J Appl Physiol 109: 1270 –1275, 2010;
doi:10.1152/japplphysiol.01353.2009.
Point:Counterpoint
Point:Counterpoint: Pulmonary edema does/does not occur in human athletes
performing heavy sea-level exercise
POINT: PULMONARY EDEMA DOES OCCUR IN HUMAN
ATHLETES PERFORMING HEAVY SEA-LEVEL EXERCISE
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My colleagues (25) have a difficult task, because it is easier
to prove a positive than a negative. A 1978 case report
documents two athletes that presented, after running the Comrades marathon, with shortness of breath, cough productive of
blood tinged and/or pink frothy sputum, crepitations on auscultation, and chest radiograph findings of pulmonary edema
(18). There can be no doubt that these athletes had pulmonary
edema, and although the Comrades marathon represents an
extraordinary exercise task because of its length (90 km), the
elevation of the route never exceeded 1,000 m. In addition,
there are numerous reports in the literature that document the
presence of pulmonary edema after exercise. These include
cases of pulmonary edema occurring as a result of swimming
(1), as distinct from pulmonary edema associated with diving,
i.e., immersion pulmonary edema (26), as well as cases of overt
edema occurring during sexual intercourse (29) and heavy
or/prolonged exercise with very modest altitude exposure (2,
17) in otherwise healthy people. Consequently these case
reports prove that pulmonary edema occurs during heavy
sea-level exercise and this debate could stop here.
However, given the sporadic nature of these reports, perhaps
a better question is why don’t more athletes develop alveolar
flooding during exercise? While the healthy human lung is
overbuilt for a sedentary existence, during maximal exercise it
is subjected to substantial physiological stressors. In particular,
ventilation and cardiac output greatly increase and pulmonary
blood volume and capillary blood volume rise (16). Even
during submaximal exercise, pulmonary arterial and occlusion
pressures (i.e., left atrial pressure) approximately double from
rest, cardiac output increases approximately fourfold (13), and
microvascular pressures rise. Starling’s law is thought to apply
to the lung microvasculature (see Ref. 28 for review), and thus
fluid balance in the lung reflects the interplay of hydrostatic
pressures and colloid osmotic pressures in the lung microvasculature and surrounding interstitium. Increases in microvascular pressure, combined with a greater surface area for fluid
filtration are expected to increase fluid exchange between the
lung vascular space and the interstitium (28). Given this, is not
difficult to imagine that lung fluid balance might be altered,
without completely overwhelming the lymphatic drainage, resulting in alveolar flooding. There are animal data supporting
this idea. In dogs, when the capillary pressure is increased, a
distinct pattern of edema formation emerges (Fig. 1). First,
there is extravasation of fluid into the interstitial space surrounding the conducting vessels and airways (27). Following
this, if the rise in pressure is prolonged, alveolar wall fluid is
increased and then finally overt alveolar flooding, gas exchange defects, and possibly alveolar collapse occur (27). In
keeping with this idea, lung lymphatic flow increases rapidly
after the onset of exercise in sheep and further increases with
increasing exercise duration (5, 20). On this basis it is to be
expected that fluid balance in the human lung is likely to follow
a similar pattern. However severe pulmonary edema with
alveolar flooding has been documented during heavy sea-level
Fig. 1. The development of acute pulmonary edema as described by Staub et
al. (27). A: the alveolar walls (left) are normal and there is no excess fluid in
the interstitial space (right). In the first stages of pulmonary edema (B), the
interstitial space is greatly increased (right) but the alveolar wall is minimally
affected (left). Once the capacity of the interstitial space is overwhelmed (C),
fluid progressively accumulates in the alveoli (D), leading to loss of stability
and collapse (bottom inset). Figure borrowed with permission from Ref. 27.
exercise only under conditions where the development is exacerbated by factors such as very prolonged exercise (18),
psychological stress (1), cold (29), moderate altitude exposure
(2, 17), and water immersion (1, 26). This suggests that the
normal lung has a large safety margin preventing the development of alveolar flooding except in the most extreme cases.
However, interstitial edema is more likely.
In humans, the evidence for the development of interstitial
edema is indirect, but very consistent. As seen in Fig. 1,
interstitial edema would be expected to compress small air-
8750-7587/10 Copyright © 2010 the American Physiological Society
http://www.jap.org
Point:Counterpoint
1271
J Appl Physiol • VOL
(27) and thus no diffusive limitation to O2 transport is expected. This is consistent with recent work showing no detectable diffusion limitation when interstitial edema is created by
volume overload in resting subjects (23).
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11. Hodges AN, Sheel AW, Mayo JR, McKenzie DC. Human lung density
is not altered following normoxic and hypoxic moderate-intensity exercise: implications for transient edema. J Appl Physiol 103: 111–118, 2007.
12. Hopkins SR. Exercise induced arterial hypoxemia: the role of ventilationperfusion inequality and pulmonary diffusion limitation. Adv Exp Med
Biol 588: 17–30, 2006.
13. Hopkins SR, Gavin TP, Siafakas NM, Haseler LJ, Olfert IM, Wagner
H, Wagner PD. Effect of prolonged, heavy exercise on pulmonary gas
exchange in athletes. J Appl Physiol 85: 1523, 1998.
14. Hopkins SR, McKenzie DC, Schoene RB, Glenny RW, Robertson HT.
Pulmonary gas exchange during exercise in athletes. I Ventilation-perfusion mismatch and diffusion limitation. J Appl Physiol 77: 912–917, 1994.
15. Johns DP, Berry D, Maskrey M, Wood-Baker R, Reid DW, Walters
EH, Walls J. Decreased lung capillary blood volume post-exercise is
compensated by increased membrane diffusing capacity. Eur J Appl
Physiol 93: 96 –101, 2004.
16. Johnson RL Jr, Spicer WS, Bishop JM, Forster RE. Pulmonary capillary
blood volume, flow and diffusing capacity during exercise. J Appl Physiol
15: 893–902, 1960.
17. Luks AM, Robertson HT, Swenson ER. An ultracyclist with pulmonary
edema during the Bicycle Race Across America. Med Sci Sports Exerc 39:
8 –12, 2007.
18. McKechnie JK, Leary WP, Noakes TD, Kallmeyer JC, MacSearraigh
ET, Olivier LR. Acute pulmonary oedema in two athletes during a 90-km
running race. S Afr Med J 56: 261–265, 1979.
19. McKenzie DC, O’Hare TJ, Mayo J. The effect of sustained heavy
exercise on the development of pulmonary edema in trained male cyclists.
Respir Physiol Neurobiol 145: 209, 2005.
20. Newman JH, Cochran CP, Roselli RJ, Parker RE, King LS. Pressure
and flow changes in the pulmonary circulation in exercising sheep:
evidence for elevated microvascular pressure. Am Rev Respir Dis 147:
921–926, 1993.
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ways and blood vessels, potentially affecting ventilation-perfusion (V̇A/Q̇) matching. In many humans, V̇A/Q̇ mismatch
increases with exercise (6, 8, 9, 13, 14, 21, 22) and the pattern
is consistent with the cause being interstitial edema. For
example, those subjects who increase V̇A/Q̇ mismatch during
exercise, have greater V̇A/Q̇ mismatch in recovery than those
subjects that do not show an increase. This difference persists
beyond the point at which ventilation and cardiac output
normalize to pre-exercise levels (24). Exercise in normobaric
hypoxia causes a greater increase in V̇A/Q̇ mismatch than in
normoxia, and this increase is relieved by breathing 100%
oxygen (9). Since hypoxia and hyperoxia alter pulmonary
arterial pressures and thus capillary filtration, this is also
consistent. The extent of V̇A/Q̇ mismatch increases with exercise duration even at relatively low exercise intensities (13). In
subjects who have had the extent of V̇A/Q̇ mismatch characterized by the multiple inert gas elimination technique
(MIGET), prolonged exercise makes the distribution of pulmonary blood flow less spatially uniform (3), as would be
expected from compression of small blood vessels, and the
extent of this derangement is correlated with the degree of
V̇A/Q̇ mismatch previously measured by MIGET.
If, as these studies suggest, a great many healthy subjects
develop interstitial edema with exercise, why don’t more
imaging studies show positive results? There are several potential explanations for negative imaging studies. The imaging
has to be performed within a time frame that allows for
detection of any pulmonary edema before it has resolved. In
upright subjects, gas exchange alterations resolve ⬃20 min
after exercise (24), although in supine subjects who are not
upright starting shortly after exercise, alterations in the spatial
heterogeneity of blood flow persist for an hour (3). Since many
studies have both long delays between the completion of
exercise and the start of imaging (7, 11, 19) and long acquisition times (11, 19), this may partly explain the lack of findings.
Mean lung density data are likely to be misleading. If interstitial edema affects small airways as well as blood vessels, this
could lead to air trapping and no net change in density,
although total lung water is increased, unless changes in lung
air volume and inflation are specifically accounted for. To be
sensitive to changes representing edema, the technique must
account for fluid shifts between the vascular compartment and
the interstitial space. Central blood volume and capillary blood
volume is first increased by exercise and then decreased following exercise (10, 15), affecting mean lung density differently depending on the timing of the measure. Application of
thresholds designed to eliminate the intravascular contribution
to lung water (11, 19) have the unwanted effect of potentially
removing lung regions of high density that represent extravascular fluid accumulation. Despite these challenges, a number of
studies have shown positive results (4, 17, 19).
It is important to recognize that despite the evidence presented above, any V̇A/Q̇ mismatch resulting from interstitial
edema is unlikely to have a large effect on pulmonary gas
exchange efficiency during exercise (reviewed in Ref. 12). This
is because despite increasing mismatch, the overall increase in
ventilation during exercise is greater than the increase in
cardiac output, and thus relatively low V̇A/Q̇ units of the lung
are at a higher V̇A/Q̇ ratio, minimizing the effect on oxygenation. In addition, as seen in Fig. 1, fluid accumulation is
unlikely to affect the alveolar wall until the edema is advanced
Point:Counterpoint
1272
Susan R. Hopkins
Division of Physiology
Department of Medicine
Pulmonary Imaging Laboratory
Department of Radiology
University of California
San Diego, La Jolla, California
e-mail: [email protected]
COUNTERPOINT: PULMONARY EDEMA DOES NOT OCCUR
IN HUMAN ATHLETES PERFORMING HEAVY
SEA-LEVEL EXERCISE
The arterial partial pressure of oxygen (PaO2) can be reduced
by as much as 30 mmHg and oxyhemoglobin saturation (SaO2)
by 15% below resting levels in some aerobically trained
athletes exercising at high intensities (3). Some have hypothesized that mild interstitial edema could develop and, through
changes in local compliance (e.g., alveolar wall edema) or
resistance (e.g., perivascular or bronchial edema), affect the
distribution of ventilation or blood flow. However, the measurement of lung density in humans in vivo is not possible, so
any discussion of whether transient pulmonary edema exists is
dependent on the validity and sensitivity of the tools used to
estimate the change in lung water. One must also consider the
pathophysiology, or at least the physiology, that would lead to
pulmonary edema in human athletes at sea level. Possible mechanisms in this population are limited but include 1) increased
pulmonary capillary permeability secondary to leakage (starling
forces) or damage (capillary stress failure); 2) increased pulmonary capillary surface area; 3) increased pulmonary capillary
hydrostatic pressure; and 4) lymphatic insufficiency. Others have
argued that it is unlikely that exercise at sea level would result in
pulmonary edema because there are important “edema safety
factors” that exist to oppose it’s formation (16, 19). Here we
J Appl Physiol • VOL
present the relevant studies that have been unsuccessful in documenting pulmonary edema.
Repeated exercise. Repeated heavy exercise does not worsen
gas exchange (13, 18) in athletes. In fact, gas exchange impairment can be lessened by prior exercise (18). This shows
that impairments to gas exchange are not caused by a mechanism that persists after the initial exercise period and is not
aggravated by subsequent exercise, as would be expected of
structural alterations to the blood-gas interface.
Transthoracic electrical impedance. Reductions in transthoracic electrical impedance (TEI) following exercise have been
reported as related to the accumulation of lung water (1). The
physiological importance of these findings remain unclear,
because the measurement of TEI is nonspecific, it does not
explain the source of hindered impedance, and may be due to
elevated intravascular volume not interstitial edema. Furthermore, others (15) have reported increased TEI following maximal exercise.
Chest radiography. There are reports of pulmonary edema in
two athletes competing in a 90-km running race (12). While the
clinical manifestations of pulmonary edema appear present,
two points should be emphasized. First, the pulmonary pressures would not be significantly elevated during this type of
exercise and the possibility of “stress failure” is low. Second,
ultra-distance running races occur worldwide without widespread reports of pulmonary edema, suggesting that the presence of edema was more likely to be related to undiagnosed
pathology. Chest radiographs were scored following three sets
of 5-min of heavy cycle exercise with an increase in a semiquantitative edema score (20). However, the pre-exercise values were not zero (i.e., no edema present) and calls into
question the meaningfulness of the scale. Changes in the
magnitude of extravascular water needs to be ⬃35% to be
detected by chest radiography (17), implying a pathology not
seen in a healthy, athletic population.
99mTc-labeled diethylenetriaminepentaacetic acid. Usage
of 99mTc-labeled diethylenetriaminepentaacetic acid (99mTcDTPA) is a sensitive method for detecting lung pathology.
Edwards et al. (4) found that pulmonary clearance of 99mTcDTPA after maximal cycle exercise was unchanged. Furthermore, there was no relationship between pulmonary clearance
and the fall in PaO2 (⫺27 mmHg), suggesting that hypoxemia
occurs despite maintenance of alveolar epithelial integrity.
Conversely, following 6 min of maximal rowing, clearance
appears to be increased (6). However, this is not direct evidence of edema. Rather, it could reflect a change in epithelial
permeability, meaning that the blood-gas barrier is simply
more permeable or it may be attributable to an increase in
pulmonary capillary blood volume and the associated increase
in pulmonary surface area.
Computed tomography. Computed tomography (CT) allows
a rapid image of the lung, but because it exposes the subjects
to ionizing radiation, it’s usefulness as a research tool in
healthy, young athletes is limited. Following completion of a
triathlon race, CT scans revealed a 19 and 21% increase in lung
density and mass, respectively (2). However, heart rate was
higher during post-race scans and the number of veins and
venules was increased reflecting increases in pulmonary blood
flow. Also, visual analysis of CT scans did not reveal an
obvious image of acute pulmonary edema. We recently conducted two studies (5, 11) where the exercise protocol was
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21. Olfert IM, Balouch J, Kleinsasser A, Knapp A, Wagner H, Wagner
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Hopkins SR, Johnson DH, Michimata H, Grassi B, Feiner J, Kurdak
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23. Prisk GK, Olfert IM, Arai TJ, Wagner PD, Hopkins SR. Rapid
intravenous infusion of 20 ml/kg saline does not impair resting pulmonary
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