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Editorial
Of Deep Waters and Thin Air
Pulmonary Edema in Swimmers Versus Mountaineers
Wolfgang M. Kuebler, MD
W
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ith reported incidences typically ≈1%,1 swimminginduced pulmonary edema (SIPE) is increasingly recognized as a not uncommon syndrome that is triggered by
strenuous swimming and characterized by dyspnea, cough,
and hemoptysis. Interestingly, SIPE shares common features
with another form of pulmonary edema that is caused by
strenuous exercise in an evolutionary nonphysiological habitat, namely high-altitude pulmonary edema (HAPE): Both
SIPE and HAPE typically affect young healthy individuals,
are triggered by strenuous exercise in a cold environment,
resolve spontaneously after return to physiological conditions, yet will recur on reexposure in prone individuals.2,3 At
the pathological level, edema fluid in both SIPE and HAPE
patients contains considerable amounts of red blood cells
and high-molecular-weight proteins in the absence of markedly elevated inflammatory markers.4,5 The pathophysiology
of both diseases has long puzzled the field and hampered the
development of effective counterstrategies, because their features tend to evade the traditional classification of pulmonary
edema.
lack of inflammatory markers in SIPE or early HAPE argues
against a classic permeability-type edema, whereas the regular presence of red blood cells and high-molecular-weight
proteins disagrees with the traditional concept of hydrostatic
pulmonary edema.
In this issue of Circulation, a seminal study by Moon and
colleagues6 now sheds new light on the pathomechanisms
driving SIPE. In 10 subjects with a previous history of SIPE,
pulmonary and systemic hemodynamics, expired gas volume
and fractions, and blood gases were monitored at supine dry
rest (baseline), after submersion in 18 to 20°C cold water,
and during moderate cycle ergometer exercise while submersed. In comparison with a historical control of 20 healthy
subjects, SIPE-susceptible subjects had higher mean pulmonary artery pressures (mPAP) and pulmonary artery wedge
pressures (PAWP) during submersed exercise despite lower
cardiac output (CO). These findings are reminiscent of studies in HAPE-susceptible subjects that show an exaggerated
mPAP response to HAPE-relevant triggers such as hypoxia
and exercise.7 None of the subjects showed signs of recurrent
SIPE. Although a direct cause-effect relationship between the
observed hemodynamic differences and the development of
SIPE thus remains to be proven, the present data are consistent
with a hydrostatic mechanism of disease because of increased
pulmonary (micro)vascular pressures.
Following pretreatment with 50 mg of the phosphodiesterase 5 inhibitor sildenafil, the protocol was repeated. Although
sildenafil only causes modest vasodilation in the systemic
circulation (with the exception of the corpora cavernosa), it
has strong vasodilatory effects in the pulmonary circulation.
At dry, supine rest, sildenafil increased CO, and, because
mPAP and mean arterial pressure remained constant or even
decreased slightly, reduced pulmonary (PVR) and systemic
vascular resistance. During submersed exercise, sildenafil
decreased mPAP and PVR in comparison with presildenafil
measurements, and mPAP and PAWP values were no longer
significantly different from the historic control group. Again,
these findings mirror studies in healthy mountaineers in which
sildenafil reduced systolic pulmonary artery pressure at rest
and during exercise at both low and high altitude.8
Given the communalities in pathology and response to
sildenafil in SIPE and HAPE, it is tempting to speculate on
similar parallels regarding 2 manifest questions: (1) If HAPE
and SIPE are forms of hydrostatic lung edema, then why is
the edema fluid rich in high-molecular-weight protein and
red blood cells? (2) What mechanisms underlie the observed
changes in pulmonary (micro)vascular pressures? Notably,
the Starling equation considers the emergence of hydrostatic
edema as the result of increased fluid flux across an intact
endothelial barrier with an unaltered permeability that at large
Article, see p 988
The classic Starling equation defines net fluid flow Jv
across the capillary barrier as
J v = Lp• A ( Pc − Pi ) − σ π ( Π c − Π i )
where Lp is hydraulic conductivity (a measure of water
permeability), A is the barrier surface area, σπ is the oncotic
reflection coefficient (a measure of the barrier´s resistance to
protein movement), and Pc, Pi, Πc, and Πi are the hydrostatic
(P) and oncotic (Π) pressures in the capillary (c) or interstitial
(i) compartment, respectively. Accordingly, we differentiate
between 2 classes of pulmonary edema, namely hydrostatic
edema caused by increased driving pressure (increased ΔP or
reduced ΔΠ), and permeability-type edema caused by high
Lp or low σπ and traditionally considered a result of infectious
or sterile inflammation. The dilemma emerges because the
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From Keenan Research Centre for Biomedical Science at St. Michael’s
Hospital, Toronto, ON, Canada; Departments of Surgery and Physiology,
University of Toronto, ON, Canada; Institute of Physiology, Charité –
Universitaetsmedizin Berlin, Germany; and German Heart Institute,
Berlin, Germany.
Correspondence to Wolfgang M. Kuebler, MD, The Keenan Research
Centre for Biomedical Science, St. Michael’s Hospital, 209 Victoria St,
M5B 1W8 Toronto, ON, Canada. E-mail [email protected]
(Circulation. 2016;133:951-953.
DOI: 10.1161/CIRCULATIONAHA.116.021553.)
© 2016 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.116.021553
951
952 Circulation March 8, 2016
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prevents the extravasation of macromolecules and blood cells.
Depending on the magnitude of the pressure increase, however, neither will endothelial permeability remain unchanged,
nor will vascular barrier integrity remain intact.9 In elegant
electron microscopic studies, the groups of West and Weibel
showed that elevated hydrostatic pressure can cause microscopic breaks in the endothelial and epithelial membranes of
the blood-gas barrier, a phenomenon now known as capillary
stress failure.10,11 Exercise-induced capillary stress failure is
common in galloping horses that routinely develop left atrial
pressures ≈70 mm Hg and accounts for pulmonary hemorrhage in highly trained thoroughbreds. Although equivalent
ultrastructural evidence is lacking in human lungs, capillary
stress failure has analogously been proposed in both SIPE and
HAPE.12,13 Yet, structural breaks of the alveolocapillary barrier typically require considerable capillary transmural pressures ≥40 mm Hg in rabbits and ≥100 mm Hg in the horse
lung. Relevant increases in vascular permeability occur, however, already at much lower pressures, because the endothelial
membrane is in fact anything but an inert barrier and responds
actively to mechanical stimuli such as pressure and stretch.
Recent work has identified the signaling pathways in the pulmonary endothelium that mediate these responses. A key element in this mechanotransduction cascade is the polymodal
Ca2+ channel transient receptor potential vanilloid 4, which
opens in response to increased lung capillary pressures, allowing for endothelial Ca2+ influx that in turn increases vascular
permeability by activating the endothelial contractile machinery.14 Consistent with a pressure-induced increase in lung vascular permeability, and in opposition to the classic Starling
concept, bronchoalveolar lavage fluid in patients with an
unequivocal diagnosis of hydrostatic lung edema shows markedly elevated protein levels, although not as high as in patients
with permeability-type lung edema.15 Hence, the presence of
high-molecular-weight proteins and even red blood cells in
the edema fluid of SIPE and HAPE patients is not in contradiction with an underlying hydrostatic mechanism of disease.
As to the mechanisms underlying the different hemodynamic responses in SIPE- and HAPE-susceptible subjects versus respective controls, the situation is less clear. Impaired left
ventricular systolic or diastolic function have been proposed
to trigger or predispose for SIPE; yet, all SIPE-susceptible
patients in the present study had normal echocardiography
at rest, and 9 of 10 had been evaluated for coronary artery
disease with no pathological results. Submersion in cold
water and concurrent increased sympathetic tone redistribute
blood volume from systemic capacitance vessels to intrathoracic organs, predominantly the lung. This effect may per se
increase transcapillary fluid flux Jv, because capillary recruitment will increase surface area A in the Starling equation. The
resulting increase in intrathoracic blood volume will cause an
acute and sustained increase in pulmonary capillary pressures.
Consistently, submersion into cold water (dunk) caused a rapid
increase in PAWP from 13.0±3.2 to 18.1±3.9 mm Hg in SIPEsusceptible subjects in the present study. Notably, postdunk
PAWP values were markedly lower (13.5 mm Hg; P=0.07) in
the historic control of healthy subjects with no prior history of
SIPE. Regrettably, baseline measurements at dry rest are not
comparable between SIPE-susceptible and control subjects
because of different positions (supine versus sitting); hence,
it remains unclear whether SIPE-susceptible subjects had a
higher baseline PAWP to start with, or an increased PAWP
response to the dunk. Both higher blood volume and increased
venous tone (either at baseline, or in response to cold water
immersion) have been proposed to account for the increased
PAWP response in SIPE-susceptible subjects.16 Notably,
however, exercise-induced pulmonary edema has also been
reported in elite cyclists, marathon runners, and cross-country
skiers,1 all of whom exercise in vertical or sitting positions
where intrathoracic blood volume shifts are expected to be
minor. Given the consistent association between exercise and
edema in these conditions, it is tempting to speculate on a critical role for CO in the onset of lung capillary leak; in the present study, however, CO was lower in SIPE-susceptible than
in control subjects during submersed exercise and increased
after treatment with sildenafil.
At this point, the comparison with HAPE may once more
be informative. At high altitude, there is an obvious connection between hypoxia and increased pulmonary artery
pressure through hypoxic pulmonary vasoconstriction; yet,
how contraction of arteriolar resistance vessels will increase
vascular pressure in downstream capillaries is less clear.
To date, 3 not mutually exclusive explanations have been
put forward: (1) HAPE may initially arise from a subset
of capillaries that branch off directly from the larger arteries and, thus, are unprotected when pulmonary artery pressures increases17; (2) capillary pressures may rise because
of concomitant pulmonary venoconstriction18; and (3) heterogeneous vasoconstriction may result in uneven distribution of perfusion and local areas of high flow and pressure.3
These concepts not only illustrate that drawing conclusions
on local microhemodynamics from macrohemodynamic
measurements can be problematic, but they also stress the
potential role of pulmonary vasoconstriction in lung edema
formation. A closer look at the data by Moon and colleagues
may suggest a similar element of vasoconstriction in SIPE:
Despite lower CO values, the transpulmonary pressure gradient (ie, the difference between mPAP and PAWP) tended
to be higher in SIPE-susceptible subjects than in controls
during both the dunk and subsequent submersed exercise.
Conversely, sildenafil reduced the transpulmonary pressure
gradient in SIPE-susceptible subjects at rest, subsequent
to the dunk, and during submersed exercise despite a concomitant increase in CO. Consequently, PVR was higher
in SIPE-susceptible subjects than in controls during submersed exercise, but decreased significantly with sildenafil.
Higher PVR values in SIPE-susceptible subjects cannot be
explained by increased total blood volumes or blood volume
shifts, because capillary dilation or recruitment would reduce
rather than increase PVR. Rather, these data strongly suggest
a vasoconstrictive component that is alleviated by sildenafil
in line with its well-characterized vasodilatory effects in the
pulmonary circulation. Vasoconstriction, by acting through
mechanisms analogous to those outlined above for HAPE,
may amplify global and, in particular, local increases in lung
capillary pressures, thereby contributing relevantly to SIPE.
Different from HAPE, however, the initial trigger for pulmonary vasoconstriction in SIPE is not hypoxia, but may
Kuebler Pulmonary Edema in Swimmers and Mountaineers 953
involve adrenergic stimulation, and reactive vasoconstriction
in response to increased capillary pressures (a phenomenon
known as Kitajew reflex), as well.
Notably, not only endothelial leak at increased hydrostatic
pressures, but also pulmonary vasoconstriction in response
to hypoxia and hypoxia-independent stimuli are mediated at
large by the Ca2+ channel transient receptor potential vanilloid
4.19 With transient receptor potential vanilloid 4 antagonists
presently undergoing clinical testing for the treatment of cardiogenic lung edema,20 transient receptor potential vanilloid 4
blockade may ultimately present a putative strategy to prevent
edema formation in SIPE- or HAPE-susceptible subjects.
Disclosures
None.
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Key Words: Editorials ◼ altitude sickness ◼ capillary permeability
◼ pulmonary circulation ◼ pulmonary edema ◼ swimming
Of Deep Waters and Thin Air: Pulmonary Edema in Swimmers Versus Mountaineers
Wolfgang M. Kuebler
Circulation. 2016;133:951-953; originally published online February 16, 2016;
doi: 10.1161/CIRCULATIONAHA.116.021553
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