Reference values for leg effort during incremental cycle ergometry in non-trained healthy men and women, aged 19-85.

Heightened sensation of leg effort contributes importantly to poor exercise tolerance in patient populations. We aim to provide a sex- and age-adjusted frame of reference to judge symptom's normalcy across progressively higher exercise intensities during incremental exercise. Two-hundred and seventy-five non-trained subjects (130 men) aged 19-85 prospectively underwent incremental cycle ergometry. After establishing centiles-based norms for Borg leg effort scores (0-10 category-ratio scale) versus work rate, exponential loss function identified the centile that best quantified the symptom's severity individually. Peak O2 uptake and work rate (% predicted) were used to threshold gradually higher symptom intensity categories. Leg effort-work rate increased as a function of age; women typically reported higher scores at a given age, particularly in the younger groups (p < 0.05). For instance, "heavy" (5) scores at the 95th centile were reported at ~200 W (<40 years) and ~90 W (≥70 years) in men versus ~130 W and ~70 W in women, respectively. The following categories of leg effort severity were associated with progressively lower exercise capacity: ≤50th ("mild"), >50th to <75th ("moderate"), ≥75th to <95th ("severe"), and ≥ 95th ("very severe") (p < 0.05). Although most subjects reporting peak scores <5 were in "mild" range, higher scores were not predictive of the other categories (p > 0.05). This novel frame of reference for 0-10 Borg leg effort, which considers its cumulative burden across increasingly higher exercise intensities, might prove valuable to judging symptom's normalcy, quantifying its severity, and assessing the effects of interventions in clinical populations.

A frame of reference for assessing the intensity of exertional dyspnoea during incremental cycle ergometry.

Assessment of dyspnoea severity during incremental cardiopulmonary exercise testing (CPET) has long been hampered by the lack of reference ranges as a function of work rate (WR) and ventilation (V' E). This is particularly relevant to cycling, a testing modality which overtaxes the leg muscles leading to a heightened sensation of leg discomfort.Reference ranges based on dyspnoea percentiles (0-10 Borg scale) at standardised work rates and V' E were established in 275 apparently healthy subjects aged 20-85 years (131 men). They were compared with values recorded in a randomly selected "validation" sample (n=451; 224 men). Their usefulness in properly uncovering the severity of exertional dyspnoea were tested in 167 subjects under investigation for chronic dyspnoea ("testing sample") who terminated CPET due to leg discomfort (86 men).Iso-work rate and, to a lesser extent, iso-V' E reference ranges (5th-25th, 25th-50th, 50-75th and 75th-95th percentiles) increased as a function of age, being systematically higher in women (p<0.01). There were no significant differences in percentiles distribution between "reference" and "validation" samples (p>0.05). Submaximal dyspnoea-work rate scores fell within the 75th-95th or >95th percentiles in 108 out of 118 (91.5%) subjects of the "testing" sample who showed physiological abnormalities known to elicit exertional dyspnoea, i.e. ventilatory inefficiency and/or critical inspiratory constraints. In contrast, dyspnoea scores typically fell in the 5th-50th range in subjects without those abnormalities (p<0.001).This frame of reference might prove useful to uncover the severity of exertional dyspnoea in subjects who otherwise would be labelled as "non-dyspnoeic" while providing mechanistic insights into the genesis of this distressing symptom.

Inspiratory Constraints and Ventilatory Inefficiency Are Superior to Breathing Reserve in the Assessment of Exertional Dyspnea in COPD.

Combining measurements of impaired lung mechanics (inspiratory constraints) with an index of increased respiratory stimuli to metabolic demand (poor ventilatory efficiency) might enhance the ability of cardiopulmonary exercise testing (CPET) in exposing a mechanistic role for ventilation on exertional dyspnea in COPD. In addition to the standard approach to suggest ventilatory limitation to exercise - a low breathing reserve (1-(peak ventilation (V̇E)/maximal voluntary ventilation × 100 < 20%) - we assessed the presence of critical inspiratory constraints (end-inspiratory lung volume (EILV)/total lung capacity (TLC) ≥ 0.9) and ventilatory inefficiency (V̇E/CO2 output (V̇CO2) nadir > 34) in 288 patients with mild to very severe COPD (FEV1 ranging from 18 to 121% predicted). We found that ∼50% of the patients with preserved breathing reserve developed critical inspiratory constraints. A low breathing reserve was weakly related to a lower peak O2 uptake (V̇O2) and/or a higher dyspnea burden; for instance, patients with low breathing reserve but without critical inspiratory constraints had similar dyspnea and peak V̇O2 than those with preserved breathing reserve (p > 0.05). In contrast, critical inspiratory constraints and ventilatory inefficiency were strongly associated with a negative outcome (likelihood ratio = 42.3 and 47.7, respectively; p < 0.001). A multiple logistic regression analysis revealed that only EILV/TLC ≥ 0.9 and V̇E/V̇CO2 nadir >34 predicted a severely reduced peak V̇O2 due to a high dyspnea burden (p < 0.001). Measurements of dynamic mechanical constraints and ventilatory inefficiency during incremental CPET are key to determine the impact of COPD on dyspnea and exercise tolerance across the spectrum of disease severity.

Excess Ventilation in Chronic Obstructive Pulmonary Disease-Heart Failure Overlap. Implications for Dyspnea and Exercise Intolerance.

RATIONALE: An increased ventilatory response to exertional metabolic demand (high [Formula: see text]e/[Formula: see text]co2 relationship) is a common finding in patients with coexistent chronic obstructive pulmonary disease and heart failure. OBJECTIVES: We aimed to determine the mechanisms underlying high [Formula: see text]e/[Formula: see text]co2 and its impact on operating lung volumes, dyspnea, and exercise tolerance in these patients. METHODS: Twenty-two ex-smokers with combined chronic obstructive pulmonary disease and heart failure with reduced left ventricular ejection fraction undertook, after careful treatment optimization, a progressive cycle exercise test with capillary (c) blood gas collection. MEASUREMENTS AND MAIN RESULTS: Regardless of the chosen metric (increased [Formula: see text]e-[Formula: see text]co2 slope, [Formula: see text]e/[Formula: see text]co2 nadir, or end-exercise [Formula: see text]e/[Formula: see text]co2), ventilatory inefficiency was closely related to PcCO2 (r values from -0.80 to -0.84; P < 0.001) but not dead space/tidal volume ratio. Ten patients consistently maintained exercise PcCO2 less than or equal to 35 mm Hg (hypocapnia). These patients had particularly poor ventilatory efficiency compared with patients without hypocapnia (P < 0.05). Despite the lack of between-group differences in spirometry, lung volumes, and left ventricular ejection fraction, patients with hypocapnia had lower resting PaCO2 and lung diffusing capacity (P < 0.01). Excessive ventilatory response in this group was associated with higher exertional PcO2. The group with hypocapnia, however, had worse mechanical inspiratory constraints and higher dyspnea scores for a given work rate leading to poorer exercise tolerance compared with their counterparts (P < 0.05). CONCLUSIONS: Heightened neural drive promoting a ventilatory response beyond that required to overcome an increased "wasted" ventilation led to hypocapnia and poor exercise ventilatory efficiency in chronic obstructive pulmonary disease-heart failure overlap. Excessive ventilation led to better arterial oxygenation but at the expense of earlier critical mechanical constraints and intolerable dyspnea.

A Simplified Approach to Select Exercise Endurance Intensity for Interventional Studies in COPD.

Time to exercise limitation (Tlim) in response to constant work rate (CWR) is sensitive to interventions in chronic obstructive pulmonary disease (COPD). This is particularly true when the pre-intervention test lasts between 3 and 8 min (Tlim3'-8'). There is, however, no simple method to select a work rate which is consistently associated with Tlim3'-8' across the spectrum of COPD severity. We assessed 59 GOLD stages II-IV patients who initially cycled to Tlim at 75% peak. In case of short (<3 min, low-endurance) or long (>8 min, high-endurance) tests, patients exercised after 60 min at 50% or 90%, respectively (CWR50%⇐75%⇒90%). Critical mechanical constraints and limiting dyspnea at 75% were reached within the desired timeframe in 27 "mid-endurance" patients (46%). Increasing work rate intensity to 90% hastened the mechanical-ventilatory responses leading to Tlim3'-8' in 23/26 (88%) "high-endurance" patients; conversely, decreasing exercise intensity to 50% slowed those responses leading to Tlim3'-8' in 5/6 (83%) "high-endurance" patients. Repeating the tests at higher (60%) or lower (80%) intensities fail to consistently produce Tlim3'-8' in "low-" and "high-endurance", respectively (p > 0.05). Compared to a fixed work rate at 75%, CWR50%⇐75%⇒90% significantly decreased Tlim's coefficient of variation; consequently, the required N to detect 100 s or 33% improvement in Tlim decreased from 82 to 26 and 41 to 14, respectively. This simplified approach to individualized work rate adjustment (CWR50%⇐75%⇒90%) might allow greater sensitivity in evaluating interventional efficacy in improving respiratory mechanics and exercise tolerance while simultaneously reducing sample size requirements in patients with COPD.

Physiological and clinical relevance of exercise ventilatory efficiency in COPD.

Exercise ventilation (V'E) relative to carbon dioxide output (V'CO2 ) is particularly relevant to patients limited by the respiratory system, e.g. those with chronic obstructive pulmonary disease (COPD). High V'E-V'CO2 (poor ventilatory efficiency) has been found to be a key physiological abnormality in symptomatic patients with largely preserved forced expiratory volume in 1 s (FEV1). Establishing an association between high V'E-V'CO2 and exertional dyspnoea in mild COPD provides evidence that exercise intolerance is not a mere consequence of detraining. As the disease evolves, poor ventilatory efficiency might help explaining "out-of-proportion" breathlessness (to FEV1 impairment). Regardless, disease severity, cardiocirculatory co-morbidities such as heart failure and pulmonary hypertension have been found to increase V'E-V'CO2 In fact, a high V'E-V'CO2 has been found to be a powerful predictor of poor outcome in lung resection surgery. Moreover, a high V'E-V'CO2 has added value to resting lung hyperinflation in predicting all-cause and respiratory mortality across the spectrum of COPD severity. Documenting improved ventilatory efficiency after lung transplantation and lung volume reduction surgery provides objective evidence of treatment efficacy. Considering the usefulness of exercise ventilatory efficiency in different clinical scenarios, the V'E-V'CO2 relationship should be valued in the interpretation of cardiopulmonary exercise tests in patients with mild-to-end-stage COPD.

Exercise Ventilatory Inefficiency Adds to Lung Function in Predicting Mortality in COPD.

Severity of resting functional impairment only partially predicts the increased risk of death in chronic obstructive pulmonary disease (COPD). Increased ventilation during exercise is associated with markers of disease progression and poor prognosis, including emphysema extension and pulmonary vascular impairment. Whether excess exercise ventilation would add to resting lung function in predicting mortality in COPD, however, is currently unknown. After an incremental cardiopulmonary exercise test, 288 patients (forced expiratory volume in one second ranging from 18% to 148% predicted) were followed for a median (interquartile range) of 57 (47) months. Increases in the lowest (nadir) ventilation to CO2 output (VCO2) ratio determined excess exercise ventilation. Seventy-seven patients (26.7%) died during follow-up: 30/77 (38.9%) deaths were due to respiratory causes. Deceased patients were older, leaner, had a greater co-morbidity burden (Charlson Index) and reported more daily life dyspnea. Moreover, they had poorer lung function and exercise tolerance (p < 0.05). A logistic regression analysis revealed that ventilation/VCO2 nadir was the only exercise variable that added to age, body mass index, Charlson Index and resting inspiratory capacity (IC)/total lung capacity (TLC) ratio to predict all-cause and respiratory mortality (p < 0.001). Kaplan-Meier analyses showed that survival time was particularly reduced when ventilation/VCO2 nadir > 34 was associated with IC/TLC ≤ 0.34 or IC/TLC ≤ 0.31 for all-cause and respiratory mortality, respectively (p < 0.001). Excess exercise ventilation is an independent prognostic marker across the spectrum of COPD severity. Physiological abnormalities beyond traditional airway dysfunction and lung mechanics are relevant in determining the course of the disease.

Exercise Ventilation in COPD: Influence of Systolic Heart Failure.

Systolic heart failure is a common and disabling co-morbidity of chronic obstructive pulmonary disease (COPD) which may increase exercise ventilation due to heightened neural drive and/or impaired pulmonary gas exchange efficiency. The influence of heart failure on exercise ventilation, however, remains poorly characterized in COPD. In a prospective study, 98 patients with moderate to very severe COPD [41 with coexisting heart failure; 'overlap' (left ventricular ejection fraction < 50%)] underwent an incremental cardiopulmonary exercise test (CPET). Compared to COPD, overlap had lower peak exercise capacity despite higher FEV1. Overlap showed lower operating lung volumes, greater ventilatory inefficiency and larger decrements in end-tidal CO2 (PETCO2) (P < 0.05). These results were consistent with those found in FEV1-matched patients. Larger areas under receiver operating characteristic curves to discriminate overlap from COPD were found for ventilation ([Formula: see text]E)-CO2 output [Formula: see text]CO2) intercept, [Formula: see text]E-[Formula: see text]CO2 slope, peak [Formula: see text]E/[Formula: see text]CO2 ratio and peak PETCO2. Multiple logistic regression analysis revealed that [Formula: see text]CO2 intercept ≤ 3.5 L/minute [odds ratios (95% CI) = 7.69 (2.61-22.65), P < 0.001] plus [Formula: see text]E-[Formula: see text]CO2 slope ≥ 34 [2.18 (0.73-6.50), P = 0.14] or peak [Formula: see text]E/[Formula: see text]CO2 ratio ≥ 37 [5.35 (1.96-14.59), P = 0.001] plus peak PETCO2 ≤ 31 mmHg [5.73 (1.42-23.15), P = 0.01] were indicative of overlapping. Heart failure increases the ventilatory response to metabolic demand in COPD. Variables reflecting excessive ventilation might prove useful to assist clinical interpretation of CPET responses in COPD patients presenting heart failure as co-morbidity.

The relationship between fat-free mass index and pulmonary hyperinflation in COPD patients.

BACKGROUND AND OBJECTIVE: Reduced fat-free mass (FFM), a common finding in chronic obstructive pulmonary disease (COPD), may indirectly impact peak exercise capacity through a greater level of pulmonary hyperinflation. We aimed to investigate if FFM index (FFM/squared height) impacts exercise induced dynamic hyperinflation in COPD patients. METHODS: Fifty-four patients with moderate-to-very severe COPD performed a symptom limited incremental cardiopulmonary exercise tests with serial measurements of inspiratory capacity (IC). FFM was measured by whole-body bioelectrical impedance. RESULTS: Patients were 66.7 ± 7.7 years old with mean forced expiratory volume in 1 s (FEV1) of 1.08 ± 0.41 L (42 ± 15% of predicted). Peak exercise IC was significantly (P < 0.05) correlated with IC at rest (r = 0.78), FEV1(r = 0.66), FVC (r = 0.59), FFM (r = 0.38) and FFM index (r = 0.29). However, only FEV1 and rest IC predict peak IC (r = 0.86; P < 0.01) in a multivariate linear regression analysis. CONCLUSIONS: FFM index was weakly associated with peak exercise IC in COPD patients. However, it ceased to be an independent predictor when corrected for expiratory airflow limitation (FEV1) and lung hyperinflation at rest (rest IC).

Mechanisms and consequences of excess exercise ventilation in fibrosing interstitial lung disease.

The causes and consequences of excess exercise ventilation (EEV) in patients with fibrosing interstitial lung disease (f-ILD) were explored. Twenty-eight adults with f-ILD and 13 controls performed an incremental cardiopulmonary exercise test. EEV was defined as ventilation-carbon dioxide output (⩒E-⩒CO2) slope ≥36 L/L. Patients showed lower pulmonary function and exercise capacity compared to controls. Lower DLCO was related to higher ⩒E-⩒CO2 slope in patients (P<0.05). 13/28 patients (46.4%) showed EEV, reporting higher dyspnea scores (P=0.033). Patients with EEV showed a higher dead space (VD)/tidal volume (VT) ratio while O2 saturation dropped to a greater extent during exercise compared to those without EEV. Higher breathing frequency and VT/inspiratory capacity ratio were observed during exercise in the former group (P<0.05). An exaggerated ventilatory response to exercise in patients with f-ILD is associated with a blunted decrease in the wasted ventilation in the physiological dead space and greater hypoxemia, prompting higher inspiratory constraints and breathlessness.

Sex- and age-adjusted reference values for dynamic inspiratory constraints during incremental cycle ergometry.

Activity-related dyspnea in chronic lung disease is centrally related to dynamic (dyn) inspiratory constraints to tidal volume expansion. Lack of reference values for exertional inspiratory reserve (IR) has limited the yield of cardiopulmonary exercise testing in exposing the underpinnings of this disabling symptom. One hundred fifty apparently healthy subjects (82 males) aged 40-85 underwent incremental cycle ergometry. Based on exercise inspiratory capacity (ICdyn), we generated centile-based reference values for the following metrics of IR as a function of absolute ventilation: IRdyn1 ([1-(tidal volume/ICdyn)] x 100) and IRdyn2 ([1-(end-inspiratory lung volume/total lung capacity] x 100). IRdyn1 and IRdyn2 standards were typically lower in females and older subjects (p<0.05 for sex and age versus ventilation interactions). Low IRdyn1 and IRdyn2 significantly predicted the burden of exertional dyspnea in both sexes (p<0.01). Using these sex and age-adjusted limits of reference, the clinician can adequately judge the presence and severity of abnormally low inspiratory reserves in dyspneic subjects undergoing cardiopulmonary exercise testing.

Impact of Real-Time Assessment of Pulse Oximetry on the 6-Min Walk Distance in Patients With Chronic Respiratory Disease.

BACKGROUND: Continuous monitoring of pulse oximetry (SpO2 ) is recommended during the 6-min walk test (6MWT) to ensure that the lowest SpO2 is recorded. In this case, severe exercise induced desaturation (EID; SpO2 < 80%) triggers walking interruption by the examiner. Our main objective was to assess the impact of this approach on 6MWT distance in patients with chronic respiratory diseases and, second, to evaluate the safety of the test without interruption due to severe EID. METHODS: 6MWTs with continuous monitoring of SpO2 were prospectively performed in subjects with chronic respiratory disease. The participants were randomly allocated to walk with or without SpO2 real-time assessment. SpO2 visualization during the test execution was available only in the first group, and walking interruption was requested by the examiner if SpO2 < 80%. RESULTS: One hundred forty-five participants were included in each group (68.6% females, 62 [52-69] y old) without differences in demographic and resting lung function parameters between them. The main respiratory conditions were COPD (n = 101), asthma (n = 73), pulmonary hypertension (n = 47), and interstitial lung disease (n = 39). The walked distance was similar comparing groups (349.5 ± 117.5 m vs 351.2 ± 105.4 m). Twenty-five subjects presented with severe EID in the group with real-time SpO2 assessment, and 20 subjects had severe EID in the group without real-time assessment respectively (overall prevalence of 15.5%). The 23 participants who had their test interrupted by the examiner due to severe EID in the first group (2 subjects stopped by themselves due to excessive symptoms) walked a shorter distance compared to the 11 subjects with severe EID without test interruption in the second group (9 subjects stopped by themselves due to excessive symptoms): 240.6 ± 100.2 m versus 345.9 ± 73.4 m. No exercise-related serious adverse events were observed. CONCLUSIONS: Interruption driven by severe EID reduced the walked distance during the 6MWT. No serious adverse event, in turn, was observed in subjects with severe desaturation without real-time SpO2 assessment.

Effectiveness of pulmonary rehabilitation in exercise capacity and quality of life in chronic obstructive pulmonary disease patients with and without global fat-free mass depletion.

OBJECTIVE: To investigate the effectiveness of pulmonary rehabilitation (PR) in exercise capacity and quality of life in patients with chronic obstructive pulmonary disease (COPD) with and without global fat-free mass (FFM) depletion. DESIGN: Retrospective case-control. SETTING: Outpatient clinic, university center. PARTICIPANTS: COPD patients (N=102) that completed PR were initially evaluated. INTERVENTION: PR including whole-body and weight training for 12 weeks, 3 times per week. MAIN OUTCOME MEASURES: St. George Respiratory Questionnaire (SGRQ), 6-minute walk distance (6MWD), and FFM evaluation applied before and after PR. RESULTS: Patients were stratified according to their FFM status measured by bioelectric impedance. They were considered depleted if the FFM index was ≤ 15 kg/m(2) in women and ≤ 16 kg/m(2) in men. From the initial sample, all depleted patients (n=31) composed the FFM depleted group. It was composed predominantly by women (68%) with a mean age ± SD of 64.4 ± 7.3 years and a forced expiratory volume in 1 second of 33.6%=-13.2% predicted. Paired for sex and age, 31 nondepleted patients were selected from the initial sample to compose the nondepleted group. Improvement in the 6MWD was similar in these 2 groups after PR. Both groups improved SGRQ scores, although the observed power was small and did not allow adequate comparison between depleted and nondepleted patients. There was no difference between groups in weight change, whereas FFM tended to be greater in depleted patients. This increase had no correlation with the 6MWD or the SGRQ. CONCLUSIONS: Benefits of PR to exercise capacity were similar comparing FFM depleted and nondepleted COPD patients. Although FFM change tended to be greater in depleted patients, this increase had no definite relation with clinical outcomes.

Exertional oscillatory ventilation in subjects without heart failure reporting chronic dyspnoea.

Oscillatory ventilation detected on incremental cardiopulmonary exercise testing might be found in subjects without heart failure reporting exertional dyspnoea despite the best available therapy for their underlying cardiopulmonary disease https://bit.ly/3Tyl7bE.

Dynamic Ventilatory Reserve During Incremental Exercise: Reference Values and Clinical Validation in Chronic Obstructive Pulmonary Disease.

Rationale: Ventilatory demand-capacity imbalance, as inferred based on a low ventilatory reserve, is currently assessed only at peak cardiopulmonary exercise testing (CPET). Peak ventilatory reserve, however, is poorly sensitive to the submaximal, dynamic mechanical ventilatory abnormalities that are key to dyspnea genesis and exercise intolerance. Objectives: After establishing sex- and age-corrected norms for dynamic ventilatory reserve at progressively higher work rates, we compared peak and dynamic ventilatory reserve for their ability to expose increased exertional dyspnea and poor exercise tolerance in mild to very severe chronic obstructive pulmonary disease (COPD). Methods: We analyzed resting functional and incremental CPET data from 275 controls (130 men, aged 19-85 yr) and 359 Global Initiative for Chronic Obstructive Lung Disease patients with stage 1-4 obstruction (203 men) who were prospectively recruited for previous ethically approved studies in three research centers. In addition to peak and dynamic ventilatory reserve (1 - [ventilation / estimated maximal voluntary ventilation] × 100), operating lung volumes and dyspnea scores (0-10 on the Borg scale) were obtained. Results: Dynamic ventilatory reserve was asymmetrically distributed in controls; thus, we calculated its centile distribution at every 20 W. The lower limit of normal (lower than the fifth centile) was consistently lower in women and older subjects. Peak and dynamic ventilatory reserve disagreed significantly in indicating an abnormally low test result in patients: whereas approximately 50% of those with a normal peak ventilatory reserve showed a reduced dynamic ventilatory reserve, the opposite was found in approximately 15% (P < 0.001). Irrespective of peak ventilatory reserve and COPD severity, patients who had a dynamic ventilatory reserve below the lower limit of normal at an isowork rate of 40 W had greater ventilatory requirements, prompting earlier attainment of critically low inspiratory reserve. Consequently, they reported higher dyspnea scores, showing poorer exercise tolerance compared with those with preserved dynamic ventilatory reserve. Conversely, patients with preserved dynamic ventilatory reserve but reduced peak ventilatory reserve reported the lowest dyspnea scores, showing the best exercise tolerance. Conclusions: Reduced submaximal dynamic ventilatory reserve, even in the setting of preserved peak ventilatory reserve, is a powerful predictor of exertional dyspnea and exercise intolerance in COPD. This new parameter of ventilatory demand-capacity mismatch may enhance the yield of clinical CPET in the investigation of activity-related breathlessness in individual patients with COPD and other prevalent cardiopulmonary diseases.

Cardiopulmonary exercise testing to indicate increased ventilatory variability in subjects with dysfunctional breathing.

BACKGROUND: Dysfunctional breathing (DB) is a common, but largely underappreciated, cause of chronic dyspnoea. Under visual inspection, most subjects with DB present with larger sequential changes in ventilation (V̇E) and breathing pattern (tidal volume (VT) and breathing frequency (f)) before and/or during incremental cardiopulmonary exercise testing (CPET). Currently, however, there are no objective criteria to indicate increased ventilatory variability in these subjects. METHODS: Twenty chronically dyspnoeic subjects with DB and 10 age- and sex-matched controls performed CPET on a cycle ergometer. Cut-offs to indicate increased V̇E, VT, f, and f/VT ratio variability (Δ = highest-lowest 20 s arithmetic mean) over the last resting minute (rest ), the 2sd min of unloaded exercise (unload ), and the 3rd min of loaded exercise (load ) were established by ROC curve analyses. RESULTS: Subjects with DB presented with increased V̇E, higher ventilatory variability, higher dyspnoea burden, and lower exercise capacity compared to controls (p < 0.05). ΔV̇Eload (>4.1 L/min), Δfrest (>5 breaths/min; bpm), Δfunload (>4 bpm), Δfload (>5 bpm), Δf/VTrest (>4.9 bpm/L), and Δf/VTload (>1.3 bpm/L) differentiated DB from a normal pattern (areas under the curve ranging from 0.729 to 0.845). High Δf, in particular, was associated with DB across all CPET phases. CONCLUSIONS: This study provides objective criteria to indicate increased ventilatory variability during incremental CPET in dyspnoeic subjects with DB. Large variability in breathing frequency seems particularly useful in this context, a finding that should be prospectively confirmed in larger studies.