Standardization of inhalation provocation tests: Influence of nebulizer output, particle size, and method of inhalation

doi:10.1016/0091-6749(81)90012-9

Journal of Allergy and Clinical Immunology

Volume 67, Issue 2, February 1981, Pages 156-161

https://doi.org/10.1016/0091-6749(81)90012-9 Get rights and content

Abstract

Standardization of inhalation tests requires a knowledge of factors that will affect the response. We measured the output and particle size of six types of nebulizers used for inhalation tests. Output varied considerably between nebulizers of different types (0.12 to 1.59 ml/min) and to a lesser extent between nebulizers of the same type. Particle size varied between 0.8 and 5.2 μm aerodynamic mass median diameter (AMMD). The influence of these two properties on bronchial response to inhaled methacholine was examined. Nebulizer output but not particle size (between 1.3 and 3.6 μm AMMD) altered the response. We also examined the effect of change in inspiratory time during inhalation from residual volume to total lung capacity on lung deposition of radiolabeled aerosol and on the provocative concentration of histamine required to reduce the 1-sec forced expiratory volume (FEV₁) by 20% (PC₂₀). A reduction in inspiratory time from 8 to 2 sec resulted in a lower total lung dose, relatively more aerosol deposited in central airways, and a higher PC₂₀. The results emphasize the importance of keeping nebulizer output and pattern of breathing constant when performing inhalation provocation tests if consistent results are to be obtained.

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Provocative dose determination for methacholine challenge test aerosols through in vitro – in silico methods
2023, Journal of Aerosol Science
Inhaled aerosols have wide-ranging applications in the treatment and diagnosis of respiratory diseases. Methacholine challenge testing (MCT) is a diagnostic test frequently used to evaluate airway hyper-reactivity. We hypothesize that a significant fraction of the inhaled dose of methacholine is exhaled during treatment, given the small droplet sizes produced by nebulizers traditionally used for MCT. Here, an in vitro – in silico approach was developed to predict respiratory tract deposition achieved with various nebulizers proposed for use with MCT.
Emitted doses, particle sizes, and the temperature and humidity of the nebulized airstream were experimentally measured for three nebulizers (RX160, Roxon Meditech; Hudson RCI Micro Mist [HRCI], Teleflex; AirLife Misty Max 10 [MM10], CareFusion) at methacholine chloride concentrations of 0.0625, 1, and 16 mg/mL in 0.9% saline solutions. Emitted doses at a concentration of 1 mg/mL were measured to be 42.0 (SD 5.1) μg from the RX160 over 120 s, 96.3 (SD 33.7) μg from the HRCI over 60 s, and 162.3 (SD 38.4) μg from the MM10 over 60 s. For a typical adult tidal inhalation, the inhaled dose was found to be half of the emitted dose. Our hygroscopic lung deposition model predicted considerable condensational growth within the respiratory tract for aerosols used with MCT. For the 1 mg/mL methacholine chloride solution, the fraction of the inhaled dose predicted to deposit in the lungs was 0.40 (8.3 μg) for the RX160, 0.62 (29.6 μg) for the HRCI, and 0.60 (48.7 μg) for the MM10. Predicted exhaled dose fractions were greatest with the RX160 (0.60) and similar for the HCRI (0.34) and MM10 (0.36). Hygroscopic modeling thus suggests that the exhaled dose obtained during methacholine challenge testing is considerable, with the characteristics of the nebulizer influencing the relative proportion of the dose that is exhaled.
A systematic review of methods of citric acid cough reflex testing
2019, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
Few studies (5%) reported testing their nebuliser output, or the reliability of their nebuliser output. Previous studies have demonstrated large variability in nebuliser outputs across and within nebulisers of the same make and model [141,142], suggesting that testing the nebuliser output is essential to ensure dose-to-dose reproducibility of the citric acid aerosol delivered across and within tests. Only one study [103] alludes to testing the reliability of the nebuliser output.
This systematic review summarises and appraises methods of citric acid cough reflex testing (CRT) documented in published literature.
Electronic databases, MEDLINE, EMBASE, CINAHL, PsychINFO, Scopus were searched up to and including 11th February 2018. Studies reporting a method of citric acid CRT, published in peer-reviewed journals in English or Spanish, were assessed for the inclusion criteria. Of the selected studies, information on the instrumentation and CRT protocol was extracted.
A total of 129 studies were included. Instrumentation and protocols differed widely across studies. Reporting of methods of citric acid CRT was sub-standard, with many crucial methodological components omitted from published manuscripts, preventing their full replication.
Considerable methodological variability exists for citric acid CRT in published literature. The findings suggest that caution is warranted in comparing citric acid cough thresholds across studies. Full replication of previously published methods of citric acid CRT is limited due to crucial elements of the citric acid CRT protocol being omitted from published manuscripts. These findings have implications on the use of citric acid CRT in clinical and pharmaceutical studies to evaluate the effects of antitussive medications and cough therapies.
Realising the potential of various inhaled airway challenge agents through improved delivery to the lungs
2018, Pulmonary Pharmacology and Therapeutics
Inhaled airway challenges provoke bronchoconstriction in susceptible subjects and are a pivotal tool in the diagnosis and monitoring of obstructive lung diseases, both in the clinic and in the development of new respiratory medicines. This article reviews the main challenge agents that are in use today (methacholine, mannitol, adenosine, allergens, endotoxin) and emphasises the importance of controlling how these agents are administered. There is a danger that the optimal value of these challenge agents may not be realised due to suboptimal inhaled delivery; thus considerations for effective and reproducible challenge delivery are provided. This article seeks to increase awareness of the importance of precise delivery of inhaled agents used to challenge the airways for diagnosis and research, and is intended as a stepping stone towards much-needed standardisation and harmonisation in the administration of inhaled airway challenge agents.
Airway Hyperresponsiveness in Asthma: Measurement and Clinical Relevance
2017, Journal of Allergy and Clinical Immunology: In Practice
Airway hyperresponsiveness is a characteristic feature of asthma, and its measurement is an important tool in its diagnosis. With a few caveats, methacholine bronchial provocation by a 2-minute tidal breathing method is highly sensitive; a negative test result (PC₂₀ > 16 mg/mL, PD₂₀ > 400 μg) rules out current asthma with reasonable certainty. A PC₂₀ value of less than 1 mg/mL/PD₂₀ value of less than 25 μg is highly specific (ie, diagnostic) but quite insensitive for asthma. For accurate interpretation of the test results, it is important to control and standardize technical factors that have an impact on nebulizer performance. In addition to its utility to relate symptoms such as cough, wheeze, and shortness of breath to variable airflow obstruction (ie, to diagnose current asthma), the test is useful to make a number of other clinical assessments. These include (1) evaluation of patients with occupational asthma, (2) evaluation of patients with exercise-induced respiratory symptoms, (3) evaluation of novel asthma medications, (4) evaluation of relative potency of inhaled bronchodilators, (5) as a biomarker to adjust anti-inflammatory therapy to improve clinical outcomes, and (6) in the evaluation of patients with severe asthma to rule out masqueraders such as laryngeal dysfunction. The actual mechanism of altered smooth muscle behavior in asthma that is assessed by direct (eg, methacholine) or indirect (eg, allergen) bronchial provocation remains one of the most fundamental questions related to asthma that needs to be determined. The test is underutilized in clinical practice.
Formulation of a novel fixed dose combination of salmeterol xinafoate and mometasone furoate for inhaled drug delivery
2015, European Journal of Pharmaceutics and Biopharmaceutics
Citation Excerpt :
Single bulk material was fed into an air-jet mill (Aljet mill, Fluid Energy, Plumsteadville, PA, USA) with a feed pressure of 80 psi and a grinding pressure of 65 psi. Each bulk material was processed until the 90% particle size was less than 10 μm and 50% reached the respirable range (1–5 μm) [33], and this process was carried out approximately 5–7 times. Samples were collected and analyzed from the collecting chamber.
Co-administration of an inhaled corticosteroid and long acting beta agonist for chronic obstructive pulmonary disease has reduced mortality compared to either drug alone. This combination reduces exacerbations, hospitalization, emergency department visits and health care costs. A novel fixed-dose combination of the long acting beta-2 agonist salmeterol xinafoate (SX) and the corticosteroid mometasone furoate (MF) were prepared in a composite particle formulation as brittle matrix powder (BMP) and investigated for suitability as an inhaled combination product. In this study, BMP fixed dose combinations of SX and MF with or without stabilizing excipients (lactose, mannitol, glycine and trehalose) were prepared and characterized with respect to their thermal properties, morphology, aerodynamic performance and physical stability. BMP combination formulations of SX and MF exhibited improved aerodynamic properties when delivered by dry powder inhalation as compared to the micronized blends of the same substances. Aerodynamic evaluation was carried out by next generation pharmaceutical impactor (NGI) with a marketed DPI device. Results demonstrated that co-deposition occurred when SX and MF were formulated together as composite particles in a BMP, while physical blends resulted in inconsistent deposition and dose uniformity. As a result of the bottom-up particle engineering approach, combination BMP formulations allow for dual API composite formulations to be dispersed as aerosolized particles. Aerosolized BMP combination formulations resulted in delivered dose uniformity and co-deposition of each API. Further, an excipient-free formulation, BMP SXMF, delivered approximately 50% of the loaded dose in the respirable range and demonstrated stability at ambient conditions for 6 months. Single dose 24-h pharmacokinetic studies in rats demonstrated that lung tissue deposition and blood circulation (AUC_0–24h) of two APIs were higher for the BMP combination group exhibiting a significantly higher lung concentration of drugs than for the crystalline physical blend. While high system drug levels are generally undesirable in lung targeted therapies, high blood levels in this rodent study could be indicative of increased pulmonary tissue exposure using BMP formulations.
The effects of particle size on measurement of airway hyperresponsiveness to methacholine
2013, Annals of Allergy, Asthma and Immunology
Citation Excerpt :
Subsequently, the Wright nebulizer with MMAD between 1.0 and 1.5 μm was suggested for use because of the notion that small particle size nebulizers give the aerosols high probability of deposition below the vocal cords when inhaled through the mouth.13–15 This practice was supported by reports indicating that the difference in particle size between small and medium size MMAD (1.0 and 3.6 μm) does not have a significant effect on the measurement of AHR and that particle size is not as important as adjusting the nebulizers to produce the required output of methacholine solution.8 On the other hand, different studies that have investigated the effect of particle size and methods of aerosols generation have demonstrated significant underestimation of methacholine provocation concentration that caused a decrease in forced expiratory volume of 1 second (FEV1) of 20% (PC20) with small particle size Wright nebulizer when compared with others with MMADs of 3 to 4 μm.9,16
The effect of particle size on methacholine provocation concentration causing a decrease in forced expiratory volume of 1 second (FEV₁) of 20% (PC₂₀) is debatable.
To evaluate the functional effects of 3 different particle size nebulizers on methacholine PC₂₀.
Participants were randomly assigned to have 3 methacholine challenges on 3 separate days. Nebulizer mass median aerodynamic diameter (MMAD) was provided by manufacturers. The Wright nebulizer (MMAD, 1.0 μm), Aeroneb (MMAD, 3 μm), and Aeroneb (MMAD, 5 μm) were calibrated, and the nebulizer outputs were calculated to administer 0.26 mL of methacholine over 120, 112, and 83 seconds, respectively. After each inhalation, spirometry was performed and the test was terminated when the PC₂₀ was achieved.
Eight nonsmoking patients with mild asthma (4 male and 4 female) completed the study. The mean (SD) age was 25 (13.9) years, and the mean (SD) baseline FEV₁ was 88% (11.3%). Patients using the Aeroneb (MMAD, 5 μm) nebulizer had the lowest PC₂₀ (bronchoconstricted at lowest methacholine concentration), with a PC₂₀ geometric mean of 0.62 mg/mL compared with patients using the Aeroneb (MMAD, 3.0 μm), who had a PC₂₀ of 1.76 mg/mL, and patients using the Wright nebulizer (MMAD, 1.0 μm), who had a PC₂₀ of 6.32 mg/mL. There was a significant difference in PC₂₀ across all particle sizes (P < .001). The pairwise differences revealed a P < .001 between 3 μm and 1 μm and between 5 μm and 1 μm and a P = .008 between 5 μm and 3 μm.
Our results reveal a variability in methacholine PC₂₀ using 3 different nebulizers, despite adjusting the nebulizers' outputs. Our results are consistent with the previous reports, which recommended using larger particle size nebulizers in the assessment of airway hyperresponsiveness in asthma.
clinicaltrials.gov Identifier: NCT00529477

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^☆: Supported by Medical Research Council of Canada.

^∗: Dr. Cockcroft was a Fellow of the Medical Research Council of Canada. Current address: Pulmonary Medicine, University Hospital, Saskatoon, Saskatchewan, Canada.

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Original articleStandardization of inhalation provocation tests: Influence of nebulizer output, particle size, and method of inhalation☆

Abstract

Br J Dis Chest

Aerosol Sci

Respir Physiol

The effects of preferential deposition of histamine in the human airway

Am Rev Respir Dis

Bronchial hyperreactivity

Am Rev Respir Dis

Protective effect of drugs on histamine-induced asthma

Thorax

Changes during 24 hours in the lung function and histamine hyperreactivity of the bronchial tree in asthmatic and bronchitic patients

Int Arch Allergy

Airways hyperreactivity and peripheral airways dysfunction in influenza A infection

Am Rev Respir Dis

Allergen-induced increase in non-allergic bronchial reactivity

Clin Allergy

Original article
Standardization of inhalation provocation tests: Influence of nebulizer output, particle size, and method of inhalation☆