Evolution of Dyspnea during Exercise in ChronicObstructive Pulmonary DiseaseImpact of Critical Volume Constraints

Pierantonio Laveneziana1,2, Katherine A. Webb1, Josuel Ora1, Karin Wadell1, and Denis E. O’Donnell1

1Respiratory Investigation Unit, Department of Medicine, Queen’s University and Kingston General Hospital, Kingston, Ontario, Canada; and2Laboratoire de Physio-Pathologie Respiratoire, Equipe de Recherche ER 10, Universite Paris VI, Faculte de Medecine Pierre et Marie Curie

(site Pitie-Salpetriere) and Service de Pneumologie et Reanimation, Groupe Hospitalier Pitie-Salpetriere, Paris, France

Rationale: Patients with chronic obstructive pulmonary disease(COPD) primarily describe their exertional dyspnea using descrip-tors alluding to increased effort orwork of breathing andunsatisfiedinspiration or inspiratory difficulty.Objectives: The purpose of this study was to examine the impact ofchanges in dynamic respiratory mechanics during incremental(INCR) and high-intensity constant work-rate (CWR) cycle exerciseon the evolution of dyspnea intensity and its major qualitativedimensions in patients with moderate-to-severe COPD.Methods: Sixteen subjects with COPD performed symptom-limitedINCRandCWRcycle exercise tests.Measurements includeddyspneaintensity and qualitative descriptors, breathing pattern, operatinglung volumes, and esophageal pressure (Pes).Measurements and Main Results: During both exercise tests, therewas an inflection in the relation between tidal volume (VT) and ven-tilation. This inflection occurred significantly earlier in time duringCWR versus INCR exercise but at a similar ventilation, VT, and tidalPes swing. Beyond this inflection, there was no further change in VT

despitea continued increase inventilationandtidal Pes.Duringbothtests, “work and effort” was the dominant dyspnea descriptor se-lected up to the inflection point, whereas after this point dyspneaintensity and the selection frequency of “unsatisfied inspiration”rose sharply.Conclusions: Regardless of the exercise test protocol, the inflection(or plateau) in the VT response marked the point where dyspneaintensity rose abruptly and there was a transition in the dominantqualitative descriptor choice from “work and effort” to “unsatisfiedinspiration.” Intensity and quality of dyspnea evolve separately andare strongly influenced by mechanical constraints on VT expansionduring exercise in COPD.

Keywords: COPD; exercise; dyspnea; respiratory mechanics

According to the lastAmericanThoracic Society statement, dysp-nea is “a subjective experience of breathing discomfort that

consists of qualitatively distinct sensations that vary in intensity”(1). Intolerable dyspnea is the most common exercise-limitingsymptom in patients with advanced chronic obstructive pulmo-nary disease (COPD) (2). The nature andmechanisms of dyspneaare complex andmultifactorial but respiratorymechanical factorsundoubtedly contribute (1, 3–5). Previous studies have shownthat the experience of respiratory discomfort at the terminationof exercise is distinctly different in health and in patients withCOPD. Thus, healthy individuals select qualitative descriptorsthat allude to increased effort or work of breathing, whereaspatients with COPD additionally select descriptors that depictthe distressing sensation of unsatisfied inspiration or inspiratorydifficulty (i.e., “I cannot get enough air in,” “breathing in requiresmore effort,” “I feel a need for more air”) (4–6). The currentstudy is the first to chart the evolution of these qualitative dimen-sions of dyspnea throughout exercise and to examine their rela-tion with dynamic respiratory mechanical events.

Previous studies using high-intensity constant work rate(CWR) cycle tests have shown that the relation between increasein dyspnea intensity and increase in the constraints on tidal volume(VT) expansion (i.e., decrease in inspiratory reserve volume[IRV]) during exercise seems biphasic (5–9). In early exercise,dyspnea intensity rises linearly up to the moderate range at theVT inflection point where IRV becomes critically reduced (phaseI), and thereafter rises steeply to very severe levels (phase II). Itis not known if this biphasic sensory response pattern is differentduring incremental (INCR) and CWR cycle testing where the

(Received in original form June 27, 2011; accepted in final form September 1, 2011)

Supported by the William Spear/Richard Start Endowment Fund, Queen’s Uni-

versity. Pierantonio Laveneziana received a John Alexander Stuart Fellowship,

Department of Medicine, Queen’s University.

Author contributions: All authors played a role in the content and writing of the

manuscript. D.E.O. was the principal investigator and contributed the original

idea for the study; D.E.O., P.L., and K.A.W. had input into the study design and

conduct of study; P.L., J.O., and K.W. collected the data; and K.A.W. and P.L.

performed data analysis and prepared it for presentation.

Correspondence and requests for reprints should be addressed to Denis

E. O’Donnell, M.D., 102 Stuart Street, Kingston, ON, K7L 2V6 Canada. E-mail:

odonnell@queensu.ca

This article has an online supplement, which is accessible from this issue’s table of

contents at www.atsjournals.org

Am J Respir Crit Care Med Vol 184. pp 1367–1373, 2011

Copyright ª 2011 by the American Thoracic Society

Originally Published in Press as DOI: 10.1164/rccm.201106-1128OC on September 1, 2011

Internet address: www.atsjournals.org

AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject

Previous studies on mechanisms of exertional dyspnea inchronic obstructive pulmonary disease (COPD) have largelyfocused on sensory intensity of respiratory discomfort and itscorrelation with increased contractile respiratory muscleeffort. Little is known about the evolution and physiologicbasis for perceived unsatisfied inspiration, which has beenshown to be a dominant qualitative dimension of dyspneain chronic obstructive pulmonary disease at the limits oftolerance.

What This Study Adds to the Field

This study charts the evolution of both the intensity andqualitative domains of dyspnea during cycle exercise inCOPD. The results show that, regardless of the exercisetesting protocol (incremental or constant work rate), theattainment of critical constraints on tidal volume expansionmarked the point where both dyspnea intensity and selec-tion of perceived unsatisfied inspiration sharply escalated.

time course of change in ventilation, operating lung volumes,breathing pattern, and esophageal pressure (Pes) generationmay be distinctly different. It is also unknown whether mechan-ical events at the VT inflection point are associated with a changein the quality of dyspnea or whether the “ventilatory history” ofthe exercise test affects the ability of the patient to identifychange in the mechanical properties of the respiratory system.We postulated that, regardless of the exercise testing protocol,critical constraints on VT displacement in the face of increasingcontractile respiratory muscle effort (and increased central neuraldrive) would lead to an increased frequency of selection of un-satisfied inspiration relative to increased effort in phase II (5).

The aims of the current study were to determine if these re-strictive constraints on volume expansion at and beyond the VT

inflection have implications for the evolution of the qualitativedimensions of dyspnea during exercise, and whether thesesensory-mechanical relations are influenced by the exercise pro-tocol selected. Operating lung volumes, breathing pattern, andPes-derived indices of respiratory mechanics were compared inpatients with COPD during INCR and high-intensity CWR cy-cle exercise, in random order on separate days. To better un-derstand the relation between dynamic respiratory mechanicsand dyspnea, the selection frequency of its main qualitativedescriptors before and after the VT inflection during both exer-cise protocols was examined. Some of the results of this studyhave previously been reported in abstract form (10).

METHODS

Subjects

Subjects included 16 clinically stable patients with COPD (FEV1/FVC,0.7) (11) and a FEV1 less than or equal to 80% predicted. Exclusioncriteria were (1) a disease other than COPD that could contribute todyspnea or exercise limitation, (2) important contraindications to clin-ical exercise testing, or (3) use of supplemental oxygen or desaturationless than 85% during exercise.

Study Design

This randomized, controlled, cross-sectional study received ethical ap-proval from Queen’s University and Affiliated Hospitals Health Scien-ces Human Research Ethics Board (DMED-906–05). After obtaininginformed consent, subjects completed three visits conducted 7–10 daysapart. Visit 1 included medical screening, evaluation of chronicactivity-related dyspnea (12, 13), familiarization with all testing proce-dures including all aspects of dyspnea evaluation, pulmonary functiontesting, and INCR cardiopulmonary cycle exercise testing. Visits 2 and3 included pulmonary function tests and either a CWR or INCR exer-cise test (randomized visit order) with detailed dynamic respiratorymechanical measurements. Before each visit, subjects withdrew short-acting inhaled bronchodilators for greater than or equal to 6 hours andavoided smoking greater than or equal to 60 minutes; caffeine, alcohol,and heavy meals greater than or equal to 4 hours; and strenuous phys-ical exertion greater than or equal to 12 hours. Visits were conducted atthe same time of day for each subject.

Procedures

Pulmonary function tests were performed using automated equipment(Vmax 229d with Autobox 6,200 DL; SensorMedics, Yorba Linda, CA)according to recommended standards (14–17). Measurements wereexpressed as percentages of predicted normal values (18–23); predictedinspiratory capacity (IC) was calculated as predicted total lung capacityminus predicted functional residual capacity.

Symptom-limited exercise tests were conducted on an electricallybraked cycle ergometer (Ergometrics 800S; SensorMedics) with a car-diopulmonary exercise testing system (Vmax229d; SensorMedics) aspreviously described (5, 24, 25). INCR tests consisted of a 1-minutewarm-up of unloaded pedaling followed by 1-minute increments of

10 W each. CWR tests consisted of a 1-minute warm-up followed byan increase in work rate to 75% of the maximal incremental work rate;endurance time was defined as the duration of loaded pedaling. Oper-ating lung volumes derived from IC maneuvers were measured at rest,every second minute during exercise, and at end-exercise (24). Pes-derived respiratory mechanical measurements were collected continu-ously with an integrated data-acquisition setup (5, 25); sniff maneuverswere performed at rest and immediately at end-exercise to obtain max-imum values for Pes (PImax) (17).Dyspnea evaluation. Intensity of dyspnea (“How strong/intense is

your breathing discomfort”?) and leg discomfort were rated using themodified 10-point Borg scale (26) at rest, every minute during exercise,and at peak exercise. The endpoints of this scale were anchored suchthat zero represented “no breathing or leg discomfort” and 10 was “themost severe breathing or leg discomfort that they could imagine expe-riencing.” Three dyspnea descriptor phrases were chosen for evalua-tion during exercise: (1) “my breathing requires more work and effort”(work and effort); (2) “I cannot get enough air in” (unsatisfied inspi-ration); and (3) “I cannot get enough air out” (unsatisfied expiration).The former two common descriptors were collected for primary anal-yses, whereas the latter was used as a control symptom that was notexpected to be selected very often. Every minute during exercise justbefore intensity ratings, subjects were asked to select the phrases fromthis list that described their sensation of breathing discomfort: none toall of the three phrases could be chosen at any one time. At end-exercise, subjects were also asked to select applicable descriptorphrases from a more comprehensive questionnaire (27).

The inflection point of the VT and ventilation ( _VE) relationship wasdetermined by two different observers (K.A.W. and P.L.) for eachsubject during each exercise protocol by examining individual Heyplots (28): if more than one inflection point was evident during exer-cise, the first was chosen. Exercise parameters were compared with thepredicted normal values of Jones (29). Analysis time-points were de-fined as follows: (1) preexercise rest was the steady-state period after atleast 3 minutes of breathing on the mouthpiece before exercise began;(2) isotime 1 and 2 were standardized exercise times of 2 minutes and4 minutes for both INCR (i.e., 20 W and 40 W) and CWR tests; (3)VT/ _VE inflection point; and (4) peak was the average of the last 30 sec-onds of loaded exercise.

Statistical Analysis

The sample size estimation of 16 was based on dyspnea intensity ratingsmeasured previously in our laboratory (5, 6) and the assumptions: a SDof approximately 1.5 units, a difference of approximately 1.5 unitsfound between the VT/ _VE inflection point and peak exercise, a two-sided test, 80% power, and a ¼ 0.05. Results are expressed as means 6SD unless otherwise specified. A P value less than 0.05 level of statis-tical significance was used for all analyses. Statistical procedures wereperformed using either SPSS 18.0 for Windows (IBM, Chicago, IL) orSystat 8.0 for Windows (Systat Software, Inc., Chicago, IL).

Between-protocol (INCR vs. CWR) comparisons at rest were madeusing paired t tests. Comparisons during exercise were made usingpaired t tests with a Bonferroni adjustment for repeated measurements:four main evaluation time-points (i.e., isotime 1, isotime 2, VT/ _VE in-flection, and peak) meant that an uncorrected P value of less than0.0125 was considered significant. McNemar exact test was used forwithin- and between-protocol analyses of dyspnea descriptors.

RESULTS

Subject characteristics and resting pulmonary function measure-ments are summarized in Table 1. There were eight subjectswith Global Initiative for Chronic Obstructive Lung Diseasestage II COPD and eight with Global Initiative for ChronicObstructive Lung Disease stage III COPD.

Physiologic Responses to INCR and CWR Exercise

Physiologic responses to INCR and CWR exercise tests are sum-marized in Table 2 and Figure E1 of the online supplement. Allmeasurements obtained at rest were similar for the INCR and

1368 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 184 2011

CWR tests. Sniff PImax was 69 6 17 cm H2O at rest for bothprotocols and did not change significantly at end-exercise. Inearly exercise (i.e., at 2 and 4 min), the patterns of responsewere significantly different between tests: oxygen consumption( _VO2), _VE, VT, Fb, and tidal Pes swings were significantly higher,whereas IC was significantly lower during CWR than INCRexercise (see online supplement). Despite these expected inten-sity and time-related differences, physiologic measurements atpeak exercise were similar for both tests (Table 2).

Whenmeasurements of breathing pattern, operating lung vol-umes, and respiratory mechanics were plotted relative to _VE,

response patterns were similar for both CWR and INCR exer-cise tests (Figure 1). A notable inflection in the VT/ _VE relation-ship occurred in most subjects during both INCR (15 of 16) andCWR (14 of 16) exercise: one subject did not have an inflectionin either test so paired comparisons were made for n ¼ 14subjects with an inflection point in both tests (Table 2). TheVT/ _VE inflection point coincided with an inflection in theIRV/ _VE relationship. Although the VT/ _VE inflection point oc-curred earlier in time in the CWR test than the INCR test (2.6vs. 5 min; P , 0.0005), the _VE and other physiologic measure-ments at this point were similar between protocols (Table 2). _VE

at the inflection point of the INCR test correlated significantlywith that of the CWR test (r ¼ 0.631; P ¼ 0.015). Beyond theinflection point during both protocols, there was no significantfurther rise in VT despite a continued increase in _VE (by in-creasing Fb) and respiratory effort (Pes/PImax).

Intensity and Quality of Exertional Dyspnea

The selection frequency of the three descriptors evaluated seri-ally during INCR and CWR exercise is shown in Figure 2A. Asexpected, the sense of unsatisfied expiration was seldom chosenduring exercise. The sense of work and effort was greater thanunsatisfied inspiration up until the VT/ _VE inflection point (atinflection: all tests, P ¼ 0.015; CWR, P ¼ 0.035; INCR, P ¼0.236); between this inflection point and peak exercise in bothtests, the selection frequency of work and effort did not rise anyfurther, whereas selection of unsatisfied inspiration increasedsteeply (all tests, P ¼ 0.001; CWR, P ¼ 0.031; INCR, P ¼0.063) to reach comparable or greater levels. At end-exercise,the selection frequency of the three main descriptor phrases(Figure 2A) and the selection frequency from the more com-prehensive descriptor questionnaire (Figure 2B) were similaracross protocols.

Similar to the physiologic variables, dyspnea intensity ratingswere significantly greater earlier in time during CWR than INCR

TABLE 1. SUBJECT CHARACTERISTICS AT VISIT ONE

Male: Female, n 9: 7

Age, yr 65 6 11

Height, cm 169 6 10

Body mass index, kg/m2 29 6 4

Smoking history, pack-years 52 6 43

Baseline Dyspnea Index, focal score (0–12) 6.8 6 1.3

MRC dyspnea scale (1–5) 2.5 6 0.7

Resting pulmonary function (% predicted)

FEV1, L 1.22 6 0.29 (48 6 9)

FEV1/FVC, % 45 6 8

IC, L 2.30 6 0.61 (83 6 11)

SVC, L 3.27 6 0.85 (89 6 10)

TLC, L 7.16 6 1.32 (120 6 14)

RV, L 3.89 6 0.76 (180 6 34)

FRC, L 4.86 6 0.99 (151 6 25)

sRaw, cm H2O d s 22.4 6 9.9 (531 6 229)

DLCO, ml/min/mm Hg 15 6 4.8 (67 6 17)

MIP, cm H2O 73 6 23 (91 6 25)

MEP, cm H2O 136 6 39 (79 6 15)

Definition of abbreviations: DLCO ¼ diffusing capacity of the lung for carbon

monoxide; IC ¼ inspiratory capacity; MEP ¼ maximal expiratory mouth pressure;

MIP ¼ maximal inspiratory mouth pressure; MRC ¼ Medical Research Council;

RV ¼ residual volume; sRaw ¼ specific airways resistance; SVC ¼ vital capacity.

Values are means 6 SD (% of predicted normal values in parentheses).

TABLE 2. MEASUREMENTS DURING INCR AND CWR EXERCISE

VT/ _VE Inflection Point* Peak

INCR CWR INCR CWR

Exercise time, min 5 6 1.7 2.6 6 0.9† 7.9 6 2.7 6 6 2.4†

Work rate, W 50 6 17 61 6 20 81 6 27 60 6 20†

Dyspnea, Borg 2.9 6 1.8 3.1 6 2.1 7 6 2.2 7 6 2.4

Leg discomfort, Borg 3.5 6 1.8 4.2 6 2.2 7.1 6 2.3 7.6 6 2.2_VO2, L/min 0.95 6 0.27 1.09 6 0.39 1.27 6 0.41 1.24 6 0.37_VO2, % predicted 55 6 16 60 6 14 68 6 18 66 6 17

Heart rate, beats/min 127 6 22 113 6 25 142 6 22 131 6 18

SpO2, % 94 6 3 94 6 3 93 6 5 93 6 5

_VE, L/min 34.1 6 10.5 38.3 6 10.6 48.3 6 14.9 46.2 6 12.1_VE/ _VCO2 41 6 8 41 6 7 40 6 8 40 6 6

Fb, breaths/min 28 6 7 30 6 6 37 6 9 36 6 8

TI/TTOT 0.41 6 0.03 0.41 6 0.03 0.41 6 0.04 0.41 6 0.04

VT, L 1.22 6 0.32 1.28 6 0.32 1.30 6 0.34 1.26 6 0.30

VT/IC, % 69 6 13 73 6 9 80 6 12 79 6 10

IC, L 1.83 6 0.49 1.77 6 0.47 1.64 6 0.41 1.63 6 0.41

IRV, L 0.60 6 0.36 0.50 6 0.23 0.33 6 0.23 0.37 6 0.21

RL, cm H2O/L/s 7.6 6 3.6 7.1 6 4.8 8.5 6 4.6 7.3 6 2.6

Tidal Pes, %PImax 37 6 15 37 6 16 54 6 20 46 6 12

Pes/PImax:VT/prVC 1.10 6 0.46 1.07 6 0.53 1.58 6 0.65 1.39 6 0.55

Inspiratory Pes, %PImax 20 6 8 24 6 8 29 6 11 28 6 7

Expiratory Pes, %MEP 10 6 6 8 6 5 14 6 8 11 6 4

Definition of abbreviations: Fb ¼ breathing frequency; IC ¼ inspiratory capacity; IRV ¼ inspiratory reserve volume; MEP ¼maximum expiratory mouth pressure; Pes ¼ esophageal pressure; PImax ¼ maximum inspiratory sniff esophageal pressure;

prVC ¼ predicted vital capacity; RL ¼ total lung resistance; SpO2¼ oxygen saturation by pulse oximetry; TI/TTOT ¼ inspiratory

duty cycle; _VCO2 ¼ carbon dioxide output; _VE ¼ minute ventilation; _VO2 ¼ oxygen consumption; VT ¼ tidal volume.

* n ¼ 14 paired tests reported for VT/ _VE inflection point.y P , 0.05 after Bonferroni adjustment: INCR versus CWR at the same measurement point.

Laveneziana, Webb, Ora, et al.: Evolution of Dyspnea during Exercise in COPD 1369

exercise but reached a similar peak value (see Figure E2). Dyspneaintensity ratings were similar for both protocols when expressedrelative to _VE (not shown); VT (Figure 3A); and IRV (Figure 3B).

The relation between dyspnea intensity and IRV was two-phased:dyspnea rose gradually to reach an inflection point (correspondingto the VT/ _VE inflection point), then rose almost vertically to reach

Figure 1. (A–F) When measurements were expressed relative to minute ventilation, responses to incremental (INCR) and constant work rate (CWR)

cycle exercise were similar. Shaded areas show the tidal esophageal pressure (Pes) swing and the tidal volume (VT) excursion during incremental

exercise: near end-exercise where tidal Pes swings continue to increase, the VT response levels off resulting in an increased effort-displacement ratio(i.e., neuromechanical dissociation). EELV ¼ end-expiratory lung volume; EILV ¼ end-inspiratory lung volume; Fb ¼ breathing frequency; IC ¼inspiratory capacity; IRV ¼ inspiratory reserve volume; min PesIC ¼ the minimum Pes value measured during a maximal inspiratory effort to TLC as

part of an IC maneuver during exercise; TLC ¼ total lung capacity.

Figure 2. (A) Selection frequency of the three

descriptor phrases evaluated during incremen-

tal (INCR) and constant work rate (CWR) exer-

cise: increased work and effort (Effort),unsatisfied inspiration (IN), and unsatisfied ex-

piration (OUT). Arrows indicate the point cor-

responding to the inflection point of the tidal

volume-ventilation relation during exercise. (B)Selection frequency of the dyspnea descriptors

collected by questionnaire at end-exercise. De-

scriptor choices were similar in both tests with

dyspnea described predominantly as a sense of“inspiratory difficulty,” “unsatisfied inspiration,”

and increased “work” of breathing.

1370 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 184 2011

the symptom-limited endpoint of exercise. As shown in a previousstudy (5), the relation between the Pes/PImax:VT/predicted VCratio and IRV was also biphasic (Figure 3C): the sharp increase indyspnea after the inflection point correlated significantly with thecorresponding increase in the effort/displacement ratio (partialr ¼ 0.125; P ¼ 0.002), with no difference in this relationship acrossprotocols (interaction term P ¼ 0.548). A biphasic relation wasalso found between the selection frequency of unsatisfied inspira-tion and IRV (Figure 3D). The selection frequency of work andeffort increased with dyspnea ratings up to the inflection point,after which they no longer changed together (Figure 3E). Therelationship between dyspnea ratings and selection of unsatisfiedinspiration was relatively linear throughout exercise for both tests(Figure 3F).

DISCUSSION

The main findings of this study are as follows: (1) despite time-related differences in metabolic and ventilatory requirementsduring INCR and high-intensity CWR tests, dyspnea intensity,breathing pattern, operating lung volumes, and respiratory me-chanical measurements were similar when expressed asa function of increasing ventilation; (2) dyspnea intensity rosesteeply during each test protocol after the VT/ _VE inflectionpoint where IRV had decreased to a critical level of approx-imately 0.5–0.6 L; and (3) regardless of the test protocol, workand effort was the dominant qualitative descriptor of dyspneabefore the VT/ _VE inflection point, whereas the selection

frequency of unsatisfied inspiration increased steeply relativeto work and effort after this inflection.

The study subjects had moderate-to-severe chronic airflowlimitation and lung hyperinflation and reported clinically impor-tant chronic activity-related dyspnea despite optimal pharmaco-therapy. Exercise performance was diminished mainly becauseof impaired dynamic ventilatory mechanics and the attendant se-vere dyspnea. At the symptom-limited termination of exerciseduring INCR and CWR tests, peak metabolic and cardiopulmo-nary parameters, dynamic respiratory mechanics, and dyspneaintensity ratings were similar.

As expected, the time course of change in metabolic and ven-tilatory requirements was different between the two protocols.Thus, _VO2 and _VE were significantly higher during CWR com-pared with INCR exercise in the first 4 minutes of exercise. Dur-ing both tests, the VT/ _VE inflection occurred when VT expandedto reach approximately 70% of the IC, a point where _VE hadreached an average of approximately 34–38 L/min. The greatermetabolic and ventilatory demand earlier during high-intensityCWR meant that the VT inflection occurred significantly earlierin time than with the INCR protocol. However, when all of thephysiologic and sensory responses to cycle exercise wereexpressed as a function of increasing _VE, there were no signif-icant differences between protocols. These data indicate that,irrespective of the ventilatory history (i.e., the time course ofchange in ventilation or the intensity of the preinflection venti-latory load), it is the ventilatory requirement of a specific phys-ical task that dictates the evolution of change in operating lung

Figure 3. (A) Exertional dyspnea intensity is shown relative to tidal volume (VT) and (B) inspiratory reserve volume (IRV). (C) The ratio between

respiratory effort (Pes/PImax) and tidal volume displacement (VT/predicted VC) is shown relative to IRV. (D) The selection frequency of the descriptor

“unsatisfied inspiration” (IN) during exercise showed an inflection when expressed relative to IRV. (E) The selection frequency of effort did not

increase in direct proportion with increasing dyspnea intensity throughout exercise, whereas (F) the selection frequency of “unsatisfied inspiration”(IN) showed a more linear relationship with increasing exertional dyspnea intensity in both exercise tests. Arrows indicate the point corresponding

to the inflection point of the tidal volume-ventilation relation during exercise. CWR ¼ constant work rate exercise; INCR ¼ incremental exercise;

Pes/PImax ¼ tidal esophageal pressure swing relative to maximum inspiratory sniff pressure; VT/predicted VC ¼ tidal volume relative to predicted

vital capacity.

Laveneziana, Webb, Ora, et al.: Evolution of Dyspnea during Exercise in COPD 1371

volumes, breathing pattern, esophageal pressure generation,and dyspnea intensity ratings.

Sensory–Mechanical Interrelationships

This study showed that, regardless of the test protocol, there wasa biphasic relationship between increasing dyspnea and decreasingIRV (or increasing VT/IC ratio). Before the inflection (phase I),dyspnea intensity rose linearly into the moderate range (Borgrating z 3) with decreasing IRV. After the inflection point,dyspnea intensity rose more steeply to intolerable levels. Thegreater metabolic and ventilatory demand in phase I duringCWR meant that dyspnea intensity as a function of time wasuniformly higher compared with INCR exercise (see online sup-plement). By contrast, after the VT inflection (phase II) duringboth CWR and INCR tests, the difference in dyspnea intensitybegan to disappear as ventilatory and mechanical abnormalitiesbecame more similar near the symptom-limited peak of exercise.

In keeping with previous studies (4–6), the major qualitativedescriptors at the termination of exercise in COPD were clus-tered in work and effort and unsatisfied inspiration categories.This study extends the previous work by showing that, regardlessof the exercise test protocol, these major qualitative descriptorsevolve separately throughout exercise and are strongly influencedby mechanical events, such as the VT inflection point. In phase I,before this inflection, subjects were more likely to select workand effort and less likely to select the unsatisfied inspiration de-scriptor. At the VT inflection point, patients selected work andeffort approximately twice as often as the unsatisfied inspirationdescriptor. However, after this point during INCR and CWRexercise, unsatisfied inspiration was increasingly selected as thedominant qualitative descriptor despite patients having the op-tion of selecting any, none, or all of the three descriptors. Clearly,differences between the two exercise tests in the time courseof change in ventilation and dynamic respiratory mechanics inphase I did not influence the ability to perceive critical mechan-ical constraints on VT expansion. Interestingly, selection of un-satisfied inspiration and dyspnea intensity ratings increasedlinearly together throughout exercise (Figure 4F), whereas simi-lar concordance was not seen with work and effort and dyspneaintensity. In phase II the selection of the work and effort descrip-tor reached a plateau despite continued increases in Pes/PImaxand _VE. It is noteworthy that patients seldom selected expiratorydifficulty as a representative descriptor. This may reflect the factthat tidal expiratory pressures at peak exercise represented only11–14% of maximal expiratory pressure.

Both the intensity of dyspnea and the selection frequency ofwork and effort increased in parallel with the concomitantincreases in tidal respiratory effort swings and ventilatory outputthroughout exercise. Neurophysiologically, increased perceivedbreathing effort is believed to reflect the awareness of increasedmotor command output to the respiratory muscles and increasedcentral corollary discharge from the respiratory motor centers tothe somatosensory cortex (3, 30, 31).

Why did unsatisfied inspiration receive more attention andbecome increasingly dominant in phase II? Static lung hyperin-flation with further dynamic increases in end-expiratory lung vol-ume in phase I resulted in end-inspiratory lung volume reachinga near minimal IRV (i.e., the VT inflection point) at a relativelylow _VE. After the VT inflection point, tidal Pes swings progres-sively increased to a peak of approximately 50% of their max-imum value in the setting of little or no further VT expansion.Thus, the effort/volume displacement ratio (Pes/PImax:VT/predicted VC) increased to almost double its resting value atpeak exercise. This is in sharp contrast to the situation in healthwhere this ratio is largely preserved from rest to peak exercise,

reflecting the operating position of the expanding VT on thelinear portion of the respiratory system’s sigmoid pressure–volume relation (4). Previous mechanistic studies have shownthat when the spontaneous increase in VT is constrained (eithervolitionally or by external imposition) in the face of increasedchemostimulation, respiratory discomfort (specifically, air hun-ger or unsatisfied inspiration) is the result (5, 27, 32–37). Wehave proposed that near the limits of tolerance in COPD thisincreasing dissociation between reflexly increased central neuraldrive (amplified by acid–base disturbances) and blunted VT dis-placement forms, at least in part, the neurophysiologic basis ofperceived unsatisfied inspiration (3, 5, 27). In support of thiscontention, bronchodilator therapy in COPD (which reducedlung hyperinflation, increased VT expansion, and improvedthe effort/displacement ratio) was associated with a significantreduction in the selection frequency of unsatisfied inspiration atend-exercise (5, 6). Besides causing VT restriction, a high end-expiratory lung volume in COPD forces VT to the upper non-compliant reaches of the respiratory system’s pressure–volumerelation and negatively affects inspiratory muscle performance.Thus, it is also possible that altered afferent information fromthe overburdened (increased elastic and threshold loading) andfunctionally weakened (altered length-tension and force-velocity characteristics) respiratory muscles may contribute di-rectly or indirectly to the intensity and quality of dyspnea inphase II.

Limitations

The primary analysis of qualitative dimensions of dyspnea duringexercise was confined to the two most common and representa-tive descriptors based on our previous studies (work and effort,unsatisfied inspiration); other descriptors not included here mayalso be relevant to the complex experience of exertional dyspneain COPD. In this study, we did not scale the sensory intensity ofthese major descriptors or evaluate their affective impact in eachindividual; during pilot testing, this more comprehensive analysiscould not be successfully applied (32). Because a healthy controlgroup is lacking in this study, we cannot comment on whetherthe described change in the quality of dyspnea with exercise ispeculiar to COPD. However, unsatisfied inspiration, the de-scriptor of interest, was rarely selected as a representative de-scriptor in healthy individuals of similar age at peak exercise ina previous study (4). Finally, it remains to be seen whether ourresults can be extrapolated to other activities, such as walking,or to specific subpopulations with additional potential sourcesof dyspnea (e.g., those with significant arterial oxygen desatura-tion during exercise). The question arises whether the sensoryresponses described here in a small group of patients with mod-erate resting lung hyperinflation are representative of thebroader COPD population with a range of mechanical impair-ment. A recent study confirmed that VT/ _VE inflection pointswith attendant biphasic dyspnea intensity responses were pres-ent across a broad range of FEV1 in a large COPD population(9). The ventilation at which the VT inflection and rise in dyspneaoccurred varied with the degree of resting lung hyperinflation(or IC).

Conclusions

During physical activity in COPD, the time course of change indynamic respiratory mechanics and the concomitant change inthe intensity and quality of dyspnea are dictated by the specificventilatory requirements of the physical task. Regardless of theexercise test protocol, the occurrence of an inflection (or plateau)in the VT response marks the point where dyspnea intensity risesmore abruptly and inspiratory difficulty becomes more frequently

1372 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 184 2011

selected as the most representative qualitative descriptor. Thepractical implication of our study is that the VT inflection duringexercise in COPD marks a reproducible mechanical event withimportant sensory consequences. This can easily be detected inmost patients by examining the VT/ _VE and the dyspnea/VT rela-tions. Therapeutic interventions that reduce ventilatory require-ments (e.g., oxygen, exercise training, or opiates) or reduce lunghyperinflation (pharmacologic or surgical volume reduction)should theoretically delay the appearance of the VT inflectionand the attendant dyspnea during physical activity.

Author Disclosures are available with the text of this article at www.atsjournals.org.

Acknowledgment: The authors thank Emiliano Brunamonti, Ph.D. (Department ofPhysiology, Queen’s University), for providing technical assistance; GiorgioScano, M.D., and Roberto Duranti, M.D. (Department of Internal Medicine,University of Florence, Florence, Italy), for thoughtful criticism of the manuscript;and Yuk-Miu Lam, Ph.D. (Department of Community Health and Epidemiology,Queen’s University), for statistical assistance.

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