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J Appl Physiol 103: 111-118, 2007. First published April 5, 2007; doi:10.1152/japplphysiol.01087.2006
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Human lung density is not altered following normoxic and hypoxic moderate-intensity exercise: implications for transient edema

Alastair N. H. Hodges,1,2 A. William Sheel,2 John R. Mayo,3 and Donald C. McKenzie1,2,3

1Allan McGavin Sports Medicine Centre, 2School of Human Kinetics, and 3Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

Submitted 26 September 2006 ; accepted in final form 3 April 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The purpose of this study was to examine the effects of exercise on extravascular lung water as it may relate to pulmonary gas exchange. Ten male humans underwent measures of maximal oxygen uptake (VO2 max) in two conditions: normoxia (N) and normobaric hypoxia of 15% O2 (H). Lung density was measured by quantified MRI before and 48.0 ± 7.4 and 100.7 ± 15.1 min following 60 min of cycling exercise in N (intensity = 61.6 ± 9.5% VO2 max) and 55.5 ± 9.8 and 104.3 ± 9.1 min following 60 min cycling exercise in H (intensity = 65.4 ± 7.1% hypoxic VO2 max), where VO2 max = 65.0 ± 7.5 ml·kg–1·min–1 (N) and 54.1 ± 7.0 ml·kg–1·min–1 (H). Two subjects demonstrated mild exercise-induced arterial hypoxemia (EIAH) [minimum arterial oxygen saturation (SaO2 min) = 94.5% and 93.8%], and seven subjects demonstrated moderate EIAH (SaO2 min = 91.4 ± 1.1%) as measured noninvasively during the VO2 max test in N. Mean lung densities, measured once preexercise and twice postexercise, were 0.177 ± 0.019, 0.181 ± 0.019, and 0.173 ± 0.019 g/ml (N) and 0.178 ± 0.021, 0.174 ± 0.022, and 0.176 ± 0.019 g/ml (H), respectively. No significant differences (P > 0.05) were found in lung density following exercise in either condition or between conditions. Transient interstitial pulmonary edema did not occur following sustained steady-state cycling exercise in N or H, indicating that transient edema does not result from pulmonary capillary leakage during sustained submaximal exercise.

pulmonary edema; magnetic resonance imaging; respiration

DURING INTENSE continuous exercise in humans, oxygen consumption (VO2) may increase 20-fold or more from rest, placing large demands on the pulmonary system to maintain arterial PO2 (PaO2) and arterial PCO2 within normal values. Typically, in humans, PaO2 is effectively maintained near resting values of ~100 Torr at sea level during exercise by a pulmonary system that meets this increase in metabolic demand. However, exercise-induced arterial hypoxemia (EIAH) has been observed in aerobically trained athletes almost half a century ago (20) and well described over the past 15 years. There is individual variation in the severity of EIAH, and although it is often considered to be a phenomenon that occurs near maximal work load in trained athletes, EIAH has also been demonstrated during moderate work (35) and in untrained individuals. Proposed mechanisms include ventilation/perfusion (VA/Qc) inequality, relative alveolar hypoventilation, right-to-left shunts, and diffusion limitation (9). Relative hypoventilation in some individuals results in relatively decreased alveolar PO2 (8, 42). Although breathing 100% O2 during exercise has been shown to eradicate EIAH (8), there is recent evidence of right-to-left shunting of blood during exercise (12).

During exercise there is an increased alveolar-to-arterial difference in partial pressure of O2 (A-aDO2), typically caused by VA/Qc inequality, right-to-left shunting of blood, or diffusion limitation (9). VA/Qc mismatch may be responsible for 50% of the A-aDO2 at rest (34) and increases with exercise intensity (43) to explain 60% of the A-aDO2 during moderate to severe exercise (17, 23). It is speculated that pulmonary diffusion limitation has an increased contribution to A-aDO2 near maximal exercise (34); however, the mechanism of increase in VA/Qc mismatch with exercise remains unclear. In their review of EIAH, Dempsey and Wagner (9) have outlined several possible mechanisms for an increased VA/Qc mismatch during exercise, including minor structural differences in airways and blood vessels, bronchoconstriction, airway secretions, variations in the modulation of airway and vascular tone, and mild interstitial edema. A limitation in the diffusion of oxygen from the alveoli to the red blood cell could contribute to EIAH and could occur primarily in one of two ways: inadequate red blood cell transit time in the pulmonary capillaries (21) or an increase in the thickness of the alveolar pulmonary capillary membrane. Hopkins and colleagues have found the integrity of the pulmonary blood-gas barrier is impaired during intense (24) but not during sustained submaximal (25) exercise. This is consistent with the pulmonary capillary stress failure theory discussed below, which may lead to diffusion limitation during exercise. It appears that alveolar epithelial integrity is maintained during exercise, suggesting that any compromise of the alveolar-pulmonary capillary membrane occurs on the endothelial side (10).

Excluding blood, the lung is ~80% water by weight. Between 30% and 50% of this water is extracellular, consisting of interstitial fluid and lymph (37). Interstitial pulmonary edema, measured as extravascular lung water (EVLW) and caused by an increase in the filtration of fluid from the pulmonary capillaries into the interstitial space between the alveolar epithelium and capillary endothelium, may interfere with gas exchange across the alveolar-capillary membrane. Pulmonary edema may occur through changes in the Starling (39) forces (pulmonary capillary leakage) and/or changes in the structure of the capillary membrane (pulmonary capillary stress failure) (2). Both of these mechanisms may be associated with an increase in mean pulmonary artery pressure (PAP), which in humans at rest is typically 15 mmHg (16) (systolic = 25 mmHg, diastolic = 8 mmHg) and rises with exercise to near-maximal exercise values of 33 mmHg. Hypoxic exposure also raises mean PAP, with resting and near-maximal exercise values reaching 34 and 54 mmHg, respectively, at an atmospheric pressure of 282 mmHg (16). Transient interstitial edema during exercise could partly explain the widened A-aDO2 observed during exercise in subjects demonstrating EIAH. Whether transient pulmonary edema occurs or not has been the subject of a number of studies and a recent review (19) but remains unresolved. Evidence of pulmonary edema following heavy exercise has been observed microscopically in swine following treadmill running for 6–7 min (36). In humans, evidence of pulmonary edema (bilateral pulmonary consolidation, upper lobe venous congestion, and cardiomegaly) was observed three decades ago in two subjects following an ultramarathon race (32). Similarly, during an ultraendurance race at an altitude of 2,300 m, a male cyclist showed signs of pulmonary edema [severe dyspnea, cyanosis, diaphoresis, hypertension, chest crackles, radiographic opacities, and arterial oxygen saturation (SaO2), measured by pulse oximetry, of 42–48%] (27). Assessment of pulmonary edema with modern imaging techniques, including radiography, computerized tomography (CT), and MRI, has led several authors to conclude that transient pulmonary edema was present in subjects following exercise (3, 7, 33, 44), one of which, however, indicates that pulmonary gas exchange was not compromised as a result (45). However, a significant number of studies have found no evidence of transient pulmonary edema following exercise (15, 28–30, 41).

Acute hypoxic exposure generally leads to an increase in extravascular lung water and may lead to the development of high-altitude pulmonary edema (HAPE). There are many intricately connected mechanisms involved in the development of HAPE, some of which may be a factor in the development of edema during exercise in hypoxia, justifying the inclusion of a hypoxic condition in this study. According to Bartsch (4), these include pulmonary vasoconstriction, increased endothelin release, decreased nitric oxide (NO) synthesis, structural damage, increased pulmonary capillary permeability, and changes in alveolar fluid clearance. In general, a high pulmonary pressure is associated with the development of HAPE (4). Pulmonary pressure is increased above resting values during exercise in normoxia, and in combination with hypoxia the effect may be accentuated.

The first step to understanding the role of transient pulmonary edema as a mechanism for diffusion limitation leading to EIAH in highly trained athletes is to establish the occurrence of and to quantify edema in the human lung during exercise. Direct measure of lung density is not possible in humans, and precise indirect measures are generally only practical or valid following rather than during exercise. Therefore, the purpose of this study was to measure in vivo lung density by quantified MRI and to describe transient pulmonary edema, through this measure, following sustained submaximal exercise in healthy athletic humans while breathing normoxic and hypoxic air. MRI may be used to provide a precise and useful measure of proton density in the lung. We refer the reader to a recent review of MRI and lung physiology in which Hopkins and colleagues (22) outline the method and benefits and limitations of a multiecho sequence to examine proton density in the lung in relation to estimation of lung water as used in this study.

We hypothesized that following sustained exercise in normoxia, mean lung density would increase over baseline values, that a greater magnitude of increase would occur in the hypoxic condition, that lung density would be diminished with time postexercise, indicating some resolution of edema, and that changes in lung density would be correlated with EIAH as observed during maximal exercise in normoxia.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects.   Ten males (age = 25.9 ± 4.7 yr, height = 184.1 ± 8.2 cm, mass = 79.4 ± 9.5 kg) participated in this study. Informed written consent was obtained from each subject, and all experimentation conformed to the standards set by the Declaration of Helsinki. The University of British Columbia Committee on Human Experimentation and the Vancouver Coastal Health Authority approved this study. Subjects reported for testing on four separate days. The first two involved maximal cycling [maximal O2 uptake (VO2 max)] tests under normoxic and hypoxic conditions in a randomized order, and a pulmonary function screening to assess forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and peak expiratory flow rate (PEFR). The second 2 days involved assessment of lung density by MRI before and following an exercise intervention in normoxia and hypoxia in a randomized order. There was a minimum of 48 h between the VO2 max test and the subsequent exercise intervention. The hypoxic condition was included in an attempt to allow observation of a graded response with an expected increase in PAP. Before this study, nine male subjects performed VO2 max tests under three conditions of hypoxia [fraction of inspired oxygen (FIO2) = 18, 15, and 12%] in our laboratory, and it was observed that all nine subjects were able to complete moderate- to high-intensity exercise at 15% O2 but not during the more severe hypoxic condition. Therefore, 15% O2 was chosen in an attempt to alter PAP while maintaining exercise capacity.

Exercise testing.   Subjects avoided exercise, alcohol, and caffeine for 24 h before each testing session. The VO2 max tests were performed on an electronically braked cycle ergometer (Quinton Excalibur, Lode, Groningen, Netherlands) starting at 0 W and increasing at a rate of 30 W/min until the subject experienced volitional fatigue and could not maintain a constant pedaling rate. Expired gases were collected and analyzed, and ventilation was measured (True One, Parvomedics, Sandy, UT) and averaged every 15 s. Heart rate was measured by telemetry (Polar Vantage XL, Kemple, Finland) and averaged every 15 s, and SaO2 was measured using an earlobe pulse oximeter (Biox 3740, Ohmeda, Madison, WI), and averaged every 15 s. During all exercise testing in this study, SaO2 was monitored by a second finger-tip oximeter (Nonin 8500, Nonin Medical Inc., Plymouth, MN) to ensure that inadequate earlobe perfusion was not an issue in assessment of SaO2; all reported data is from the ear oximeter. VO2 max was calculated as the average of the four highest consecutive readings. In the hypoxic condition, following delivery from a tank, the inspired gas was humidified and subjects breathed through a two-way valve (Hans Rudolph, Kansas City, MO). Due to limited flow through the tank regulator, a Douglas Bag was used to store the humidified air before delivery to the subject to allow adequate ventilation during high-intensity exercise. In this condition exercise was terminated if SaO2 fell below 70%. This occurred during testing of one subject (subject 8) for whom the hypoxic VO2 max test was terminated at 11.5 min. This subject was able to complete the sustained hypoxic exercise intervention and was therefore not excluded from the study.

Approximately 1 h (62.3 ± 9.6 min for normoxic condition; 62.0 ± 7.5 min for hypoxic condition) following the completion of the baseline MR scan, subjects began the exercise intervention. This consisted of 60 min of cycling exercise while breathing either normal room air or hypoxic gas. The cycling was performed on the same ergometer and with the same metabolic equipment and gas delivery system as the previous VO2 max tests. Initial workloads were set at between 55 and 60% of peak power achieved in the VO2 max tests. Subjects had control of the workload on the cycling ergometer and were instructed to perform as much work as possible in 60 min. The rationale for this exercise intensity was to create the conditions in which pulmonary capillary leakage might occur, while avoiding very high-intensity workloads associated with sprinting, which would be more likely to induce pulmonary capillary stress failure. Workload intensities were monitored throughout the exercise, and feedback was given to the subjects in an attempt to maximize work accomplished. Approximately 50 min (48.0 ± 7.4 min, normoxic condition; 55.5 ± 9.8 min, hypoxic condition) and 100 min (100.7 ± 15.1 min, normoxic condition; 104.3 ± 9.1 min, hypoxic condition) following the exercise intervention, subjects underwent identical MR scans as before exercise.

Subjects were weighed before the first and second MR scans and immediately before and following the exercise interventions in each condition. Following exercise and before the first postexercise MRI scan, subjects were required to drink the volume of water corresponding to the mass loss during the exercise intervention. Heart rates (HR) were recorded at the initiation of each MR scan. The time delay between the preexercise scan and the two postexercise scans was controlled and recorded.

MRI.   Subjects were imaged with the body coil on a 1.5-T General Electric Horizon Echospeed MR scanner (General Electric Medical Systems, Milwaukee, WI, 5.7 software release) while lying supine during normal tidal volume breathing as described previously (33). In this study an eight-echo pulse sequence was used with the General Electric Medical Systems 5.7 software release. The images were obtained using a 320-mm field of view and 256 x 128-mm matrix.

Output was eight images of each sagittal section, which were transferred to Matlab software (MathWorks, Milwaukee, WI). After extrapolation to echo time (TE) = 0, a water content map was generated on a Linux workstation using multiexponential spin-spin time (T2) analysis as described previously (13, 14). Each scan was then analyzed for density compared with the known density of one of the water phantoms. The same water phantom was used for all analyses. A region of interest (ROI) was drawn manually on the water phantom. The phantom pixel intensity was calibrated to the known density of the phantom, and an ROI of the sagittal section of the right lung was drawn manually including as much lung tissue as possible, while definitively excluding any nonlung tissues at the margin of the lung to avoid partial voluming. Pixel thickness, height, and width were 10.0, 1.0, and 1.0 mm, respectively, providing a slice thickness of 10.0 mm.

To account for vascular components of the lung, all pixels above a set density threshold were removed during the calculation of lung density. Mean lung slice density values were calculated and recorded at density thresholds of 0.25, 0.30, 0.35, 0.4, 0.45, and 1.0 g/ml. This technique has been used previously (33) in which pixels above a density of 0.30 g/ml were excluded; however, in this study data were calculated on a range of threshold densities for comparison. For each scan, the area removed was compared visually with areas of high density to verify the total area removed. It was observed that a threshold of 0.30 g/ml corresponded to the removal of major blood vessels while avoiding the removal of other tissues. Further, it was noted that for each threshold value, the lung density for each segment of lung on an anterior-posterior scale did not exceed 0.30 g/ml. For these reasons, the data obtained with a threshold value of 0.30 g/ml was used for analyses. Ultimately the measurements were performed at the wide variety of threshold densities to ensure that increased extravascular water following exercise was not missed as a result of discarding certain densities of tissues, and it can be stated with confidence that this objective was met.

To assess lung density gradient, lung density was measured at three regions anterior to posterior: the anterior 5 cm, the middle 5 cm, and the posterior 5 cm of each lung image. For each image, an equation of the lung density gradient was calculated from these three values by regression. The slope of this equation represented the density gradient for the particular image, and was expressed as milligrams per milliliter per centimeter.

All analyses described above were performed in an identical manner by the same observer. For intraobserver reliability purposes, 20 of the images were analyzed twice, and a correlation was calculated between the mean slice densities of each group of analyses. Twenty images were analyzed by a second observer, and interobserver reliability between two observers was calculated in an identical manner on these 20 scans.

Statistical analyses.   Repeated-measures ANOVA was used to examine the differences between the following variables during maximal exercise and during sustained exercise in each condition: VO2 max, power, SaO2, HR, and VE. A repeated-measures two x three ANOVA was used to analyze the density data between the pre- and the two postmeasures and between normoxia and hypoxia. An ANOVA with Tukey's honestly significant difference post hoc test was performed on the data of HR and mass at the initiation of the MR scans and on the time delay between scans. Paired one-tailed t-tests were performed on the data of mass loss during exercise for each of the two conditions.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
All subjects had normal resting pulmonary function: FVC = 5.9 ± 1.2 liters (100.9 ± 15.4% predicted), FEV1/FVC = 82.7 ± 2.6%, and PEFR = 11.0 ± 1.0 l/s.

Exercise.   In the hypoxic condition, VO2 max, peak power, and minimum SaO2 (SaO2 min) during maximal exercise were significantly lower than in the normoxic condition (Table 1). Two subjects demonstrated mild EIAH (SaO2 min = 94.5% and 93.8%) and seven demonstrated moderate EIAH (SaO2 min = 91.4 ± 1.1%), as defined by Dempsey and Wagner (9), during the normoxic VO2 max test. During the exercise intervention, subjects cycled at 61.6 ± 9.5 and 65.4 ± 7.1% VO2 max (56.6 ± 4.1% and 57.2 ± 6.9% peak power) in the normoxic and hypoxic conditions, respectively. In the hypoxic condition, mean VO2, SaO2, and power output during the sustained exercise were significantly lower than in the normoxic condition (Table 2).


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  		Table 1. Maximal exercise data

 

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  		Table 2. Exercise intervention data averaged over the last 50 min (initial 10 min of exercise do not represent steady-state exercise)

 
Lung density.   There were no significant differences in lung density between conditions [F(1,54) = 0.13; P = 0.72] or scan times [F(2,54) = 0.23; P = 0.80], nor was there an interaction effect between condition and scan time [F(2,54) = 0.37; P = 0.70 (see Table 3)]. Individual lung densities for each condition are presented in Figs. 1 and 2.


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  		Table 3. Lung densities pre- and postexercise

 

Figure 1
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  		Fig. 1. Individual lung densities following normoxic exercise. Pre, before exercise. Post, after normoxic exercise.

 

Figure 2
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  		Fig. 2. Individual lung densities following hypoxic exercise. Pre, before exercise. Post, after hypoxic exercise.

 
During the exercise intervention, there were significant (P < 0.05) decreases in mass of 1.4 ± 0.5 and 1.1 ± 0.5 kg in the normoxic and hypoxic conditions, respectively. Compared with the preexercise scans, HR was significantly (P < 0.05) higher at the initiation of the first postexercise scan in both the normoxic (59.7 ± 8.5 vs. 53.3 ± 5.2 beats/min) and hypoxic (58.3 ± 7.0 vs. 51.7 ± 2.1 beats/min) conditions. No other significant differences in HR or mass were found between scans. There were no significant differences between the two conditions in the time between the preexercise and the two postexercise scans. As described above, for each scan a range of threshold densities was used, above which density all pixels were discarded before calculation of mean slice density. A sample MR image of a right lung sagittal slice from this study is presented in Fig. 3, with images of computer representations of the scan showing the discarded pixels at each threshold used. Mean lung densities (0.177 ± 0.019 g/ml) are consistent with established values in the literature (31, 33) using similar technology. The variation between subjects was relatively small (coefficient of variation = 8.0%) and the repeatability of resting slice density within subjects gave a significant casewise correlation of r2 = 0.73 (P < 0.05). The casewise correlations for intraobserver and interobserver repeatability on 20 randomly selected scans were both r2 = 0.97 (P < 0.05).


Figure 3
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  		Fig. 3. A: sample MRI image of right sagittal lung slice. B–G: computerized image of the lung scan showing areas of pixel removal. Dark areas within the lung represent areas of pixel removal using a threshold of 0.25 g/ml (B), 0.30 g/ml (C), 0.35 g/ml (D), 0.40 g/ml (E), 0.45 g/ml (F), and 1.0 g/ml (G).

 
Lung density gradient.   Mean lung density gradient (anterior to posterior) in the normoxic condition was 5.7 ± 1.8, 5.6 ± 1.9, and 6.9 ± 1.4 mg·ml–1·cm–1 in the resting and the first and second postexercise scans, respectively. In the hypoxic condition, the corresponding lung density gradients were 6.5 ± 1.2, 6.5 ± 1.6, and 6.8 ± 1.5 mg·ml–1·cm–1. In the normoxic condition, the mean anterior-to-posterior distances used in the preexercise scans were 5.0 ± 0.0, 73.8 ± 8.3, and 144.5 ± 16.3 mm, with corresponding tissue densities of 0.137 ± 0.025, 0.179 ± 0.020, and 0.216 ± 0.023 g/ml.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The purpose of this study was to assess measurement of in vivo lung density by MRI and to describe transient pulmonary edema, through this measure, following sustained submaximal exercise in healthy athletic humans while breathing normoxic and hypoxic air. While several of the well-trained participants demonstrated EIAH during maximal normoxic exercise, no difference in mean lung density was found following sustained exercise in either condition, indicating that pulmonary edema did not occur.

Previously, MR technology has been used to measure lung density both in vitro in animals (13, 14, 31) and in vivo in humans (18, 31, 33) with good results compared with known values for lung density. Validation for the MR measure of lung density in this study is provided by previous work (13, 14, 31) that has demonstrated agreement between gravimetric and MR measures of water content. The fact that a very linear relationship was observed between anterior-to-posterior distance and lung density (r2 = 0.999994) and that mean lung density gradient was consistent anterior to posterior across all scans confirms that changes in mean lung density were not missed simply through variance in the pattern of density across each scan slice.

There is no clear consensus in the literature on change in EVLW in humans following exercise, with several studies in humans indicating that some increase is observed or likely (3, 6, 7, 32, 33, 44), and several indicating no such change (15, 28, 30, 41). At first observation, the results of this study could simply be added to the group of studies demonstrating no change in EVLW following exercise. However, the novel components of this study involve the measure of lung density by MRI, which is presently one of the most accurate indirect measures available for in vivo studies, and the exercise intensity aimed specifically at edema from pulmonary capillary leakage. Other techniques have proven useful in the examination of edema. Ultrasound has recently been used to produce images from which comet tail sign may be used as an indication of extravascular water (1). The comet tail technique provides an alternative nonradiological method of assessment of extravascular water, and in future studies it may be appropriate to augment our current MRI measure with the comet tail measure as it provides data on the likelihood of pulmonary edema rather than a more global measure of lung density. There are, however, also technical difficulties associated with accurately performing the lung comet method during strenuous exercise. Additionally, analysis of bronchoalveolar lavage fluid (BALF) has proven useful in providing evidence of increased red blood cell and protein concentrations following intense exercise in both normoxia and hypoxia (11, 24). A lack of difference in erythrocyte content in BALF following sustained submaximal exercise (25) appears in agreement with the results of this study.

This study specifically used sustained exercise of a moderate intensity as the intervention in an attempt to investigate the possibility of transient pulmonary edema as a result of pulmonary capillary leakage rather than stress failure. It is imperative to compare these results with those of a recent study from our laboratory (33) in which an increase in lung density following exercise was observed using the same technology as this study. We offer several possibilities when attempting to explain the discrepancy in results between this study and the previous one using MRI assessment of lung density in humans.

First, the exercise intervention was different between these two studies. The previous study used an intervention of 45 min of cycling exercise at 77% of VO2 max. For 3 min at the end of the exercise, subjects were encouraged to sprint and increased power outputs to 35 W below peak values obtained in a VO2 max test and increased HR to within 1 beat/min of maximal values. By contrast, in this study subjects cycled for 60 min at a workload of 61% of VO2 max during the normoxic condition while avoiding sprinting. Theoretically, the greater exercise intensity (for a shorter duration) could produce greater cardiac output and pulmonary capillary pressures leading to stress failure and increased EVLW, while the lower intensity exercise (for a longer duration) may not have provided this stimulus. With this in mind, it is also worth comparing absolute VO2 between the two studies. In the previous work (33), during 45 min of exercise, mean VO2 is reported as 3.7 ± 0.3 l/min, while in the present study, over 60 min of exercise, mean VO2 was 3.1 ± 0.1 l/min. While merely speculative without further measures, it is possible that this difference of absolute exercise intensity had an effect on pulmonary capillary recruitment, in turn affecting pulmonary capillary pressures and capillary fluid filtration.

Second, it is possible that demonstration of increased EVLW is an individual response not uniformly observed across the population of aerobically trained humans. The previous study (33) found increased EVLW in only four of eight subjects with the remaining four showing no change. It is possible that a segment of this population demonstrates increased EVLW following exercise (responders) while the remainder does not (nonresponders), and the previous work happened to include some of these responder subjects while the present study did not. Interestingly, when the subject pool reported by McKenzie and colleagues (33) is divided into two groups, those that demonstrated an increase in lung density following exercise and those that did not, there is a significant difference in resting values of lung density between the two groups (0.243 ± 0.009 vs. 0.203 ± 0.007 g/ml, P < 0.05), and none of the subjects' resting lung density in the present study exceeded 0.201 g/ml. However, any physiological significance of this is speculative given the data in this study.

Third, it is possible that any change in lung density that may have occurred disappeared during the time period between end of exercise and MR scan. In the previous study from our laboratory, using similar MRI techniques, change in lung density was detected 90 min postexercise (33). The exercise intervention in these two studies was different, so the time delay between end of exercise and MR scan remains an important issue in this study and may explain why no increase in lung density was found. However, this discrepancy with the previous findings does lend confidence that the lack of change in lung density in this study was relevant to the exercise protocol itself and not simply a result of excessive time between exercise and MR scan.

Recent work by Snyder and colleagues (38) has demonstrated a decrease in lung water, assessed by combining density data from CT scan with pulmonary capillary volume (Vc) data from diffusing capacity tests, following hypoxic (FIO2 = 12.5%) exercise. The exercise consisted of submaximal work following 17 h of continuous hypoxic exposure, with pulmonary artery pressures, calculated from the tricuspid regurgitation velocity, of 37 ± 8 mmHg during exercise. This work appears in agreement with our findings of no evidence of increased EVLW following exercise, and the technique of incorporating measures of Vc in the CT measure of lung density adds credence that observed changes indeed reflect EVLW. However, it should be noted that the subjects involved in the work by Snyder and colleagues (38) were notably less fit than in our work and, given the potential differences in pulmonary hemodynamics with fitness, this fact alone may preclude proper comparison.

It is important to note that increased PAP clearly does not always result in pulmonary edema. Therefore, the increase in PAP likely induced in this study may simply not have resulted in a change in EVLW. Further, a change in EVLW is only relevant as it pertains to changes in physiological function. In this study, mild to moderate EIAH was observed in nine subjects during the normoxic VO2 max. Therefore, from the findings of this study we must conclude that EIAH may occur in individuals who do not demonstrate an increase in lung density during prolonged exercise. As it relates to EIAH, the important finding from this study is that it appears EIAH does not occur in relation to pulmonary edema resulting from pulmonary capillary leakage of a non-stress failure nature. To avoid inducing stress failure in the subjects, the intervention involved moderate-intensity exercise of a sustained duration rather than high-intensity short-duration exercise. However, caution must be used in relating the EIAH observed during the normoxic VO2 max tests and the lack of change in lung density observed following sustained moderate-intensity exercise during which EIAH was not clearly observed (mean SaO2 = 95.2 ± 0.1) given the difference in exercise intensity and duration. We believe we can conclude with confidence that the interventions used in this work have no functional significance in terms of pulmonary gas exchange.

One of the limitations of lung density measures in humans is that they are necessarily indirect. Further, the techniques that offer the most sensitive quantitative measure of lung density, including CT and MR scans, generally require a period of time between the end of exercise and measurement of lung density to allow pulmonary blood flow to return to normal resting values. As a result, there is uncertainty whether transient pulmonary edema occurred and resolved before the MR scan, or whether no transient pulmonary edema occurred during exercise. Clearance of alveolar edema is a complicated process involving active transepithelial sodium transport by sodium-potassium ATPase (5, 40) and is likely to take an extended period of time to occur, but interstitial edema, which is perhaps the more likely level of edema to result from the perturbations used in this study given that none of the clinical signs of alveolar edema were observed, may clear more quickly. Furthermore, exercise-induced hyperpnea has been shown to increase lymph clearance of interstitial edema in sheep (26), indicating that the exercise these subjects performed may have paradoxically assisted in the clearance of any edema that did occur. Unfortunately, at least in human subjects, this limitation is unlikely to be resolved in the near future with present imaging techniques.

The main questions raised in this study are whether sustained moderate-intensity exercise can cause increased EVLW through pulmonary capillary leakage and, if so, whether this response can be quantified through the use of a hypoxic condition. This is answered quite decisively by the lack of difference in lung density between any of the MRI scans. Arterial oxyhemoglobin saturation during exercise in the hypoxic condition was in the range of 80–85%, indicating that the perturbations of exercise in combination with hypoxia met the conditions associated with raised mean pulmonary arterial pressure. However, even following 60 min of sustained intense exercise in hypoxia, no subject in this study demonstrated an increase in lung density of any significance. The greatest increase in lung density by any single subject was 0.011 g/ml, which is much less than the range of changes reported in a similar previous study (33) of 0.02–0.071 g/ml for the four subjects that showed increased EVLW and the change of 0.04 g/ml (as measured by CT) reported in subjects following a triathlon (7). Furthermore, in the present study, the greatest decrease in lung density by a single subject was 0.024 g/ml, which exceeds the greatest single increase. Therefore, we conclude that sustained exercise of moderate intensity in normoxia or hypoxia does not alter lung density ~50 min postexercise.


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 ABSTRACT
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The British Columbia Lung Association and the British Columbia Sports Medicine Research Foundation funded this study. A. W. Sheel was supported by a Scholar Award from the Michael Smith Foundation for Health Research and a New Investigator Award from the Canadian Institutes of Health Research.


   ACKNOWLEDGMENTS
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We are grateful to the subjects for participation and to Dr. Alex MacKay, Thorarin Bjarnason, Diana Jespersen, and the MRI technologists at the University of British Columbia Hospital for technical assistance with this study.


   FOOTNOTES
 

Address for reprint requests and other correspondence: A. Hodges, School of Health and Human Performance, Faculty of Health Professions, Dalhousie Univ., 6230 South St., Halifax, NS, Canada B3H 3J5 (e-mail: alastairhodges{at}hotmail.com)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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 REFERENCES
 

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