Targeting inhaled aerosol delivery to upper airways in children: Insight from computational fluid dynamics (CFD)

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Abstract

Despite the prevalence of inhalation therapy in the treatment of pediatric respiratory disorders, most prominently asthma, the fraction of inhaled drugs reaching the lungs for maximal efficacy remains adversely low. By and large drug delivery devices and their inhalation guidelines are typically derived from adult studies with child dosages adapted according to body weight. While it has long been recognized that physiological (e.g. airway sizes, breathing maneuvers) and physical transport (e.g. aerosol dynamics) characteristics are critical in governing deposition outcomes, such knowledge has yet to be extensively adapted to younger populations. Motivated by such shortcomings, the present work leverages in a first step in silico computational fluid dynamics (CFD) to explore opportunities for augmenting aerosol deposition in children based on respiratory physiological and physical transport determinants. Using an idealized, anatomically-faithful upper airway geometry, airflow and aerosol motion are simulated as a function of age, spanning a five year old to an adult. Breathing conditions mimic realistic age-specific inhalation maneuvers representative of Dry Powder Inhalers (DPI) and nebulizer inhalation. Our findings point to the existence of a single dimensionless curve governing deposition in the conductive airways via the dimensionless Stokes number (Stk). Most significantly, we uncover the existence of a distinct deposition peak irrespective of age. For the DPI simulations, this peak (∼ 80%) occurs at Stk ≈ 0.06 whereas for nebulizer simulations, the corresponding peak (∼ 45%) occurs in the range of Stk between 0.03-0.04. Such dimensionless findings hence translate to an optimal window of micron-sized aerosols that evolves with age and varies with inhalation device. The existence of such deposition optima advocates revisiting design guidelines for optimizing deposition outcomes in pediatric inhalation therapy.

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Most cited references 83

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Global burden of asthma among children.

I Asher, N Pearce (2014)

About 334 million people worldwide suffer from asthma, and this figure may be an underestimation. It is the most common chronic disease in children. Asthma is among the top 20 chronic conditions for global ranking of disability-adjusted life years in children; in the mid-childhood ages 5-14 years it is among the top 10 causes. Death rates from asthma in children globally range from 0.0 to 0.7 per 100 000. There are striking global variations in the prevalence of asthma symptoms (wheeze in the past 12 months) in children, with up to 13-fold differences between countries. Although asthma symptoms are more common in many high-income countries (HICs), some low- and middle-income countries (LMICs) also have high levels of asthma symptom prevalence. The highest prevalence of symptoms of severe asthma among children with wheeze in the past 12 months is found in LMICs and not HICs. From the 1990s to the 2000s, asthma symptoms became more common in some high-prevalence centres in HICs; in many cases, the prevalence stayed the same or even decreased. At the same time, many LMICs with large populations showed increases in prevalence, suggesting that the overall world burden is increasing, and that therefore global disparities in asthma prevalence are decreasing. The costs of asthma, where they have been estimated, are relatively high. The global burden of asthma in children, including costs, needs ongoing monitoring using standardised methods.

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What the pulmonary specialist should know about the new inhalation therapies.

B L Laube, H M Janssens, F H C de Jongh … (2011)

A collaboration of multidisciplinary experts on the delivery of pharmaceutical aerosols was facilitated by the European Respiratory Society (ERS) and the International Society for Aerosols in Medicine (ISAM), in order to draw up a consensus statement with clear, up-to-date recommendations that enable the pulmonary physician to choose the type of aerosol delivery device that is most suitable for their patient. The focus of the consensus statement is the patient-use aspect of the aerosol delivery devices that are currently available. The subject was divided into different topics, which were in turn assigned to at least two experts. The authors searched the literature according to their own strategies, with no central literature review being performed. To achieve consensus, draft reports and recommendations were reviewed and voted on by the entire panel. Specific recommendations for use of the devices can be found throughout the statement. Healthcare providers should ensure that their patients can and will use these devices correctly. This requires that the clinician: is aware of the devices that are currently available to deliver the prescribed drugs; knows the various techniques that are appropriate for each device; is able to evaluate the patient's inhalation technique to be sure they are using the devices properly; and ensures that the inhalation method is appropriate for each patient.

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Low-dose inhaled corticosteroids and the prevention of death from asthma.

S Suissa, P. Ernst, S Benayoun … (2000)

Although inhaled corticosteroids are effective for the treatment of asthma, it is uncertain whether their use can prevent death from asthma. We used the Saskatchewan Health data bases to form a population-based cohort of all subjects from 5 through 44 years of age who were using antiasthma drugs during the period from 1975 through 1991. We followed subjects until the end of 1997, their 55th birthday, death, emigration, or termination of health insurance coverage; whichever came first. We conducted a nested case-control study in which subjects who died of asthma were matched with controls within the cohort according to the length of follow-up at the time of death of the case patient (the index date), the date of study entry, and the severity of asthma. We calculated rate ratios after adjustment for the subject's age and sex; the number of prescriptions of theophylline, nebulized and oral beta-adrenergic agonists, and oral corticosteroids in the year before the index date; the number of canisters of inhaled beta-adrenergic agonists used in the year before the index date; and the number of hospitalizations for asthma in the two years before the index date. The cohort consisted of 30,569 subjects. Of the 562 deaths, 77 were classified as due to asthma. We matched the 66 subjects who died of asthma for whom there were complete data with 2681 controls. Fifty-three percent of the case patients and 46 percent of the control patients had used inhaled corticosteroids in the previous year, most commonly low-dose beclomethasone. The mean number of canisters was 1.18 for the patients who died and 1.57 for the controls. On the basis of a continuous dose-response analysis, we calculated that the rate of death from asthma decreased by 21 percent with each additional canister of inhaled corticosteroids used in the previous year (adjusted rate ratio, 0.79; 95 percent confidence interval, 0.65 to 0.97). The rate of death from asthma during the first three months after discontinuation of inhaled corticosteroids was higher than the rate among patients who continued to use the drugs. The regular use of low-dose inhaled corticosteroids is associated with a decreased risk of death from asthma.

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Author and article information

Contributors

Prashant Das: Role: InvestigationRole: Writing – original draft

Eliram Nof: Role: Writing – review & editing

Israel Amirav:

ORCID: http://orcid.org/0000-0002-6917-5285

Role: ConceptualizationRole: Writing – review & editing

Stavros C. Kassinos: Role: Writing – review & editing

Josué Sznitman:

ORCID: http://orcid.org/0000-0001-8217-3842

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: SupervisionRole: Writing – original draft

Roi Gurka: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2018

Publication date (Electronic): 20 November 2018

Volume: 13

Issue: 11

Electronic Location Identifier: e0207711

Affiliations

[1 ] Department of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel

[2 ] Department of Pediatrics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada

[3 ] Computational Sciences Laboratory (UCY-CompSci), Department of Mechanical and Manufacturing Engineering, University of Cyprus, Kallipoleos Avenue 75, Nicosia 1678, Cyprus

Coastal Carolina University, UNITED STATES

Author notes

Competing Interests: The authors have declared that no competing interests exist.

* E-mail: sznitman@ 123456bm.technion.ac.il

Author information

Israel Amirav http://orcid.org/0000-0002-6917-5285

Josué Sznitman http://orcid.org/0000-0001-8217-3842

Article

Publisher ID: PONE-D-18-17680

DOI: 10.1371/journal.pone.0207711

PMC ID: 6245749

PubMed ID: 30458054

SO-VID: 84b00cec-440d-4f22-bb92-eb33a25783a6

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 14 June 2018

Date accepted : 3 November 2018

Page count

Figures: 6, Tables: 2, Pages: 20

Funding

Funded by: funder-id http://dx.doi.org/10.13039/501100000781, European Research Council;

Award ID: 677772

Award Recipient :

ORCID: http://orcid.org/0000-0001-8217-3842

Josué Sznitman

This work was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 677772). The authors acknowledge COST Action MP1404 SimInhale ‘Simulation and pharmaceutical technologies for advanced patient-tailored inhaled medicines’, supported by the European Cooperation in Science and Technology (COST).

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Targeting inhaled aerosol delivery to upper airways in children: Insight from computational fluid dynamics (CFD)

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Most cited references 83

Global burden of asthma among children.

What the pulmonary specialist should know about the new inhalation therapies.

Low-dose inhaled corticosteroids and the prevention of death from asthma.

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