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Original Research: ASTHMA |

Dynamic Hyperinflation During Bronchoconstriction in Asthma*: Implications for Symptom Perception FREE TO VIEW

M. Diane Lougheed, MD, FCCP; Thomas Fisher, RRT; Denis E. O’Donnell, MD, FCCP
Author and Funding Information

*From the Asthma Research Unit (Drs. Lougheed and Fisher) and Respiratory Investigation Unit (Dr. O’Donnell), Department of Medicine, Queen’s University, Kingston, ON, Canada.

Correspondence to: M. Diane Lougheed, MD, FCCP, 102 Stuart St, Kingston, ON, K7L 2V6, Canada; e-mail: mdl@post.queensu.ca



Chest. 2006;130(4):1072-1081. doi:10.1378/chest.130.4.1072
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Objective: The objective of this study was to examine the relationship between respiratory symptom intensity and quality and dynamic lung hyperinflation (DH) during induced bronchoconstriction in asthma.

Patients and methods: Subjects with asthma (n = 116) underwent baseline spirometry and lung volume measurement followed by high-dose methacholine challenge testing (MCT) [maximum decrease in FEV1 of 50% from baseline]. Dyspnea intensity (Borg scale) was measured after each dose of methacholine. Qualitative descriptors of breathlessness and functional residual capacity (FRC) were measured at the doses nearest to the provocative concentration of methacholine causing a 20% fall in FEV (PC20) and at the highest dose of methacholine (maximum response).

Results: FEV1 decreased by 24.7 ± 0.7% (mean ± SEM) at the dose nearest to PC20 and by 46.1 ± 1.1% at maximum response. Inspiratory capacity decreased by 0.62 ± 0.04 L at the dose nearest to PC20 and 1.06 ± 0.06 L at maximum response. The descriptor clusters “inspiratory difficulty,” “chest tightness,” “unsatisfied inspiration,” and “work” were selected at the dose nearest to PC20 but were more frequently selected at maximum response (p < 0.0001). Individuals who reported chest tightness at maximum response had greater airflow obstruction and higher FRC (percentage of predicted) than those who did not report chest tightness.

Conclusions: Four dominant qualities of dyspnea in asthma (inspiratory difficulty, chest tightness, unsatisfied inspiration, and work) were reported early in the course of MCT and evolved in parallel, becoming more prevalent at maximum response. Significant DH accompanied even mild bronchoconstriction during MCT in asthma, making it difficult to separate mechanisms of chest tightness from other dominant respiratory sensations.

Figures in this Article

Effective self-management of asthma relies in part on the accurate assessment by patients and physicians of symptoms during episodes of bronchoconstriction. However, the origins and mechanisms responsible for the perception of respiratory discomfort in asthma remain controversial.12 Dyspnea intensity correlates to a certain extent with spirometric measurements of maximal airflow rates such as FEV1 during induced bronchoconstriction.6 Emerging evidence suggests that the intensity of dyspnea in asthma is more directly related to concurrent changes in lung mechanics, specifically dynamic lung hyperinflation (DH).12,56

Analysis of qualitative aspects of respiratory sensations may enhance our understanding of the sensory mechanisms of symptom perception in asthma.1 This is based on the assumption that specific qualitative dimensions may have specific neurophysiologic underpinnings. Previous studies1,58 have supported the hypothesis that the dominant respiratory sensations evolve in sequence during progressive bronchoconstriction. Accordingly, chest tightness is perceived early during mild bronchoconstriction7; the sense of increased effort or work accompanies more severe bronchoconstriction when the inspiratory muscles become overloaded and functionally weakened1,5,7,9; critical DH and inspiratory threshold loading may provoke the distressing perception of unsatisfied inspiration56,10; while air hunger appears to be a discrete sensation that arises in the setting of acute (hypercarbic) respiratory failure.11 This hypothesis fails to consider the time course of DH during bronchoconstriction or its potential role in modulating the quality and intensity of dyspnea.

The purpose of this study was to reliably track the progression of respiratory symptoms and mechanical responses during bronchoprovocation in asthma. We hypothesized that chest tightness and unsatisfied inspiration would be prevalent qualities throughout bronchoprovocation because significant DH would occur during mild bronchoconstriction. To test this hypothesis, we compared the mechanical responses, and the intensity and quality of dyspnea at the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) and after the highest does of methacholine delivered (maximum response) during high-dose methacholine challenge testing (MCT). Secondary objectives of the study were to compare the mechanical responses of individuals reporting different qualitative dimensions during bronchoconstriction, to determine if gender differences in perceptual acuity or quality were present, and to explore potential mechanisms of DH during MCT.

Subjects

Subjects with mild, moderate, and severe asthma were recruited from newspaper advertisements and Kingston General Hospital (KGH) asthma and general respirology clinics. All subjects met the American Thoracic Society criteria for a diagnosis of asthma.12Clinical stability was defined as the absence of an exacerbation necessitating an alteration in medication for 3 weeks prior to the study. Subjects were excluded if they had a medical contraindication to MCT.13 All subjects gave written informed consent and were free to withdraw from the study at any time during testing. Study approval was received from the university research ethics board.

Study Design

Bronchodilators were withheld prior to MCT according to published recommendations: short-acting β-agonists (8 h), long-acting β-agonists (LABAs) [48 h], and leukotriene receptor antagonists (48 h).13 Inhaled corticosteroid (ICS) use was not altered unless taken in combination with an LABA, in which case the combination product was withheld for 48 h prior to testing. Oral steroid doses were not altered for the study. Following baseline spirometry and measurement of plethysmographic lung volumes, subjects underwent high-dose MCT to a maximum decrease in FEV1 of 50% from baseline, or symptom tolerance. Spirometry was recorded after inhalation of nebulized normal saline solution, and after each dose of methacholine. Plethysmographic lung volumes were measured at the dose nearest to PC20 and at “maximum response” (defined below).

MCT

High-dose MCT was performed according to standardized protocols1415 as previously described.56 Spirometry was performed 30 s and 90 s after each dose, and values from the flow-volume loop with the lowest postdose FEV1 were used for analysis. The test was terminated when the FEV1 decreased by 50% of the baseline value, when a plateau was reached (< 5% change in FEV1 over two or more dose steps after a fall of > 20% from the baseline value), when the highest dose of methacholine had been administered (256 mg/mL), or when the patient asked to stop due to symptoms (termed maximum response measurable in this study). Bronchial responsiveness, expressed as PC20, was calculated by linear interpolation of the log10 dose-response curve. To reverse bronchoconstriction, salbutamol (200 μg) was administered by metered-dose inhaler every 10 min until the FEV1 was within 10% of the baseline value.

Measurements

Spirometry (FEV1, FVC, peak expiratory flow [PEF], forced expiratory flow at 50% of FVC [FEF50], and forced expiratory flow during middle half of FVC) was performed according to American Thoracic Society standards16(6200 Autobox Dl; SensorMedics; Yorba Linda, CA). Inspiratory capacity (IC) was measured from the flow-volume loop. The plethysmograph system was used to measure functional residual capacity (FRC) and specific airway resistance. Panting frequency was standardized at 1 Hz to minimize the potential for frequency dependent overestimation of thoracic gas volume during bronchoconstriction.17 Total lung capacity (TLC) was calculated as the sum of FRC and IC at baseline, the dose nearest to PC20, and at maximum response. Predicted values for spirometry, lung volumes, and airway resistance were those of Morris and coworkers,18 Goldman and Becklake,19and Briscoe and Dubois,20 respectively. Heart rate and oxygen saturation were monitored continuously (502 Pulse Oximeter; Critcare Systems; Waukesha, WI).

Evaluation of Dyspnea

Dyspnea was defined as “the unpleasant sensation of labored or difficult breathing.” The intensity of dyspnea was evaluated with the modified Borg scale21 during bronchoconstriction (after each dose of methacholine) and after recovery. Prior to testing, subjects were familiarized with the Borg scale, and its end points were anchored such that “0” and “10” represented “no dyspnea” and “the most severe dyspnea that the subjects had previously experienced or could imagine,” respectively. Subjects also rated the magnitude of perceived inspiratory difficulty (“difficulty breathing in”) on the Borg scale at maximum response.

Subjects selected qualitative descriptors of breathlessness immediately after measurements at the dose nearest to PC20 and at maximum response using a questionnaire that we have previously modified2223 from Simon et al.24 Subjects were instructed to circle as many of the 16 descriptors as were applicable. In addition to individual descriptors, the clusters analyzed in this study are outlined in Table 1 .

Statistical Analysis

Results are expressed as mean ± SEM. The conventional level of statistical significance (p < 0.05) was used in all analyses. All variables were analyzed for changes over time using statistical methods for repeated measures and longitudinal data. Statistical comparisons between baseline, the dose nearest to PC20, and maximum response were done using one-way analysis of variance and the Bonferroni correction for multiple comparisons. To determine factors associated with DH, multivariable linear modeling was performed with change (Δ) from baseline in IC (percentage of predicted) as the dependent variable and concurrent changes in relevant spirometric parameters as candidate independent variables.

Comparisons between genders and between groups that did and did not select the clusters “chest tightness” and “unsatisfied inspiration” were done using unpaired t statistics, Fisher exact tests, and χ2 tests. A sample size of > 100 subjects was chosen to avoid a type 2 error in this planned subgroup analysis, based on preliminary findings that only approximately 10% of subjects did not report “unsatisfied inspiration” at maximum response,25The overall variability in the frequency of the descriptors and descriptor clusters reported by level of bronchoconstriction (at PC20 and at maximum response) was tested using a logistic mixed-effects model with a random effect for subject. This model was also used to compare responses between levels of bronchoconstriction, asthma severity, and use of ICS. The model was estimated by restricted pseudo-likelihood approach (%GLIMMIX macro, SAS V8.2; SAS Institute; Cary, NC).26 Pairwise comparisons were performed if the overall (global) test reached a 0.05 significance level. A McNemar test was used to assess the statistical significance of all pairwise comparisons. Analyses were performed using statistical software (Systat Version 6.1; Systat Software; Point Richmond, CA; and SAS Version 8.2; SAS Institute).

Subjects

One hundred sixteen subjects (39 men and 77 women; mean age, 34 ± 1 years [mean ± SEM] mild intermittent (n = 39), mild persistent (n = 7), moderate persistent (n = 42), and severe persistent (n = 28) asthma according to the Global Initiative for Asthma classification of severity27 participated in the study. Mean duration of asthma was 17.5 ± 1.1 years. There were 26 current smokers, 32 ex-smokers, and 58 life-long nonsmokers. Baseline spirometry and lung volumes are outlined in Table 2 . Airway responsiveness to methacholine (PC20) ranged from 0.03 to 15.5 mg/mL (mean, 2.7 ± 0.3 mg/mL). Medication use prior to the day of testing included short-acting β-agonists (97%), ICS (59%), LABAs (35%), oral corticosteroids (5%), and leukotriene receptor antagonists (9%).

Responses to Methacholine

Spirometric and lung volume responses to methacholine are outlined in Table 2. The mean ± SEM (range) doses of methacholine at the doses nearest to PC20 and maximum response were 3.9 ± 0.7 mg/mL (< 0.0625 to 16 mg/mL) and 33.8 ± 5.8 mg/mL (0.125 to 256 mg/mL). Three subjects stopped due to symptoms, with Borg scores of 7, 7, and 8, respectively. FEV1 decreased by 0.72 ± 0.03 L (24.7 ± 0.7%) from baseline to the dose nearest to PC20, and by 1.34 ± 0.05 L (46.1 ± 1.1%) from baseline to maximum response. IC decreased by 0.62 ± 0.04 L (21.5 ± 1.4% of predicted) from baseline to the dose nearest to PC20 and by 1.06 ± 0.06 L (36.8 ± 1.6% of predicted) from baseline to maximum response.

Only 30 subjects did not hyperinflate > 300 mL by the PC20 level. Forty-seven subjects did not hyperinflate by > 15% of predicted IC (equal to 1 SD in IC). There were no differences in descriptor choices or clusters between individuals who did and did not hyperinflate those amounts.

Spirometric Correlates of Hyperinflation

There were significant correlations (all Bonferroni probabilities p < 0.001) between change in IC (percentage of predicted) and changes in FEV1 (percentage of predicted) [r = 0.726]; PEF (percentage of predicted) [r = 0.653]; FEF50 (percentage of predicted) [r = 0.587], forced expiratory flow during middle half of FVC (percentage of predicted) [r = 0.560]; and forced expiratory flow at 75% of FVC (FEF75; percentage of predicted) [r = 0.479]. There were also statistically significant interrelationships between these variables (Bonferroni probabilities all p < 0.001). Stepwise multiple regression selected change in FEV1 (percentage of predicted), PEF (percentage of predicted), and FEF75 (percentage of predicted) as the strongest correlates of change in IC (percentage of predicted): ΔIC (percentage of predicted) = − 0.965 + 0.774 ΔFEV1 (percentage of predicted) + 0.187 ΔPEF (percentage of predicted) − 0.114 ΔFEF75 (percentage of predicted) [squared multiple R = 0.534; F ratio, 191.907; p < 0.001].

Intensity of Dyspnea During Bronchoconstriction

Borg scores for overall dyspnea and inspiratory difficulty increased significantly from “very, very slight” at baseline to “mild” at PC20 and “severe” at maximum response (Table 2). There was no significant difference during MCT between Borg scores for overall dyspnea and inspiratory difficulty. Analysis of variance revealed no significant differences in Borg scores for overall dyspnea or inspiratory difficulty between categories of asthma severity either at baseline, PC20, or maximum response.

Descriptors of Breathlessness and Descriptor Cluster Frequencies

The frequency of selection of qualitative descriptors of breathlessness and descriptor clusters are illustrated in Figures 1, 2 , respectively. The overall tests based on the logistic mixed-effects model showed that there were significant differences between the selection frequencies of the individual descriptors (p < 0.001) and the clusters (p < 0.001). Overall, the descriptors and the clusters were selected more frequently at maximum response compared to PC20 (both p < 0.001). There was not an interaction between the relative frequencies of symptoms in the two states (PC20 or maximum response; both p > 0.20 for interaction). There were no significant differences in descriptors or clusters between individuals with mild (intermittent and persistent) and severe asthma either at PC20 or maximum response. There were also no significant differences in descriptors or clusters between those receiving ICS and those not receiving ICS either at PC20 or maximum response.

Descriptors of Breathlessness

The most frequent descriptors selected at PC20 and maximum response were as follows: “my chest feels tight,” “breathing in requires effort,” and “my breathing requires more work.” There were no statistically significant differences between the frequencies of these descriptors by pairwise testing at either PC20 or maximum response. A fourth descriptor (“I feel a need for more air”) was selected as frequently as breathing in requires effort (p = 0.14) and my breathing requires more work (p = 0.11) at maximum response.

Descriptor Clusters

The most frequent descriptor clusters at PC20 and maximum response were inspiratory difficulty, chest tightness, unsatisfied inspiration, and work. Pairwise testing revealed that inspiratory difficulty was more prevalent at PC20 than unsatisfied inspiration (p = 0.02), and as prevalent as chest tightness (p = 0.09) and work (p = 0.07). At PC20, the chest tightness cluster was comparable in prevalence to unsatisfied inspiration (p = 0.88) and inspiratory difficulty (p = 0.09). Inspiratory difficulty, chest tightness, unsatisfied inspiration, and work were all more prevalent (p < 0.01) than “expiratory difficulty,” “heavy,” and “hunger.”

Pairwise testing revealed that all of the descriptor clusters were more prevalent at maximum response than at PC20 (p < 0.001). At maximum response, there were no significant differences between the prevalence of inspiratory difficulty, chest tightness, unsatisfied inspiration, and work. These four descriptor clusters were all more prevalent (p < 0.01) than expiratory difficulty, heavy, and hunger.

Gender Differences in Descriptors and Descriptor Clusters

There were no significant differences between men and women in Borg scores for overall dyspnea at PC20 (1.9 ± 0.2 and 2.0 ± 0.2, respectively; p = 0.68) or maximum response (3.7 ± 0.3 and 4.3 ± 0.2, respectively; p = 0.11), or for inspiratory difficulty at PC20 (2.0 ± 0.2 and 2.2 ± 0.2, respectively; p = 0.52) or maximum response (4.0 ± 0.3 and 4.6 ± 0.2, respectively; p = 0.14). At PC20, there were no gender differences in descriptors or clusters. At maximum response, women were more likely than men to select descriptors in the chest tightness cluster (92% vs 76%; p = 0.02).

Mechanical Responses by Descriptor Clusters

There were no statistically significant differences in baseline FEV1 or FRC in individuals who did or did not select descriptors in the clusters chest tightness or unsatisfied inspiration clusters. There was a nonsignificant trend toward a smaller resting IC (percentage of predicted) in subjects who selected unsatisfied inspiration at maximum response (p = 0.09). Tables 3, 4 outline spirometry and lung volumes in subjects who did and did not report these clusters at PC20 and at maximum response, respectively.

Substantial DH occurred in this study even when FEV1 had only declined by an average of 25% of its baseline value, likely secondary to expiratory flow limitation (EFL), which has important implications for symptom perception in asthma. Four dominant qualitative descriptors of dyspnea in asthma emerged early in MCT when dyspnea intensity was only mild (inspiratory difficulty, chest tightness, unsatisfied inspiration, and work) and were even more prevalent at maximal response when dyspnea intensity was severe. Finally, there were no significant gender differences in perceived dyspnea intensity during MCT, and qualitative descriptor choices were generally similar in men and women.

Bronchoprovocation testing is commonly used in laboratory investigations of asthma and symptom perception. Although it does not fully mimic the pathophysiologic processes of spontaneous asthma that might impact respiratory sensation, particularly eosinophilic airway inflammation, it reliably mimics the main mechanical aberrations of spontaneous bronchoconstriction, specifically EFL and DH.1,56 Although dyspnea intensity during histamine-induced and spontaneous bronchoconstriction did not correlate well,28 we and others5,29 have shown that MCT reliably simulates the intensity and quality of dyspnea of spontaneous asthma.

DH During Mild Bronchoconstriction

The majority of previous studies utilizing MCT in asthma concentrated on symptoms experienced during mild bronchoconstriction (at the PC20 level) without considering or reliably measuring attendant DH. In this study, we used high-dose MCT and plethysmography to examine sensory responses to a broad range of stimuli from mild bronchoconstriction to moderately severe DH. Notably, significant DH (approximately 0.62 L) was already present at the dose nearest to PC20 during bronchoprovocation (25% change in FEV1). Thus, even at low levels of bronchoconstriction significant mechanical derangements are present, which potentially contribute to the quality of respiratory sensations experienced.

The mechanism of DH during acute bronchoconstriction is controversial. The two main theories are as follows: (1) persistent activity of inspiratory rib cage musculature during expiration, termed active inspiratory muscle braking3031; and (2) DH is the passive mechanical consequence of EFL and reflects compromised lung emptying and air trapping during tidal breathing.32 In support of the latter, we have shown that quadriplegic subjects (who lack the capacity for rib cage braking) show reductions in IC comparable to neurologically intact subjects with asthma and have EFL (overlap of the tidal and maximum expiratory curve) during MCT.6,33 The close correlation between the reductions in IC and maximal expiratory flow rates in the effort-independent range in the current study lends further support to this theory.

Respiratory Sensation During Mild Bronchoconstriction

The predominant qualitative dimensions throughout methacholine-induced bronchoconstriction were inspiratory difficulty, tight chest, unsatisfied inspiration, and work. Chest tightness was reported by 57% of the subjects in this study at the PC20 level. Although chest tightness is regarded as a typical symptom of mild bronchoconstriction, classically attributed to direct sensory effects of airway narrowing (via vagal afferent inputs),7 other explanations are equally plausible. Previous studies that used respiratory inductive plethysmography rather than body plethysmography to track DH7,29 and application of positive end-expiratory pressure to induce hyperinflation29 may have lead to erroneous conclusions that DH does not contribute to chest tightness. The application of positive end-expiratory pressure does not impose an inspiratory threshold load, which is known to contribute to dyspnea intensity in asthma.6 Furthermore, Fessler and Permutt reported that mechanical hyperinflation induced by an expiratory solenoid valve that does result in an inspiratory threshold load resulted in the perception of chest tightness even in the absence of bronchoconstriction.34 While chest wall afferents may normally contribute to this sensation, quadriplegics retain the ability to perceive the intensity of dyspnea and quality (including chest tightness),33 suggesting that afferent input traveling via the vagus and/or phrenic nerves contributes to these respiratory sensations.

Accurate measurements of lung volumes in the current study have revealed that significant DH is present during mild bronchoconstriction, which could contribute to chest tightness. Furthermore, in contrast to the study by Moy et al,7but in keeping with another report,8 the prevalence of chest tightness increased during MCT and was reported in > 80% of subjects at maximum response. Although we cannot rule out chest tightness being the prominent quality of dyspnea in asthma with minor bronchoconstriction of < 20% change in FEV1, beyond that degree of airway narrowing we cannot partition the effects of airway narrowing from those of concomitant DH. As such, it is not possible to attribute chest tightness or the other main qualities of dyspnea prevalent at PC20 (inspiratory difficulty, unsatisfied inspiration, and work) to airway narrowing alone.

The minimum clinically significant change in IC with respect to symptom generation has not been determined in asthma. In COPD, improvements in IC of as little as 0.13 L (or approximately 10% of predicted) were associated with important improvements in exertional dyspnea and exercise endurance.35 In this study, a threshold change in IC associate with the sensation of unsatisfied inspiration was not determined.

DH and Respiratory Sensation at Maximum Response

At maximum response, severe hyperinflation was present (approximately 1.1 L). The mechanical load encountered under these circumstances is substantial, including an inspiratory threshold load of approximately 7 cm H2O.6 Thoracic expansion is mechanically restricted when the respiratory system is forced to operate near TLC: inspiratory reserve volume is diminished, and tidal volume represents a larger percentage of IC. The inspiratory muscles, already functionally weakened by altered length-tension relationships, must cope with resistive, inspiratory threshold and elastic loads secondary to reduced dynamic compliance, and severe dyspnea ensues. We and others56,2223,36 have postulated that neuromechanical dissociation that ensues in this setting is perceived as unsatisfied inspiration. The trend toward a smaller resting IC (percentage of predicted) in individuals who reported descriptors in the unsatisfied inspiration and tight at maximum response clusters may be relevant for symptom generation. As IC further diminishes during bronchoconstriction, there is greater encroachment on the inspiratory reserve volume and TLC at the top noncompliant portion of the pressure-volume relationship of the respiratory system. Thus, for a given change in end-expiratory lung volume, individuals with a small resting IC end up having less “room” to breathe. Esophageal pressure-derived mechanical measurements would shed light on this hypothesis.

Air hunger, a quality typically provoked by carbon dioxide loading,11,37 is a frightening sensation that has been likened to a breath hold, being “starved for air,” having “an increased urge to breathe,” and even a “sense of imminent crisis” feeling of being about to die.11,37 It was reported in < 30% of subjects even at maximum response and appears to be distinct from the other clusters.

Asthma Severity and ICS Use

Chronicity and reversibility of airway obstruction and prior use of ICS are several factors reported to affect symptom perception in asthma.3840 In this study, we found no difference in dyspnea intensity or quality throughout MCT between mild and severe asthma or between individuals who were and were not receiving ICS.

Gender Issues

The lungs and airways of female subjects are anatomically smaller and the mass of respiratory musculature is reduced compared with age-matched male subjects. Theoretically, this may predispose female subjects to greater dyspnea for a given level of bronchoconstriction and DH, and may result in different descriptors choices than in male subjects. Indeed, population studies4142 suggest that female subjects with airway obstructive disorders have greater dyspnea at a given decline in FEV1 than male subjects. However, we could detect no consistent gender differences in either the intensity or quality of dyspnea during MCT in our study population.

In summary, this is the first study to demonstrate that decline in FEV1 in the order of 25% during MCT in a large sample of asthma patients was associated with significant DH of approximately 0.6 L. Acute DH during MCT appears to occur as a consequence of EFL. There are four dominant qualitative descriptors of dyspnea in asthma: inspiratory difficulty, chest tightness, unsatisfied inspiration, and work. These descriptors are reported early in the course of MCT. Unsatisfied inspiration is reported less commonly than inspiratory difficulty at the dose nearest to PC20. All four dominant qualities evolve in parallel rather than in sequence, becoming more prevalent at maximum response during MCT. Consequently it is not possible to reliably separate the physiologic mechanisms underlying chest tightness from those underlying other discrete sensations that allude to difficult or unsatisfied inspiration. Clinicians and researchers should consider the attendant level of DH when evaluating the symptoms of spontaneous or induced bronchoconstriction.

Abbreviations: DH = dynamic lung hyperinflation; EFL = expiratory flow limitation; FEF50 = forced expiratory flow at 50% of FVC; FEF75 = forced expiratory flow at 75% of FVC; FRC = functional residual capacity; IC = inspiratory capacity; ICS = inhaled corticosteroid/corticosteroids; KGH = Kingston General Hospital; LABA = long-acting β-agonist; MCT = methacholine challenge testing; PC20 = provocative concentration of methacholine causing a 20% fall in FEV1; PEF = peak expiratory flow; TLC = total lung capacity

This work was supported by the Ontario Thoracic Society and Physicians’ Services Incorporated Foundation. Dr. O’Donnell is funded by the Ontario Ministry of Health.

The authors have no conflicts of interest to disclose.

Table Graphic Jump Location
Table 1. Revised Descriptors of Breathlessness Questionnaire*
* 

Modified from O’Donnell et al23 and Simon et al.24

 

Cluster names did not appear on the actual questionnaire.

Table Graphic Jump Location
Table 2. Responses to Methacholine at Baseline, PC20, and Maximum Response*
* 

Data are presented as mean ± SEM or mean ± SEM (% of predicted).

Figure Jump LinkFigure 1. Descriptors of breathlessness (n = 116) are similar but more prevalent at maximum response (Max) than at the dose nearest to PC20 during methacholine-induced bronchoconstriction. *p < 0.05, **p < 0.01, ***p < 0.001 maximum response vs PC20.Grahic Jump Location
Figure Jump LinkFigure 2. Descriptor clusters (n = 116) are similar but more prevalent at maximum response (Max) than at the dose nearest to PC20 during methacholine-induced bronchoconstriction. *p < 0.05, **p < 0.01, ***p < 0.001 maximum response vs PC20.Grahic Jump Location
Table Graphic Jump Location
Table 3. Spirometry and Lung Volumes by Descriptor Clusters at PC20 (n = 116)*
* 

Data are presented as mean ± SEM of mean ± SEM (% of predicted).

 

p < 0.05, yes vs no.

Table Graphic Jump Location
Table 4. Spirometry and Lung Volumes by Descriptor Clusters at Maximum Response (n = 116)*
* 

Data are presented as mean ± SEM or mean ± SEM (% of predicted).

 

p < 0.05, yes vs no.

The authors thank Sonja McCauley, Lori Verton, Robert Hawes, and Sheryl Ross of the KGH Asthma Research Unit for assistance with data collection, Katherine Webb of the KGH Respiratory Investigation Unit for technical assistance and review of the manuscript, and Andrew Day and Yinghua Su of the KGH Clinical Research Centre for assistance with the statistical analysis.

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Lougheed, MD, O’Donnell, DE Respiratory symptoms during induced bronchoconstriction in asthma: comparison between PC20and maximum response [abstract].Am J Respir Crit Care Med2001;163,A813
 
Wolfinger, R, O’Connell, M Generalized linear mixed models: a pseudo-likelihood approach.J Stat Comput Simul1993;48,233-243. [CrossRef]
 
 Global Initiative for Asthma: global strategy for asthma management and prevention. 2003; National Heart, Lung, and Blood Institute, National Institutes of Health. Betheseda, MD: No. 02–3659.
 
Boudreau, D, Styhler, A, Gray-Donald, K, et al A comparison of breathlessness during spontaneous asthma and histamine-induced bronchoconstriction.Clin Invest Med1995;18,25-32. [PubMed]
 
Binks, AP, Moosavi, SH, Banzett, RB, et al “Tightness” sensation of asthma does not arise from the work of breathing.Am J Respir Crit Care Med2002;165,78-82. [PubMed]
 
Martin, JG, Powell, E, Shore, S, et al The role of respiratory muscles in the hyperinflation of bronchial asthma.Am Rev Respir Dis1980;121,441-447. [PubMed]
 
Tantucci, C, Ellaffi, M, Duguet, A, et al Dynamic hyperinflation and flow limitation during methacholine-induced bronchoconstriction in asthma.Eur Respir J:1999;14,295-301. [CrossRef] [PubMed]
 
Pellegrino, R, Violante, B, Nava, S, et al Expiratory flow limitation and hyperinflation during methacholine-induced bronchoconstriction.J Appl Physiol1993;75,1720-1727. [PubMed]
 
Lougheed, MD, Flannery, JF, Webb, KA, et al Respiratory sensation and ventilatory mechanics during induced bronchoconstriction in low cervical, spontaneously breathing quadriplegics.Am J Respir Crit Care Med2002;166,370-376. [CrossRef] [PubMed]
 
Permutt, S, Fessler, HE, Brower, RG, et al Breathlessness in acute asthma: breathlessness; the Campbell Symposium1992,60-65 Norman L. Jones. Hamilton, ON:
 
O’Donnell, DE, Lam, M, Webb, KA Spirometric correlates of improvement in exercise performance after anticholinergic therapy in chronic obstructive pulmonary disease.Am J Respir Crit Care Med1999;160,542-549. [PubMed]
 
Lougheed, MD, Lawson, B, McBride, I, et al Partitioning the effects of hyperinflation and bronchoconstriction on dyspnea in asthma [abstract]. Am J Respir Crit Care Med. 2002;;165 ,.:A266
 
Banzett, RB, Lansing, RW, Brown, R, et al “Air hunger” from increased Pco2persists after complete neuromuscular block in humans.Respir Physiol1990;81,1-18. [CrossRef] [PubMed]
 
James, AL, Carroll, N, DeKlerk, N, et al Increased perception of airway narrowing in patients with mild asthma.Respirology1998;3,241-245. [CrossRef] [PubMed]
 
Ottanelli, R, Rosi, E, Romagnoli, I, et al Do inhaled corticosteroids affect perception of dyspnea during bronchoconstriction in asthma?Chest2001;120,770-777. [CrossRef] [PubMed]
 
Boulet, LP, Turcotte, H, Cartier, A, et al Influence of beclomethasone and salmeterol on the perception of methacholine-induced bronchoconstriction.Chest1998;114,373-379. [CrossRef] [PubMed]
 
Becklake, MR, Kauffmann, F Gender differences in airway behaviour over the human life span.Thorax1999;54,1119-1138. [CrossRef] [PubMed]
 
Weiner, P, Magadle, R, Massarwa, F, et al Influence of gender and inspiratory muscle training on the perception of dyspnea in patients with asthma.Chest2002;122,197-201. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Descriptors of breathlessness (n = 116) are similar but more prevalent at maximum response (Max) than at the dose nearest to PC20 during methacholine-induced bronchoconstriction. *p < 0.05, **p < 0.01, ***p < 0.001 maximum response vs PC20.Grahic Jump Location
Figure Jump LinkFigure 2. Descriptor clusters (n = 116) are similar but more prevalent at maximum response (Max) than at the dose nearest to PC20 during methacholine-induced bronchoconstriction. *p < 0.05, **p < 0.01, ***p < 0.001 maximum response vs PC20.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Revised Descriptors of Breathlessness Questionnaire*
* 

Modified from O’Donnell et al23 and Simon et al.24

 

Cluster names did not appear on the actual questionnaire.

Table Graphic Jump Location
Table 2. Responses to Methacholine at Baseline, PC20, and Maximum Response*
* 

Data are presented as mean ± SEM or mean ± SEM (% of predicted).

Table Graphic Jump Location
Table 3. Spirometry and Lung Volumes by Descriptor Clusters at PC20 (n = 116)*
* 

Data are presented as mean ± SEM of mean ± SEM (% of predicted).

 

p < 0.05, yes vs no.

Table Graphic Jump Location
Table 4. Spirometry and Lung Volumes by Descriptor Clusters at Maximum Response (n = 116)*
* 

Data are presented as mean ± SEM or mean ± SEM (% of predicted).

 

p < 0.05, yes vs no.

References

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Lougheed, MD, O’Donnell, DE Respiratory symptoms during induced bronchoconstriction in asthma: comparison between PC20and maximum response [abstract].Am J Respir Crit Care Med2001;163,A813
 
Wolfinger, R, O’Connell, M Generalized linear mixed models: a pseudo-likelihood approach.J Stat Comput Simul1993;48,233-243. [CrossRef]
 
 Global Initiative for Asthma: global strategy for asthma management and prevention. 2003; National Heart, Lung, and Blood Institute, National Institutes of Health. Betheseda, MD: No. 02–3659.
 
Boudreau, D, Styhler, A, Gray-Donald, K, et al A comparison of breathlessness during spontaneous asthma and histamine-induced bronchoconstriction.Clin Invest Med1995;18,25-32. [PubMed]
 
Binks, AP, Moosavi, SH, Banzett, RB, et al “Tightness” sensation of asthma does not arise from the work of breathing.Am J Respir Crit Care Med2002;165,78-82. [PubMed]
 
Martin, JG, Powell, E, Shore, S, et al The role of respiratory muscles in the hyperinflation of bronchial asthma.Am Rev Respir Dis1980;121,441-447. [PubMed]
 
Tantucci, C, Ellaffi, M, Duguet, A, et al Dynamic hyperinflation and flow limitation during methacholine-induced bronchoconstriction in asthma.Eur Respir J:1999;14,295-301. [CrossRef] [PubMed]
 
Pellegrino, R, Violante, B, Nava, S, et al Expiratory flow limitation and hyperinflation during methacholine-induced bronchoconstriction.J Appl Physiol1993;75,1720-1727. [PubMed]
 
Lougheed, MD, Flannery, JF, Webb, KA, et al Respiratory sensation and ventilatory mechanics during induced bronchoconstriction in low cervical, spontaneously breathing quadriplegics.Am J Respir Crit Care Med2002;166,370-376. [CrossRef] [PubMed]
 
Permutt, S, Fessler, HE, Brower, RG, et al Breathlessness in acute asthma: breathlessness; the Campbell Symposium1992,60-65 Norman L. Jones. Hamilton, ON:
 
O’Donnell, DE, Lam, M, Webb, KA Spirometric correlates of improvement in exercise performance after anticholinergic therapy in chronic obstructive pulmonary disease.Am J Respir Crit Care Med1999;160,542-549. [PubMed]
 
Lougheed, MD, Lawson, B, McBride, I, et al Partitioning the effects of hyperinflation and bronchoconstriction on dyspnea in asthma [abstract]. Am J Respir Crit Care Med. 2002;;165 ,.:A266
 
Banzett, RB, Lansing, RW, Brown, R, et al “Air hunger” from increased Pco2persists after complete neuromuscular block in humans.Respir Physiol1990;81,1-18. [CrossRef] [PubMed]
 
James, AL, Carroll, N, DeKlerk, N, et al Increased perception of airway narrowing in patients with mild asthma.Respirology1998;3,241-245. [CrossRef] [PubMed]
 
Ottanelli, R, Rosi, E, Romagnoli, I, et al Do inhaled corticosteroids affect perception of dyspnea during bronchoconstriction in asthma?Chest2001;120,770-777. [CrossRef] [PubMed]
 
Boulet, LP, Turcotte, H, Cartier, A, et al Influence of beclomethasone and salmeterol on the perception of methacholine-induced bronchoconstriction.Chest1998;114,373-379. [CrossRef] [PubMed]
 
Becklake, MR, Kauffmann, F Gender differences in airway behaviour over the human life span.Thorax1999;54,1119-1138. [CrossRef] [PubMed]
 
Weiner, P, Magadle, R, Massarwa, F, et al Influence of gender and inspiratory muscle training on the perception of dyspnea in patients with asthma.Chest2002;122,197-201. [CrossRef] [PubMed]
 
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