patient-specific tracheobronchial airway tree using an efficient computational fluid and particle dynamics model and compare the pulmonary distribution of inhaled aerosol between those delivered via the oropharyngeal route (oral administration) and those delivered via the ETT (intubated route). Although the secondary objectives have been studied and discussed in detail (Alzahrany & Banerjee, 2015a; Lin et al., 2007b; Xi & Longest, 2007), they have not been addressed in the context of the current study and therefore are crucial. The integrated in vitro in silico framework would enable physicians to optimize drug delivery through a ventilator circuit and assist in identifying particle sizes that would deliver higher doses of the drug to specific regions of interest in the lung.
Section snippets
Materials and methods
The in vitro experiments reported in this study were conducted at the Pediatric Aerosol Research Laboratory, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas. The computations were performed at the Department of Mechanical Engineering and Mechanics at Lehigh University, Bethlehem, PA.
Experimental
The particle size distribution of nebulized albuterol measured with the nebulizer alone and at the tip of the ETT for the various configurations is summarized in Table 3 (see Table A in appendix for detailed bin-wise particle size distribution data).
Conclusions
The aerosol size distribution was characterized by conducting in vitro experiments in an adult ventilator circuit. The mass of the dosage that enters the tracheobronchial tree was sampled using a Next Generation Impactor. Two types of nebulizers (JN and VMN) were placed at two different sites in the ventilator circuit (before the humidifier and before the Y-piece). The aerosols experienced changes as they traveled through the circuit. The particle deposition and penetration through the
Author disclosure statement
Rahul R Rajendran, Sathyanand Kumaran, and Arindam Banerjee declare they have no conflicts of interest. Ariel Berlinski: Principal investigator in studies sponsored by: AbbVie, Allergan, Anthera, DCI, Cempra, Cystic Fibrosis Foundation, National Institute of Health, Novartis, Therapeutic Development Network, Trudell Medical International, Vertex and Vivus. Science advisor for International Pharmaceutical Aerosol Consortium on Regulation and Science.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
Sathyanand Kumaran was supported by a Summer Research Fellowship (University of Arkansas for Medical Science, College of Pharmacy).
Rahul Rajendran is interested in investigating airway mucus clearance and aerosolized drug delivery to the human lung airways through computational fluid and particle dynamics modeling. He received a Ph.D. in Mechanical Engineering from Lehigh University in 2021 under the guidance of Dr. Arindam Banerjee. He has 8+ combined years of research and work experience in development and application of physics-based modeling and simulation of various biological systems. He has keen interest in product
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Rahul Rajendran is interested in investigating airway mucus clearance and aerosolized drug delivery to the human lung airways through computational fluid and particle dynamics modeling. He received a Ph.D. in Mechanical Engineering from Lehigh University in 2021 under the guidance of Dr. Arindam Banerjee. He has 8+ combined years of research and work experience in development and application of physics-based modeling and simulation of various biological systems. He has keen interest in product design and development of biomedical devices and currently works as a Modeling and Simulations Scientist.
Sathyanand Kumaran received his Pharm.D degree from the University of Arkansas for Medical Sciences in 2018. Currently he works as a Clinical Pharmacist at Metropolitan Methodist Hospital, San Antonio, Texas. Previously, he had a career in Fisheries Science. His work in fish nutrition was published in the North American Journal of Aquaculture. Owing to his interest in chemistry and human medicine, he pursued a career in Pharmacy. During the program, he received research fellowship from the University of Arkansas for Medical Sciences to conduct research in the area of aerosol delivery at Arkansas Children's Hospital under the supervision of Dr. Berlinski.
Arindam Banerjee is a Professor and Chair of Mechanical Engineering and Mechanics at Lehigh University in Bethlehem, PA (USA). His research interest lies in multi-scale fluid-dynamics with emphasis on energy- and biological-systems. His research goal is to enhance our limited understanding of fundamental issues related to space and scale interactions in turbulent flows. The current research focus of his research group lies in fluid dynamics in extreme environments--understanding hydrodynamics of inertial confinement fusion; renewable energy applications—river/tidal and wave energy harvesting; and, computational pulmonary therapeutics—pulmonary drug delivery under different mechanical ventilation conditions.
Ariel Berlinski is a Professor of Pediatrics at the University of Arkansas for Medical Sciences and a Pediatric Pulmonologist at Arkansas Children's Hospital. He is the founding Director of the Pediatric Aerosol Research Laboratory at Arkansas Children's Research Institute. He is interested in evaluation of aerosol drug delivery that occurs in patients/models receiving different types of ventilator support. He is also interested on evaluating the effects of human errors on inhaled drug delivery.