The Key Roles of Negative Pressure Breathing and Exercise in the Development of Interstitial Pulmonary Edema in Professional Male SCUBA Divers
Castagna et al. Sports Medicine - Open
The Key Roles of Negative Pressure Breathing and Exercise in the Development of Interstitial Pulmonary Edema in Professional Male SCUBA Divers
Olivier Castagna 3 4
Jacques Regnard 2
Emmanuel Gempp 7
Pierre Louge 8
François Xavier Brocq 6
Bruno Schmid 4
Anne-Virginie Desruelle 4
Valentin Crunel 4
Adrien Maurin 4
Romain Chopard 5
David Hunter MacIver 0 1
0 Musgrove Park, Taunton & Somerset Hospital , Taunton , UK
1 Biological Physics Group, University of Manchester , Manchester , UK
2 EA3920, University Bourgogne Franche-Comté and University Hospitals , Besançon , France
3 Laboratory of Human Motricity, Education Sport and Health , LAMHESS (EA 6312), Toulon , France
4 Underwater Research Team (ERRSO) from the Military Biomedical Research Institute (IRBA) , Toulon , France
5 Department of Cardiology EA3920, Franche Comté University and University Hospital , Besançon , France
6 Department of Cardiology, HIA St Anne Military Hospital , Toulon , France
7 French Navy Diving School , Toulon , France
8 Department of Hyperbaric Medicine, HIA St Anne Military Hospital , Toulon , France
Background: Immersion pulmonary edema is potentially a catastrophic condition; however, the pathophysiological mechanisms are ill-defined. This study assessed the individual and combined effects of exertion and negative pressure breathing on the cardiovascular system during the development of pulmonary edema in SCUBA divers. Methods: Sixteen male professional SCUBA divers performed four SCUBA dives in a freshwater pool at 1 m depth while breathing air at either a positive or negative pressure both at rest or with exercise. Echocardiography and lung ultrasound were used to assess the cardiovascular changes and lung comet score (a measure of interstitial pulmonary edema). Results: The ultrasound lung comet score was 0 following both the dives at rest regardless of breathing pressure. Following exercise, the mean comet score rose to 4.2 with positive pressure breathing and increased to 15.1 with negative pressure breathing. The development of interstitial pulmonary edema was significantly related to inferior vena cava diameter, right atrial area, tricuspid annular plane systolic excursion, right ventricular fractional area change, and pulmonary artery pressure. Exercise combined with negative pressure breathing induced the greatest changes in these cardiovascular indices and lung comet score. Conclusions: A diver using negative pressure breathing while exercising is at greatest risk of developing interstitial pulmonary edema. The development of immersion pulmonary edema is closely related to hemodynamic changes in the right but not the left ventricle. Our findings have important implications for divers and understanding the mechanisms of pulmonary edema in other clinical settings.
Atrial natriuretic peptide; Echocardiography; Exercise; Hydrostatic transrespiratory pressure; Immersion pulmonary edema; Inspiratory breathing effort; Lung ultrasonography; Negative pressure breathing; Right heart preload; Work of breathing
The exercise-induced increase in tidal volume
during immersion elevates right heart preload,
triggering a right to left ventricular imbalance and
Exercising with negative pressure breathing further
increases the inspiratory work of breathing, right
ventricle loading, right to left heart imbalance, and
rate of interstitial lung water accumulation.
Positive pressure breathing decreases cardiovascular
changes and pulmonary edema during immersion
Plasma levels of atrial natriuretic peptide increase
with inspiratory work and correlates with lung
An altered right to left heart imbalance provokes the
development of immersion pulmonary edema when
inspiratory work is high, e.g., during swimming at
high intensity level or SCUBA diving with negative
pressure breathing setting.
Immersion pulmonary edema (IPE) is accompanied by
the onset of dyspnea while diving or swimming. IPE may
be accompanied by cough, hemoptysis, and severe
hypoxemia and can result in death [
]. Resting and
normobaric oxygen therapy usually results in rapid relief of
symptoms without sequelae. IPE can occur in both
young athletes as well as older subjects especially if
cardiovascular co-morbidities are present [
In healthy subjects, the main predisposing factors to
] are cold water [
] and exertion [
predisposing factors are age > 50 years, hypertension,
and left heart disease [
]. The condition has also been
reported in highly fit subjects such as military swimmers
and triathletes [
]. IPE symptoms can vary in
severity , and the accumulation of interstitial pulmonary
edema without overt symptoms is common after normal
diving without significant exertional effort [
Moderate fin swimming exercise leads to increasing interstitial
pulmonary edema [
]. The rise in transmural
pulmonary capillary pressure causes transudation initially into
the interstitial tissues, [
] as evidenced by the
appearance of ultrasound “lung comet tails,” [
reaching the alveolar air spaces [
We recently reported that 30-min finning during
SCUBA air dive at shallow depth resulted in interstitial
pulmonary edema in 11 of 15 study subjects [
increased preload and a right-left heart imbalance
correlated with the accumulation of extravascular lung water
(EVLW). We showed that changes in right ventricular
physiology, rather than left ventricular indices,
correlated with the development of interstitial pulmonary
edema. The severity of interstitial pulmonary edema was
significantly correlated with measures of increased right
ventricular filling, right ventricular area change (a
surrogate of right ventricle ejection fraction), and pulmonary
artery pressure. Left ventricle ejection fraction (LVEF)
and left ventricle stroke volume (LVSV) did not change.
We concluded that the imbalance between right and left
heart stroke volumes during effort is central to the
development of immersion pulmonary edema.
The effort of breathing is greater during immersion than
on land because the external hydrostatic pressure creates
a greater transpulmonary pressure difference [
results in a more negative breathing pressure (NPB). NPB
is present during swimming because the airway pressure
is lower than the hydrostatic pressure surrounding the
thorax and the abdomen [
8, 10, 16
]. During diving, when
the open diving regulator is held at the mouth, NPB
occurs when changing from prone to upright posture as
arises when returning towards surface [
NPB, the inspiratory effort increases, generates a lower
pleural and airway pressures, and results in greater tidal
swings in thoracic pressure while preserving the airway
flow rate. Conversely, positive pressure breathing (PPB) or
inspiratory assistance decreases the transpulmonary
pressure gradient [
]. Although an increased
inspiratory effort is recognized as a respiratory burden to divers,
17, 21, 22
] no previous study, to our knowledge, has
directly assessed the cardiovascular and pulmonary effect
of airway pressure during immersed exercise.
NPB increases the transmural hydrostatic pressure
difference between the lumen of the lung capillaries and
interstitial fluid in bronchial bundles and alveoli. NPB
also alters cardiac function [
] and can trigger acute
pulmonary edema on land [
]. The increase in capillary
transmural pressure is considered a key factor in the
mechanism of IPE occurrence as expected from the
Starling equation [
]. Indeed, on land, NPB-induced
interstitial pulmonary edema is similar to that observed
during finning exercise, i.e., an increase in right
ventricular function without an increase in the left ventricle
function. We proposed, therefore, that the effects of
immersion and NPB might individually alter heart
function and amplify the risks of developing IPE.
During immersion, the rise in peripheral venous return
to the heart induces a release of atrial natriuretic peptide
]. On land, NPB increases transmural pressure
of atrial wall, and triggers ANP release [
an elevated ANP might encourage the development of IPE
because ANP increases capillary permeability [
We, therefore, designed a study to investigate both the
independent and combined effects of (i) inspiratory
breathing pressure setting and (ii) exercising on
cardiovascular physiology and the development of interstitial
Sixteen professional male SCUBA divers were recruited.
All volunteers were healthy and non-smokers and had no
history of cardiovascular or pulmonary disease. Each gave
written informed consent for participation in this study.
The characteristics of these subjects were as follows
(mean ± SD): age 34.4 ± 12.1 year, height 1.84 ± 0.12 m,
and body weight 68.4 ± 7.7 kg. All experimental
procedures were conducted in line with the Declaration of
Helsinki, and the study protocol was approved by the local
Ethics Committee (Comité de Protection des
PersonnesCPP Sud Méditerranée V, ref 16.077). The methods and
potential hazards were explained to participants in detail
before beginning the experiments.
Each diver completed four 30-min air-breathing dives
in a 29 °C freshwater pool, at shallow depth (≈ 1 m). The
four sessions were randomly allocated and 72 h apart.
The divers refrained from exercise and any dive for 24 h
before each experimental session. On each dive, they
wore trunks without a wetsuit and used the same
closed-circuit rebreather SCUBA setting (Triton®, MS3,
Tourves, France) and remained in prone position.
The static conditions (Static) consisted in floating at
rest, breathing with a positive pressure when the
rebreather was attached anteriorly (StPPB), and with a
negative pressure when the rebreather was attached
posteriorly (StNPB) (Fig. 1a, b). During exercise (Exercise),
subjects were asked to fin swim throughout the 30 min
of immersion while maintaining a heart rate (HR) of
110 ± 10 bpm (monitored with a Polar® V800, Finland)
to achieve constant moderate work intensity.
Prior to immersion, resting cardiovascular indices
and the absence of EVLW were assessed based on
cardiopulmonary ultrasonography. During immersion,
ventilatory flow and pressure were continuously
measured in the mouthpiece. Transthoracic
echocardiography was performed immediately after exertion while
still submerged. Lung ultrasound was used to assess
for the presence of EVLW, and a single-breath gas
transfer capacity of the lung (TLCO) was measured.
Pulmonary artery pressure was assessed from the
tricuspid regurgitant jet. Two venous blood samples
were taken from the antecubital vein before and
immediately after immersion.
TLCO was measured prior to immersion and 20 min
after emersion using a computerized Quark Pulmonary
Function Test device (Cosmed, Rome, Italy).
Ultrasonographic examinations were performed using a
Vivid i device (General Electric, Milwaukee, USA) with a
1.3–4.0-MHz array transducer. Cardiac chamber sizes
were assessed according to recent guidelines [
The same device was used to monitor EVLW based
on the number of B-lines or ultrasound lung comet
tails (ULC) counted on images [
] using the
protocol recommended by Gargani et al. [
ULC score was the sum of each B-lines assessed in all
Venous blood samples were drawn to assay plasma
concentrations of adrenaline and noradrenaline with
high-pressure liquid chromatography coupled with
electrochemical detection. The plasma concentrations of
ANP and BNP were also measured as the stoichiometric
pro-peptides whose longer half-lives provide a good
assessment of the cumulated release over a 30-min
period (respectively proANP—using the enzymatic
immunoassay kit Nt-proANP: Biomedica, Wien, Austria,
and proBNP—using the Elecsys Nt-proBNP
immunoassay kit: Roche Diagnostics, Indianapolis, USA).
The work of breathing (WOB) was assessed for every
breath, using a bespoke electronic
pneumo-barotachograph placed between the SCUBA regulator and
the mouthpiece. Assessing the tidal pressure cycle at
the mouth allows calculating the WOB (Joules) from
the area of the pressure-Vt loop. The WOB/Vt defines
the pressure required to perform one unit (L) tidal
volume as suggested by Warkander et al. [
cumulative WOB is the total work done performing the
breathing cycle during each of the 30-min sessions
Statistical analysis was performed with the Prism 6
software (GraphPad Software, La Jolla California
USA). Each subject served as his own control. Data
distribution was assessed using a
Kolmogorov–Smirnov test. For values obtained at four-time points,
two-way repeated-measures analysis of variance
(positive or negative pressure breathing, and rest or fin
exercising immersion) was performed (with the post
hoc Holm–Sidak test) when the data were normally
distributed. For non-normally distributed data,
comparisons relied on a Friedman’s test and on the post
hoc dichotomous comparisons with a Dunn’s test.
Correlations between ULC score and cardiac function
were assessed using Pearson’s test. The same test was
used to assess correlations between cWOB and cardiac
indices. Differences between groups were considered
statistically significant at p < 0.05. All values are
expressed as mean ± SD.
Heart Rate and Ventilatory Status at the End of Each
Session (Table 1)
Mean heart rate was the same 110 min−1 after 30-min
static (resting) dives performed in either positive and
negative pressure breathing condition in line with the
protocol. Tidal volume and breathing rate were similar
during both static and exercise dives and independent of
breathing pressure (Fig. 2a, b). On average, exercise tidal
volume was almost three times the static value while the
breathing rate almost doubled with exercise. Minute
ventilation was the same in the two static sessions and
during the two exercise sessions and about five times
higher during exercise compared with the static dives
(p < 0.001). As expected, the peak inspiratory and
expiratory pressures were dependent on transpulmonary
pressure difference (i.e., the static lung load) both without
and with exercise. Peak inspiratory and expiratory
pressures were slightly but significantly greater at the end of
exercise compared with rest sessions in both PPB and
NPB groups. The tidal and cumulated inspiratory work of
breathing were higher following the static NPB than PPB
dive. Exercise increased the inspiratory WOB twofold with
PPB and threefold with NPB. The cumulated inspiratory
work of breathing over 30 min was increased fourfold
with PPB and fivefold with NPB.
No lung comets were seen prior the dives or after
resting dives, whereas there was an average of 4.2
comets following exercise with PPB and 15.1 comets
with NPB (p < 0.05).
109.8 ± 45.5a
3.5 ± 0.2a
40.3 ± 9.6a
11.5 ± 2.2a
− 27.6 ± 1.58b
− 15.3 ± 1.9b
− 21.4 ± 1.1b
9.5 ± 0.9ab
2.8 ± 0.2b
+ 3345 ± 868ab
15.1 ± 15.3ab
Two-way analysis of variance (ANOVA) with repeated-measures and the post hoc Holm–Sidak test were used to compare values in the four conditions for
Abbreviations: Static dive session simply floating without physical activity, Fin exercise dive with continuous fin swimming, PPB positive pressure breathing
condition caused by positive transpulmonary hydrostatic difference or positive static lung load, NPB negative pressure breathing condition caused by negative
transpulmonary hydrostatic difference or negative static lung load, SLL static lung load, WOB insp. breathing work for one tidal inspiration, WOB/Vt insp. one-cycle
inspiratory work of breathing per volume unit, cWOB work of breathing cumulated over the 30-min session
aExercise different from static dive
bStatic-NPB different from static-PPB, or exercise-NPB different from exercise-PPB
Effects on Venous Return, Right Heart Function, and
Pulmonary Artery Pressure (Table 2 and Fig. 2)
Pre-dive values were no different between the four
sessions, in any variable: diameter of inferior vena cava
(IVCdiam), right atria area (RAa), right ventricle
enddiastolic area (RVEDa), tricuspid annular plane systolic
excursion (TAPSE), and systolic pulmonary artery
pressure (sPAP). Pulmonary artery pressure was calculated
in 11 of the 16 subjects. At the end of static dives,
IVCdiam and RAa were significantly increased by
approximately 20% as compared to pre-dive values, and
sPAP by 80%, in both PPB and NPB conditions. The
end-of-dive TAPSE increased significantly following NPB
session (p < 0.001). In summary, 30-min static dive
triggered a rise in right heart preload and pulmonary arterial
pressure compared with baseline values. In addition, NPB
caused a greater RV contractility (TAPSE) compared with
PPB (p < 0.001).
At the end of exercise dives, the values of IVCdiam,
RAa, RVEDa, TAPSE, and sPAP were all higher than
their pre-dive counterparts and substantially higher than
their static sessions. PPB during exercise markedly
increased venous return, right heart preload, right
ventricle contractility, and pulmonary artery pressure
compared with the resting dives. This confirmed the
changes observed in our previous report where divers
used an open-circuit breathing device in open water
]. Performing an identical exercise level with NPB
amplified these changes in venous return and right heart
preload, triggering the highest TAPSE values and a more
than doubling sPAP as compared to pre-dive assessment
3.2 ± 0.5abc
22.1 ± 3.0abc
28.2 ± 4.5abc
12.7 ± 2.9
55.7 ± 7.3ab
28.6 ± 1.7abc
24.5 ± 2.9abc
(p < 0.0001). These results show a stepwise increasing
loading of right heart and pulmonary vascular bed
through (1) resting immersion, (2) PPB with exercise,
and (3) NPB with exercise.
Effects on Left Heart Function (Table 2)
There were no differences between the four pre-dive
values in left atrial area, left ventricular ejection fraction,
stroke volume, heart rate, end-diastolic and end-systolic
areas of left ventricle, ratio of right to left ventricle areas,
early and E-wave peak velocity and E-wave deceleration
time. Heart rate and cardiac output were lower at the end
of both PPB and NPB static dives than pre-dive (p < 0.001).
Left atrial area was moderately increased after both static
PPB and NPB dives (p < 0.001). Left ventricle end-diastolic
area increased after the NBP dive (p < 0.001), whereas
endsystolic area was unchanged after both dives. The early
filling velocity (E) was higher after the NPB dive (p < 0.035).
The late filling velocity (A) was lower after the PPB dive
(p < 0.024). Both the PPB and NPB dives increased
the E/A ratio (p < 0.042), decreased the early
deceleration time (p < 0.0001), and increased the RV/LV area
ratio (p < 0.015). Exercise dives almost doubled heart rate
and cardiac output in both PPB and NPB (p < 0.0001),
without a change in left ventricular stroke volume.
Plasma Concentrations of Catecholamines and Natriuretic
Peptides and Lung Transfer of Carbon Monoxide (Table 3)
Adrenaline levels decreased after the two static
dives (p < 0.0001) and increased after the exercise dives
4.5 ± 0.5 4.7 ± 0.5 4.7 ± 0.4 4.7 ± 0.5 4.1 ± 0.3a 4.7 ± 0.5 3.9 ± 0.3ab
Plasma concentration was determined before and after each dive. Time-and condition-linked differences in each variable were assessed using
two-way repeated-measures analysis of variance (with the post hoc test).
Static PPB static (rest) dive with positive pressure breathing setting, Static NPB static dive with negative pressure breathing setting, Exercise PPB and
Exercise NPB exercises dives with respectively positive and negative pressure breathing conditions, Nt-proANP N-terminal fraction of pro-atrial natriuretic
peptide, Nt-proBNP N-terminal fraction of pro-brain natriuretic peptide, TLCO lung transfer factor for carbon monoxide, TLCO/VA ratio of lung transfer
factor for carbon monoxide to alveolar volume assessed during the apnea maneuver
aPost-dive different from pre-dive in the same session
bNPB different from PPB
cPost-exercise dive different from post-static dive in similar transpulmonary pressure condition
(p < 0.0001). Plasma noradrenaline was unchanged by the
two static dives but was markedly increased after the
exercise dives (p < 0.0001).
After static dives, Nt-proANP concentrations
increased by approximately threefold compared to the
pre-dive regardless of breathing pressure (p < 0.0001).
Nt-proANP concentrations at the end of PPB and NPB
exercise dive were respectively five and nine times the
pre-dives counterparts (p < 0.0001). Conversely, there
was no change in Nt-proBNP plasma concentration with
Dlco and Dlco/Va were unchanged after both static
immersions but were significantly reduced after the dives
with fin exercise (p < 0.0001). Dlco and Dlco/Va were
significantly lower after ExNPB compared with ExPPB
(p < 0.0001).
The study resulted in four important findings. Firstly, we
showed that SCUBA diving (immersion) at rest causes a
moderate rise in venous return, right heart preload,
vascular pulmonary congestion, and ANP release. These
findings at rest were independent of breathing pressure.
Secondly, exercise combined with PPB breathing
increased the cardiovascular effects (i.e., changes in the
right heart but not left ventricular indices with the
associated right/left heart imbalance) and triggered
significant extravascular lung water accumulation thus
confirming our previous results [
]. Thirdly, each of these
hemodynamic effects as well as the development of
interstitial pulmonary edema during exercise was
substantially amplified by negative pressure breathing.
Fourthly, the cardiovascular changes described
correlated with the number of ultrasound lung comet tails
representing the degree of extravascular lung water
Our findings are important because negative pressure
breathing is frequently encountered during SCUBA diving
16, 17, 30, 31
]. Diving may increase the effort of
breathing due to cold-induced bronchoconstriction, elevated
hydrostatic pressure on the chest wall, and resistance of
air flow through breathing apparatus [
5, 17, 29, 30
]. In the
present study, tidal volumes and breathing frequency
increased during exercise and ventilatory flow rates were
reduced to one third of the value expected during exercise
on land [
22, 29, 30, 32
Significant small increases in IVC diameter, diastolic
right atrial, and ventricle areas were observed during
immersion at rest and without substantial difference
between the PPB and NPB conditions. The systolic
pulmonary artery pressure increased by 80% by immersion
alone and is consistent with direct intravascular
]. These changes were compatible with the
immersion-induced redistribution of systemic venous
blood into the thorax [
]. The compression of limb
muscles by external hydrostatic pressure reduces the
systemic venous volume, forces venous return, and results
in high central venous pressure [
]. A higher central
venous pressure results in increased right ventricular
contractility via the Frank-Starling mechanism and
increases pulmonary artery pressure [
]. A higher
pulmonary artery pressure increases capillary hydrostatic
pressure and predisposes to the development of
interstitial edema [
]. At the end of the dive, the left atrium
was enlarged with a corresponding increase in E/A ratio
and decreased EDT, consistent with elevated left
ventricle filling pressures secondary to the higher
pulmonary artery pressures [
]. After the NPB dive, the
increased RV/LV area ratio, an increased TAPSE, and
elevated E/A ratio each suggest that a right to left preload
imbalance was exacerbated by the negative pressure
breathing (Fig. 2) [
Heart rate and minute ventilation were increased
similarly in both PPB and NPB following dives with exercise.
Lung comet tails, however, were much more numerous
with NPB compared with PPB (Table 1) and correlated
with the imbalance between right and left heart indices
(Fig. 3). NPB substantially amplified the hemodynamic
changes caused by exercise, and these changes also
correlated with accumulation of extravascular lung water.
Exercise increased all the indices linked to venous return
such as the diameter of inferior vena cava and areas of
both right heart chambers. In addition, tricuspid annular
displacement and right ventricular fractional area change
were increased indicating an increased right ventricle
contractility and stroke volume. In contrast, left atrial
cross-sectional area increased only mildly and without
changes in left ventricular end-diastolic area or stroke
volume. The unchanged left ventricular dimensions
concomitant with a markedly enlarged right heart are
consistent with a picture of relative insufficient left heart
output despite the increased right heart preload. In such
a scheme, left atrial pressure would be increased because
of an increased right ventricular contractility. Indeed,
changes in E/A ratio and EDT displayed a pattern of
rapid early filling of left ventricle, indicating increased
left atrial pressure with effort, findings which were more
marked in the NPB group. Differential changes of right
and left cardiac indices suggest an important right to left
stroke volume mismatch and an associated increase in
pulmonary capillary pressure [
]. The large right heart
volume may also limit left ventricular volume within the
pericardial sack and exacerbate the right to left stroke
volume mismatch (ventricular-ventricular interdependence).
In a study by Marabotti et al., E/A values were higher and
EDT was lower during SCUBA breathing at 10 and 5 m
depth than pre- and post-dive in air and described by the
authors as “typical of restrictive left ventricular diastolic
]. Their observations are consistent
with our results.
Plasma noradrenaline levels were increased by exercise
in both the PPB and NPB groups. These changes were
similar to changes seen with exercise in other studies
]. The increases in plasma ANP levels in the NPB
were almost double of the values in PPB group. Such
high plasma ANP levels have not been reported
previously in healthy subjects during exercising in water or
during maximal exercising levels on land [
levels of ANP probably resulted from the unusually high
degree of atrial stretching through the combined effects
of (i) immersion, (ii) exercise, and (iii) negative pressure
breathing. Interestingly, plasma BNP did not change
possibly because there was a no increase in left ventricle
volumes or the exercise duration was sufficient [
Plasma ANP levels correlated with the lung comet tail
score in both exercise sessions (Fig. 3). The elevated
levels of ANP during exercise may have exacerbated
EVLW accumulation by increasing capillary permeability
] or by impeding the lymphatic collection of
interstitial fluid [
] consequently limiting the removal of
interstitial fluid. Finally, the high pressures in vena cava may
also limit pulmonary lymphatic flow from the lymphatic
Pulmonary edema due to negative pressure on land
may develop when a high inspiratory effort generates
large negative intrathoracic and alveolar pressure [
more negative intra-thoracic pressure increases the
dimension of right atria and ventricle, resulting in a fall in
pressure (increasing the vena cava to right atrial pressure
gradient), creating an increase in blood volume
returning to the right heart [
] and right ventricular
contractility through the Frank-Starling mechanism [
combination of a higher pulmonary capillary hydrostatic
pressure and a lower lung interstitial pressure promotes
plasma fluid extravasation initially into interstitial tissues
and then across the alveolar membrane into the alveolar
air space [
We found that combining exercise with negative
pressure breathing produced the highest values of TAPSE
and mitral E/A ratio. The cumulated inspiratory work of
breathing was strongly correlated with right atria area,
plasma ANP concentration, the TAPSE, and the RV/LV
area ratio (Fig. 4), i.e., the variables strongly linked to
right heart preload.
After the NPB dive with exercise, left atrial volume
was only moderately increased but LVEF and SV had
not changed from pre-exercise. The RV/LV ratio was
also strongly correlated with the cumulated work of
breathing (Fig. 4). Recently, we suggested that a
discrepancy between the current stroke volumes in the two
sides of the heart would cause acute pulmonary edema
]. At higher heart rates, a relatively small mismatch
between right and left ventricular stroke volumes will
create extravascular lung water and pulmonary edema
because the volume mismatch per minute is increased
Diving while prone leads to positive pressure
breathing; however, on assuming an upright posture, for
example, while surfacing, the breathing pressure becomes
more negative thus increasing the risk of developing
interstitial edema. Extending the duration and intensity
of exercise also increases the risk of developing
interstitial pulmonary edema (e.g., triathlon) [
authors have suggested genetic variants may lead to
vascular susceptibility to pulmonary edema . The
correlations displayed in Figs. 3 and 4, however, clearly show
the direct coupling between inspiratory effort,
components of heart function, and lung comet score in fit and
SCUBA-trained healthy men.
According to the mechanism outlined in this study,
any undocumented left heart disease could promote the
occurrence of immersed pulmonary edema [
catecholamine release may also cause a stress
]. A higher systemic vascular resistance, as
commonly occurs in essential hypertension, may also
reduce the ability of the left ventricular stroke volume to
increase with effort. The limited increase in left
ventricular stroke volume combined with an unhindered
increase in right ventricular stroke volume with exercise
would promote the development of immersion-induced
pulmonary edema. The higher heart rates of exercise,
furthermore, exacerbate the ventricular imbalance by
increasing the fluid extravasation each minute [
The clinical assessment of divers should carefully
consider the predisposing and precipitating factors such as
left heart disease and hypertension. Similarly, in an
individual who has had a previous episode of
immersion-induced pulmonary edema, careful
considerations surrounding the event and an appropriate cardiac
evaluation should be undertaken before resuming diving
to prevent recurrences.
The study only included 16 individuals but because of
the crossover design, with each individual examined in
eight different conditions, we were able to produce
highly statistically significant results. The study was not
blinded to the participants or ultrasonographer but was
analyzed in a blind fashion by an independent
researcher. Our study did not determine the effects of
depth of a dive; the effects of depth may be important
because the gas density is an important determinant of
breathing work [
29, 30, 32
]. Scores of lung comet tails
have also been found to be increased at the end of
apnea dives either at depth or close to surface when
“struggling” inspiratory efforts developed [
]. In the
latter study, a 50-m dive apnea caused compressive
reduction of lung gas volume and a very large increase in
thoracic blood volume. Diaphragmatic contractions
during free diving cause lowering of airways and
mediastinal pressure similar to the negative transpulmonary
pressure breathing seen in our study. It can be
surmised that the markedly larger increase in lung comet
score found in our study compared with in the apnea
diving study was due to the combination of several
hemodynamic consequences of negative
transpulmonary pressure with larger tidal volumes and of a longer
duration. We only investigated men; we are not able to
comment on the effects in women. We were unable to
determine the independent effects of natriuretic
peptides. Right ventricular fraction area change was used
instead of the ejection fraction because of the
difficulties in calculating the latter by echocardiography. We
did not look for the presence of patent foramen ovale
in our subjects despite its hypothetical protection from
This is the first study, to our knowledge, to assess the
specific impact of exercise on hemodynamics, cardiac
function, and effect of breathing pressures in divers. Our
study showed that immersion at rest causes modest
increases in right heart preload, pulmonary artery
pressures, and an imbalance in right and left ventricular
physiology but without the development of interstitial
pulmonary edema. Negative pressure breathing
combined with exercise resulted in much greater increases in
right heart preload, pulmonary artery systolic pressure, a
greater ventricular mismatch, and worsening interstitial
edema. The changes in right heart preload, right to left
ventricular imbalance, tricuspid annulus displacement,
and pulmonary artery systolic pressures each correlated
with the lung comet score. Positive pressure breathing
diminishes the cardiovascular changes and decreases
the development of interstitial pulmonary edema
We demonstrated that physically fit young and
healthy male divers frequently develop interstitial
pulmonary edema during exercise particularly while
breathing at a negative pressure. Demonstrating the
important influence of breathing pressure on cardiac
function during immersed activities has significant
implications for preventing the potentially catastrophic
condition of immersion-induced pulmonary edema and
drowning. The study also highlights the central role of
the right ventricle and a right heart-left heart mismatch
in generating acute pulmonary edema in cardiovascular
This study was funded by the French Ministry for Defense
(grant No. PMH1-SMO-2-0719).
Availability of Data and Materials
OC, VC, AM, BS, AVD, FXB, and RC contributed to the study design and to
the data collection, data analysis, and interpretation of results. OC, EG, PL, JR,
and DHM contributed to the writing and revision of the manuscript. All
authors read and approved the final manuscript.
Ethics Approval and Consent to Participate
All experimental procedures were conducted in line with the Declaration of
Helsinki, and the study protocol was approved by the local Ethics Committee
(Comité de Protection des Personnes-CPP Sud Méditerranée V, ref. 16.077).
Informed consent was obtained from all individual participants included in
Olivier Castagna, Jacques Regnard, Emmanuel Gempp, Pierre Louge,
François-Xavier Brocq, Bruno Schmid, Anne-Virginie Desruelle, Valentin
Crunel, Adrien Maurin, Romain Chopard, and David MacIver declare that they
have no conflict of interest.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
1. Pons M , Blickenstorfer D , Oechslin E , Hold G , Greminger P , Franzeck UK , et al. Pulmonary oedema in healthy persons during scuba-diving and swimming . Eur Respir J . 1995 ; 8 ( 5 ): 762 - 7 .
2. Bates ML , Farrell ET , Eldridge MW . The curious question of exercise-induced pulmonary edema . Pulm Med . 2011 ; 2011 : 361931 .
3. Koehle MS , Lepawsky M , McKenzie DC . Pulmonary oedema of immersion . Sports Med . 2005 ; 35 ( 3 ): 183 - 90 .
4. Peacher DF , Martina SD , Otteni CE , Wester TE , Potter JF , Moon RE . Immersion pulmonary edema and comorbidities: case series and updated review . Med Sci Sports Exerc . 2015 ; 47 ( 6 ): 1128 - 34 .
5. Pendergast DR , Moon RE , Krasney JJ , Held HE , Zamparo P . Human physiology in an aquatic environment . Compr Physiol . 2015 ; 5 ( 4 ): 1705 - 50 .
6. Wilmshurst PT , Nuri M , Crowther A , Webb-Peploe MM . Cold-induced pulmonary oedema in scuba divers and swimmers and subsequent development of hypertension . Lancet . 1989 ; 1 ( 8629 ): 62 - 5 .
7. Hampson NB , Dunford RG . Pulmonary edema of scuba divers . Undersea Hyperb Med . 1997 ; 24 ( 1 ): 29 - 33 .
8. Shupak A , Weiler-Ravell D , Adir Y , Daskalovic YI , Ramon Y , Kerem D . Pulmonary oedema induced by strenuous swimming: a field study . Respir Physiol . 2000 ; 121 ( 1 ): 25 - 31 .
9. Casey H , Dastidar AG , MacIver D. Swimming-induced pulmonary oedema in two triathletes: a novel pathophysiological explanation . J R Soc Med . 2014 ; 107 ( 11 ): 450 - 2 .
10. Adir Y , Shupak A , Gil A , Peled N , Keynan Y , Domachevsky L , et al. Swimming-induced pulmonary edema: clinical presentation and serial lung function . Chest . 2004 ; 126 ( 2 ): 394 - 9 .
11. Ljubkovic M , Gaustad SE , Marinovic J , Obad A , Ivancev V , Bilopavlovic N , et al. Ultrasonic evidence of acute interstitial lung edema after SCUBA diving is resolved within 2-3h . Respir Physiol Neurobiol . 2010 ; 171 ( 2 ): 165 - 70 .
12. Castagna O , Gempp E , Poyet R , Schmid B , Desruelle AV , Crunel V , et al. Cardiovascular mechanisms of extravascular lung water accumulation in divers . Am J Cardiol . 2017 ; 119 ( 6 ): 929 - 32 .
13. Staub NC , Nagano H , Pearce ML . The sequence of events during fluid accumulation in acute pulmonary edema . Jpn Heart J . 1967 ; 8 ( 6 ): 683 - 9 .
14. Volpicelli G , Skurzak S , Boero E , Carpinteri G , Tengattini M , Stefanone V , et al. Lung ultrasound predicts well extravascular lung water but is of limited usefulness in the prediction of wedge pressure . Anesthesiology . 2014 ; 121 ( 2 ): 320 - 7 .
15. West JB , Mathieu-Costello O . Vulnerability of pulmonary capillaries in heart disease . Circulation . 1995 ; 92 ( 3 ): 622 - 31 .
16. Lundgren CE . Immersion effects . In: Lundgren CE , Miller JN , editors. The lung at depth . New York: Dekker; 1999 . p. 91 - 128 .
17. Moon RE , Cherry AD , Stolp BW , Camporesi EM . Pulmonary gas exchange in diving . J Appl Physiol ( 1985 ). 2009 ; 106 ( 2 ): 668 - 77 .
18. Coulange M , Rossi P , Gargne O , Gole Y , Bessereau J , Regnard J , et al. Pulmonary oedema in healthy SCUBA divers: new physiopathological pathways . Clin Physiol Funct Imaging . 2010 ; 30 ( 3 ): 181 - 6 .
19. Johnson BD , Saupe KW , Dempsey JA . Mechanical constraints on exercise hyperpnea in endurance athletes . J Appl Physiol ( 1985 ). 1992 ; 73 ( 3 ): 874 - 86 .
20. Harms CA , Babcock MA , McClaran SR , Pegelow DF , Nickele GA , Nelson WB , et al. Respiratory muscle work compromises leg blood flow during maximal exercise . J Appl Physiol ( 1985 ). 1997 ; 82 ( 5 ): 1573 - 83 .
21. Warkander DE , Nagasawa GK , Lundgren CE . Effects of inspiratory and expiratory resistance in divers' breathing apparatus . Undersea Hyperb Med . 2001 ; 28 ( 2 ): 63 - 73 .
22. Peacher DF , Pecorella SR , Freiberger JJ , Natoli MJ , Schinazi EA , Doar PO , et al. Effects of hyperoxia on ventilation and pulmonary hemodynamics during immersed prone exercise at 4.7 ATA: possible implications for immersion pulmonary edema . J Appl Physiol ( 1985 ). 2010 ; 109 ( 1 ): 68 - 78 .
23. Lemyze M , Mallat J . Understanding negative pressure pulmonary edema . Intensive Care Med . 2014 ; 40 ( 8 ): 1140 - 3 .
24. MacIver DH , Clark AL . The vital role of the right ventricle in the pathogenesis of acute pulmonary edema . Am J Cardiology . 2015 ; 115 ( 7 ): 992 - 1000 .
25. Epstein M , Norsk P , Loutzenhiser R. Effects of water immersion on atrial natriuretic peptide release in humans . Am J Nephrol . 1989 ; 9 ( 1 ): 1 - 24 .
26. Yalkut D , Lee LY , Grider J , Jorgensen M , Jackson B , Ott C . Mechanism of atrial natriuretic peptide release with increased inspiratory resistance . J Lab Clin Med . 1996 ; 128 ( 3 ): 322 - 8 .
27. Curry FR . Atrial natriuretic peptide: an essential physiological regulator of transvascular fluid, protein transport, and plasma volume . J Clin Inves . 2005 ; 115 ( 6 ): 1458 - 61 .
28. Gargani L , Volpicelli G . How I do it: lung ultrasound . Cardiovasc Ultrasound . 2014 ; 12 : 25 .
29. Warkander DE , Norfleet WT , Nagasawa GK , Lundgren CE . Physiologically and subjectively acceptable breathing resistance in divers' breathing gear . Undersea Biomed Res . 1992 ; 19 ( 6 ): 427 - 45 .
30. Held HE , Pendergast DR . Relative effects of submersion and increased pressure on respiratory mechanics, work, and energy cost of breathing . J Appl Physiol ( 1985 ). 2013 ; 114 ( 5 ): 578 - 91 .
31. Taylor NA , Morrison JB . Static respiratory muscle work during immersion with positive and negative respiratory loading . J Appl Physiol ( 1985 ). 1999 ; 87 ( 4 ): 1397 - 403 .
32. Thalmann ED , Sponholtz DK , Lundgren CE . Effects of immersion and static lung loading on submerged exercise at depth . Undersea Biomed Res . 1979 ; 6 ( 3 ): 259 - 90 .
33. Wester TE , Cherry AD , Pollock NW , Freiberger JJ , Natoli MJ , Schinazi EA , et al. Effects of head and body cooling on hemodynamics during immersed prone exercise at 1 ATA . J Appl Physiol ( 1985 ). 2009 ; 106 ( 2 ): 691 - 700 .
34. Lange L , Lange S , Echt M , Gauer OH . Heart volume in relation to body posture and immersion in a thermo-neutral bath. A roentgenometric study . Pflugers Archiv . 1974 ; 352 ( 3 ): 219 - 26 .
35. Christie JL , Sheldahl LM , Tristani FE , Wann LS , Sagar KB , Levandoski SG , et al. Cardiovascular regulation during head-out water immersion exercise . J Appl Physiol . 1990 ; 69 ( 2 ): 657 - 64 .
36. Moon RE , Martina SD , Peacher DF , Potter JF , Wester TE , Cherry AD , et al. Swimming-induced pulmonary edema: pathophysiology and risk reduction with sildenafil . Circulation . 2016 ; 133 ( 10 ): 988 - 96 .
37. MacIver DH , Adeniran I , MacIver IR , Revell A , Zhang H . Physiological mechanisms of pulmonary hypertension . Am Heart J . 2016 ; 180 : 1 - 11 .
38. Marabotti C , Scalzini A , Menicucci D , Passera M , Bedini R , L ' Abbate A. Cardiovascular changes during SCUBA diving: an underwater Doppler echocardiographic study . Acta Physiol (Oxf) . 2013 ; 209 ( 1 ): 62 - 8 .
39. Connelly TP , Sheldahl LM , Tristani FE , Levandoski SG , Kalkhoff RK , Hoffman MD , et al. Effect of increased central blood volume with water immersion on plasma catecholamines during exercise . J Appl Physiol . 1990 ; 69 ( 2 ): 651 - 6 .
40. Nagashima K , Nose H , Yoshida T , Kawabata T , Oda Y , Yorimoto A , et al. Relationship between atrial natriuretic peptide and plasma volume during graded exercise with water immersion . J Appl Physiol . 1995 ; 78 ( 1 ): 217 - 24 .
41. Perrault H , Cantin M , Thibault G , Brisson GR , Brisson G , Beland M. Plasma atriopeptin response to prolonged cycling in humans . J Appl Physiol ( 1985 ). 1991 ; 70 ( 3 ): 979 - 87 .
42. Sheldahl LM , Tristani FE , Connelly TP , Levandoski SG , Skelton MM , Cowley AW Jr. Fluid-regulating hormones during exercise when central blood volume is increased by water immersion . Am J Phys . 1992 ; 262 ( 5 Pt 2 ): R779 - 85 .
43. Vogelsang TW , Yoshiga CC , Hojgaard M , Kjaer A , Warberg J , Secher NH , et al. The plasma atrial natriuretic peptide response to arm and leg exercise in humans: effect of posture . Exp Physiol . 2006 ; 91 ( 4 ): 765 - 71 .
44. Gempp E , Blatteau JE , Louge P , Drouillard I , Galland FM . N-terminal pro brain natriuretic peptide increases after 1-h scuba dives at 10 m depth . Aviat Space Environ Med . 2005 ; 76 ( 2 ): 114 - 6 .
45. Neilan TG , Januzzi JL , Lee-Lewandrowski E , Ton-Nu TT , Yoerger DM , Jassal DS , et al. Myocardial injury and ventricular dysfunction related to training levels among nonelite participants in the Boston marathon . Circulation . 2006 ; 114 ( 22 ): 2325 - 33 .
46. Scallan JP , Davis MJ , Huxley VH . Permeability and contractile responses of collecting lymphatic vessels elicited by atrial and brain natriuretic peptides . J Physiol . 2013 ; 591 (Pt 20): 5071 - 81 .
47. Lloyd TC Jr. Control of breathing in anesthetized dogs by a left-heart baroreflex . J Appl Physiol ( 1985 ). 1986 ; 61 ( 6 ): 2095 - 101 .
48. Buda AJ , Pinsky MR , Ingels NB Jr, Daughters GT 2nd, Stinson EB , Alderman EL . Effect of intrathoracic pressure on left ventricular performance . New Engl J Med . 1979 ; 301 ( 9 ): 453 - 9 .
49. Staub NC , Nagano H , Pearce ML . Pulmonary edema in dogs, especially the sequence of fluid accumulation in lungs . J Appl Physiol . 1967 ; 22 ( 2 ): 227 - 40 .
50. Shupak A , Guralnik L , Keynan Y , Yanir Y , Adir Y. Pulmonary edema following closed-circuit oxygen diving and strenuous swimming . Aviat Space Environ Med . 2003 ; 74 ( 11 ): 1201 - 4 .
51. Cialoni D , Marabotti C , Sponsiello N , Pieri M , Balestra C , Lucchini V , Marroni A . Genetic predisposition to breath-hold diving-induced hemoptysis: preliminary study . Undersea Hyperb Med . 2015 ; 42 ( 1 ): 75 - 83 .
52. Chenaitia H , Coulange M , Benhamou L , Gerbeaux P . Takotsubo cardiomyopathy associated with diving . Eur J Emerg Med . 2010 ; 17 ( 2 ): 103 - 6 .
53. Lambrechts K , Germonpré P , Charbel B , Cialoni D , Musimu P , Sponsiello N , Marroni A , Pastouret F , Balestra C . Ultrasound lung “comets” increase after breath-hold diving . Eur J Appl Physiol . 2011 ; 111 : 707 - 13 .