- Email: [email protected]
Respiratory Duty Cycles in Individuals With and Without Airway Hyperresponsiveness
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Original Research
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Respiratory Duty Cycles in Individuals With and Without Airway Hyperresponsiveness Christianne M. Blais, MSc, MBA; Beth E. Davis, PhD; Brian L. Graham, PhD; and Donald W. Cockcroft, MD
The respiratory duty cycle (Ti/Ttot) can influence bronchoprovocation test results and nebulized drug delivery. The Ti/Ttot has not yet been examined in individuals with airway hyperresponsiveness (AHR) in typical bronchoprovocation test conditions. This study investigated the mean Ti/Ttot in participants with and without AHR and whether the Ti/Ttot changes with increasing bronchoconstriction. BACKGROUND:
Fifteen participants with AHR and fifteen participants without AHR completed this randomized crossover study. An ultrasonic spirometer was used for continuous measurement of the Ti/Ttot as participants inhaled room air or aerosolized solution. Each participant completed two methacholine challenges, one using a continuous-output vibrating mesh nebulizer/ultrasonic spirometer and one with the nebulizer only. Prior to each methacholine challenge, participants inhaled room air and aerosolized saline through the nebulizer/spirometer setup to record baseline Ti/Ttot data.
METHODS:
RESULTS: The mean Ti/Ttot findings [95% CIs] during room air inhalation were 0.392 [0.3780.406] and 0.447 [0.426-0.468] in participants with and without AHR, respectively (P < .001). The mean Ti/Ttot during saline inhalation were 0.389 [0.373-0.405] and 0.424 [0.398-0.450] in participants with and without AHR (P ¼ .040). The Ti/Ttot showed a nonsignificant downward trend with progressive methacholine-induced bronchoconstriction.
The mean Ti/Ttot in participants with AHR closely resembles the assumed Ti/ Ttot of 0.40 recommended for standard use when calculating methacholine challenge results. Since the Ti/Ttot did not change significantly over the course of a methacholine challenge, the same Ti/Ttot can be used to calculate the dose of methacholine inhaled, regardless of the level of bronchoconstriction. CONCLUSIONS:
TRIAL REGISTRY:
ClinicalTrials.gov; No.: NCT03505489; URL: www.clinicaltrials.gov. CHEST 2019;
KEY WORDS:
aerosols; airway hyperresponsiveness; provocation test; pulmonary function test
ABBREVIATIONS: AHR = airway hyperresponsiveness; ICC = intraclass correlation coefficient; MCT = methacholine challenge test; PD20 = provocative dose of methacholine causing a 20% fall in FEV1; sGAW = specific airway conductance; Ti/Ttot = respiratory duty cycle; UAO = upper airway obstruction AFFILIATIONS: From the Division of Respirology, Critical Care and Sleep Medicine, Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada. FUNDING/SUPPORT: This work was supported by the Canadian Society of Allergy and Clinical Immunology.
chestjournal.org
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CORRESPONDENCE TO: Donald W. Cockcroft, MD, Division of Respirology, Critical Care and Sleep Medicine, Department of Medicine, University of Saskatchewan, 103 Hospital Dr, Ellis Hall, 5th Floor, Saskatoon, SK, S7N 0W8 Canada; e-mail: [email protected] Copyright Ó 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2019.09.005
1
One factor that could hinder the accuracy and comparability of bronchoprovocation test results is the respiratory duty cycle (Ti/Ttot), the ratio of inspiration time to total time for one full breath during tidal breathing. When using continuous-flow delivery devices, it is important to know the Ti/Ttot because it influences the amount of nebulized aerosol inhaled and available to deposit in the airways. To date, there are limited prospective data on the Ti/Ttot; reported Ti/Ttot values range from 0.31 to 0.49, and previous study designs differ from the laboratory environment involved in bronchoprovocation testing.1-6 It also remains unknown if induced airway constriction influences the Ti/Ttot as the bronchoprovocation test progresses.
The primary purpose of the current study was to estimate the mean Ti/Ttot in participants with airway hyperresponsiveness (AHR). Secondary objectives included the variability in Ti/Ttot within participants when measurements were repeated, when they experienced progressive airway constriction, and when they inhaled room air vs aerosolized saline. A control group of non-AHR participants was recruited to determine whether the Ti/Ttot differs based on the presence of AHR. We hypothesized that the mean Ti/Ttot would be lower in those with AHR than in those without AHR and would decline with progressive airway constriction.
Subjects and Methods
with the standard setup of the vibrating mesh nebulizer/filter and one with the modified setup of the nebulizer/ultrasonic spirometer, ensured that the modified setup did not interfere with withinparticipant repeatability of the methacholine PD20. Consistency in breathing during each inhalation period was monitored via flow-time graphs generated by using WBreath software (Fig 1).
Participants All participants were recruited from the local community within 1 month of study start, were aged $ 18 years, and had a baseline FEV1 $ 65% of predicted.7 Participants with AHR had a positive methacholine challenge (provocative dose causing a 20% fall in FEV1 [PD20] # 400 mg). Participants without AHR did not have a current or historical respiratory condition, allergies causing nasal/respiratory symptoms, or a positive methacholine challenge test (MCT) result. If an individual enrolled as a participant without AHR but was found to have a positive MCT result, he or she was reassigned to the AHR participant group. Individuals enrolled as participants with AHR could not be reassigned to the non-AHR participant group if they had a negative MCT result, and they were withdrawn. Eligible participants could not be pregnant, breastfeeding, or have cardiovascular problems. Smokers with a smoking history < 10 packyears were eligible and avoided smoking for $ 1 h prior to testing. Salbutamol was avoided for 6 h prior to testing. Individuals could not take long-acting bronchodilator or anticholinergic agents. Each participant provided written informed consent prior to enrolling. This study was approved by the University of Saskatchewan Biomedical Research Ethics Board (Bio ID 1132). Study Design This randomized crossover study involved two MCTs, each lasting approximately 1 h; the two MCTs were separated by at least 24 h and up to 1 week and were performed at the same time of day (1.5 h). One MCT was performed per the established volumetric method with a vibrating mesh nebulizer and filter as described elsewhere.8 The other MCT was performed identically except that the filter was replaced with an ultrasonic spirometer (Easy on-PC spirometer; ndd Medical Technologies). Both the AHR and the non-AHR participants were randomly assigned the order in which they completed the two types of MCT. Measurement of Ti/Ttot The ultrasonic spirometer uses ultrasound signals that provide continuous measurement of respiratory gas flow, which is used to calculate the duration of Ti and Ttot, respiratory rate, and number of breaths. A T-piece, mouthpiece, and vibrating mesh nebulizer (Aerogen Solo nebulizer; Aerogen Ltd.) were connected to the spirometer via a modified breathing tube to continuously monitor participants’ respiratory gas flow during each inhalation period using WBreath software (ndd Medical Technologies). Repeat MCTs, one
2 Original Research
Methacholine Challenges Each study visit began with spirometry performed in triplicate by using a KoKo Sx 1000 spirometer (nSpire Health Inc.). Participants next inhaled room air for 2 min using tidal breathing through the ultrasonic spirometer fitted with a T-piece, mouthpiece, and vibrating mesh nebulizer. After a 3-min break, participants inhaled nebulized saline through the same spirometer/nebulizer setup until the nebulizer had completely aerosolized 0.5 mL of saline. FEV1 maneuvers were performed at 30 and 90 s postinhalation. The MCT proceeded using either the spirometer/nebulizer combination or the standard setup (nebulizer, T-piece, mouthpiece, and filter)8 for the delivery of aerosolized methacholine (Provocholine; Methapharm Inc.). Five minutes after the start of the saline inhalation period, participants inhaled 0.5 mL of lowdose methacholine, followed by FEV1 maneuvers at 30 and 90 s postinhalation. The MCT continued with increasing doubling doses of methacholine within the range of 3 to 400 mg until a minimum 20% fall in FEV1 was reached or until the 400 mg dose was administered. Participants used tidal breathing to inhale aerosolized solution, wore nose clips for each inhalation period and FEV1 maneuver, and were seated for the duration of each methacholine challenge. The methacholine PD20 in participants with AHR was calculated in two ways. The first method used the assumed Ti/Ttot of 0.40,9 and the second method used each participant’s actual Ti/Ttot during their last two inhalation periods: Methacholine dose ¼ concentration ðmg=mLÞ volume ð0:5 mLÞ Ti =Ttot Methacholine PD20 ¼ ½ð20 R1Þ=ðR2 R1Þ ðlog D2 log D1Þ þ log D1; where D1 ¼ second-to-last dose administered, D2 ¼ last dose administered, R1 ¼ FEV1 fall after D1, and R2 ¼ FEV1 fall after D2.8 Statistical Analysis Raw Ti/Ttot data were first averaged for each inhalation period in each participant. The test-retest repeatability in Ti/Ttot when
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1 0.8 0.6 0.4
Flow (L/s)
0.2 0 –0.2 –0.4 –0.6 –0.8 –1 –1.2 0
20
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60 Time (s)
80
100
120
Figure 1 – Example flow-time graph illustrating inspiratory and expiratory airflow over 2 min of tidal breathing of room air in a participant with airway hyperresponsiveness.
inhaling room air or when inhaling nebulized saline was evaluated by using intraclass correlation coefficient (ICC) analyses. One-way analysis of variance tests assessed differences in the Ti/Ttot data between the AHR and non-AHR groups, the Ti/Ttot data obtained when inhaling room air vs when inhaling saline, and the repeat methacholine PD20 within each participant with AHR. Repeated
measures analysis of variance tests were used to assess the within-participant variability in Ti/Ttot over the duration of the MCT.
Results
positive MCT result and were thus included in the AHR group. One individual in the non-AHR group completed the study but was subsequently excluded; two of the subject’s average Ti/Ttot results did not make physiological sense and likely resulted from an equipment malfunction (eg, Ti/Ttot ¼ 0.09). Altogether, data from 15 individuals of different ethnic origin were included in each of the study groups (Table 1).
Participants
A total of 15 participants enrolled in the AHR group, and 19 enrolled in the non-AHR group. Three individuals enrolled in the AHR group were withdrawn, one for inadequate baseline lung function and two for a negative MCT result. Of the 19 participants who originally enrolled in the non-AHR group, three had a TABLE 1
Ti/Ttot data are presented with the respective 95% CIs in square brackets unless otherwise stated.
] Participant Demographic Characteristics
Characteristic Age, mean SD, y
AHR Group (n ¼ 15) 33 14
Non-AHR Group (n ¼ 15) 27 10
Sex Male Female Height, mean SD, cm Weight, mean SD, kg Mean highest screening FEV1, % predicted (range) Geometric mean PD20, mg Smoking status, all < 10 pack-years
5
5
10
10
165 12
165 6
73 19
64 11
95 (75-116)
97 (72-117)
106
NA
3 past, 1 current
1 current, 2 casual
AHR ¼ airway hyperresponsiveness; NA ¼ not applicable; PD20 ¼ provocative dose of methacholine causing a 20% fall in FEV1.
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Respiratory Duty Cycle
The mean Ti/Ttot in the AHR group during room air and saline inhalations were 0.392 [0.378-0.406] and 0.389 [0.373-0.405], respectively. The mean Ti/Ttot in the non-AHR group during room air and saline inhalation cycles were 0.447 [0.426-0.468] and 0.424 [0.398-0.450], respectively. The room air (P < .001) and saline (P ¼ .040) Ti/Ttot differed significantly between the two study groups. ICC analyses of repeat Ti/Ttot measures yielded the following: AHR participants’ repeat room air Ti/Ttot ICC ¼ 0.646, AHR participants’ repeat saline Ti/Ttot ICC ¼ 0.760, non-AHR participants’ repeat room air Ti/Ttot ICC ¼ 0.904, and non-AHR participants’ repeat saline Ti/Ttot ICC ¼ 0.956. Individual Ti/Ttot values from each inhalation period are illustrated in Figure 2. Room air and saline Ti/Ttot data were statistically similar in AHR participants (P ¼ .675) but significantly different in non-AHR participants (P ¼ .022). Repeat Ti/Ttot findings over the course of an MCT were not significantly different in AHR participants (P ¼ .326) but did differ significantly in non-AHR participants (P ¼ .008).
A
Neither the room air nor the saline Ti/Ttot differed significantly from the last methacholine dose Ti/Ttot in AHR participants (P ¼ .138 and P ¼ .095, respectively). Among non-AHR participants, only the room air (P ¼ .012) and not the saline (P ¼ .160) Ti/ Ttot differed significantly from the last methacholine dose Ti/Ttot. No significant relation was found in either participant group between the Ti/Ttot and several factors, including respiration rate, number of breaths taken per inhalation period, and percent fall in FEV1. Although not statistically significant, there was a downward trend in Ti/Ttot with an increasing fall in FEV1 (Fig 3). Methacholine PD20
Repeat methacholine PD20 results did not differ significantly (P ¼ .163) between the spirometer/ nebulizer and nebulizer-only MCTs. Methacholine PD20 calculated by using participants’ actual Ti/Ttot did not differ significantly from those calculated by using the assumed Ti/Ttot of 0.40 (P ¼ .472) (Fig 4). All participants’ PD20 results remained within the accepted variability range of 1.5 doubling doses.10
B 0.60
0.60 Non-AHR Group n = 15
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Figure 2 – Individual mean respiratory duty cycles of participants with AHR (A) and without AHR (B) for each inhalation period. AHR ¼ airway hyperresponsiveness.
4 Original Research
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16
0.5 0.48
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Respiratory Duty Cycle
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0.3 Saline
0%-9.9% Fall FEV1
10%-19.9% Fall 20%-29.9% Fall FEV1 FEV1
>30% Fall FEV1
Figure 3 – The number of participants in each study group (bars) whose data were included in the mean respiratory duty cycle calculation (line-andscatter) for each range of percent fall in FEV1. The airway hyperresponsiveness group data are illustrated in red, and the non-airway hyperresponsiveness group data are illustrated in blue.
Baseline Lung Function
The highest baseline FEV1 measured prior to each MCT did not differ significantly based on MCT method or test order in AHR participants (P ¼ .888 and P ¼ .916, respectively) or in non-AHR participants (P ¼ .767 and P ¼ .797, respectively).
Discussion The mean Ti/Ttot in participants with AHR was 0.392 [0.378-0.406] during room air inhalation and 0.389 [0.373-0.405] during saline inhalation; these values agree with the assumed Ti/Ttot of 0.40 recommended by the European Respiratory Society for use in methacholine PD20 calculations.9 In participants without AHR, the mean Ti/Ttot was significantly higher at 0.447 [0.4260.468] during room air inhalation and 0.424 [0.3980.450] during saline inhalation. Participants without AHR exhibited a larger range of Ti/Ttot data and reported a significant change following inhalation of aerosolized saline compared with room air; a possible explanation is that anxiety and the novelty of aerosol inhalation contributed to this significant drop in Ti/Ttot, which was not observed in AHR participants, most of
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whom had previously undergone bronchoprovocation testing. Participants without AHR showed excellent repeatability in Ti/Ttot, and participants with AHR exhibited moderate repeatability. We can only speculate regarding the cause of the significant difference in Ti/Ttot between participant groups. It is possible that individuals with AHR have bronchoconstriction and/or airway inflammation at rest, resulting in hyperinflation and gas trapping in the lungs11; these effects influence expiratory efficiency and may increase the expiratory time per breath, leading to a lower Ti/Ttot. The Ti/Ttot is particularly relevant in research and aerosol delivery (eg, medication). It is challenging to standardize bronchoprovocation test calculations if laboratories use different assumed Ti/Ttot. Past studies have used multiple assumed Ti/Ttot, including 0.33,12 0.35,13-15 and 0.40.8,16 In addition, the Ti/Ttot influences the amount of medication delivered via continuous-flow nebulization, as aerosol is only delivered to the airways during inspiration; when dosage is especially important, care must be taken to
5
at baseline, 0.45 with mild UAO, 0.47 with moderate UAO, and 0.56 with severe UAO. Chadha et al18 assessed the effect of bronchoconstriction on the Ti/Ttot of healthy participants using body plethysmography based on percent fall in specific airway conductance (sGAW) as opposed to the percent fall in FEV1 that is now widely used. A small sample of six healthy semirecumbent participants had a mean baseline Ti/Ttot of 0.412 0.013, 0.407 0.024 after a PD causing a 25% fall in sGAW, 0.394 0.016 after a PD causing a 35% fall in sGAW, and 0.353 0.027 after a PD causing a 55% fall in sGAW. Although this progressive change in Ti/Ttot was not statistically significant, it indicates a downward trend with increasing bronchoconstriction.
400
Methacholine PD20 (µg)
100
25
6
1.5
n = 15 P = .472 Assumed Ti/Ttot (0.40)
Individual Measured Ti/Ttot
Figure 4 – Comparison of individual PD20 results calculated from assumed (0.40) vs actual measured Ti/Ttot. PD20 ¼ provocative dose of methacholine causing a 20% fall in FEV1; Ti/Ttot ¼ respiratory duty cycle.
ensure that the appropriate amount of medication is indeed inhaled. Past studies have identified an average Ti/Ttot in various patient populations under different laboratory conditions. In supine, awake healthy participants, Askanazi et al1 found that 30 individuals had a mean SD Ti/Ttot of 0.395 0.043 when inhaling room air through a canopy-computer-spirometry system. In semi-recumbent healthy participants, Bendixen et al17 measured an average Ti/Ttot of 0.352 in 16 female subjects and 0.363 in 12 male subjects using strain gauge pneumography. In children with cystic fibrosis, Coates et al2 used a pneumotachograph and measured the Ti/ Ttot of 43 seated children during the inhalation of tobramycin; the Ti/Ttot data ranged from 0.36 to 0.64, with a mean of 0.44 0.05. Variability in Ti/Ttot during airway obstruction has been studied in healthy individuals by using methods different from those considered standard for bronchoprovocation testing. To investigate the effect of upper airway obstruction (UAO) on Ti/Ttot, Schneider et al3 induced varying levels of UAO by altering nasal pressure to change the mean inspiratory airflow; the mean Ti/Ttot of 26 sleeping supine participants was 0.40
6 Original Research
The findings of Schneider et al3 and Chadha et al18 suggest that bronchoconstriction affects the Ti/Ttot of individuals with AHR. Schneider et al reported an increasing Ti/Ttot with progressive UAO in healthy participants, which is expected as UAO affects inspiration; it would thus be anticipated that inspiratory time would increase to deliver sufficient air into the lungs despite increased resistance to inspired air flow.11 Bronchoconstriction or lower airway obstruction affects exhalation due to hyperinflation and gas trapping, and thus is anticipated to increase exhalation time and decrease the Ti/Ttot. Although a downward trend in Ti/ Ttot data with progressive bronchoconstriction was observed in both the current study and that by Chadha et al,18 this change was not statistically significant and was not consistent between all participants with AHR or without AHR. An assumed Ti/Ttot of 0.39 or 0.40 should not significantly affect the bronchoprovocation test results of most individuals; however, there are likely outliers whose Ti/Ttot differ sufficiently to have a significant effect. Our findings show that the Ti/Ttot generally does not vary enough over the course of an MCT to significantly influence test results. The lack of change in methacholine PD20 between repeat challenges indicates that the spirometer/nebulizer setup did not influence the integrity of the MCT. The main study limitation was the potential influence of the laboratory environment on participants’ breathing pattern and rate. Participants were encouraged to distract themselves with their cellphones during the inhalation periods to reduce the attention they paid to their breathing. A typical MCT is performed in an identical environment, and thus participants’ breathing should be relatively consistent in this setting. Although it would be ideal to routinely record Ti/Ttot for methacholine PD20 calculations, it would not be
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practical given the specialized equipment, software, and logistics involved in measuring the Ti/Ttot. The Ti/Ttot results may not translate as well for use in nebulized medication delivery calculations in a nonlaboratory setting. Although a significant relation was not found between level of bronchoconstriction and Ti/Ttot, it is possible that a larger bronchoconstriction response is needed to yield significant changes in Ti/Ttot.
Conclusions The mean Ti/Ttot of 15 participants with AHR was comparable to the recommended assumed value of
Acknowledgements Author contributions: D. W. C. is the guarantor of the content of the article, including the data and analysis. All four authors contributed substantially to the study design, analysis and interpretation of data, and manuscript writing, and have met the requirements for authorship. Each author revised the work critically for important intellectual content, gave final approval of the manuscript, and agree to be held accountable for all aspects of the work.
0.40. In contrast, participants without AHR exhibited a significantly higher mean Ti/Ttot. Despite some variability in Ti/Ttot between participants, there was no significant change in methacholine PD20 regardless of the use of actual or assumed Ti/Ttot in test result calculations. The Ti/Ttot also did not significantly change with progressive airway constriction. Future studies may investigate the Ti/ Ttot with greater induced bronchoconstriction in individuals with AHR or in individuals who exhibit greater baseline bronchoconstriction such as those with COPD.
3. Schneider H, Krishnan V, Pichard LE, Patil SP, Smith PL, Schwartz AR. Inspiratory duty cycle responses to flow limitation predict nocturnal hypoventilation. Eur Respir J. 2009;33(5): 1068-1076. 4. Vassilakopoulos T, Zakynthinos S, Roussos C. The tension-time index and the frequency/tidal volume ratio are the major pathologic determinants of weaning failure and success. Am J Respir Crit Care Med. 1998;158(2):378-385.
Financial/nonfinancial disclosures: The authors have reported to CHEST the following: D. W. C. is an advisory board member for Methapharm, Inc. None declared (C. M. B., B. E. D., B. L. G.).
5. Wilkens H, Weingard B, Mauro AL, et al. Breathing pattern and chest wall volumes during exercise in patients with cystic fibrosis, pulmonary fibrosis and COPD before and after lung transplantation. Thorax. 2010;65(9): 808-814.
Role of sponsors: The Canadian Society of Allergy and Clinical Immunology had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
6. Neder JA, Dal Corso S, Malaguti C, et al. The pattern and timing of breathing during incremental exercise: a normative study. Eur Respir J. 2003;21(3):530-538.
Other contributions: The authors thank the Lung Association of Saskatchewan for its loan of an Easy on-PC ultrasonic spirometer. The authors also thank the Canadian Society of Allergy and Clinical Immunology for its financial support of the study.
7. Quanjer PH, Stanojevic S, Cole TJ, et al. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the Global Lung Function 2012 equations. Eur Respir J. 2012;40(6):1324-1343.
References 1. Askanazi J, Milic-Emili J, Broell JR, Hyman AI, Kinney JM. Influence of exercise and CO2 on breathing pattern of normal man. J Appl Physiol Respir Environ Exerc Physiol. 1979;47(1):192-196. 2. Coates AL, Allen PD, Eng M, MacNeish CF, Ho SL, Lands LC. Effect of size and disease on estimated deposition of drugs administered using jet nebulization in children with cystic fibrosis. Chest. 2001;119(4):1123-1130.
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8. Davis BE, Simonson SK, Blais CM, Cockcroft DW. Methacholine challenge testing: a novel method for reporting PD20. Chest. 2017;152(6):1251-1257. 9. Coates AL, Wanger J, Cockcroft DW, et al. ERS technical standard on bronchial challenge testing: general considerations and performance of methacholine challenge tests. Eur Respir J. 2017;49(5): 1601526. 10. Dehaut P, Rachiele A, Martin RR, Malo JL. Histamine dose-response curves in asthma: reproducibility and sensitivity of different indices to assess response. Thorax. 1983;38(7):516-522.
11. Macklem PT. The physiology of small airways. Am J Respir Crit Care Med. 1998;157(5 pt 2):S181-S183. 12. Michotte JB, Jossen E, Roeseler J, Liistro G, Reychler G. In vitro comparison of five nebulizers during noninvasive ventilation: analysis of inhaled and lost doses. J Aerosol Med Pulm Drug Deliv. 2014;27(6):430440. 13. Blais CM, Cockcroft DW, Veilleux J, et al. Methacholine challenge: comparison of airway responsiveness produced by a vibrating mesh nebulizer versus a jet nebulizer. J Aerosol Med Pulm Drug Deliv. 2018;31(2):88-93. 14. Cockcroft DW, Davis BE, Todd DC, Smycniuk AJ. Methacholine challenge: comparison of two methods. Chest. 2005;127(3):839-844. 15. El-Gammal AI, Killian KJ, Scime TX, et al. Comparison of the provocative concentration of methacholine causing a 20% fall in FEV1 between the AeroEclipse II breath-actuated nebulizer and the Wright nebulizer in adult participants with asthma. Ann Am Thorac Soc. 2015;12(7):10391043. 16. McPeck M, Tandon R, Hughes K, Smaldone GC. Aerosol delivery during continuous nebulization. Chest. 1997;111(5):1200-1205. 17. Bendixen HH, Smith GM, Mead J. Pattern of ventilation in young adults. J Appl Physiol. 1964;19(2):195-198. 18. Chadha TS, Schneider AW, Birch S, Jenouri G, Sackner MA. Breathing pattern during induced bronchoconstriction. J Appl Physiol Respirat Environ Exercise Physiol. 1984;56(4):1053-1059.
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Original Research
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Respiratory Duty Cycles in Individuals With and Without Airway Hyperresponsiveness Christianne M. Blais, MSc, MBA; Beth E. Davis, PhD; Brian L. Graham, PhD; and Donald W. Cockcroft, MD
The respiratory duty cycle (Ti/Ttot) can influence bronchoprovocation test results and nebulized drug delivery. The Ti/Ttot has not yet been examined in individuals with airway hyperresponsiveness (AHR) in typical bronchoprovocation test conditions. This study investigated the mean Ti/Ttot in participants with and without AHR and whether the Ti/Ttot changes with increasing bronchoconstriction. BACKGROUND:
Fifteen participants with AHR and fifteen participants without AHR completed this randomized crossover study. An ultrasonic spirometer was used for continuous measurement of the Ti/Ttot as participants inhaled room air or aerosolized solution. Each participant completed two methacholine challenges, one using a continuous-output vibrating mesh nebulizer/ultrasonic spirometer and one with the nebulizer only. Prior to each methacholine challenge, participants inhaled room air and aerosolized saline through the nebulizer/spirometer setup to record baseline Ti/Ttot data.
METHODS:
RESULTS: The mean Ti/Ttot findings [95% CIs] during room air inhalation were 0.392 [0.3780.406] and 0.447 [0.426-0.468] in participants with and without AHR, respectively (P < .001). The mean Ti/Ttot during saline inhalation were 0.389 [0.373-0.405] and 0.424 [0.398-0.450] in participants with and without AHR (P ¼ .040). The Ti/Ttot showed a nonsignificant downward trend with progressive methacholine-induced bronchoconstriction.
The mean Ti/Ttot in participants with AHR closely resembles the assumed Ti/ Ttot of 0.40 recommended for standard use when calculating methacholine challenge results. Since the Ti/Ttot did not change significantly over the course of a methacholine challenge, the same Ti/Ttot can be used to calculate the dose of methacholine inhaled, regardless of the level of bronchoconstriction. CONCLUSIONS:
TRIAL REGISTRY:
ClinicalTrials.gov; No.: NCT03505489; URL: www.clinicaltrials.gov. CHEST 2019;
KEY WORDS:
aerosols; airway hyperresponsiveness; provocation test; pulmonary function test
ABBREVIATIONS: AHR = airway hyperresponsiveness; ICC = intraclass correlation coefficient; MCT = methacholine challenge test; PD20 = provocative dose of methacholine causing a 20% fall in FEV1; sGAW = specific airway conductance; Ti/Ttot = respiratory duty cycle; UAO = upper airway obstruction AFFILIATIONS: From the Division of Respirology, Critical Care and Sleep Medicine, Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada. FUNDING/SUPPORT: This work was supported by the Canadian Society of Allergy and Clinical Immunology.
chestjournal.org
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CORRESPONDENCE TO: Donald W. Cockcroft, MD, Division of Respirology, Critical Care and Sleep Medicine, Department of Medicine, University of Saskatchewan, 103 Hospital Dr, Ellis Hall, 5th Floor, Saskatoon, SK, S7N 0W8 Canada; e-mail: [email protected] Copyright Ó 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2019.09.005
1
One factor that could hinder the accuracy and comparability of bronchoprovocation test results is the respiratory duty cycle (Ti/Ttot), the ratio of inspiration time to total time for one full breath during tidal breathing. When using continuous-flow delivery devices, it is important to know the Ti/Ttot because it influences the amount of nebulized aerosol inhaled and available to deposit in the airways. To date, there are limited prospective data on the Ti/Ttot; reported Ti/Ttot values range from 0.31 to 0.49, and previous study designs differ from the laboratory environment involved in bronchoprovocation testing.1-6 It also remains unknown if induced airway constriction influences the Ti/Ttot as the bronchoprovocation test progresses.
The primary purpose of the current study was to estimate the mean Ti/Ttot in participants with airway hyperresponsiveness (AHR). Secondary objectives included the variability in Ti/Ttot within participants when measurements were repeated, when they experienced progressive airway constriction, and when they inhaled room air vs aerosolized saline. A control group of non-AHR participants was recruited to determine whether the Ti/Ttot differs based on the presence of AHR. We hypothesized that the mean Ti/Ttot would be lower in those with AHR than in those without AHR and would decline with progressive airway constriction.
Subjects and Methods
with the standard setup of the vibrating mesh nebulizer/filter and one with the modified setup of the nebulizer/ultrasonic spirometer, ensured that the modified setup did not interfere with withinparticipant repeatability of the methacholine PD20. Consistency in breathing during each inhalation period was monitored via flow-time graphs generated by using WBreath software (Fig 1).
Participants All participants were recruited from the local community within 1 month of study start, were aged $ 18 years, and had a baseline FEV1 $ 65% of predicted.7 Participants with AHR had a positive methacholine challenge (provocative dose causing a 20% fall in FEV1 [PD20] # 400 mg). Participants without AHR did not have a current or historical respiratory condition, allergies causing nasal/respiratory symptoms, or a positive methacholine challenge test (MCT) result. If an individual enrolled as a participant without AHR but was found to have a positive MCT result, he or she was reassigned to the AHR participant group. Individuals enrolled as participants with AHR could not be reassigned to the non-AHR participant group if they had a negative MCT result, and they were withdrawn. Eligible participants could not be pregnant, breastfeeding, or have cardiovascular problems. Smokers with a smoking history < 10 packyears were eligible and avoided smoking for $ 1 h prior to testing. Salbutamol was avoided for 6 h prior to testing. Individuals could not take long-acting bronchodilator or anticholinergic agents. Each participant provided written informed consent prior to enrolling. This study was approved by the University of Saskatchewan Biomedical Research Ethics Board (Bio ID 1132). Study Design This randomized crossover study involved two MCTs, each lasting approximately 1 h; the two MCTs were separated by at least 24 h and up to 1 week and were performed at the same time of day (1.5 h). One MCT was performed per the established volumetric method with a vibrating mesh nebulizer and filter as described elsewhere.8 The other MCT was performed identically except that the filter was replaced with an ultrasonic spirometer (Easy on-PC spirometer; ndd Medical Technologies). Both the AHR and the non-AHR participants were randomly assigned the order in which they completed the two types of MCT. Measurement of Ti/Ttot The ultrasonic spirometer uses ultrasound signals that provide continuous measurement of respiratory gas flow, which is used to calculate the duration of Ti and Ttot, respiratory rate, and number of breaths. A T-piece, mouthpiece, and vibrating mesh nebulizer (Aerogen Solo nebulizer; Aerogen Ltd.) were connected to the spirometer via a modified breathing tube to continuously monitor participants’ respiratory gas flow during each inhalation period using WBreath software (ndd Medical Technologies). Repeat MCTs, one
2 Original Research
Methacholine Challenges Each study visit began with spirometry performed in triplicate by using a KoKo Sx 1000 spirometer (nSpire Health Inc.). Participants next inhaled room air for 2 min using tidal breathing through the ultrasonic spirometer fitted with a T-piece, mouthpiece, and vibrating mesh nebulizer. After a 3-min break, participants inhaled nebulized saline through the same spirometer/nebulizer setup until the nebulizer had completely aerosolized 0.5 mL of saline. FEV1 maneuvers were performed at 30 and 90 s postinhalation. The MCT proceeded using either the spirometer/nebulizer combination or the standard setup (nebulizer, T-piece, mouthpiece, and filter)8 for the delivery of aerosolized methacholine (Provocholine; Methapharm Inc.). Five minutes after the start of the saline inhalation period, participants inhaled 0.5 mL of lowdose methacholine, followed by FEV1 maneuvers at 30 and 90 s postinhalation. The MCT continued with increasing doubling doses of methacholine within the range of 3 to 400 mg until a minimum 20% fall in FEV1 was reached or until the 400 mg dose was administered. Participants used tidal breathing to inhale aerosolized solution, wore nose clips for each inhalation period and FEV1 maneuver, and were seated for the duration of each methacholine challenge. The methacholine PD20 in participants with AHR was calculated in two ways. The first method used the assumed Ti/Ttot of 0.40,9 and the second method used each participant’s actual Ti/Ttot during their last two inhalation periods: Methacholine dose ¼ concentration ðmg=mLÞ volume ð0:5 mLÞ Ti =Ttot Methacholine PD20 ¼ ½ð20 R1Þ=ðR2 R1Þ ðlog D2 log D1Þ þ log D1; where D1 ¼ second-to-last dose administered, D2 ¼ last dose administered, R1 ¼ FEV1 fall after D1, and R2 ¼ FEV1 fall after D2.8 Statistical Analysis Raw Ti/Ttot data were first averaged for each inhalation period in each participant. The test-retest repeatability in Ti/Ttot when
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1 0.8 0.6 0.4
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80
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Figure 1 – Example flow-time graph illustrating inspiratory and expiratory airflow over 2 min of tidal breathing of room air in a participant with airway hyperresponsiveness.
inhaling room air or when inhaling nebulized saline was evaluated by using intraclass correlation coefficient (ICC) analyses. One-way analysis of variance tests assessed differences in the Ti/Ttot data between the AHR and non-AHR groups, the Ti/Ttot data obtained when inhaling room air vs when inhaling saline, and the repeat methacholine PD20 within each participant with AHR. Repeated
measures analysis of variance tests were used to assess the within-participant variability in Ti/Ttot over the duration of the MCT.
Results
positive MCT result and were thus included in the AHR group. One individual in the non-AHR group completed the study but was subsequently excluded; two of the subject’s average Ti/Ttot results did not make physiological sense and likely resulted from an equipment malfunction (eg, Ti/Ttot ¼ 0.09). Altogether, data from 15 individuals of different ethnic origin were included in each of the study groups (Table 1).
Participants
A total of 15 participants enrolled in the AHR group, and 19 enrolled in the non-AHR group. Three individuals enrolled in the AHR group were withdrawn, one for inadequate baseline lung function and two for a negative MCT result. Of the 19 participants who originally enrolled in the non-AHR group, three had a TABLE 1
Ti/Ttot data are presented with the respective 95% CIs in square brackets unless otherwise stated.
] Participant Demographic Characteristics
Characteristic Age, mean SD, y
AHR Group (n ¼ 15) 33 14
Non-AHR Group (n ¼ 15) 27 10
Sex Male Female Height, mean SD, cm Weight, mean SD, kg Mean highest screening FEV1, % predicted (range) Geometric mean PD20, mg Smoking status, all < 10 pack-years
5
5
10
10
165 12
165 6
73 19
64 11
95 (75-116)
97 (72-117)
106
NA
3 past, 1 current
1 current, 2 casual
AHR ¼ airway hyperresponsiveness; NA ¼ not applicable; PD20 ¼ provocative dose of methacholine causing a 20% fall in FEV1.
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Respiratory Duty Cycle
The mean Ti/Ttot in the AHR group during room air and saline inhalations were 0.392 [0.378-0.406] and 0.389 [0.373-0.405], respectively. The mean Ti/Ttot in the non-AHR group during room air and saline inhalation cycles were 0.447 [0.426-0.468] and 0.424 [0.398-0.450], respectively. The room air (P < .001) and saline (P ¼ .040) Ti/Ttot differed significantly between the two study groups. ICC analyses of repeat Ti/Ttot measures yielded the following: AHR participants’ repeat room air Ti/Ttot ICC ¼ 0.646, AHR participants’ repeat saline Ti/Ttot ICC ¼ 0.760, non-AHR participants’ repeat room air Ti/Ttot ICC ¼ 0.904, and non-AHR participants’ repeat saline Ti/Ttot ICC ¼ 0.956. Individual Ti/Ttot values from each inhalation period are illustrated in Figure 2. Room air and saline Ti/Ttot data were statistically similar in AHR participants (P ¼ .675) but significantly different in non-AHR participants (P ¼ .022). Repeat Ti/Ttot findings over the course of an MCT were not significantly different in AHR participants (P ¼ .326) but did differ significantly in non-AHR participants (P ¼ .008).
A
Neither the room air nor the saline Ti/Ttot differed significantly from the last methacholine dose Ti/Ttot in AHR participants (P ¼ .138 and P ¼ .095, respectively). Among non-AHR participants, only the room air (P ¼ .012) and not the saline (P ¼ .160) Ti/ Ttot differed significantly from the last methacholine dose Ti/Ttot. No significant relation was found in either participant group between the Ti/Ttot and several factors, including respiration rate, number of breaths taken per inhalation period, and percent fall in FEV1. Although not statistically significant, there was a downward trend in Ti/Ttot with an increasing fall in FEV1 (Fig 3). Methacholine PD20
Repeat methacholine PD20 results did not differ significantly (P ¼ .163) between the spirometer/ nebulizer and nebulizer-only MCTs. Methacholine PD20 calculated by using participants’ actual Ti/Ttot did not differ significantly from those calculated by using the assumed Ti/Ttot of 0.40 (P ¼ .472) (Fig 4). All participants’ PD20 results remained within the accepted variability range of 1.5 doubling doses.10
B 0.60
0.60 Non-AHR Group n = 15
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Figure 2 – Individual mean respiratory duty cycles of participants with AHR (A) and without AHR (B) for each inhalation period. AHR ¼ airway hyperresponsiveness.
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16
0.5 0.48
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0.3 Saline
0%-9.9% Fall FEV1
10%-19.9% Fall 20%-29.9% Fall FEV1 FEV1
>30% Fall FEV1
Figure 3 – The number of participants in each study group (bars) whose data were included in the mean respiratory duty cycle calculation (line-andscatter) for each range of percent fall in FEV1. The airway hyperresponsiveness group data are illustrated in red, and the non-airway hyperresponsiveness group data are illustrated in blue.
Baseline Lung Function
The highest baseline FEV1 measured prior to each MCT did not differ significantly based on MCT method or test order in AHR participants (P ¼ .888 and P ¼ .916, respectively) or in non-AHR participants (P ¼ .767 and P ¼ .797, respectively).
Discussion The mean Ti/Ttot in participants with AHR was 0.392 [0.378-0.406] during room air inhalation and 0.389 [0.373-0.405] during saline inhalation; these values agree with the assumed Ti/Ttot of 0.40 recommended by the European Respiratory Society for use in methacholine PD20 calculations.9 In participants without AHR, the mean Ti/Ttot was significantly higher at 0.447 [0.4260.468] during room air inhalation and 0.424 [0.3980.450] during saline inhalation. Participants without AHR exhibited a larger range of Ti/Ttot data and reported a significant change following inhalation of aerosolized saline compared with room air; a possible explanation is that anxiety and the novelty of aerosol inhalation contributed to this significant drop in Ti/Ttot, which was not observed in AHR participants, most of
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whom had previously undergone bronchoprovocation testing. Participants without AHR showed excellent repeatability in Ti/Ttot, and participants with AHR exhibited moderate repeatability. We can only speculate regarding the cause of the significant difference in Ti/Ttot between participant groups. It is possible that individuals with AHR have bronchoconstriction and/or airway inflammation at rest, resulting in hyperinflation and gas trapping in the lungs11; these effects influence expiratory efficiency and may increase the expiratory time per breath, leading to a lower Ti/Ttot. The Ti/Ttot is particularly relevant in research and aerosol delivery (eg, medication). It is challenging to standardize bronchoprovocation test calculations if laboratories use different assumed Ti/Ttot. Past studies have used multiple assumed Ti/Ttot, including 0.33,12 0.35,13-15 and 0.40.8,16 In addition, the Ti/Ttot influences the amount of medication delivered via continuous-flow nebulization, as aerosol is only delivered to the airways during inspiration; when dosage is especially important, care must be taken to
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at baseline, 0.45 with mild UAO, 0.47 with moderate UAO, and 0.56 with severe UAO. Chadha et al18 assessed the effect of bronchoconstriction on the Ti/Ttot of healthy participants using body plethysmography based on percent fall in specific airway conductance (sGAW) as opposed to the percent fall in FEV1 that is now widely used. A small sample of six healthy semirecumbent participants had a mean baseline Ti/Ttot of 0.412 0.013, 0.407 0.024 after a PD causing a 25% fall in sGAW, 0.394 0.016 after a PD causing a 35% fall in sGAW, and 0.353 0.027 after a PD causing a 55% fall in sGAW. Although this progressive change in Ti/Ttot was not statistically significant, it indicates a downward trend with increasing bronchoconstriction.
400
Methacholine PD20 (µg)
100
25
6
1.5
n = 15 P = .472 Assumed Ti/Ttot (0.40)
Individual Measured Ti/Ttot
Figure 4 – Comparison of individual PD20 results calculated from assumed (0.40) vs actual measured Ti/Ttot. PD20 ¼ provocative dose of methacholine causing a 20% fall in FEV1; Ti/Ttot ¼ respiratory duty cycle.
ensure that the appropriate amount of medication is indeed inhaled. Past studies have identified an average Ti/Ttot in various patient populations under different laboratory conditions. In supine, awake healthy participants, Askanazi et al1 found that 30 individuals had a mean SD Ti/Ttot of 0.395 0.043 when inhaling room air through a canopy-computer-spirometry system. In semi-recumbent healthy participants, Bendixen et al17 measured an average Ti/Ttot of 0.352 in 16 female subjects and 0.363 in 12 male subjects using strain gauge pneumography. In children with cystic fibrosis, Coates et al2 used a pneumotachograph and measured the Ti/ Ttot of 43 seated children during the inhalation of tobramycin; the Ti/Ttot data ranged from 0.36 to 0.64, with a mean of 0.44 0.05. Variability in Ti/Ttot during airway obstruction has been studied in healthy individuals by using methods different from those considered standard for bronchoprovocation testing. To investigate the effect of upper airway obstruction (UAO) on Ti/Ttot, Schneider et al3 induced varying levels of UAO by altering nasal pressure to change the mean inspiratory airflow; the mean Ti/Ttot of 26 sleeping supine participants was 0.40
6 Original Research
The findings of Schneider et al3 and Chadha et al18 suggest that bronchoconstriction affects the Ti/Ttot of individuals with AHR. Schneider et al reported an increasing Ti/Ttot with progressive UAO in healthy participants, which is expected as UAO affects inspiration; it would thus be anticipated that inspiratory time would increase to deliver sufficient air into the lungs despite increased resistance to inspired air flow.11 Bronchoconstriction or lower airway obstruction affects exhalation due to hyperinflation and gas trapping, and thus is anticipated to increase exhalation time and decrease the Ti/Ttot. Although a downward trend in Ti/ Ttot data with progressive bronchoconstriction was observed in both the current study and that by Chadha et al,18 this change was not statistically significant and was not consistent between all participants with AHR or without AHR. An assumed Ti/Ttot of 0.39 or 0.40 should not significantly affect the bronchoprovocation test results of most individuals; however, there are likely outliers whose Ti/Ttot differ sufficiently to have a significant effect. Our findings show that the Ti/Ttot generally does not vary enough over the course of an MCT to significantly influence test results. The lack of change in methacholine PD20 between repeat challenges indicates that the spirometer/nebulizer setup did not influence the integrity of the MCT. The main study limitation was the potential influence of the laboratory environment on participants’ breathing pattern and rate. Participants were encouraged to distract themselves with their cellphones during the inhalation periods to reduce the attention they paid to their breathing. A typical MCT is performed in an identical environment, and thus participants’ breathing should be relatively consistent in this setting. Although it would be ideal to routinely record Ti/Ttot for methacholine PD20 calculations, it would not be
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practical given the specialized equipment, software, and logistics involved in measuring the Ti/Ttot. The Ti/Ttot results may not translate as well for use in nebulized medication delivery calculations in a nonlaboratory setting. Although a significant relation was not found between level of bronchoconstriction and Ti/Ttot, it is possible that a larger bronchoconstriction response is needed to yield significant changes in Ti/Ttot.
Conclusions The mean Ti/Ttot of 15 participants with AHR was comparable to the recommended assumed value of
Acknowledgements Author contributions: D. W. C. is the guarantor of the content of the article, including the data and analysis. All four authors contributed substantially to the study design, analysis and interpretation of data, and manuscript writing, and have met the requirements for authorship. Each author revised the work critically for important intellectual content, gave final approval of the manuscript, and agree to be held accountable for all aspects of the work.
0.40. In contrast, participants without AHR exhibited a significantly higher mean Ti/Ttot. Despite some variability in Ti/Ttot between participants, there was no significant change in methacholine PD20 regardless of the use of actual or assumed Ti/Ttot in test result calculations. The Ti/Ttot also did not significantly change with progressive airway constriction. Future studies may investigate the Ti/ Ttot with greater induced bronchoconstriction in individuals with AHR or in individuals who exhibit greater baseline bronchoconstriction such as those with COPD.
3. Schneider H, Krishnan V, Pichard LE, Patil SP, Smith PL, Schwartz AR. Inspiratory duty cycle responses to flow limitation predict nocturnal hypoventilation. Eur Respir J. 2009;33(5): 1068-1076. 4. Vassilakopoulos T, Zakynthinos S, Roussos C. The tension-time index and the frequency/tidal volume ratio are the major pathologic determinants of weaning failure and success. Am J Respir Crit Care Med. 1998;158(2):378-385.
Financial/nonfinancial disclosures: The authors have reported to CHEST the following: D. W. C. is an advisory board member for Methapharm, Inc. None declared (C. M. B., B. E. D., B. L. G.).
5. Wilkens H, Weingard B, Mauro AL, et al. Breathing pattern and chest wall volumes during exercise in patients with cystic fibrosis, pulmonary fibrosis and COPD before and after lung transplantation. Thorax. 2010;65(9): 808-814.
Role of sponsors: The Canadian Society of Allergy and Clinical Immunology had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
6. Neder JA, Dal Corso S, Malaguti C, et al. The pattern and timing of breathing during incremental exercise: a normative study. Eur Respir J. 2003;21(3):530-538.
Other contributions: The authors thank the Lung Association of Saskatchewan for its loan of an Easy on-PC ultrasonic spirometer. The authors also thank the Canadian Society of Allergy and Clinical Immunology for its financial support of the study.
7. Quanjer PH, Stanojevic S, Cole TJ, et al. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the Global Lung Function 2012 equations. Eur Respir J. 2012;40(6):1324-1343.
References 1. Askanazi J, Milic-Emili J, Broell JR, Hyman AI, Kinney JM. Influence of exercise and CO2 on breathing pattern of normal man. J Appl Physiol Respir Environ Exerc Physiol. 1979;47(1):192-196. 2. Coates AL, Allen PD, Eng M, MacNeish CF, Ho SL, Lands LC. Effect of size and disease on estimated deposition of drugs administered using jet nebulization in children with cystic fibrosis. Chest. 2001;119(4):1123-1130.
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8. Davis BE, Simonson SK, Blais CM, Cockcroft DW. Methacholine challenge testing: a novel method for reporting PD20. Chest. 2017;152(6):1251-1257. 9. Coates AL, Wanger J, Cockcroft DW, et al. ERS technical standard on bronchial challenge testing: general considerations and performance of methacholine challenge tests. Eur Respir J. 2017;49(5): 1601526. 10. Dehaut P, Rachiele A, Martin RR, Malo JL. Histamine dose-response curves in asthma: reproducibility and sensitivity of different indices to assess response. Thorax. 1983;38(7):516-522.
11. Macklem PT. The physiology of small airways. Am J Respir Crit Care Med. 1998;157(5 pt 2):S181-S183. 12. Michotte JB, Jossen E, Roeseler J, Liistro G, Reychler G. In vitro comparison of five nebulizers during noninvasive ventilation: analysis of inhaled and lost doses. J Aerosol Med Pulm Drug Deliv. 2014;27(6):430440. 13. Blais CM, Cockcroft DW, Veilleux J, et al. Methacholine challenge: comparison of airway responsiveness produced by a vibrating mesh nebulizer versus a jet nebulizer. J Aerosol Med Pulm Drug Deliv. 2018;31(2):88-93. 14. Cockcroft DW, Davis BE, Todd DC, Smycniuk AJ. Methacholine challenge: comparison of two methods. Chest. 2005;127(3):839-844. 15. El-Gammal AI, Killian KJ, Scime TX, et al. Comparison of the provocative concentration of methacholine causing a 20% fall in FEV1 between the AeroEclipse II breath-actuated nebulizer and the Wright nebulizer in adult participants with asthma. Ann Am Thorac Soc. 2015;12(7):10391043. 16. McPeck M, Tandon R, Hughes K, Smaldone GC. Aerosol delivery during continuous nebulization. Chest. 1997;111(5):1200-1205. 17. Bendixen HH, Smith GM, Mead J. Pattern of ventilation in young adults. J Appl Physiol. 1964;19(2):195-198. 18. Chadha TS, Schneider AW, Birch S, Jenouri G, Sackner MA. Breathing pattern during induced bronchoconstriction. J Appl Physiol Respirat Environ Exercise Physiol. 1984;56(4):1053-1059.
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