Ventilatory Responses to Exercise by Age, Sex, and Health Status.

ABSTRACT: An understanding of the normal pulmonary responses to incremental exercise is requisite for appropriate interpretation of findings from clinical exercise testing. The purpose of this review is to provide concrete information to aid the interpretation of the exercise ventilatory response in both healthy and diseased populations. We begin with an overview of the normal exercise ventilatory response to incremental exercise in the healthy, normally trained young-to-middle aged adult male. The exercise ventilatory responses in two nonpatient populations (females, elderly) are then juxtaposed with the responses in healthy males. The review concludes with overviews of the exercise ventilatory responses in four patient populations (obesity, chronic obstructive pulmonary disease, asthma, congestive heart failure). Again, we use the normal response in healthy adults as the framework for interpreting the responses in the clinical groups. For each healthy and clinical population, recent, impactful research findings will be presented.

Artificial neural network identification of exercise expiratory flow-limitation in adults.

Identification of ventilatory constraint is a key objective of clinical exercise testing. Expiratory flow-limitation (EFL) is a well-known type of ventilatory constraint. However, EFL is difficult to measure, and commercial metabolic carts do not readily identify or quantify EFL. Deep machine learning might provide a new approach for identifying EFL. The objective of this study was to determine if a convolutional neural network (CNN) could accurately identify EFL during exercise in adults in whom baseline airway function varied from normal to mildly obstructed. 2931 spontaneous exercise flow-volume loops (eFVL) were placed within the baseline maximal expiratory flow-volume curves (MEFV) from 22 adults (15 M, 7 F; age, 32 yrs) in whom lung function varied from normal to mildly obstructed. Each eFVL was coded as EFL or non-EFL, where EFL was defined by eFVLs with expired airflow meeting or exceeding the MEFV curve. A CNN with seven hidden layers and a 2-neuron softmax output layer was used to analyze the eFVLs. Three separate analyses were conducted: (1) all subjects (n = 2931 eFVLs, [GRALL]), (2) subjects with normal spirometry (n = 1921 eFVLs [GRNORM]), (3) subjects with mild airway obstruction (n = 1010 eFVLs, [GRLOW]). The final output of the CNN was the probability of EFL or non-EFL in each eFVL, which is considered EFL if the probability exceeds 0.5 or 50%. Baseline forced expiratory volume in 1 s/forced vital capacity was 0.77 (94% predicted) in GRALL, 0.83 (100% predicted) in GRNORM, and 0.69 (83% predicted) in GRLOW. CNN model accuracy was 90.6, 90.5, and 88.0% in GRALL, GRNORM and GRLOW, respectively. Negative predictive value (NPV) was higher than positive predictive value (PPV) in GRNORM (93.5 vs. 78.2% for NPV vs. PPV). In GRLOW, PPV was slightly higher than NPV (89.5 vs. 84.5% for PPV vs. NPV). A CNN performed very well at identifying eFVLs with EFL during exercise. These findings suggest that deep machine learning could become a viable tool for identifying ventilatory constraint during clinical exercise testing.

Effect of exercise-induced bronchoconstriction on the configuration of the maximal expiratory flow-volume curve in adults with asthma.

We determined the effect of exercise-induced bronchoconstriction (EIB) on the shape of the maximal expiratory flow-volume (MEFV) curve in asthmatic adults. The slope-ratio index (SR) was used to quantitate the shape of the MEFV curve. We hypothesized that EIB would be accompanied by increases in SR and thus increased curvilinearity of the MEFV curve. Adult asthmatic ( n  = 10) and non-asthmatic control subjects ( n  = 9) cycled for 6-8 min at 85% of peak power. Following exercise, subjects remained on the ergometer and performed a maximal forced exhalation every 2 min for a total 20 min. In each MEFV curve, the slope-ratio index (SR) was calculated in 1% volume increments beginning at peak expiratory flow (PEF) and ending at 20% of forced vital capacity (FVC). Baseline spirometry was lower in asthmatics compared to control subjects (FEV1 % predicted, 89.1 ± 14.3 vs. 96.5 ± 12.2% [SD] in asthma vs. control; p  < 0.05). In asthmatic subjects, post-exercise FEV1 decreased by 29.9 ± 13.2% from baseline (3.48 ± 0.74 and 2.24 ± 0.59 [SD] L for baseline and post-exercise nadir; p  < 0.001). At baseline and at all timepoints after exercise, average SR between 80 and 20% of FVC was larger in asthmatic than control subjects (1.48 ± 0.02 vs. 1.23 ± 0.02 [SD] for asthma vs. control; p < 0.005). This averaged SR did not change after exercise in either subject group. In contrast, post-exercise SR between PEF and 75% of FVC was increased from baseline in subjects with asthma, suggesting that airway caliber heterogeneity increases with EIB. These findings suggest that the SR-index might provide useful information on the physiology of acute airway narrowing that complements traditional spirometric measures.

Exercise-induced Bronchodilation Equalizes Exercise Ventilatory Mechanics despite Variable Baseline Airway Function in Asthma.

PURPOSE: We quantified the magnitude of exercise-induced bronchodilation in adult asthmatics under conditions of narrowed and dilated airways. We then assessed the effect of the bronchodilation on ventilatory capacity and the extent of ventilatory limitation during exercise. METHODS: Eleven asthmatics completed three exercise bouts on a cycle ergometer. Exercise was preceded by no treatment (trialCON), inhaled ß2 agonist (trialBD), or a eucapnic voluntary hyperpnea challenge (trialBC). Maximal expiratory flow-volume maneuvers (MEFV) were performed before and within 40 s of exercise cessation. Exercise tidal flow-volume loops were placed within the preexercise and postexercise MEFV curve and used to determine expiratory flow limitation and maximum ventilatory capacity (V˙ECap). RESULTS: Preexercise airway function was different among the trials (forced expiratory volume 1 s during trialCON, trialBD, and trialBC = 3.3 ± 0.8 L, 3.8 ± 0.8 L, and 2.9 ± 0.8 L, respectively; P < 0.05). Maximal expired airflow increased with exercise during all three trials, but the increase was greatest during trialBC (delta forced expiratory volume 1 s during trialCON, trialBD, and trialBC = +12.2% ± 13.1%, +5.2% ± 5.7%, +28.1% ± 15.7%). Thus, the extent of expiratory flow limitation decreased, and V˙ECap increased, when the postexercise MEFV curve was used. During trialCON and trialBC, actual exercise ventilation exceeded V˙ECap calculated with the preexercise MEFV curve in seven and nine subjects, respectively. CONCLUSIONS: These findings demonstrate the critical importance of exercise bronchodilation in the asthmatic with narrowed airways. Of clinical relevance, the results also highlight the importance of assessing airway function during or immediately after exercise in asthmatic persons; otherwise, mechanical limitations to exercise ventilation will be overestimated.

Spirometric Response to Bronchodilator and Eucapnic Voluntary Hyperpnea in Adults With Asthma.

BACKGROUND: The spirometric response to fast-acting bronchodilator is used clinically to diagnose asthma and in clinical research to verify its presence. However, bronchodilator responsiveness does not correlate with airway hyper-responsiveness measured with the direct-acting stimulus of methacholine, demonstrating that bronchodilator responsiveness is a problematic method for diagnosing asthma. The relationship between bronchodilator responsiveness and airway hyper-responsiveness assessed with indirect-acting stimuli is not known. METHODS: Retrospectively, the spirometric responses to inhaled bronchodilator and a eucapnic voluntary hyperpnea challenge (EVH) were compared in 39 non-smoking adult subjects with asthma (26 male, 13 female; mean ± SD age 26.9 ± 7.8 y; mean ± SD body mass index 26.3 ± 4.7 kg/m2). All subjects met one or both of 2 criteria: ≥ 12% and 200 mL increase in FEV1 after inhaled bronchodilator, and ≥ 10% decrease in FEV1 after an EVH challenge. RESULTS: Overall, FEV1 increased by 9.9 ± 7.9% after bronchodilator (3.93 ± 0.97 to 4.28 ± 0.91 L, P < .001) and decreased by 23.9 ± 15.0% after the EVH challenge (3.89 ± 0.89 to 2.96 ± 0.88 L, P < .001). However, the change in FEV1 after bronchodilator did not correlate with the change after EVH challenge (r = 0.062, P = .71). Significant bronchodilator responsiveness predicted a positive response to EVH challenge in 9 of 33 subjects (sensitivity 27%). Following EVH, the change in FEV1 strongly correlated with the change in FVC (FEV1 percent change vs FVC percent change, r = 0.831, P < .001; FEV1 ΔL vs FVC ΔL, r = 0.799, P < .001). CONCLUSIONS: These results extend previous findings that demonstrate a lack of association between bronchodilator responsiveness and methacholine responsiveness. Given the poor concordance between the spirometric response to fast-acting bronchodilator and the EVH challenge, these findings suggest that the airway response to inhaled ß2-agonist must be interpreted with caution and in the context of its determinants and limitations.

Acute and daily effects of repeated voluntary hyperpnea on pulmonary function in healthy adults.

PURPOSE: Hyperpnea training has been used as a method for both improving exercise performance in healthy persons and improving ventilatory capacity in patients with pulmonary disease. However, voluntary hyperpnea causes acute declines in pulmonary function, but the effects of repeated days of hyperpnea on airway function are not known. The purpose of this study was to determine the effects of repeated normocapnic hyperpnea on daily and post-hyperpnea pulmonary function in healthy adults. METHODS: Ten healthy adults (21 years; 170 cm; 66 kg) completed ten hyperpnea training sessions within 17-days (TR). Training sessions consisted of 20-minutes of normocapnic hyperpnea with gradually increased minute ventilation over the 10 days. Spirometry was assessed at baseline and serially following hyperpnea during each experimental day. A control group (24 years; 171 cm; 66 kg) completed 10 days of spirometry with no hyperpnea training (CON). RESULTS: In both CON and TR subjects, baseline pulmonary function was unchanged during the 10 days. In TR subjects, pulmonary function was decreased at 5 mins after hyperpnea but thereafter increased to pre-hyperpnea values by 30 mins. Furthermore, these changes in pulmonary function were consistent during the 10 training days. In TR subjects, maximal voluntary ventilation decreased by 10.4 ± 8.9% (168-150 L min-1) over the 10 days (P < 0.05), whereas it was unchanged in CON subjects. CONCLUSIONS: These findings demonstrate that voluntary hyperpnea acutely decreases airway function in healthy subjects. However, there does not appear to be a cumulative effect of repeated hyperpnea, as daily pulmonary function was unchanged.

No effect of elevated operating lung volumes on airway function during variable workrate exercise in asthmatic humans.

In asthmatic adults, airway caliber fluctuates during variable intensity exercise such that bronchodilation (BD) occurs with increased workrate whereas bronchoconstriction (BC) occurs with decreased workrate. We hypothesized that increased lung mechanical stretch would prevent BC during such variable workrate exercise. Ten asthmatic and ten nonasthmatic subjects completed two exercise trials on a cycle ergometer. Both trials included a 28-min exercise bout consisting of alternating four min periods at workloads equal to 40 % (Low) and 70% (High) peak power output. During one trial, subjects breathed spontaneously throughout exercise (SVT), such that tidal volume (VT) and end-inspiratory lung volume (EILV) were increased by 0.5 and 0.6 liters during the high compared with the low workload in nonasthmatic and asthmatic subjects, respectively. During the second trial (MVT), VT and EILV were maintained constant when transitioning from the high to the low workload. Forced exhalations from total lung capacity were performed during each exercise workload. In asthmatic subjects, forced expiratory volume 1.0 s (FEV1.0) increased and decreased with the increases and decreases in workrate during both SVT (Low, 3.3 ± 0.3 liters; High, 3.6 ± 0.2 liters; P < 0.05) and MVT (Low, 3.3 ± 0.3 liters; High, 3.5 ± 0.2 liters; P < 0.05). Thus increased lung stretch during MVT did not prevent decreases in airway caliber when workload was reduced. We conclude that neural factors controlling airway smooth muscle (ASM) contractile activity during whole body exercise are more robust determinants of airway caliber than the ability of lung stretch to alter ASM actin-myosin binding and contraction.

Effects of altered airway function on exercise ventilation in asthmatic adults.

PURPOSE: Variable airway function is a central feature of the asthmatic condition. Thus, habitually active asthmatics are certain to exercise under conditions of variable airway (dys)function. The purpose of this study was to determine the effects of variable preexercise airway function on ventilation during whole-body exercise in asthmatic adults. METHODS: Eight mild asthmatic (age = 26 yr; V˙O2peak = 49 mL·kg·min) and nine nonasthmatic (age = 30 yr; V˙O2peak = 46 mL·kg·min) adults performed constant workrate cycling exercise to exhaustion after four separate interventions: 1) a control trial (CON); 2) inhalation of fast-acting ß2-agonist (BD); 3) eucapnic voluntary hyperpnea challenge (BC); and 4) sham to the hyperpnea (SHAM). Pulmonary function was assessed at baseline and after each intervention. Exercise ventilation and operating lung volumes were compared among the four exercise trials in both control and asthmatic subjects. RESULTS: Baseline pulmonary function was significantly lower in asthmatic subjects compared with control subjects. In asthmatic subjects, postintervention (i.e., preexercise) forced expiratory volume 1.0 s was significantly different among the four exercise trials (CON = 3.5 ± 0.4, BD = 4.1 ± 0.4, SHAM = 3.6 ± 0.3, BC = 2.8 ± 0.3 L, P < 0.05), whereas it was not different in control subjects. There were no differences in exercise ventilation or operating lung volumes during exercise among the four trials either within asthmatic subjects or between control and asthmatic subjects. CONCLUSIONS: These findings suggest that the state of airway function-whether bronchodilated or bronchoconstricted-before exercise in the mild asthmatic does not affect the exercise ventilatory response. Thus, ventilatory system function in the asthmatic appears to be responsive to the acute requirement for increased airflow during whole-body exercise.