Feasibility and acceptability of home monitoring with portable spirometry in young adults with asthma.

OBJECTIVE: Self-monitoring asthma control is a key component of asthma management. Few studies have reported usability and acceptability of portable spirometry among young adults with asthma. Portable spirometry offers a practical solution to monitoring airway narrowing at home. The purpose of this paper was to determine if self-administered spirometry is feasible and acceptable in young adults with asthma and whether regular monitoring resulted in improved airway function as measured by forced expiratory volume in one second (FEV1). METHODS: Sixty-seven young adults (18-26 years) with self-reported asthma participated in a clinical trial during wildfire season which measured FEV1 as an outcome measure. Data was collected at baseline, week 4, and week 8 using a portable spirometer linked to a smartphone application. A subset of intervention participants completed spirometry twice daily. Acceptability of self-administered spirometry was evaluated after the trial among participants that volunteered to submit a survey and be interviewed. RESULTS: At baseline, all 67 participants (100.0%) completed their scheduled spirometry readings which declined to 94.0% (n = 63) at week 4 and 86.6% (n = 58) at week 8. Daily readings were completed 83.2% of the time in the mornings and 84.3% of the time in the evenings. Mean FEV1 values were lower than predicted values, but above the lower limit of expected. FEV1 remained steady throughout the study period. Over two-thirds of participants used the notes feature in the application and described symptoms, asthma triggers, mitigating actions and test-taking issues. CONCLUSIONS: Young adults in our sample were highly compliant with regular, self-administered spirometry.

Variability in Cardiopulmonary Exercise Testing Biologic Controls.

BACKGROUND: Cardiopulmonary exercise testing is an increasingly common test and is considered the accepted standard for assessing exercise capacity. Quantifying variability is important to assess the instrument for quality control purposes. Though guidelines recommend biologic control testing, there are minimal data on how to do it. We sought to describe variability for oxygen consumption (V̇O2 ), carbon dioxide production (V̇CO2 ), and minute ventilation (V̇E) at various work rates under steady-state conditions in multiple subjects over a 1-y period to provide a practical approach to assess and perform biologic control testing. METHODS: We performed a single-center, prospective study with 4 healthy subjects, 2 men and 2 women. Subjects performed constant work rate exercise tests for 6 min each at 25-100 W intervals on a computer-controlled cycle ergometer. Data were averaged over the last 120 s at each work rate to reflect stepwise steady-state conditions. Descriptive statistics, including the mean, median, range, SD, and coefficient of variation (CoV) are reported for each individual across the 4 work rates and all repetitions. As these data were normative, z-scores were utilized, and a value greater than ± 1.96 z-scores was used to define significant test variability. RESULTS: Subjects performed 16-39 biocontrol studies over 1-y. The mean CoV for all subjects in V̇O2 was 6.59%, V̇CO2 was 6.41%, and V̇E was 6.32%. The ± 1.96 z-scores corresponded to a 9.4-18.1% change in V̇O2 , a 9.6-18.1% change in V̇CO2 , and a 9-21.5% change in V̇E across the 4 workloads. CONCLUSIONS: We report long-term variability for steady-state measurement of V̇O2 , V̇CO2 , and V̇E obtained during biocontrol testing. Utilizing ± 1.96 z-scores allows one to determine if a result exceeds expected variability, which may warrant investigation of the instrument.

Quantifying the shape of maximal expiratory flow-volume curves in healthy humans and asthmatic patients.

Differences in the absolute flow and volume of maximal expiratory flow-volume (MEFV) curves have been studied extensively in health and disease. However, the shapes of MEFV curves have received less attention. We questioned if the MEFV curve shape was associated with (i) expiratory flow limitation (EFL) in health and (ii) changes in bronchial caliber in asthmatics. Using the slope-ratio (SR) index, we quantified MEFV curve shape in 84 healthy subjects and 8 matched asthmatics. Healthy subjects performed a maximal exercise test to assess EFL. Those with EFL during had a greater SR (1.15 ± 0.20 vs. 0.85 ± 0.20, p<0.05) yet, there was no association between maximal oxygen consumption and SR (r=0.14, p>0.05). Asthmatics average SR was greater than the healthy subjects (1.35 ± 0.03 vs. 0.90 ± 0.11, p<0.05), but there were no differences when bronchial caliber was manipulated. In conclusion, a greater SR is related to EFL and this metric could aid in discriminating between groups known to differ in the absolute size of MEFV curves.

Quantifying the shape of the maximal expiratory flow-volume curve in mild COPD.

Maximal expiratory flow-volume (MEFV) curve evaluation using absolute and percent predicted values of flow and volume are used to diagnose respiratory disease, but the shape of the curve is rarely used. Three mathematical methods were used to quantify shape of MEFV curves in subjects with mild COPD (n=19) and matched healthy controls (n=15). Those with mild COPD had a significantly greater slope-ratio (SR) (1.90 ± 0.24 vs. 1.28 ± 0.32) and Beta-angle (160 ± 6.7 vs. 186 ± 15.0) compared to healthy individuals (p<0.05). The flow-ratio method showed no difference between groups. A significant positive SR-volume relationship during expiration was observed in a greater number of mild COPD subjects (94%) compared to controls (20%) (p<0.001). With its increased spatial resolution and the potential to discern etiology behind specific curvature, we suggest using the SR method when available. The change in SR throughout expiration could help identify those who fall within the lower limit of normal lung function and those who may have pathological obstruction.

Inhaled salmeterol and/or fluticasone alters structure/function in a murine model of allergic airways disease.

BACKGROUND: The relationship between airway structural changes (remodeling) and airways hyperresponsiveness (AHR) is unclear. Asthma guidelines suggest treating persistent asthma with inhaled corticosteroids and long acting beta-agonists (LABA). We examined the link between physiological function and structural changes following treatment fluticasone and salmeterol separately or in combination in a mouse model of allergic asthma. METHODS: BALB/c mice were sensitized to intraperitoneal ovalbumin (OVA) followed by six daily inhalation exposures. Treatments included 9 daily nebulized administrations of fluticasone alone (6 mg/ml), salmeterol (3 mg/ml), or the combination fluticasone and salmeterol. Lung impedance was measured following methacholine inhalation challenge. Airway inflammation, epithelial injury, mucus containing cells, and collagen content were assessed 48 hours after OVA challenge. Lungs were imaged using micro-CT. RESULTS AND DISCUSSION: Treatment of allergic airways disease with fluticasone alone or in combination with salmeterol reduced AHR to approximately naüve levels while salmeterol alone increased elastance by 39% compared to control. Fluticasone alone and fluticasone in combination with salmeterol both reduced inflammation to near naive levels. Mucin containing cells were also reduced with fluticasone and fluticasone in combination with salmeterol. CONCLUSIONS: Fluticasone alone and in combination with salmeterol reduces airway inflammation and remodeling, but salmeterol alone worsens AHR: and these functional changes are consistent with the concomitant changes in mucus metaplasia.

Transpulmonary passage of 99mTc macroaggregated albumin in healthy humans at rest and during maximal exercise.

We have demonstrated that 50-mum-diameter arteriovenous pathways exist in isolated, healthy human and baboon lungs, ventilated and perfused under physiological pressures. These findings have been confirmed and extended by demonstrating the passage of 25-microm microspheres through the lungs of exercising dogs, but not at rest. Determination of blood flow through these large-diameter intrapulmonary arteriovenous pathways would be an important first step to establish a physiological role for these vessels. Currently, we sought to estimate blood flow through these arteriovenous pathways using technetium-99m ((99m)Tc)-labeled macroaggregated albumin (MAA) in healthy humans at rest and during maximal treadmill exercise. We hypothesized that the percentage of (99m)Tc MAA able to traverse the pulmonary circulation (%transpulmonary passage) would increase during exercise. Seven male subjects without patent foramen ovale were injected with (99m)Tc MAA at rest on 1 day and during maximal treadmill exercise on a separate day (>6 days). Within 5 min after injection, subjects began whole body imaging in the supine position. Six of the seven subjects showed an increase in transpulmonary passage of MAA with maximal exercise. Using two separate analysis methods, percent transpulmonary passage significantly increased with exercise from baseline to absolute values of 1.2 +/- 0.8% (P = 0.008) and 1.3 +/- 1.0% (P = 0.016), respectively (means +/- SD; paired t-test). We conclude that MAA may be traversing the pulmonary circulation via large-diameter intrapulmonary arteriovenous conduits in healthy humans during exercise. Recruitment of these pathways may divert blood flow away from pulmonary capillaries during exercise and compromise the lung's function as a biological filter.

Update in the understanding of respiratory limitations to exercise performance in fit, active adults.

This review addresses three types of causes of respiratory system limitations to O(2) transport and exercise performance that are experienced by significant numbers of active, highly fit younger and older adults. First, flow limitation in intrathoracic airways may occur during exercise because of narrowed, hyperactive airways or secondary to excessive ventilatory demands superimposed on a normal maximum flow-volume envelope. Narrowing of the extrathoracic, upper airway also occurs in some athletes at very high flow rates during heavy exercise. Examination of the breath-by-breath tidal flow-volume loop during exercise is key to a noninvasive diagnosis of flow limitation and to differentiation between intrathoracic and extrathoracic airway narrowing. Second exercise-induced arterial hypoxemia occurs secondary to an excessively widened alveolar-arterial oxygen pressure difference. This inefficient gas exchange may be attributable in part to small intracardiac or intrapulmonary shunts of deoxygenated mixed venous blood during exercise. The existence of these shunts at rest and during exercise may be determined by using saline solution contrast echocardiography. Finally, fatigue of the respiratory muscles resulting from sustained, high-intensity exercise and the resultant vasoconstrictor effects on limb muscle vasculature will also compromise O(2) transport and performance. Exercise in the hypoxic environments of even moderately high altitudes will greatly exacerbate the negative influences of these respiratory system limitations to exercise performance, especially in highly fit individuals.

Computational assessment of airway wall stiffness in vivo in allergically inflamed mouse models of asthma.

Allergic inflammation is known to cause airway hyperresponsiveness in mice. However, it is not known whether inflammation affects the stiffness of the airway wall, which would alter the load against which the circumscribing smooth muscle shortens when activated. Accordingly, we measured the time course of airway resistance immediately following intravenous methacholine injection in acutely and chronically allergically inflamed mice. We estimated the effective stiffness of the airway wall in these animals by fitting to the airway resistance profiles a computational model of a dynamically narrowing airway embedded in elastic parenchyma. Effective airway wall stiffness was estimated from the model fit and was found not to change from control in either the acute or chronic inflammatory groups. However, the acutely inflamed mice were hyperresponsive compared with controls, which we interpret as reflecting increased delivery of methacholine to the airway smooth muscle through a leaky pulmonary endothelium. These results support the notion that acutely inflamed BALB/c mice represent an animal model of functionally normal airway smooth muscle in a transiently abnormal lung.

Intrapulmonary shunting and pulmonary gas exchange during normoxic and hypoxic exercise in healthy humans.

Exercise-induced intrapulmonary arteriovenous shunting, as detected by saline contrast echocardiography, has been demonstrated in healthy humans. We have previously suggested that increases in both pulmonary pressures and blood flow associated with exercise are responsible for opening these intrapulmonary arteriovenous pathways. In the present study, we hypothesized that, although cardiac output and pulmonary pressures would be higher in hypoxia, the potent pulmonary vasoconstrictor effect of hypoxia would actually attenuate exercise-induced intrapulmonary shunting. Using saline contrast echocardiography, we examined nine healthy men during incremental (65 W + 30 W/2 min) cycle exercise to exhaustion in normoxia and hypoxia (fraction of inspired O(2) = 0.12). Contrast injections were made into a peripheral vein at rest and during exercise and recovery (3-5 min postexercise) with pulmonary gas exchange measured simultaneously. At rest, no subject demonstrated intrapulmonary shunting in normoxia [arterial Po(2) (Pa(O(2))) = 98 +/- 10 Torr], whereas in hypoxia (Pa(O(2)) = 47 +/- 5 Torr), intrapulmonary shunting developed in 3/9 subjects. During exercise, approximately 90% (8/9) of the subjects shunted during normoxia, whereas all subjects shunted during hypoxia. Four of the nine subjects shunted at a lower workload in hypoxia. Furthermore, all subjects continued to shunt at 3 min, and five subjects shunted at 5 min postexercise in hypoxia. Hypoxia has acute effects by inducing intrapulmonary arteriovenous shunt pathways at rest and during exercise and has long-term effects by maintaining patency of these vessels during recovery. Whether oxygen tension specifically regulates these novel pathways or opens them indirectly via effects on the conventional pulmonary vasculature remains unclear.

The synergistic interactions of allergic lung inflammation and intratracheal cationic protein.

RATIONALE: Airways hyperresponsiveness (AHR) is a hallmark feature of asthma, and can be caused by various disparate mechanisms. Mouse models of AHR have been useful for studying these mechanisms in isolation, but such models still typically do not exhibit the same degree of AHR as seen in severe human asthma. We hypothesized that more severe AHR in mice could be achieved by imbuing them with more than one mechanism of AHR. OBJECTIVES: We sought to determine if the airway wall thickening accompanying allergic inflammation and the exaggerated smooth muscle shortening induced by intratracheal cationic protein could act together to produce a severe form of AHR. METHODS: We used the forced oscillation technique to measure methacholine responsiveness in BALB/c mice that had been sensitized and challenged with ovalbumin followed by an intratracheal instillation of poly-l-lysine. MEASUREMENTS AND MAIN RESULTS: We found that both ovalbumin and poly-l-lysine treatment alone caused moderate levels of AHR. When the two treatments were combined, however, they synergized in terms of their effect on lung stiffness to an extent that could even be fatal, reflecting a significantly enhanced level of airway closure. CONCLUSIONS: Our results suggest that mechanistic synergy between airway wall thickening and exaggerated smooth muscle shortening produces a more germane mouse model of asthma that may have particular relevance to the pathophysiology of the acute severe asthma exacerbation.

Treatment of airway inflammation improves exercise pulmonary gas exchange and performance in asthmatic subjects.

BACKGROUND: Asthma is an inflammatory disease of the airways that can lead to impaired arterial blood oxygenation during exercise. OBJECTIVE: We asked whether treatment of airway inflammation in asthmatic subjects would improve arterial blood gases during whole-body exercise. METHODS: By using a double-blind parallel-group design, 19 asthmatic subjects completed treadmill exercise to exhaustion on 2 occasions: (1) before and (2) after 6 weeks' treatment with an inhaled corticosteroid (ICS; n = 9) or placebo (n = 10). RESULTS: The ICS group had improved resting pulmonary function, decreased exercise-induced bronchospasm, and decreased postexercise sputum histamine during the posttreatment study compared with that during the pretreatment study. In the ICS group exercise Pao(2) was significantly increased after treatment (84.8 to 93.8 mm Hg). Increased alveolar ventilation (arterial Pco(2) decreased from 36.9 to 34.1 mm Hg) accounted for 37% of the increased Pao(2) and improved gas exchange efficiency (alveolar-to-arterial Po(2) difference decreased from 22.5 to 16.3 mm Hg) accounted for the remaining 63% of the increased Pao(2) after treatment. In the ICS group exercise time to exhaustion was increased from 9.9 minutes during the pretreatment study to 14.8 minutes during the posttreatment study. CONCLUSION: Treatment of airway inflammation in asthmatic subjects can improve arterial blood oxygenation during exercise by (1) improving airway function, thereby allowing increased alveolar ventilation during exercise, and (2) improving the efficiency of alveolar-to-arterial blood O(2) exchange. CLINICAL IMPLICATIONS: In asthmatic patients ICSs not only attenuate exercise-induced bronchospasm but also improve arterial blood oxygenation during exercise.

Excessive gas exchange impairment during exercise in a subject with a history of bronchopulmonary dysplasia and high altitude pulmonary edema.

A 27-year-old male subject (V(O2 max)), 92% predicted) with a history of bronchopulmonary dysplasia (BPD) and a clinically documented case of high altitude pulmonary edema (HAPE) was examined at rest and during exercise. Pulmonary function testing revealed a normal forced vital capacity (FVC, 98.1% predicted) and diffusion capacity for carbon monoxide (D(L(CO)), 91.2% predicted), but significant airway obstruction at rest [forced expiratory volume in 1 sec (FEV(1)), 66.5% predicted; forced expiratory flow at 50% of vital capacity (FEF(50)), 34.3% predicted; and FEV(1) /FVC 56.5%] that was not reversible with an inhaled bronchodilator. Gas exchange worsened from rest to exercise, with the alveolar to arterial P(O2) difference (AaD(O2)) increasing from 0 at rest to 41 mmHg at maximal normoxic exercise (VO(2) = 41.4 mL/kg/min) and from 11 to 31 mmHg at maximal hypoxic exercise (VO(2) = 21.9 mL/kg/min). Arterial P(O2) decreased to 67.8 and 29.9 mmHg at maximal normoxic and hypoxic exercise, respectively. These data indicate that our subject with a history of BPD is prone to a greater degree of exercise-induced arterial hypoxemia for a given VO(2) and F(I(O2)) than healthy age-matched controls, which may increase the subject's susceptibility to high altitude illness.

Intrinsic and antigen-induced airway hyperresponsiveness are the result of diverse physiological mechanisms.

Airway hyperresponsiveness (AHR) is a defining feature of asthma. We have previously shown, in mice sensitized and challenged with antigen, that AHR is attributable to normal airway smooth muscle contraction with exaggerated airway closure. In the present study we sought to determine if the same was true for mice known to have intrinsic AHR, the genetic strain of mice, A/J. We found that A/J mice have AHR characterized by minimal increase in elastance following aerosolized methacholine challenge compared with mice (BALB/c) that have been antigen sensitized and challenged [concentration that evokes 50% change in elastance (PC(50)): 22.9 +/- 5.7 mg/ml for A/J vs. 3.3 +/- 0.4 mg/ml for antigen-challenged and -sensitized mice; P < 0.004]. Similar results were found when intravenous methacholine was used (PC(30) 0.22 +/- 0.08 mg/ml for A/J vs. 0.03 +/- 0.004 mg/ml for antigen-challenged and -sensitized mice). Computational model analysis revealed that the AHR in A/J mice is dominated by exaggerated airway smooth muscle contraction and that when the route of methacholine administration was changed to intravenous, central airway constriction dominates. Absorption atelectasis was used to provide evidence of the lack of airway closure in A/J mice. Bronchoconstriction during ventilation with 100% oxygen resulted in a mean 9.8% loss of visible lung area in A/J mice compared with 28% in antigen-sensitized and -challenged mice (P < 0.02). We conclude that the physiology of AHR depends on the mouse model used and the route of bronchial agonist administration.

Effect of acute severe hypoxia on peripheral fatigue and endurance capacity in healthy humans.

We hypothesized that severe hypoxia limits exercise performance via decreased contractility of limb locomotor muscles. Nine male subjects [mean +/- SE maximum O(2) uptake (Vo(2 max)) = 56.5 +/- 2.7 ml x kg(-1) x min(-1)] cycled at > or =90% Vo(2 max) to exhaustion in normoxia [NORM-EXH; inspired O(2) fraction (Fi(O(2))) = 0.21, arterial O(2) saturation (Sp(O(2))) = 93 +/- 1%] and hypoxia (HYPOX-EXH; Fi(O(2)) = 0.13, Sp(O(2)) = 76 +/- 1%). The subjects also exercised in normoxia for a time equal to that achieved in hypoxia (NORM-CTRL; Sp(O(2)) = 96 +/- 1%). Quadriceps twitch force, in response to supramaximal single (nonpotentiated and potentiated 1 Hz) and paired magnetic stimuli of the femoral nerve (10-100 Hz), was assessed pre- and at 2.5, 35, and 70 min postexercise. Hypoxia exacerbated exercise-induced peripheral fatigue, as evidenced by a greater decrease in potentiated twitch force in HYPOX-EXH vs. NORM-CTRL (-39 +/- 4 vs. -24 +/- 3%, P < 0.01). Time to exhaustion was reduced by more than two-thirds in HYPOX-EXH vs. NORM-EXH (4.2 +/- 0.5 vs. 13.4 +/- 0.8 min, P < 0.01); however, peripheral fatigue was not different in HYPOX-EXH vs. NORM-EXH (-34 +/- 4 vs. -39 +/- 4%, P > 0.05). Blood lactate concentration and perceptions of limb discomfort were higher throughout HYPOX-EXH vs. NORM-CTRL but were not different at end-exercise in HYPOX-EXH vs. NORM-EXH. We conclude that severe hypoxia exacerbates peripheral fatigue of limb locomotor muscles and that this effect may contribute, in part, to the early termination of exercise.

Inspiratory muscles do not limit maximal incremental exercise performance in healthy subjects.

We investigated whether the inspiratory muscles affect maximal incremental exercise performance using a placebo-controlled, crossover design. Six cyclists each performed six incremental exercise tests. For three trials, subjects exercised with proportional assist ventilation (PAV). For the remaining three trials, subjects underwent sham respiratory muscle unloading (placebo). Inspiratory muscle pressure (P(mus)) was reduced with PAV (-35.9+/-2.3% versus placebo; P<0.05). Furthermore, V(O2) and perceptions of dyspnea and limb discomfort at submaximal exercise intensities were significantly reduced with PAV. Peak power output, however, was not different between placebo and PAV (324+/-4W versus 326+/-4W; P>0.05). Diaphragm fatigue (bilateral phrenic nerve stimulation) did not occur in placebo. In conclusion, substantially unloading the inspiratory muscles did not affect maximal incremental exercise performance. Therefore, our data do not support a role for either inspiratory muscle work or fatigue per se in the limitation of maximal incremental exercise.

Effect of exercise-induced arterial hypoxemia on quadriceps muscle fatigue in healthy humans.

The effect of exercise-induced arterial hypoxemia (EIAH) on quadriceps muscle fatigue was assessed in 11 male endurance-trained subjects [peak O2 uptake (VO2 peak) = 56.4 +/- 2.8 ml x kg(-1) x min(-1); mean +/- SE]. Subjects exercised on a cycle ergometer at >or=90% VO2 peak) to exhaustion (13.2 +/- 0.8 min), during which time arterial O2 saturation (Sa(O2)) fell from 97.7 +/- 0.1% at rest to 91.9 +/- 0.9% (range 84-94%) at end exercise, primarily because of changes in blood pH (7.183 +/- 0.017) and body temperature (38.9 +/- 0.2 degrees C). On a separate occasion, subjects repeated the exercise, for the same duration and at the same power output as before, but breathed gas mixtures [inspired O2 fraction (Fi(O2)) = 0.25-0.31] that prevented EIAH (Sa(O2) = 97-99%). Quadriceps muscle fatigue was assessed via supramaximal paired magnetic stimuli of the femoral nerve (1-100 Hz). Immediately after exercise at Fi(O2) 0.21, the mean force response across 1-100 Hz decreased 33 +/- 5% compared with only 15 +/- 5% when EIAH was prevented (P < 0.05). In a subgroup of four less fit subjects, who showed minimal EIAH at Fi(O2) 0.21 (Sa(O2) = 95.3 +/- 0.7%), the decrease in evoked force was exacerbated by 35% (P < 0.05) in response to further desaturation induced via Fi(O2) 0.17 (Sa(O2) = 87.8 +/- 0.5%) for the same duration and intensity of exercise. We conclude that the arterial O2 desaturation that occurs in fit subjects during high-intensity exercise in normoxia (-6 +/- 1% DeltaSa(O2) from rest) contributes significantly toward quadriceps muscle fatigue via a peripheral mechanism.

Effect of inspiratory muscle work on peripheral fatigue of locomotor muscles in healthy humans.

The work of breathing required during maximal exercise compromises blood flow to limb locomotor muscles and reduces exercise performance. We asked if force output of the inspiratory muscles affected exercise-induced peripheral fatigue of locomotor muscles. Eight male cyclists exercised at > or = 90% peak O2 uptake to exhaustion (CTRL). On a separate occasion, subjects exercised for the same duration and power output as CTRL (13.2 +/- 0.9 min, 292 W), but force output of the inspiratory muscles was reduced (-56% versus CTRL) using a proportional assist ventilator (PAV). Subjects also exercised to exhaustion (7.9 +/- 0.6 min, 292 W) while force output of the inspiratory muscles was increased (+80%versus CTRL) via inspiratory resistive loads (IRLs), and again for the same duration and power output with breathing unimpeded (IRL-CTRL). Quadriceps twitch force (Q(tw)), in response to supramaximal paired magnetic stimuli of the femoral nerve (1-100 Hz), was assessed pre- and at 2.5 through to 70 min postexercise. Immediately after CTRL exercise, Q(tw) was reduced -28 +/- 5% below pre-exercise baseline and this reduction was attenuated following PAV exercise (-20 +/- 5%; P < 0.05). Conversely, increasing the force output of the inspiratory muscles (IRL) exacerbated exercise-induced quadriceps muscle fatigue (Q(tw) = -12 +/- 8% IRL-CTRL versus-20 +/- 7% IRL; P < 0.05). Repeat studies between days showed that the effects of exercise per se, and of superimposed inspiratory muscle loading on quadriceps fatigue were highly reproducible. In conclusion, peripheral fatigue of locomotor muscles resulting from high-intensity sustained exercise is, in part, due to the accompanying high levels of respiratory muscle work.

Responses and limitations of the respiratory system to exercise.

During maximal exercise, the gas exchange function of the lung is challenged because of the major cardiopulmonary changes that must occur to meet the increased metabolic demands imposed by exercise. In healthy untrained young adults, the respiratory system is able to meet these demands imposed on it during maximal exercise by implementing several key mechanisms. Nonetheless, there are several exceptional cases in which the lung is unable to accommodate the demands of exercise because of vascular or airway limitations.

Exercise-induced intrapulmonary arteriovenous shunting in healthy humans.

We hypothesized that increasing exercise intensity recruits dormant arteriovenous intrapulmonary shunts, which may contribute to the widened alveolar-arterial oxygen difference seen with exercise. Twenty-three healthy volunteers (13 men and 10 women, aged 23-48 yr) with normal lung function and a wide range of fitness (mean maximal oxygen uptake = 126% predicted; range = 78-200% predicted) were studied by agitated saline contrast echocardiography (4-chamber apical view). All 23 subjects had normal resting contrast echocardiograms without evidence of intracardiac or intrapulmonary shunting. However, with cycle ergometer exercise, 21 of 23 (91%) of the subjects showed a delayed (>3 cardiac cycles) appearance of contrast bubbles in the left heart. This pattern is consistent with passage of contrast bubbles through the pulmonary circulation. Because the contrast bubbles are known to be significantly larger than pulmonary capillaries, we propose that they are traveling through direct arteriovenous intrapulmonary shunts. In all cases, the intrapulmonary shunting developed at submaximal oxygen uptakes [%maximal oxygen uptake = 59 +/- 20 (SD)] and once evident persisted at all subsequent work rates. Within 3 min of exercise termination, the contrast echocardiograms with bubble injection showed no evidence of intrapulmonary shunting. These dynamic shunts will contribute significantly to the widened alveolar-arterial oxygen difference seen with exercise. They may also act as a protective parallel vascular network limiting the rise in regional pulmonary vascular pressure while preserving cardiac output during exercise.