0
Recent Advances in Chest Medicine |

Update in the Understanding of Respiratory Limitations to Exercise Performance in Fit, Active Adults FREE TO VIEW

Jerome A. Dempsey, PhD; Donald C. McKenzie, MD, PhD; Hans C. Haverkamp, PhD; Marlowe W. Eldridge, MD
Author and Funding Information

*From the University of Wisconsin (Drs. Dempsey and Eldridge), Madison, WI; the University of British Columbia (Dr. McKenzie), Vancouver, BC, Canada; and Johnson State College (Dr. Haverkamp), Johnson, Vermont.

Correspondence to: Jerome A. Dempsey, PhD, University of Wisconsin–Madison, 4245 MSC, 1300 University Ave, Madison, WI 53706; e-mail: jdempsey@wisc.edu


The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Chest. 2008;134(3):613-622. doi:10.1378/chest.07-2730
Text Size: A A A
Published online

This review addresses three types of causes of respiratory system limitations to O2 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 O2 transport and performance. Exercise in the hypoxic environments of even moderately high alitudes will greatly exacerbate the negative influences of these respiratory system limitations to exercise performance, especially in highly fit individuals.

Figures in this Article

The motivation for writing this review stems from the inquiries that some of us who are engaged in integrative physiologic research have received over many years from practicing physicians concerning respiratory system-related exercise limitations in otherwise healthy patients who are habitually active, including endurance-trained athletes. The typical symptoms are excessive “shortness of breath” during heavy-intensity exercise and postexercise cough, negatively impacting exercise performance. Cardiopulmonary exercise testing reveals excessive exercise-induced arterial O2 desaturation, as estimated noninvasively via pulse oximetry. Based on these observations and symptoms, exercise-induced asthma (EIA) is commonly assumed to be present and can be treated, often with positive outcomes. However, in many cases little or no relief of symptoms or change in O2 desaturation or performance occurs. What then is causing these symptoms, the exercise-induced hypoxemia and the compromised exercise performance? How can we best modify our testing procedures to diagnose these problems? In whom are they most likely to occur and under what conditions? How might they be treated, or at least how should the athlete be counseled to minimize the effects of these problems? We start with a brief consideration of the physiologic determinants of exercise performance in healthy subjects.

The capability for maximum O2 transport (or the product of arterial O2 content × blood flow) to the working locomotor muscles and, in turn, diffusion from muscle capillaries to mitochondria are major determinants of maximum oxygen uptake (V̇O2max) in the muscle, of peripheral muscle fatigue, and, by implication, of exercise performance.1,2 Exercise performance is also dictated by the perception of effort of the brain and its inhibitory effects on central motor drive to the periphery.3 We believe that these peripheral and central factors are closely linked, with the development of peripheral fatigue influencing the rate of development of “central” fatigue, operating through neural feedback pathways from working muscle to the motor control areas of the CNS.35

It is generally viewed that, in health, the capacity of the respiratory system (ie, lung parenchyma, airways, and respiratory muscles) are overbuilt for the demands placed on ventilation and gas exchange by high-intensity short-term or long-term exercise.1,2,6 However, there is a growing awareness that the magnitude of the stresses placed on the airways, gas-exchange mechanisms, and the chest wall in some endurance-trained individuals may present a significant limitation to their performance. Respiratory system limitations to exercise in the trained individual appear to be in part due to the relative specificity of aerobic physical training (or the endowment of a highly trained state) to increase the capacity of the cardiovascular and skeletal muscles for oxygen transport and utilization, but appear to have little (or perhaps even a detrimental) effect on the structural and functional capacities of the lung and airways.7 Accordingly, the capacities for ventilation and alveolar-to-arterial oxygen transport, which are more than adequate for all exercise intensities in untrained individuals, are no longer able to meet the higher metabolic demands in some trained individuals. We first outline the respiratory responses to exercise obtained in a healthy untrained state and then discuss how the trained individual may differ from this norm.

The ventilatory demands of heavy-intensity exercise require airway flow rates that often exceed 10 times resting levels and tidal volumes that approach 5 times resting levels. In order to avoid an increase in airway resistance causing excessive work of the respiratory muscles, adaptations must occur in the airways, including the following: (1) maximum relaxation of the bronchial smooth muscle due to withdrawal of parasympathetic tone; (2) increases in tidal end-inspiratory lung volumes, which expand intrathoracic airways via radial traction; and (3) precise synchronous activation of upper airway dilator skeletal muscles just milliseconds in advance of the chest wall inspiratory muscles, so as to maximize the diameter of the pharyngeal airway and glottal aperture. Furthermore, a progressive recruitment of expiratory muscles from mild through maximum exercise causes a reduction in end-expiratory lung volume. These key adaptations ensure that airway resistance stays near resting levels even in the face of marked increases in flow rate, that the increases in tidal volume occur over a range of lung volumes that require minimal amounts of (elastic) work by the respiratory muscles, that the increases in flow rate remain within the maximum flow-volume envelope, and that the distribution of ventilation is nearly perfectly uniform. The increases in alveolar ventilation match those in metabolic demand, ensuring constant arterial PCO2 and PO2; furthermore, a substantial ventilatory response is achieved with minimal increments in respiratory muscle work and few or no symptoms of dyspnea.

Evidence is accumulating that many endurance-trained athletes of all ages experience three types of airway problems during exercise. Each of these is discussed below.

Intrathoracic Airways

EIA is almost exclusively manifested immediately on recovery from heavy-intensity exercise. At the onset of exercise, bronchodilation occurs even in persons with relatively severe asthma who are bronchoconstricted at rest.8 Nevertheless, the absolute airway diameters of large and small airways are likely compromised to some extent during exercise in the asthmatic patient. Even relatively minor reductions in airway diameter will have substantial deleterious effects on breathing mechanics and ventilation distribution in the face of high ventilatory requirements.9 Accordingly, arterial hypoxemia, secondary to ventilatory limitation and inefficient widened alveolar-arterial oxygen pressure difference (P[A-a]O2), is prevalent during heavy-intensity exercise in the habitually active asthmatic young adult.8,10

A high prevalence of EIA has been reported11,12 in the endurance-trained athlete. In some sports, such as cross-country skiing, involving high-intensity repetitive exercise in cold environments, a training-induced remodeling of the epithelium of intrathoracic airways has been documented.13 Similar effects of a combination of intense training with environmental contaminants present in indoor ice arenas and swimming pools may also contribute to the high prevalence of EIA that has been reported in skaters and swimmers.14

So, EIA is a serious and prevalent effector of health and exercise performance in many athletes, but it is also a condition that requires careful diagnosis through the use of appropriate airway challenge tests.11,12 Exercise-related symptoms reported by the athlete are poor predictors of EIA, and commonly used measures of peak flow rates, by themselves, are not sufficiently specific to the assessment of airway reactivity.15,16 The prescription of inhaled β2-adrenoreceptor agonists or corticosteroids may have long-lasting adverse systemic effects in the nonasthmatic individuals,17,18 and their frequent use may even contribute to the development of airway hyperresponsiveness in individuals without asthma.19 This hyperresponsiveness has been attributed at least in part, to β2-agonist effects on mast cell degranulation.19,20

Extrathoracic, Upper Airway

Some athletes undergo sudden-onset, paradoxical narrowing of the glottic aperture (called vocal cord dysfunction [VCD]) during exercise of severe intensity. This event immediately precipitates flow limitation, CO2 retention, hypoxemia, and dyspnea (Fig 1). Evidence is accumulating2123 to suggest that a highly significant portion of these VCD cases are inadequately diagnosed as asthma and therefore improperly treated, often with high doses of inhaled corticosteroids over many years. Exercise-induced VCD seems to be especially prevalent in the highly competitive young adult or adolescent endurance athlete of both sexes. In a large group of elite endurance athletes, about 5% of the group experienced symptoms of inspiratory stridor during heavy exercise; about one half of these patients showed both VCD and EIA.24

Figure Jump LinkFigure 1 Top, A: tidal flow-volume loops (FVLs) obtained during exercise at 50%, 75%, and 90% of peak oxygen uptake (V̇O2peak) [left], and during maximal exercise before and after the development of an extrathoracic obstruction (right). FVLs were created by taking the average of 10 tidal breaths. Note the significant drop in both inspiratory and expiratory flows during maximal exercise after the appearance of symptoms, and the sawtooth pattern in the inspiratory flows even at submaximal exercise prior to the development of symptoms (from Haverkamp et al23). Bottom, B: breath-by-breath analysis of V̇E, peak inspiratory tidal flow (Insp flow) and expiratory tidal flow (Exp flow), and partial pressures of end-tidal O2 (PetO2) and CO2 (PetCO2) during the entire period of exercise at the maximal workload in a 22-year-old competitive female cyclist. Breath 1 represents the first breath of the maximal workload, and breath 43 represents the final breath of the workload. The vertical line indicates the breath at which dyspnea symptoms suddenly appeared. The subject was able to exercise for a total of 75 s, even though the flow limitation appeared at 37 s into the workload. At the onset of symptoms, note the abrupt marked reduction in flow rates, and the subsequent CO2 retention and arterial hypoxemia. Maximum flow rates returned to normal within 5 min of terminating exercise. Adapted from Haverkamp et al.23Grahic Jump Location

The key to detecting exercise-induced VCD is to understand that this problem involves extrathoracic airway narrowing in both inspiration and expiration, and that it occurs only during heavy-intensity exercise with sudden onset when flow rates are high. Immediately following the cessation of exercise, as air flow rate falls precipitously, the extrathoracic airway diameter is usually no longer compromised. Therefore, the appropriate (noninvasive) test for detecting VCD is to examine the characteristics of the breath-by-breath tidal flow rate and flow-volume envelope during exercise, because the usual means of examining forced maximum expiratory maneuvers, before or after exercise, will most often miss the event (Fig 1).23 Accompanying sudden increases in end-tidal PCO2 and reductions in arterial oxygen saturation (SaO2) are also helpful markers of VCD (Fig 1). For diagnostic purposes, it is especially important that heavy-intensity exercise demanding high flow rates be employed.

Perhaps the starting point here is for the clinician to recognize that not all symptoms of exercise-induced shortness of breath in the competitive athlete are attributable to the intrathoracic airway. Furthermore, the failure of routine spirometry or acute bronchodilator or airway provocation tests to detect significant asthma may not be due solely to the high intraindividual and interindividual variability in these tests. Please consider the upper airway.

There are many endurance athletes who show significant expiratory flow limitation (EFL) in heavy exercise resulting in hyperinflation of their end-expiratory lung volume2527 (Fig 2). These athletes, unlike those discussed above with EIA or VCD, have “normal” airways and normal age-predicted maximal flow-volume envelopes. However, their high peak exercise capacities demand extreme ventilations and flow rates, resulting in EFL, hyperinflation, and reduced inspiratory capacity.

Figure Jump LinkFigure 2 Spontaneous tidal flow-volume loops during progressive treadmill running exercise in young, fit adult men (left, A) [V̇O2max = 180% of predicted normal values) [adapted from Johnson et al25] and in older fit men (right, B) [V̇O2max = 185% of predicted normal values] (adapted from Johnson et al30). For both panels, the largest loop represents the maximum voluntary inspiratory and expiratory efforts determined within 2 to 3 min following the termination of the peak exercise load. The remaining loops are the average of 10 tidal breaths determined at rest (smallest loop) and at each of several increasing work loads to maximum exercise. For young adults (left, A) the V̇E of 117 L/min corresponds to the average V̇E achieved by untrained subjects at their V̇O2max (45 mL/kg/min); the 169 L/min corresponds to the average V̇E achieved by the trained subjects at their higher V̇O2max. Note that the tidal expiratory loop began to intersect with the maximal loop (ie, EFL) as V̇E exceeds about 120 L/min.Grahic Jump Location

On the one hand, hyperinflation allows further increases in expiratory flow rate and minute ventilation (V̇E). However, several additional consequences exert negative effects on exercise performance, as follows: (1) reduced dynamic lung compliance increases the elastic work of breathing and limits the hyperventilatory response to heavy-intensity exercise, contributes to arterial hypoxemia, and exacerbates dyspnea2527; (2) stroke volume and cardiac output are compromised, secondary to the afterload placed on the left ventricle by positive expiratory intrapleural pressures, which often exceed the critical closing pressure of the airway2530; (3) tidal volume plateaus at a lower V̇E and tachypnea prevails; and (4) inspiratory muscle fatigue is exacerbated because these muscles are working at a shorter than optimal length and a higher velocity of shortening, and therefore are very close to their dynamic capacity for force generation.25

These types of EFLs and hyperinflation are diagnosed noninvasively by use of the inspiratory capacity maneuver and the assessment of the tidal flow-volume loop (Fig 2, left, A). We caution that this method may overestimate EFL, primarily because thoracic gas compression during maximal expulsive maneuvers will underestimate the true capacity for flow generation.31,32 However, in health, estimates of EFL during exercise do agree closely with those provided by the proximity of the tidal expiratory esophageal pressure to the critical closing pressure of the airway.25,30

Exercise-induced EFL and its sequelae, as outlined above, are especially likely to occur in young adult female athletes and older endurance athletes.26,27 Relative to their male contemporaries, women have reduced lung volumes for their stature and narrower airway diameters for a given lung volume.33 Also, normal aging, even in nonsmokers and in highly trained individuals,26,30 causes a substantial loss of lung elastic recoil, leading to reductions in the maximum flow-volume envelope and higher proportions of dead space ventilation at rest and exercise (Fig 2, right, B). Thus, the master athlete with superior exercise capacity requires greater ventilatory responses and therefore experiences significant EFL and its sequelae.

During exercise in all healthy subjects, the P(A-a)O2 widens progressively with increasing exercise intensity. A significant portion of male and female young and older adults with high V̇O2max show an exaggeration of this inefficiency in gas exchange during progressive and sustained heavy-intensity exercise,34 especially when running.35 When this excessive P(A-a)O2 is combined with a limited hyperventilatory response along with an acid pH-induced rightward shift of the hemoglobin-O2 dissociation curve, significant arterial O2 desaturation occurs, often in the range of 85 to 90% SaO2. Even relatively mild arterial O2 desaturation (< 94% SaO2) is associated with significantly reduced V̇O2max and endurance performance, and with an enhanced rate of development of peripheral muscle fatigue.4,5

Why does P(A-a)O2 widen abnormally in many highly trained athletes during maximum exercise, and even in some during submaximal exercise? Alveolar- capillary diffusion disequilibrium has been implicated because of the high pulmonary blood flows and the increased pulmonary vascular pressures, and, therefore, the potential for interstitial pulmonary edema in the athlete.34,36 Some evidence that the alveolar-capillary barrier might be disrupted has been shown via measurements of plasma proteins in BAL fluid following maximal exercise in highly trained individuals.35,37 Rarely, even frank alveolar edema has been reported during ultra-endurance exercise under extreme environmental conditions.38 Theoretically, even a relatively small shunt of 2 to 3% of cardiac output could also become an important determinant of arterial oxygenation during exercise, because mixed venous blood returning to the lung is progressively deoxygenated as working limb muscles extract increasing amounts of oxygen. Muscle O2 extraction is only 25% of the delivered O2 at rest but rises to ≥ 90% at maximal exercise.

Two types of shunts, intracardiac or intrapulmonary, may occur during exercise. Potential intracardiac shunts from patent foramen ovale (PFO) are thought to be present in > 20 to 25% of the general population.39 However, whether these shunts are manifested during exercise will depend on the gradient of pressures developed between the right and left atrium. These pressure differences are usually negative during exercise; therefore, the higher left atrial pressure would promote closure of the flap valve against the septum secunda, thereby preventing the right-to-left venous admixture. Nevertheless, significant right-to-left intracardiac shunting has been reported during exercise in the presence of pulmonary hypertension40 and in hypoxic environments.41 To date, we are aware only of anecdotal case reports that have linked the existence of intracardiac shunts to exercise-induced hypoxemia in the athlete.

Intrapulmonary arteriovenous shunt pathways > 50 μm diameter are present under conditions of physiologic perfusion pressures in isolated human lungs.42,43 Evidence44 from the past few years has suggested that these intrapulmonary arteriovenous shunt pathways might be recruited during exercise in many healthy subjects who have no evidence of an intrapulmonary or intracardiac shunt at rest. The magnitude of the P(A-a)O2 and pulmonary arterial pressure during exercise was shown to correlate positively with the presence of these exercise-induced intrapulmonary shunts,45 but this does not prove cause and effect. Venoarterial shunts also allow for the passage of emboli that would normally be trapped by the pulmonary vasculature.46

Arteriovenous shunt pathways at rest and exercise may be sensitively detected by using echocardiography with a saline solution contrast medium, whereby sterile saline solution is agitated to create bubbles that are then injected into a peripheral vein (Fig 3). Saline solution contrast echocardiography is considered to be the most sensitive and reliable method for detecting arteriovenous shunt pathways47,48 and will distinguish intracardiac shunting from intrapulmonary shunting (Fig 3).

Figure Jump LinkFigure 3 Top, A: contrast echocardiograms at 100, 230, and 260 W exercise in one subject. At 100 W, there is no evidence of intracardiac or intrapulmonary shunting, because the left heart is free of contrast bubbles. The first evidence of intrapulmonary shunting is seen at 230 W (V̇O2max, 85%). Note the delayed appearance (more than five cycles) of contrast bubbles in the left heart. The same pattern is seen at 260 W. All images are apical four-chamber views. LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle (from Eldridge et al44). Bottom, B: contrast echocardiograms from a 28-year-old woman during exercise at 100 W (V̇O2max, 40%) showing the delayed appearance of contrast bubbles in the left heart. Each sequential image (left to right and top to bottom) is separated in time by 1 s. The first evidence of shunting is in the fifth image (arrow), which is eight cardiac cycles after contrast appears in the right atrium. If an individual has an intracardiac shunt due to a PFO, contrast bubbles appear in the left heart immediately (less than three cardiac cycles). However, if (as in this example) contrast bubbles appear in the left heart after a delay (three or more cardiac cycles), this is diagnostic of an intrapulmonary shunt (from Eldridge et al44).Grahic Jump Location

The diaphragm is certainly a very special skeletal muscle with many unique fatigue-resistant properties compared to limb muscle.49 However, during sustained heavy-intensity exercise, at > 80% of maximum in both untrained and highly trained subjects, objective measurements (ie, assessing changes in diaphragmatic force in response to supramaximal motor nerve stimulation) show a significant fatigue of both the diaphragm and the expiratory abdominal muscles.50,51 This fatigue does not compromise alveolar ventilation but will reflexively induce sympathetically mediated vasoconstrictor activity, thereby compromising blood flow to the active limb muscles.5254 In turn, blood flow and O2 transport to the working muscle are reduced, thereby exacerbating limb fatigue and compromising exercise performance.55 Given this link of respiratory muscle work to limb muscle fatigue, the common practice of contrasting the exercising subject's ratings of perceptions of dyspnea vs limb discomfort to differentiate between central (respiratory) and peripheral (limb muscle) as sources of exercise limitation may be misleading.

The hypoxic environment of high altitude has major effects on the cardiorespiratory responses to exercise, and causes decrements in exercise capacity and performance, which average about 5 to 10% per 1,000 feet of elevation. Some of the key respiratory maladaptations to exercise in hypoxic environments include the following: (1) arterial hypoxemia achieved via enhanced alveolar-capillary diffusion limitation36; (2) pulmonary hypertension and an enhanced propensity for pulmonary interstitial edema achieved via a combination of hypoxia-induced pulmonary vasoconstriction and high pulmonary blood flow37 (subjects with PFO have been reported to experience more significant arterial hypoxemia and are especially susceptible to pulmonary hypertension and edema at high altitudes, even at rest41); and (3) a greater stimulus for the hyperventilatory response to exercise in the presence of hypoxia means more EFL, increased respiratory muscle work and fatigue, and greater swings in intrathoracic pressures, all of which compromise blood flow to working muscles and intensify perceptions of dyspnea during exercise.56,57

The endurance-trained athlete's performance suffers much more than does the untrained sea-level native as a result of a sojourn to high altitudes, even at 1,000 or 2,000 feet above sea level. This increased susceptibility to hypoxia in the highly trained individual is attributable in part to the fact that many of these trained subjects are already experiencing (or very close to experiencing) respiratory system limitation while exercising at sea level.

The practice of sleeping in hypoxia while training in normoxia (ie, live high/train low) has gained great popularity as a legal alternative to the dangerous and illegal practice of blood doping. Several studies58,59 have been conducted, unfortunately, none as yet with true placebo control subjects, showing small but positive effects on sea-level performance in many athletes, but certainly not in all. Maladaptive responses to acute and chronic hypoxia (both constant and intermittent hypoxia) include pulmonary vasoconstriction, greatly augmented sympathetic vasoconstrictor activity, impaired endothelial function, and remodeled vascular smooth muscle.60 These potential long-term effects, which also persist following the cessation of the hypoxic exposure, have not yet been studied for the live high/train low paradigm. We would not predict these problems to occur in otherwise healthy subjects when the intermittent hypoxic exposures are in the range of 2,500 m altitude (resting SaO2, > 90%); however, this practice could potentially present serious problems in those athletes who choose to further enhance their RBC production by exposure to altitudes over 3,000 m, at which resting SaO2 (< 90%) resides on the steep, volatile portion of the hemoglobin-O2 disassociation curve. Periodic breathing is also common during sleep at these altitudes and, when present, will greatly exacerbate the degree of arterial hypoxemia at any given altitude.61 Given the recent tendency for athletes to sleep at these higher altitudes for their live high/train low regimen, further careful study of the long-term cardiovascular effects of intermittent hypoxia in healthy subjects is warranted.

We have outlined the ways in which the compromised function of the intrathoracic and extrathoracic airways, gas exchange, and respiratory muscles present significant limitations to exercise performance in otherwise healthy endurance-trained individuals. Airway and gas-exchange limitations occur rarely, mostly at the extremes of exercise intensity and primarily in highly trained individuals of all ages and both sexes; women and the elderly are especially vulnerable. Exercise-induced diaphragm fatigue and its cardiovascular sequelae can be elicited in all healthy subjects engaging in sufficiently intense and sustained exhaustive exercise. In these cases, the athlete most often presents with general complaints of shortness of breath, “fatigue,” and compromised performance. We suggest that at least some potential causes of these respiratory limitations can be determined when specific, mostly minimally invasive or noninvasive measurements are incorporated into exercise testing, including the tidal flow-volume loop and the use of saline solution contrast echocardiography. It is also important to employ specific airway reactivity tests to improve the diagnostic reliability for EIA,12,14 thereby avoiding the potentially harmful effects of prescribed pharmacologic treatments on the normal airway.

A limited number of respiratory system limitations are amenable to treatment with concomitant improvements in performance. For example, consider the following: (1) airway function and gas-exchange abnormalities attending EIA can be markedly improved, along with exercise performance, following several weeks of treatment with relatively low doses of inhaled corticosteroids10,62; (2) feedback therapy has been successful in treating some cases of exercise-induced vocal cord abduction63; (3) selected use of vasodilator agents administered at high altitudes are able to reduce pulmonary vascular vasoconstriction, improve arterial oxygenation, and slightly improve exercise capacity in persons with hypoxia64,65; and (4) although there are many negative published findings concerning the effect of specific respiratory muscle training on exercise performance, some carefully controlled studies66 have suggested that this type of specific training will delay the onset of exercise-induced respiratory muscle fatigue and its cardiovascular sequelae, and will elicit small but significant increases in endurance performance.

On the other hand, we caution that some of these therapeutic approaches are still highly experimental and have not yet been tested in large numbers of subjects. Also, EFL as well as many cases of exercise-induced hypoxemia are not amenable to treatment in subjects with healthy intrathoracic and extrathoracic airways. Given the evidence that athletes with respiratory system limitations would have significant difficulty in competing or training in hypoxic environments, they should be counseled on the potential limitations inherent in such practices.

EFL

expiratory flow limitation

EIA

exercise- induced asthma

P(A-a)O2

alveolar-arterial oxygen pressure difference

PFO

patent foramen ovale

SaO2

arterial oxygen saturation

VCD

vocal cord dysfunction

V̇E

minute ventilation

V̇O2max

maximum oxygen uptake

This work was supported in part by the National Heart, Lung, and Blood Institute and the American Heart Association.

Saltin B, Calbet JA. Point: in health and in a normoxic environment, VO2 max is limited primarily by cardiac output and locomotor muscle blood flow. J Appl Physiol. 2006;100:744-745. [PubMed] [CrossRef]
 
Wagner PD. Counterpoint: in health and in normoxic environment VO2max is limited primarily by cardiac output and locomotor muscle blood flow. J Appl Physiol. 2006;100:745-747. [PubMed]
 
Gandevia SC. Spinal and supraspinal factors in human muscle fatigue. Physiol Rev. 2001;81:1725-1789. [PubMed]
 
Amann M, Eldridge MW, Lovering AT, et al. Arterial oxygenation influences central motor output and exercise performance via effects on peripheral locomotor muscle fatigue in humans. J Physiol. 2006;575:937-952. [PubMed]
 
Romer LM, Haverkamp HC, Lovering AT, et al. Effect of exercise-induced arterial hypoxemia on quadriceps muscle fatigue in healthy humans. Am J Physiol Regul Integr Comp Physiol. 2006;290:R365-R375. [PubMed]
 
Olafsson S, Hyatt RE. Ventilatory mechanics and expiratory flow limitation during exercise in normal subjects. J Clin Invest. 1969;48:564-573. [PubMed]
 
Dempsey JA, J.B. Wolffe memorial lecture: is the lung built for exercise? Med Sci Sports Exerc. 1986;18:143-155. [PubMed]
 
Haverkamp HC, Dempsey JA, Miller JD, et al. Repeat exercise normalizes the gas-exchange impairment induced by a previous exercise bout in asthmatic subjects. J Appl Physiol. 2005;99:1843-1852. [PubMed]
 
Haverkamp HC, Dempsey JA, Miller JD, et al. Gas exchange during exercise in habitually active asthmatic subjects. J Appl Physiol. 2005;99:1938-1950. [PubMed]
 
Haverkamp HC, Dempsey J, Pegelow D, et al. Treatment of airway inflamation improves exercise pulmonary gas exchange and performance in asthmatic subjects. J Allergy Clin Immunol. 2007;120:39-47. [PubMed]
 
Anderson SD, Fitch K, Perry CP, et al. Responses to bronchial challenge submitted for approval to use inhaled β2-agonists before an event at the 2002 Winter Olympics. J Allergy Clin Immunol. 2003;111:45-50. [PubMed]
 
Anderson SD, Sue-Chu M, Perry CP, et al. Bronchial challenges in athletes applying to inhale a β2-agonist at the 2004 Summer Olympics. J Allergy Clin Immunol. 2006;117:767-773. [PubMed]
 
Karjalainen EM, Laitinen A, Sue-Chu M, et al. Evidence of airway inflammation and remodeling in ski athletes with and without bronchial hyperresponsiveness to methacholine. Am J Respir Crit Care Med. 2000;161:2086-2091. [PubMed]
 
Langdeau JB, Turcotte H, Bowie DM, et al. Airway hyperresponsiveness in elite athletes. Am J Respir Crit Care Med. 2000;161:1479-1484. [PubMed]
 
Holzer K, Anderson SD, Douglass J. Exercise in elite summer athletes: challenges for diagnosis. J Allergy Clin Immunol. 2002;110:374-380. [PubMed]
 
Rundell KW, Im J, Mayers LB, et al. Self-reported symptoms and exercise-induced asthma in the elite athlete. Med Sci Sports Exerc. 2001;33:208-213. [PubMed]
 
Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med. 1999;159:941-955. [PubMed]
 
Anderson SD, Kippelen P. Exercise-induced bronchoconstriction: pathogenesis. Curr Allergy Asthma Rep. 2005;5:116-122. [PubMed]
 
Evans DW, Salome CM, King GG, et al. Effect of regular inhaled salbutamol on airway responsiveness and airway inflammation in rhinitic non-asthmatic subjects. Thorax. 1997;52:136-142. [PubMed]
 
Cockcroft DW, McParland CP, Britto SA, et al. Regular inhaled salbutamol and airway responsiveness to allergen. Lancet. 1993;342:833-837. [PubMed]
 
Fallon KE. Upper airway obstruction masquerading as exercise induced bronchospasm in an elite road cyclist. Br J Sports Med. 2004;38:E9. [PubMed]
 
McFadden ER Jr, Zawadski DK. Vocal cord dysfunction masquerading as exercise-induced asthma. a physiologic cause for “choking” during athletic activities. Am J Respir Crit Care Med. 1996;153:942-947. [PubMed]
 
Haverkamp H, Miller J, Rodman J, et al. Extrathoracic obstruction and hypoxemia occurring during exercise in a competitive female cyclist. Chest. 2003;124:1602-1605. [PubMed]
 
Rundell KW, Spiering BA. Inspiratory stridor in elite athletes. Chest. 2003;123:468-474. [PubMed]
 
Johnson BD, Saupe KW, Dempsey JA. Mechanical constraints on exercise hyperpnea in endurance athletes. J Appl Physiol. 1992;73:874-886. [PubMed]
 
McClaran SR, Harms CA, Pegelow DF, et al. Smaller lungs in women affect exercise hyperpnea. J Appl Physiol. 1998;84:1872-1881. [PubMed]
 
Guenette JA, Witt JD, McKenzie DC, et al. Respiratory mechanics during exercise in endurance-trained men and women. J Physiol. 2007;581:1309-1322. [PubMed]
 
Stark-Leyva KN, Beck KC, Johnson BD. Influence of expiratory loading and hyperinflation on cardiac output during exercise. J Appl Physiol. 2004;96:1920-1927. [PubMed]
 
Miller JD, Hemauer SJ, Smith CA, et al. Expiratory threshold loading impairs cardiovascular function in health and chronic heart failure during submaximal exercise. J Appl Physiol. 2006;101:213-227. [PubMed]
 
Johnson BD, Reddan WG, Seow KC, et al. Mechanical constraints on exercise hyperpnea in a fit aging population. Am Rev Respir Dis. 1991;143:968-977. [PubMed]
 
Ingram RH Jr, Schilder DP. Effect of gas compression on pulmonary pressure, flow, and volume relationship. J Appl Physiol. 1966;21:1821-1826. [PubMed]
 
Mota S, Casan P, Drobnic F, et al. Expiratory flow limitation during exercise in competition cyclists. J Appl Physiol. 1999;86:611-616. [PubMed]
 
Martin TR, Castile RG, Fredberg JJ, et al. Airway size is related to sex but not lung size in normal adults. J Appl Physiol. 1987;63:2042-2047. [PubMed]
 
Dempsey JA, Wagner PD. Exercise-induced arterial hypoxemia. J Appl Physiol. 1999;87:1997-2006. [PubMed]
 
Hopkins SR, Schoene RB, Henderson WR, et al. Intense exercise impairs the integrity of the pulmonary blood-gas barrier in elite athletes. Am J Respir Crit Care Med. 1997;155:1090-1094. [PubMed]
 
Wagner PD, Gale GE, Moon RE, et al. Pulmonary gas exchange in humans exercising at sea level and simulated altitude. J Appl Physiol. 1986;61:260-270. [PubMed]
 
Eldridge MW, Braun RK, Yoneda KY, et al. Effects of altitude and exercise on pulmonary capillary integrity: evidence for subclinical high-altitude pulmonary edema. J Appl Physiol. 2006;100:972-980. [PubMed]
 
McKechnie JK, Leary WP, Noakes TD, et al. Acute pulmonary oedema in two athletes during a 90-km running race. S Afr Med J. 1979;56:261-265. [PubMed]
 
Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc. 1984;59:17-20. [PubMed]
 
Sun XG, Hansen JE, Oudiz RJ, et al. Gas exchange detection of exercise-induced right-to-left shunt in patients with primary pulmonary hypertension. Circulation. 2002;105:54-60. [PubMed]
 
Allemann Y, Hutter D, Lipp E, et al. Patent foramen ovale and high-altitude pulmonary edema. JAMA. 2006;296:2954-2958. [PubMed]
 
Lovering AT, Stickland MK, Kelso AJ, et al. Direct demonstration of 25- and 50-microm arteriovenous pathways in healthy human and baboon lungs. Am J Physiol Heart Circ Physiol. 2007;292:H1777-H1781. [PubMed]
 
Tobin CE. Arteriovenous shunts in the peripheral pulmonary circulation in the human lung. Thorax. 1966;21:197-204. [PubMed]
 
Eldridge MW, Dempsey JA, Haverkamp HC, et al. Exercise-induced intrapulmonary arteriovenous shunting in healthy humans. J Appl Physiol. 2004;97:797-805. [PubMed]
 
Stickland MK, Welsh RC, Haykowsky MJ, et al. Intra-pulmonary shunt and pulmonary gas exchange during exercise in humans. J Physiol. 2004;561:321-329. [PubMed]
 
Womack CJ, Nagelkirk PR, Coughlin AM. Exercise-induced changes in coagulation and fibrinolysis in healthy populations and patients with cardiovascular disease. Sports Med. 2003;33:795-807. [PubMed]
 
Barzilai B, Waggoner AD, Spessert C, et al. Two-dimensional contrast echocardiography in the detection and follow-up of congenital pulmonary arteriovenous malformations. Am J Cardiol. 1991;68:1507-1510. [PubMed]
 
Woods TD, Patel A. A critical review of patent foramen ovale detection using saline contrast echocardiography: when bubbles lie. J Am Soc Echocardiogr. 2006;19:215-222. [PubMed]
 
Aaker A, Laughlin MH. Diaphragm arterioles are less responsive to α1-adrenergic constriction than gastrocnemius arterioles. J Appl Physiol. 2002;92:1808-1816. [PubMed]
 
Taylor BJ, How SC, Romer LM. Exercise-induced abdominal muscle fatigue in healthy humans. J Appl Physiol. 2006;100:1554-1562. [PubMed]
 
Johnson BD, Babcock MA, Suman OE, et al. Exercise-induced diaphragmatic fatigue in healthy humans. J Physiol. 1993;460:385-405. [PubMed]
 
Harms CA, Babcock MA, McClaran SR, et al. Respiratory muscle work compromises leg blood flow during maximal exercise. J Appl Physiol. 1997;82:1573-1583. [PubMed]
 
Hill JM. Discharge of group IV phrenic afferent fibers increases during diaphragmatic fatigue. Brain Res. 2000;856:240-244. [PubMed]
 
St. Croix CM, Morgan BJ, Wetter TJ, et al. Fatiguing inspiratory muscle work causes reflex sympathetic activation in humans. J Physiol. 2000;529:493-504. [PubMed]
 
Harms CA, Wetter TJ, St. Croix CM, et al. Effects of respiratory muscle work on exercise performance. J Appl Physiol. 2000;89:131-138. [PubMed]
 
Thoden JS, Dempsey JA, Reddan WG, et al. Ventilatory work during steady-state response to exercise. Fed Proc. 1969;28:1316-1321. [PubMed]
 
Amann M, Pegelow DF, Jacques AJ, et al. Inspiratory muscle work in acute hypoxia influences locomotor muscle fatigue and exercise performance of healthy humans. Am J Physiol Regul Integr Comp Physiol. 2007;293:R2036-R2045. [PubMed]
 
Levine BD, Stray-Gundersen J. Point: positive effects of intermittent hypoxia (live high:train low) on exercise performance are mediated primarily by augmented red cell volume. J Appl Physiol. 2005;99:2053-2055. [PubMed]
 
Gore CJ, Hopkins WG. Counterpoint: positive effects of intermittent hypoxia (live high:train low) on exercise performance are not mediated primarily by augmented red cell volume. J Appl Physiol. 2005;99:2055-2057. [PubMed]
 
Hansen J, Sander M. Sympathetic neural overactivity in healthy humans after prolonged exposure to hypobaric hypoxia. J Physiol. 2003;546:921-929. [PubMed]
 
Berssenbrugge A, Dempsey J, Iber C, et al. Mechanisms of hypoxia-induced periodic breathing during sleep in humans. J Physiol. 1983;343:507-526. [PubMed]
 
Djukanovic R, Wilson JW, Britten KM, et al. Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am Rev Respir Dis. 1992;145:669-674. [PubMed]
 
Wilson JJ, Wilson EM. Practical management: vocal cord dysfunction in athletes. Clin J Sport Med. 2006;16:357-360. [PubMed]
 
Faoro V, Lamotte M, Deboeck G, et al. Effects of sildenafil on exercise capacity in hypoxic normal subjects. High Alt Med Biol. 2007;8:155-163. [PubMed]
 
Richalet JP, Gratadour P, Robach P, et al. Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. Am J Respir Crit Care Med. 2005;171:275-281. [PubMed]
 
McConnell AK, Lomax M. The influence of inspiratory muscle work history and specific inspiratory muscle training upon human limb muscle fatigue. J Physiol. 2006;577:445-457. [PubMed]
 

Figures

Figure Jump LinkFigure 1 Top, A: tidal flow-volume loops (FVLs) obtained during exercise at 50%, 75%, and 90% of peak oxygen uptake (V̇O2peak) [left], and during maximal exercise before and after the development of an extrathoracic obstruction (right). FVLs were created by taking the average of 10 tidal breaths. Note the significant drop in both inspiratory and expiratory flows during maximal exercise after the appearance of symptoms, and the sawtooth pattern in the inspiratory flows even at submaximal exercise prior to the development of symptoms (from Haverkamp et al23). Bottom, B: breath-by-breath analysis of V̇E, peak inspiratory tidal flow (Insp flow) and expiratory tidal flow (Exp flow), and partial pressures of end-tidal O2 (PetO2) and CO2 (PetCO2) during the entire period of exercise at the maximal workload in a 22-year-old competitive female cyclist. Breath 1 represents the first breath of the maximal workload, and breath 43 represents the final breath of the workload. The vertical line indicates the breath at which dyspnea symptoms suddenly appeared. The subject was able to exercise for a total of 75 s, even though the flow limitation appeared at 37 s into the workload. At the onset of symptoms, note the abrupt marked reduction in flow rates, and the subsequent CO2 retention and arterial hypoxemia. Maximum flow rates returned to normal within 5 min of terminating exercise. Adapted from Haverkamp et al.23Grahic Jump Location
Figure Jump LinkFigure 2 Spontaneous tidal flow-volume loops during progressive treadmill running exercise in young, fit adult men (left, A) [V̇O2max = 180% of predicted normal values) [adapted from Johnson et al25] and in older fit men (right, B) [V̇O2max = 185% of predicted normal values] (adapted from Johnson et al30). For both panels, the largest loop represents the maximum voluntary inspiratory and expiratory efforts determined within 2 to 3 min following the termination of the peak exercise load. The remaining loops are the average of 10 tidal breaths determined at rest (smallest loop) and at each of several increasing work loads to maximum exercise. For young adults (left, A) the V̇E of 117 L/min corresponds to the average V̇E achieved by untrained subjects at their V̇O2max (45 mL/kg/min); the 169 L/min corresponds to the average V̇E achieved by the trained subjects at their higher V̇O2max. Note that the tidal expiratory loop began to intersect with the maximal loop (ie, EFL) as V̇E exceeds about 120 L/min.Grahic Jump Location
Figure Jump LinkFigure 3 Top, A: contrast echocardiograms at 100, 230, and 260 W exercise in one subject. At 100 W, there is no evidence of intracardiac or intrapulmonary shunting, because the left heart is free of contrast bubbles. The first evidence of intrapulmonary shunting is seen at 230 W (V̇O2max, 85%). Note the delayed appearance (more than five cycles) of contrast bubbles in the left heart. The same pattern is seen at 260 W. All images are apical four-chamber views. LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle (from Eldridge et al44). Bottom, B: contrast echocardiograms from a 28-year-old woman during exercise at 100 W (V̇O2max, 40%) showing the delayed appearance of contrast bubbles in the left heart. Each sequential image (left to right and top to bottom) is separated in time by 1 s. The first evidence of shunting is in the fifth image (arrow), which is eight cardiac cycles after contrast appears in the right atrium. If an individual has an intracardiac shunt due to a PFO, contrast bubbles appear in the left heart immediately (less than three cardiac cycles). However, if (as in this example) contrast bubbles appear in the left heart after a delay (three or more cardiac cycles), this is diagnostic of an intrapulmonary shunt (from Eldridge et al44).Grahic Jump Location

Tables

References

Saltin B, Calbet JA. Point: in health and in a normoxic environment, VO2 max is limited primarily by cardiac output and locomotor muscle blood flow. J Appl Physiol. 2006;100:744-745. [PubMed] [CrossRef]
 
Wagner PD. Counterpoint: in health and in normoxic environment VO2max is limited primarily by cardiac output and locomotor muscle blood flow. J Appl Physiol. 2006;100:745-747. [PubMed]
 
Gandevia SC. Spinal and supraspinal factors in human muscle fatigue. Physiol Rev. 2001;81:1725-1789. [PubMed]
 
Amann M, Eldridge MW, Lovering AT, et al. Arterial oxygenation influences central motor output and exercise performance via effects on peripheral locomotor muscle fatigue in humans. J Physiol. 2006;575:937-952. [PubMed]
 
Romer LM, Haverkamp HC, Lovering AT, et al. Effect of exercise-induced arterial hypoxemia on quadriceps muscle fatigue in healthy humans. Am J Physiol Regul Integr Comp Physiol. 2006;290:R365-R375. [PubMed]
 
Olafsson S, Hyatt RE. Ventilatory mechanics and expiratory flow limitation during exercise in normal subjects. J Clin Invest. 1969;48:564-573. [PubMed]
 
Dempsey JA, J.B. Wolffe memorial lecture: is the lung built for exercise? Med Sci Sports Exerc. 1986;18:143-155. [PubMed]
 
Haverkamp HC, Dempsey JA, Miller JD, et al. Repeat exercise normalizes the gas-exchange impairment induced by a previous exercise bout in asthmatic subjects. J Appl Physiol. 2005;99:1843-1852. [PubMed]
 
Haverkamp HC, Dempsey JA, Miller JD, et al. Gas exchange during exercise in habitually active asthmatic subjects. J Appl Physiol. 2005;99:1938-1950. [PubMed]
 
Haverkamp HC, Dempsey J, Pegelow D, et al. Treatment of airway inflamation improves exercise pulmonary gas exchange and performance in asthmatic subjects. J Allergy Clin Immunol. 2007;120:39-47. [PubMed]
 
Anderson SD, Fitch K, Perry CP, et al. Responses to bronchial challenge submitted for approval to use inhaled β2-agonists before an event at the 2002 Winter Olympics. J Allergy Clin Immunol. 2003;111:45-50. [PubMed]
 
Anderson SD, Sue-Chu M, Perry CP, et al. Bronchial challenges in athletes applying to inhale a β2-agonist at the 2004 Summer Olympics. J Allergy Clin Immunol. 2006;117:767-773. [PubMed]
 
Karjalainen EM, Laitinen A, Sue-Chu M, et al. Evidence of airway inflammation and remodeling in ski athletes with and without bronchial hyperresponsiveness to methacholine. Am J Respir Crit Care Med. 2000;161:2086-2091. [PubMed]
 
Langdeau JB, Turcotte H, Bowie DM, et al. Airway hyperresponsiveness in elite athletes. Am J Respir Crit Care Med. 2000;161:1479-1484. [PubMed]
 
Holzer K, Anderson SD, Douglass J. Exercise in elite summer athletes: challenges for diagnosis. J Allergy Clin Immunol. 2002;110:374-380. [PubMed]
 
Rundell KW, Im J, Mayers LB, et al. Self-reported symptoms and exercise-induced asthma in the elite athlete. Med Sci Sports Exerc. 2001;33:208-213. [PubMed]
 
Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med. 1999;159:941-955. [PubMed]
 
Anderson SD, Kippelen P. Exercise-induced bronchoconstriction: pathogenesis. Curr Allergy Asthma Rep. 2005;5:116-122. [PubMed]
 
Evans DW, Salome CM, King GG, et al. Effect of regular inhaled salbutamol on airway responsiveness and airway inflammation in rhinitic non-asthmatic subjects. Thorax. 1997;52:136-142. [PubMed]
 
Cockcroft DW, McParland CP, Britto SA, et al. Regular inhaled salbutamol and airway responsiveness to allergen. Lancet. 1993;342:833-837. [PubMed]
 
Fallon KE. Upper airway obstruction masquerading as exercise induced bronchospasm in an elite road cyclist. Br J Sports Med. 2004;38:E9. [PubMed]
 
McFadden ER Jr, Zawadski DK. Vocal cord dysfunction masquerading as exercise-induced asthma. a physiologic cause for “choking” during athletic activities. Am J Respir Crit Care Med. 1996;153:942-947. [PubMed]
 
Haverkamp H, Miller J, Rodman J, et al. Extrathoracic obstruction and hypoxemia occurring during exercise in a competitive female cyclist. Chest. 2003;124:1602-1605. [PubMed]
 
Rundell KW, Spiering BA. Inspiratory stridor in elite athletes. Chest. 2003;123:468-474. [PubMed]
 
Johnson BD, Saupe KW, Dempsey JA. Mechanical constraints on exercise hyperpnea in endurance athletes. J Appl Physiol. 1992;73:874-886. [PubMed]
 
McClaran SR, Harms CA, Pegelow DF, et al. Smaller lungs in women affect exercise hyperpnea. J Appl Physiol. 1998;84:1872-1881. [PubMed]
 
Guenette JA, Witt JD, McKenzie DC, et al. Respiratory mechanics during exercise in endurance-trained men and women. J Physiol. 2007;581:1309-1322. [PubMed]
 
Stark-Leyva KN, Beck KC, Johnson BD. Influence of expiratory loading and hyperinflation on cardiac output during exercise. J Appl Physiol. 2004;96:1920-1927. [PubMed]
 
Miller JD, Hemauer SJ, Smith CA, et al. Expiratory threshold loading impairs cardiovascular function in health and chronic heart failure during submaximal exercise. J Appl Physiol. 2006;101:213-227. [PubMed]
 
Johnson BD, Reddan WG, Seow KC, et al. Mechanical constraints on exercise hyperpnea in a fit aging population. Am Rev Respir Dis. 1991;143:968-977. [PubMed]
 
Ingram RH Jr, Schilder DP. Effect of gas compression on pulmonary pressure, flow, and volume relationship. J Appl Physiol. 1966;21:1821-1826. [PubMed]
 
Mota S, Casan P, Drobnic F, et al. Expiratory flow limitation during exercise in competition cyclists. J Appl Physiol. 1999;86:611-616. [PubMed]
 
Martin TR, Castile RG, Fredberg JJ, et al. Airway size is related to sex but not lung size in normal adults. J Appl Physiol. 1987;63:2042-2047. [PubMed]
 
Dempsey JA, Wagner PD. Exercise-induced arterial hypoxemia. J Appl Physiol. 1999;87:1997-2006. [PubMed]
 
Hopkins SR, Schoene RB, Henderson WR, et al. Intense exercise impairs the integrity of the pulmonary blood-gas barrier in elite athletes. Am J Respir Crit Care Med. 1997;155:1090-1094. [PubMed]
 
Wagner PD, Gale GE, Moon RE, et al. Pulmonary gas exchange in humans exercising at sea level and simulated altitude. J Appl Physiol. 1986;61:260-270. [PubMed]
 
Eldridge MW, Braun RK, Yoneda KY, et al. Effects of altitude and exercise on pulmonary capillary integrity: evidence for subclinical high-altitude pulmonary edema. J Appl Physiol. 2006;100:972-980. [PubMed]
 
McKechnie JK, Leary WP, Noakes TD, et al. Acute pulmonary oedema in two athletes during a 90-km running race. S Afr Med J. 1979;56:261-265. [PubMed]
 
Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc. 1984;59:17-20. [PubMed]
 
Sun XG, Hansen JE, Oudiz RJ, et al. Gas exchange detection of exercise-induced right-to-left shunt in patients with primary pulmonary hypertension. Circulation. 2002;105:54-60. [PubMed]
 
Allemann Y, Hutter D, Lipp E, et al. Patent foramen ovale and high-altitude pulmonary edema. JAMA. 2006;296:2954-2958. [PubMed]
 
Lovering AT, Stickland MK, Kelso AJ, et al. Direct demonstration of 25- and 50-microm arteriovenous pathways in healthy human and baboon lungs. Am J Physiol Heart Circ Physiol. 2007;292:H1777-H1781. [PubMed]
 
Tobin CE. Arteriovenous shunts in the peripheral pulmonary circulation in the human lung. Thorax. 1966;21:197-204. [PubMed]
 
Eldridge MW, Dempsey JA, Haverkamp HC, et al. Exercise-induced intrapulmonary arteriovenous shunting in healthy humans. J Appl Physiol. 2004;97:797-805. [PubMed]
 
Stickland MK, Welsh RC, Haykowsky MJ, et al. Intra-pulmonary shunt and pulmonary gas exchange during exercise in humans. J Physiol. 2004;561:321-329. [PubMed]
 
Womack CJ, Nagelkirk PR, Coughlin AM. Exercise-induced changes in coagulation and fibrinolysis in healthy populations and patients with cardiovascular disease. Sports Med. 2003;33:795-807. [PubMed]
 
Barzilai B, Waggoner AD, Spessert C, et al. Two-dimensional contrast echocardiography in the detection and follow-up of congenital pulmonary arteriovenous malformations. Am J Cardiol. 1991;68:1507-1510. [PubMed]
 
Woods TD, Patel A. A critical review of patent foramen ovale detection using saline contrast echocardiography: when bubbles lie. J Am Soc Echocardiogr. 2006;19:215-222. [PubMed]
 
Aaker A, Laughlin MH. Diaphragm arterioles are less responsive to α1-adrenergic constriction than gastrocnemius arterioles. J Appl Physiol. 2002;92:1808-1816. [PubMed]
 
Taylor BJ, How SC, Romer LM. Exercise-induced abdominal muscle fatigue in healthy humans. J Appl Physiol. 2006;100:1554-1562. [PubMed]
 
Johnson BD, Babcock MA, Suman OE, et al. Exercise-induced diaphragmatic fatigue in healthy humans. J Physiol. 1993;460:385-405. [PubMed]
 
Harms CA, Babcock MA, McClaran SR, et al. Respiratory muscle work compromises leg blood flow during maximal exercise. J Appl Physiol. 1997;82:1573-1583. [PubMed]
 
Hill JM. Discharge of group IV phrenic afferent fibers increases during diaphragmatic fatigue. Brain Res. 2000;856:240-244. [PubMed]
 
St. Croix CM, Morgan BJ, Wetter TJ, et al. Fatiguing inspiratory muscle work causes reflex sympathetic activation in humans. J Physiol. 2000;529:493-504. [PubMed]
 
Harms CA, Wetter TJ, St. Croix CM, et al. Effects of respiratory muscle work on exercise performance. J Appl Physiol. 2000;89:131-138. [PubMed]
 
Thoden JS, Dempsey JA, Reddan WG, et al. Ventilatory work during steady-state response to exercise. Fed Proc. 1969;28:1316-1321. [PubMed]
 
Amann M, Pegelow DF, Jacques AJ, et al. Inspiratory muscle work in acute hypoxia influences locomotor muscle fatigue and exercise performance of healthy humans. Am J Physiol Regul Integr Comp Physiol. 2007;293:R2036-R2045. [PubMed]
 
Levine BD, Stray-Gundersen J. Point: positive effects of intermittent hypoxia (live high:train low) on exercise performance are mediated primarily by augmented red cell volume. J Appl Physiol. 2005;99:2053-2055. [PubMed]
 
Gore CJ, Hopkins WG. Counterpoint: positive effects of intermittent hypoxia (live high:train low) on exercise performance are not mediated primarily by augmented red cell volume. J Appl Physiol. 2005;99:2055-2057. [PubMed]
 
Hansen J, Sander M. Sympathetic neural overactivity in healthy humans after prolonged exposure to hypobaric hypoxia. J Physiol. 2003;546:921-929. [PubMed]
 
Berssenbrugge A, Dempsey J, Iber C, et al. Mechanisms of hypoxia-induced periodic breathing during sleep in humans. J Physiol. 1983;343:507-526. [PubMed]
 
Djukanovic R, Wilson JW, Britten KM, et al. Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am Rev Respir Dis. 1992;145:669-674. [PubMed]
 
Wilson JJ, Wilson EM. Practical management: vocal cord dysfunction in athletes. Clin J Sport Med. 2006;16:357-360. [PubMed]
 
Faoro V, Lamotte M, Deboeck G, et al. Effects of sildenafil on exercise capacity in hypoxic normal subjects. High Alt Med Biol. 2007;8:155-163. [PubMed]
 
Richalet JP, Gratadour P, Robach P, et al. Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. Am J Respir Crit Care Med. 2005;171:275-281. [PubMed]
 
McConnell AK, Lomax M. The influence of inspiratory muscle work history and specific inspiratory muscle training upon human limb muscle fatigue. J Physiol. 2006;577:445-457. [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
Guidelines
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543