Mechanisms of exertional dyspnoea in symptomatic smokers without COPD

Amany F. Elbehairy, Jordan A. Guenette, Azmy Faisal, Casey E. Ciavaglia, Katherine A. Webb, Dennis Jensen, Andrew H. Ramsook, J. Alberto Neder, Denis E. O'Donnell  on behalf of the Canadian Respiratory Research Network
European Respiratory Journal 2016 48: 694-705; DOI: 10.1183/13993003.00077-2016

Abstract

Dyspnoea and activity limitation can occur in smokers who do not meet spirometric criteria for chronic obstructive pulmonary disease (COPD) but the underlying mechanisms are unknown.

Detailed pulmonary function tests and sensory–mechanical relationships during incremental exercise with respiratory pressure measurements and diaphragmatic electromyography (EMGdi) were compared in 20 smokers without spirometric COPD and 20 age-matched healthy controls.

Smokers (mean±sd post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity 75±4%, mean±sd FEV1 104±14% predicted) had greater activity-related dyspnoea, poorer health status and lower physical activity than controls. Smokers had peripheral airway dysfunction: higher phase-III nitrogen slopes (3.8±1.8 versus 2.6±1.1%·L−1) and airway resistance (difference between airway resistance measured at 5 Hz and 20 Hz 19±11 versus 12±7% at 5 Hz) than controls (p<0.05). Smokers had significantly (p<0.05) lower peak oxygen uptake (78±40 versus 107±45% predicted) and ventilation (61±26 versus 97±29 L·min−1). Exercise ventilatory requirements, operating lung volumes and cardio-circulatory responses were similar. However, submaximal dyspnoea ratings, resistive and total work of breathing were increased in smokers compared with controls (p<0.05); diaphragmatic effort (transdiaphragmatic pressure/maximumal transdiaphragmatic pressure) and fractional inspiratory neural drive to the diaphragm (EMGdi/maximal EMGdi) were also increased (p<0.05) mainly reflecting the reduced denominator.

Symptomatic smokers at risk for COPD had greater exertional dyspnoea and lower exercise tolerance compared with healthy controls in association with greater airways resistance, contractile diaphragmatic effort and fractional inspiratory neural drive to the diaphragm.

Abstract

Exertional dyspnoea in smokers without COPD is linked to higher inspiratory neural drive to the crural diaphragm http://ow.ly/e9Z7302uFM6

Introduction

Smokers who do not meet spirometric criteria for chronic obstructive pulmonary disease (COPD) [1], but who report persistent respiratory symptoms (cough, sputum production or dyspnoea) have a higher risk of all-cause mortality and accelerated decline of lung function compared with healthy reference populations [2–4]. This sub-population has formerly been designated as Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 “at risk” for COPD [5]. Recent population studies have confirmed that current and former smokers without spirometric COPD have poorer perceived quality of life, greater respiratory symptoms (including exertional dyspnoea) and lower exercise tolerance when compared with healthy non-smokers [4, 6–8]. Accordingly, the main purpose of the current study was to better understand the nature and extent of physiological impairment and mechanisms of dyspnoea and exercise intolerance in smokers at risk for COPD.

It is well known that normal spirometry in cigarette smokers may obscure heterogeneous disease of the peripheral airways, lung parenchyma and its vasculature [9, 10]. Extensive small airway inflammation has been described in smokers who do not fit conventional diagnostic criteria for COPD [10]. Small airways (<2 mm in diameter) are believed to be an important site of increased airflow resistance in such individuals [11]. Small airway dysfunction is associated with delayed mechanical time constants for lung emptying within the lungs which can become further amplified by increasing breathing frequency and ventilation (e.g. during exercise). Thus, pulmonary gas trapping and dynamic lung hyperinflation during exercise may be early manifestations of peripheral airway dysfunction in some individuals [12]. It follows that the inspiratory muscles in smokers with small airway dysfunction may be faced with combined increases in resistive and elastic loading with potential negative sensory consequences. The current study is the first to use diaphragm electromyography (EMGdi) and manometry to explore mechanisms of dyspnoea in smokers without spirometrically defined COPD.

We reasoned that peripheral airway dysfunction in smokers is likely to develop insidiously over time, allowing compensatory physiological adaptations to emerge. Such strategies might include increased neural drive to the inspiratory muscles to maintain ventilation appropriate to metabolic demand when the respiratory system is stressed [13]. Our hypothesis was that, while these adaptations would help preserve near normal ventilatory responses to exercise (commensurate with metabolic demands), the attendant increased contractile respiratory muscle effort and fractional inspiratory neural drive to the diaphragm (relative to healthy non-smoking controls) would result in greater perceived respiratory discomfort and earlier exercise termination in smokers at risk for COPD. To test this hypothesis, we compared dyspnoea intensity, breathing pattern, ventilatory efficiency, inspiratory neural drive to the crural diaphragm (indirectly assessed by EMGdi) and dynamic respiratory mechanics in groups of symptomatic smokers at risk for COPD and age-matched healthy non-smokers during symptom-limited incremental exercise.

Materials and methods

Subjects

20 symptomatic current or ex-smokers without spirometric evidence of COPD (post-bronchodilator forced expiratory volume in 1 s (FEV1) >80% predicted and FEV1/forced vital capacity (FVC) >0.7 and more than the lower limit of normal [1, 14]) were selected during screening for COPD at the Respiratory Investigation Unit (Queen's University and Kingston General Hospital, Kingston, ON, Canada). Smokers were determined to be symptomatic if they had cough/sputum and/or chronic activity-related dyspnoea (modified Medical Research Council dyspnoea scale ≥2 or COPD Assessment Test (CAT) score ≥10 or baseline dyspnoea index score ≤9) [15–17]. Other inclusion criteria were age ≥40 years and smoking history ≥20 pack–years. Exclusion criteria included: presence of asthma; other medical conditions that could contribute to dyspnoea or exercise limitation; contraindications to exercise testing; body mass index (BMI) <18.5 or ≥35 kg·m−2. 20 age-matched, non-smoking healthy controls, recruited from the Respiratory Investigation Unit database registry, were used for comparison.

Study design

This cross-sectional study received ethical approval from the Queen's University and Affiliated Teaching Hospitals Research Ethics Board (DMED-1319-10). After written informed consent, subjects completed two visits. Visit 1 included screening for eligibility, medical history, symptom and activity assessment questionnaires [15–19]; Charlson Comorbidity Index [20]; pre- and post-bronchodilator (400 μg salbutamol) pulmonary function tests; tests of small airway function (pre-bronchodilator); and an incremental cycle cardiopulmonary exercise test (CPET) for familiarisation. Visit 2 included spirometry followed by an incremental cycle CPET with EMGdi and respiratory pressure measurements. Subjects refrained from smoking ≥1 h before visits and avoided caffeine, heavy meals, alcohol and vigorous exercise ≥4 h before visits. Subjects were not tested if they had upper or lower respiratory tract infections within the previous 3 weeks and 3 months respectively.

Procedures

Detailed pulmonary function tests were performed using automated equipment (Vmax229d and Autobox V62J; and MasterScreen impulse oscillometry (IOS); SensorMedics, Yorba Linda, CA) [21–26]. Tests of small airway function included single-breath nitrogen washout [26] and IOS [25]. CPETs were conducted on an electronically braked cycle ergometer (Ergoline 800s; SensorMedics) using a SensorMedics Vmax229d system according to clinical exercise testing guidelines [27] as previously described [13]. Tests consisted of steady-state rest followed by 20-Watt stepwise increases in work rate every 2 mins until symptom limitation. Measurements included: standard breath-by-breath cardiorespiratory and breathing pattern parameters; oxygen saturation by pulse oximetry (SpO2); heart rate by 12-lead electrocardiography; dynamic operating lung volumes calculated from inspiratory capacity manoeuvres [28]; dyspnoea intensity measured by the modified 10-point Borg scale [29].

EMGdi and respiratory pressures

EMGdi and respiratory pressures were recorded continuously during exercise and analysed as previously described [13, 30]. A combined EMGdi electrode catheter with oesophageal and gastric balloons was inserted nasally and positioned as previously described [31]. The raw EMGdi signal was sampled at 2000 Hz (PowerLab, model ML880; ADInstruments, CastleHill, Australia), band-pass filtered between 20 and 1000 Hz (Bioamplifier model RA-8; Guangzhou Yinghui Medical Equipment Co. Ltd, Guangzhou, China) and converted to a root mean square. The largest value from the five electrode pairs in each inspiration was used for the analysis. Maximal EMGdi (EMGdi,max) was determined during serial inspiratory capacity manoeuvres [32]; EMGdi,max measured in this way often produces greater values than during sniff manoeuvres, and has been shown to be highly reproducible and remains unchanged during ventilatory stimulation by exercise or hypercapnia (see online supplement). EMGdi/EMGdi,max was used as an index of inspiratory neural drive to the crural diaphragm based on a number of assumptions [31, 33, 34], that were discussed in the online supplement of our recent publication [33]. The oesophageal and gastric balloon catheters were connected to differential pressure transducers (model DP15-34; Validyne Engineering, Northridge, CA, USA) to obtain oesophageal (Poes) and gastric pressures (Pga); transdiaphragmatic pressure (Pdi) was calculated as Pga minus Poes. The PowerLab system received continuous flow signal input from the Vmax229d system for offline analysis. Maximal inspiratory Pdi (Pdi,max) and inspiratory Poes (Pi,max) were determined during inspiratory capacity manoeuvres. Tidal Poes swings were expressed relative to the maximum inspiratory/expiratory excursion (Poes,max); the latter measured as the difference between the most negative Poes and the most positive Poes acquired during maximal inspiratory capacity and FVC manoeuvres, respectively. Poes/Poes,max and inspiratory Pdi/Pdi,max were used as indices of respiratory muscle effort and diaphragmatic effort, respectively. Accepted formulae were used to calculate: total lung resistance; dynamic lung compliance (CLdyn); total work of breathing as well as inspiratory elastic and resistive work; and the tension-time index of the inspiratory muscles (TTIoes) and diaphragm (TTIdi). Details are provided in the online supplement.

Statistical analysis

A sample size of 20 was estimated to provide >80% power to detect a between-group difference in dyspnoea intensity at a standardised work rate during exercise of 1 Borg unit, based on a standard deviation of 1 unit, α=0.05 and a two-tailed test of significance. Based on our previous experience in mild COPD patients [13], we estimated that sample sizes between 12 and 16 would be large enough to detect significant between-group differences in EMGdi and respiratory pressure measurements. Reasons for stopping exercise were compared between groups using the Fisher's exact test. Unpaired t-tests was used to compare differences in: 1) pulmonary function tests and measurements of small airway function; 2) dyspnoea intensity, cardiorespiratory, metabolic, gas exchange, operating lung volumes, EMGdi and respiratory pressures at rest, iso-work rates and peak exercise. A multivariable linear regression model was used to evaluate the relationship between dyspnoea intensity and relevant independent variables (i.e. EMGdi/EMGdi,max, inspiratory Pdi/Pdi,max) during exercise: group was included as a categorical effect, an interaction term was used to determine whether the relationship was similar across groups (independent variable×group), and subjects were treated as random effects to account for serial measurements (subject nested within group). Results are reported as mean±sd unless otherwise specified. A p-value <0.05 was considered significant.

Results

Both groups had similar age, height, body mass and BMI (table 1). Smokers had worse activity-related dyspnoea and quality of life, lower habitual physical activity and higher CAT scores compared with controls (table 1). Smokers were not on any inhaled medications at the time of the study except for two subjects who occasionally used a short-acting β2-agonist. Smokers had a significant smoking history (range: 21–96 pack–years) and 70% were current smokers. Controls were never-smokers except for two subjects who had an insignificant smoking history (≤2 pack–years) and had stopped smoking >20 years before the study.

View this table:
TABLE 1

Subject characteristics

Pulmonary function and small airway function

Pulmonary function tests are summarised in table 2. Smokers had normal spirometry and plethysmographic lung volumes except for a slight but significant reduction in maximal mid-expiratory flow (FEF25–75%) compared with controls. Smokers had evidence of peripheral airway dysfunction (higher differential change in airway resistance from 5 to 20 Hz and resonant frequency) and maldistribution of ventilation (higher phase-III nitrogen slope) compared with controls. The average diffusing capacity of the lung for carbon monoxide (DLCO) was within normal limits for both groups, although 25% of smokers had values <80% predicted. There were no significant differences in resting pulmonary function and IOS measurements between active and ex-smokers (all p>0.05).

View this table:
TABLE 2

Resting pulmonary function

Exercise responses, respiratory mechanics and diaphragmatic function

Measurements at peak exercise are summarised in tables 3 and 4. Peak work rate, oxygen uptake (V′O2), ventilation (V′E) and heart rate were significantly lower in smokers compared with controls. There were no differences in ventilatory requirements, operating lung volumes, SpO2 and cardio-circulatory responses during exercise between groups (figure 1, figure E1). V′E–carbon dioxide production (V′CO2) relationships expressed as slope (26.3±2.9 versus 26.6±3.2), intercept (3.7±1.7 versus 3.1±1.8) and nadir (28.7±3.3 versus 27.9±3.3) were not different in smokers versus controls (all p>0.05). Smokers with a V′E/V′CO2 nadir above the median (n=10) had a lower peak V′O2 than those below the median (n=10): 56±24 versus 101±41% predicted, respectively (p=0.007) (figure E2). The anaerobic threshold occurred at a similar V′O2 in smokers and controls (1.4±0.5 versus 1.6±0.5 L·min−1, p=0.1).

View this table:
TABLE 3

Measurements at the peak of symptom-limited incremental cycle exercise

View this table:
TABLE 4

Selected diaphragm electromyography and respiratory mechanical parameters at peak exercise

FIGURE 1
FIGURE 1

Ventilatory, breathing pattern and operating lung volume responses to incremental cycle exercise in smokers without chronic obstructive pulmonary disease (COPD) and age-matched healthy controls. Data are presented as mean±sem. Dashed line in e indicates total lung capacity (TLC) for smokers at risk for COPD while the solid line is for controls. V′E: minute ventilation; V′CO2: carbon dioxide production; V′E/V′CO2: ventilatory equivalent for carbon dioxide; PETCO2: end-tidal carbon dioxide; SpO2: oxygen saturation measured by pulse oximetry; TLC: total lung capacity; EELV: end-expiratory lung volume; EILV: end-inspiratory lung volume; fR: respiratory frequency; VT: tidal volume; IC: inspiratory capacity.

14 subjects in each group accepted insertion of the EMGdi pressure catheter. In both smokers and healthy controls, subject characteristics, pulmonary function and standard exercise test parameters were similar in each subgroup with EMGdi pressure measurements (n=14) compared with their respective total group (n=20). There was no between-group difference in inspiratory elastic work of breathing but total lung resistance and total and inspiratory resistive work of breathing were significantly higher for a given work rate and V′E during exercise in smokers compared with controls (figure 2, figure E3). EMGdi/EMGdi,max was greater in smokers at rest and for a given work rate during exercise compared with controls (figure 3). Looking at individual data, there were several smokers with tidal EMGdi values at rest and early in exercise that were higher than any seen in the control group. In addition, the majority of smokers had EMGdi,max values during their serial inspiratory capacity manoeuvres in the low range (i.e. <100 µV) in contrast to the control group where the majority had values in the higher range (i.e. >150 µV) (figure E4); EMGdi,max during the highest inspiratory capacity was lower in smokers versus controls (113±65 versus 165±56 µV, p=0.028). Thus, the higher EMGdi/EMGdi,max reflected differences in both the numerator (tidal EMGdi) and the denominator (EMGdi,max) which varied between smokers (figure 3). The EMGdi/EMGdi,max was higher in smokers versus controls regardless of how the denominator (EMGdi,max) was measured, i.e. during serial inspiratory capacity manoeuvres or during the highest value obtained during either inspiratory capacity or sniff manoeuvres throughout the test (figure E5). Inspiratory Pdi was similar for a given work rate and V′E, while inspiratory Pdi/Pdi,max was greater in smokers at rest and during exercise due to reduced Pdi,max (figure 3, figure E3). Poes-derived indices of global inspiratory muscle effort (inspiratory Poes/Pi,max) and expiratory muscle activity (expiratory rise in Pga) were not significantly different between groups (figure 3, figures E1 and E3). During submaximal exercise in all subjects, EMGdi/EMGdi,max and inspiratory Pdi/Pdi,max correlated with inspiratory resistive work (R=0.343, p<0.001 and R=0.362, p<0.001, respectively).

FIGURE 2
FIGURE 2

Elastic, total and resistive work of breathing and total lung resistance are shown during incremental cycle exercise in smokers without chronic obstructive pulmonary disease (COPD) and age-matched healthy controls. Data are presented as mean±sem. *: p<0.05 smokers without COPD versus healthy controls at rest and at standardised work rates. WOB: work of breathing.

FIGURE 3
FIGURE 3

Diaphragm electromyography (EMGdi), transdiaphragmatic pressure (Pdi) and oesophageal pressure (Poes) are shown during incremental cycle exercise in smokers without chronic obstructive pulmonary disease (COPD) and age-matched healthy controls. Dynamic maximal measurements during inspiratory capacity (IC) manoeuvres are also shown. Data are presented as mean±sem. *: p<0.05 smokers without COPD versus healthy controls at rest, at standardised work rates or at peak exercise. Insp: inspiratory; Exp: expiratory.

Throughout exercise, dyspnoea intensity at a given work rate was higher in smokers than controls: the mean difference at the highest equivalent work rate (80 W) was 1.9 Borg units (figure 4). Dyspnoea–V′E slopes were also greater in smokers than controls: 0.108±0.05 versus 0.067±0.04 Borg units·L−1·min−1 (p=0.008) (figure 4). Dyspnoea ratings increased in direct proportion to increases in EMGdi/EMGdi,max and inspiratory Pdi/Pdi,max (figure 4). There was a strong relationship between dyspnoea intensity and both EMGdi/EMGdi,max (partial R2=0.67; p<0.0005) and inspiratory Pdi/Pdi,max (partial R2=0.61; p<0.0005); both relationships were similar across groups. Of note, intensity of leg discomfort was significantly higher during exercise in smokers than controls (figure E1).

FIGURE 4
FIGURE 4

Exertional dyspnoea intensity is shown relative to a) work rate, b) ventilation, c) diaphragm electromyography relative to maximum (EMGdi/EMGdi,max) and d) inspiratory transdiaphragmatic pressure relative to maximum (Pdi/Pdi,max). Square symbols represent the points at the highest equivalent work rate (80W): the mean difference (Δ) in dyspnoea intensity at 80W between smokers without chronic obstructive pulmonary disease (COPD) and age-matched healthy controls was 1.9 Borg units (p=0.009). Data are presented as mean±sem. *: p<0.05 smokers without COPD versus healthy controls at rest and at standardised work rates. #: p<0.05 dyspnoea/ventilation slopes in smokers without COPD versus healthy controls.

Discussion

The novel finding of this study was that symptomatic smokers who did not meet spirometric criteria for COPD had greater inspiratory resistive work, Pdi/Pdi,max, EMGdi/EMGdi,max, and dyspnoea intensity ratings during exercise compared with healthy controls. The results partly support the hypothesis that adaptations to preserve appropriate ventilatory responses to exercise in the face of increased mechanical loading, negatively influence respiratory sensation and exercise performance in smokers at risk for COPD.

Smokers had greater chronic activity-related dyspnoea, poorer perceived health status and lower self-reported daily physical activity compared with controls [4, 6–8]. In this context, such individuals had a lower mean symptom-limited peak V′O2 by over 25% compared with controls and this reduction is considered clinically significant [27]. The smokers stopped exercise primarily because of intolerable symptoms of severe dyspnoea and leg discomfort at a significantly lower peak work rate and V′O2, a point where apparent cardiopulmonary reserve was present by traditional criteria [27].

Previous studies in mild COPD (established by spirometry) have confirmed heterogeneous physiological impairment of small airway and pulmonary microvascular function [12, 13, 35]. In the smoker group of the current study, decreased reactance (X5), increased frequency dependence of dynamic resistance (R5–20) and maldistribution of ventilation comprised the most consistent abnormalities. Notably, the post-bronchodilator FEV1/FVC ratio, lung volumes and DLCO were within the normal range and not significantly different from age-matched healthy controls.

During incremental exercise, the increase in ventilation in tandem with metabolic demand was similar in both groups (figure 1). On average, measures of ventilatory efficiency (V′E/V′CO2 nadir, V′E–V′CO2 slope and intercept) in smokers were not different from those of healthy controls. These results are in contrast to those of several previous studies in patients with mild airway obstruction meeting GOLD stage 1 criteria for COPD where ventilatory efficiency was consistently lower than healthy controls [12, 13, 35]. However, considerable variability in this measurement was evident among smokers in the current study. Moreover, there was an inverse relationship between the V′E/V′CO2 nadir and peak V′O2 (figure E2).

Ventilation and breathing pattern were similar in smokers and controls throughout much of exercise (figure 1). Since operating lung volumes, CLdyn and elastic work were similar in smokers and controls during exercise, the small increases in total work of breathing in smokers compared with controls mainly reflected the increased resistive work (figure 2).

Fractional inspiratory neural drive to the diaphragm was increased both at rest and during exercise in smokers compared with controls (figure 3). The data reveal that both compensatory increases in inspiratory EMGdi to overcome increased airways resistance and lower maximal voluntary diaphragm activation and force generation during inspiratory capacity manoeuvres (singly or in combination) account for the higher fractional inspiratory neural drive to the diaphragm in smokers (figure E4). It is also plausible that, in some smokers, increased chemo-stimulation as a result of higher physiological dead space (increased V′E/V′CO2, figure E2) may have contributed to a higher inspiratory EMGdi during tidal breathing [35].

The lower EMGdi,max and Pdi,max during both inspiratory capacity and sniff manoeuvres in smokers was unexpected and could not be explained by between-group differences in motivational effort during the inspiratory capacity manoeuvres since peak negative inspiratory Poes was similar in both groups. Accordingly, the lower EMGdi,max and Pdi,max in smokers likely reflects reduced contribution of the diaphragm to overall pressure generation during maximal inhalation to TLC. Indeed, the lower Pdi,max (Pga,max–Poes,max) can be mathematically explained by relatively lower intra-abdominal pressures (Pga,max) since Poes,max was similar. This is compatible with a relatively greater contribution of the rib-cage and accessory muscles to maximal negative pressure generation during inspiratory capacity manoeuvres in smokers.

This is a novel observation and the precise mechanisms are unclear. We speculate that this may represent a strategy to limit maximal voluntary activation of the mechanically stressed diaphragm to minimise respiratory discomfort. Alternatively or in addition, isolated diaphragm weakness due to inflammatory injury from smoking has been described on the basis of muscle biopsy findings in patients with COPD (including GOLD stage 1). However the average Pdi,max for the group was ∼60 cmH2O which is in the lower range of normal based on previous studies making this mechanism less likely [36].

This is the first study to examine mechanisms of exertional dyspnoea in symptomatic smokers with minor spirometric abnormalities. Dyspnoea intensity ratings during exercise increased in association with the increasing diaphragmatic contractile effort and EMGdi/EMGdi,max (figure 4). Since the dyspnoea–Pdi/Pdi,max and dyspnoea–EMGdi/EMGdi,max relationships during exercise were similar in both groups, the higher intensity ratings at a standardised work rate in smokers reflected higher diaphragmatic effort and electrical activation (both relative to maximum) (figure 4). The results are consistent with the frequent observation in multiple studies that dyspnoea intensity during exercise in health and in pulmonary diseases generally correlates well with physiological ratios that fundamentally reflect demand/capacity imbalance (e.g. VʹE/maximum ventilatory capacity, Poes/Poes,max, tidal volume/inspiratory capacity, EMGdi/EMGdi,max) [13, 28, 33, 37, 38]. The results of the current study once more underline the importance of considering “the capacity denominator” when examining the origins of perceived respiratory discomfort during exercise. Our results are in accordance with current neurophysiological constructs that emphasise the association between increasing dyspnoea and awareness of increased efferent activity from bulbopontine and cortical motor centres in the brain to the inspiratory muscles [39, 40].

Severe to very severe leg discomfort also contributed to exercise intolerance in the smoker group and was selected as the dominant exercise-limiting symptom by both groups. Previous studies in GOLD 1 COPD have also shown that perceived leg discomfort is often the main sensory locus of exercise limitation although the underlying mechanisms are not fully understood [12, 13, 35, 41]. Our smoker group reported lower habitual physical activity than controls but definitive evidence of skeletal muscle deconditioning in conjunction with lower cardiorespiratory fitness is lacking. In the presence of peripheral muscle weakness, greater motor command output and perceived effort (relative to maximum) would be required for a given force generation by these muscles during exercise [42]. However, this hypothesis was not formally tested in the current study.

Limitations

Not all subjects consented to EMGdi and respiratory pressure measurements due to the invasiveness of this procedure. However, the subgroup sample size (n=14) was sufficient to uncover consistent differences in the relevant sensory and physiological parameters of interest between smokers and healthy controls. We selected current and former smokers with respiratory symptoms for study inclusion, so our results cannot be generalised to asymptomatic smokers. We obtained EMG measurements of the crural diaphragm only and cannot comment on concomitant electrical activation or activity of the ribcage and accessory muscles engaged in supporting ventilation during exercise.

Conclusions and implications

Our results showed that symptomatic smokers at risk for COPD with evidence of small airway dysfunction successfully met the ventilatory requirements of incremental exercise. However, they did so at the cost of greater perceived dyspnoea at relatively low work rates due partly to the effects of increased mechanical loading. The increased fractional inspiratory neural drive to the diaphragm in smokers was multifactorial and reflected not only the effects of increased mechanical impedance but also (and more importantly) lower maximal voluntary activation and force generation of the diaphragm. Regardless of the nature of the underlying physiological impairment in individual smokers, higher dyspnoea intensity ratings at a given work rate compared with controls were associated with higher contractile diaphragmatic effort and fractional inspiratory neural drive to the diaphragm.

The results add to the accumulating evidence that exclusive reliance on spirometry to assess respiratory impairment related to smoking may obscure clinically significant physiological derangements in some symptomatic individuals. Careful interrogation of the heterogeneous physiological impairment in symptomatic smokers without overt COPD (in conjunction with biological and imaging markers) should facilitate more precise phenotyping and ultimately, individualised targeted therapies.

Acknowledgements

Authors' contributions: All authors played a role in the content and writing of the manuscript. In addition: Denis E. O'Donnell was the principal investigator and contributed the original idea for the study; Denis E. O'Donnell and Katherine A. Webb had input into the study design and conduct of study; Katherine A. Webb, Jordan A. Guenette, Casey E. Ciavaglia and Amany F. Elbehairy collected the data; Amany F. Elbehairy, Jordan A. Guenette, Casey E. Ciavaglia, Katherine A. Webb, Azmy Faisal and Andrew H. Ramsook performed data analysis and prepared it for presentation.

Footnotes

  • Editorial comment in Eur Respir J 2016; 48: 604–607.

  • This article has supplementary material available from erj.ersjournals.com

  • Support statement: Ontario Thoracic Society; William Spear/Richard Start Endowment Fund, Queen's University; The Canadian Respiratory Research Network (CRRN). The CRRN is supported by grants from the Canadian Institutes of Health Research (CIHR) - Institute of Circulatory and Respiratory Health; Canadian Lung Association (CLA)/Canadian Thoracic Society (CTS); British Columbia Lung Association; and Industry Partners Boehringer Ingelheim Canada Ltd, AstraZeneca Canada Inc., and Novartis Canada Ltd. Jordan A. Guenette was supported by a Scholar Award from the Michael Smith Foundation for Health Research. Dennis Jensen was supported by a Chercheurs-Boursiers Junior 1 Salary Award from the Fonds de Recherche du Québec-Santé and by a William Dawson Research Scholars Award (McGill University). The funders had no role in the study design, data collection and analysis, or preparation of the manuscript. Funding information for this article has been deposited with the Open Funder Registry.

  • Conflict of Interest: Disclosures can be found alongside this article at erj.ersjournals.com

  • Received January 11, 2016.
  • Accepted May 16, 2016.

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Mechanisms of exertional dyspnoea in symptomatic smokers without COPD
Amany F. Elbehairy, Jordan A. Guenette, Azmy Faisal, Casey E. Ciavaglia, Katherine A. Webb, Dennis Jensen, Andrew H. Ramsook, J. Alberto Neder, Denis E. O'Donnell
European Respiratory Journal Sep 2016, 48 (3) 694-705; DOI: 10.1183/13993003.00077-2016
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