Echocardiographic detection of transpulmonary bubble transit during acute respiratory distress syndrome
Boissier et al. Annals of Intensive Care
Echocardiographic detection of transpulmonary bubble transit during acute respiratory distress syndrome
Florence Boissier 0 1 2 3 4
Keyvan Razazi 1 4
Arnaud W Thille 1 4 8
Ferran Roche-Campo 1 4 7
Rusel Leon 1 4 6
Emmanuel Vivier 1 4 5
Laurent Brochard 9
Christian Brun-Buisson 0 1 2 3 4
Armand Mekontso Dessap 0 1 2 3 4
0 INSERM, Unite U955 (IMRB) , 8 rue du General Sarrail, Creteil 94010 , France
1 AP-HP, Hopital Henri Mondor, DHU A-TVB, Service de Reanimation Medicale, Groupe de recherche CARMAS, 51 Av Mal de Lattre de Tassigny , Creteil 94010 , France
2 Faculte de Medecine, Universite Paris Est Creteil , 8, rue du General Sarrail, Creteil 94010 , France
3 INSERM, Unite U955 (IMRB) , 8 rue du General Sarrail, Creteil 94010 , France
4 AP-HP, Hopital Henri Mondor, DHU A-TVB, Service de Reanimation Medicale, Groupe de recherche CARMAS, 51 Av Mal de Lattre de Tassigny , Creteil 94010 , France
5 Centre Hospitalier Saint Luc Saint Joseph , Reanimation Polyvalente, 20, quai Claude Bernard, 69007 Lyon , France
6 Centre Hospitalier Intercommunal de Creteil , Reanimation polyvalente, 40 avenue de Verdun, 94010 Creteil , France
7 Servei de Medicina Intensiva, Hospital Verge de la Cinta , Carrer de les Esplanetes, 14, 43500 Tortosa, Tarragona , Spain
8 CHU de Poitiers , Reanimation medicale, Poitiers , France; INSERM CIC 1402 (equipe 5 ALIVE), Universite de Poitiers , 2 Rue de la Miletrie, 86021 Poitiers , France
9 Saint Michael's Hospital , 30 Bond Street, ON M5B 1 W8 Toronto , Canada
Background: Transpulmonary bubble transit (TPBT) detected with contrast echocardiography is reported as a sign of intrapulmonary shunt during cirrhosis or exercise in healthy humans. However, its physiological meaning is not clear during acute respiratory distress syndrome (ARDS). Our aim was to determine the prevalence, significance, and prognosis of TPBT detection during ARDS. Methods: This was a prospective observational study in an academic medical intensive care unit in France. Two hundred and sixteen consecutive patients with moderate-to-severe ARDS underwent transesophageal echocardiography with modified gelatine contrast. Moderate-to-large TPBT was defined as right-to-left passage of at least ten bubbles through a pulmonary vein more than three cardiac cycles after complete opacification of the right atrium. Patients with intra-cardiac shunt through patent foramen ovale were excluded. Results: The prevalence of moderate-to-large TPBT was 26% (including 42 patients with moderate and 15 with large TPBT). Patients with moderate-to-large TPBT had higher values of cardiac index and heart rate as compared to those without TPBT. There was no significant difference in PaO2/FIO2 ratio between groups, and TPBT was not influenced by end-expiratory positive pressure level in 93% of tested patients. Prevalence of septic shock was higher in the group with moderate-to-large TPBT. Patients with moderate-to-large TPBT had fewer ventilator-free days and intensive care unit-free days within the first 28 days, and higher in-hospital mortality as compared to others. Conclusions: Moderate-to-large TPBT was detected with contrast echocardiography in 26% of patients with ARDS. This finding was associated with a hyperdynamic and septic state, but did not influence oxygenation.
Echocardiography; Acute respiratory distress syndrome; Shunt
Determinants of hypoxemia during acute respiratory
distress syndrome (ARDS) are multiple. They may include
effect of low mixed venous oxygen tension (PvO2) on
arterial oxygen tension , intra-cardiac right-to-left shunt
, low ventilation-perfusion ratio , or
intrapulmonary shunt . Intrapulmonary shunt during ARDS may
result from perfused but non-aerated lung areas
secondary to dilated pulmonary vessels or to alveolar edema
and collapse. Areas of alveolar edema and collapse
predominate in the basal and dependant regions of the lung.
Mechanical ventilation and positive end-expiratory
pressure (PEEP) may alter the distribution of ventilation and
perfusion and the magnitude of intrapulmonary shunt
[4,5]. Measurement of intrapulmonary shunt could help
assessing ARDS severity and the effect of some
therapeutic interventions on perfused but non-aerated lung
areas. Intrapulmonary shunt measurement is difficult,
and two main methods have been evaluated: estimation
of functional shunt (using Rileys venous admixture Qs/Qt)
 and estimation of anatomical shunt (using multiple
inert gas technique  or lung computed tomography
Contrast echocardiography is able to detect
transpulmonary bubble transit (TPBT) at bedside. This method
is routinely used to detect physiological intrapulmonary
shunt in healthy humans at rest  or during exercise
 and hepato-pulmonary syndrome in cirrhosis .
However, TPBT may not be strictly ascribable to
intrapulmonary shunt in the context of ARDS. The objectives
of our study were to determine the prevalence,
physiological significance, and prognosis of TPBT detected with
contrast echocardiography during ARDS. This study
includes some patients previously described in reports
focusing on patent foramen ovale and acute cor pulmonale
during ARDS [2,12].
Patients who met the Berlin definition criteria for
moderateto-severe ARDS (respiratory failure within 1 week of a
known clinical insult or new or worsening respiratory
symptoms; with bilateral chest opacities not fully
explained by effusions or lobar/lung collapse or nodule, and
not fully explained by cardiac failure or fluid overload; and
a PaO2/FiO2 ratio 200 mmHg with PEEP 5 cmH2O)
 and who underwent transesophageal
echocardiography (TEE) within the first three days after the diagnosis
were included prospectively between June 2004 and
August 2011 at the medical intensive care unit (ICU) of
Henri Mondor Hospital (Creteil, France). Non-inclusion
criteria were contraindications to TEE (esophageal disease
or major uncontrolled bleeding), and chronic
pulmonary disease requiring long-term oxygen therapy or home
mechanical ventilation. The study was approved by the
institutional ethics committee of the French Society
of Intensive Care (Socit de Ranimation de Langue
Franaise). Because we routinely use TEE to assess the
circulatory status of mechanically ventilated patients with
ARDS in our ICU, TEE was considered a component of
standard care and patients consent was waived. Written
and oral information about the study was given to
the families. Follow-up for the study was until hospital
Ventilation was in volume-assist control mode, with a
target tidal volume (VT) of 6 mL/kg of predicted body weight.
In patients with persistent severe hypoxemia (PaO2/FiO2 <
100 mmHg) despite a PEEP level as high as possible
without exceeding a maximal inspiratory plateau pressure
(Pplat) of 28 to 30 cmH2O , prone positioning and/or
inhaled nitric oxide were used at the discretion of the
attending physician. If Pplat exceeded the maximal
threshold, VT could be lowered until Pplat was less than 30
cmH2O; to counterbalance the effect of VT reduction on
alveolar ventilation, the respiratory rate was increased to
the highest rate that did not induce intrinsic PEEP .
Driving pressure was defined as the difference between
Pplat and PEEP. Oxygenation index was computed as
FiO2*[(2*plateau pressure + PEEP)/3]/PaO2 .
TEE was performed using a Sonos 5500, Envisor, or a IE 33
system (Philips Ultrasound, Bothell, WA, USA) equipped
with a multiplane 5-MHz transesophageal
echocardiographic transducer, by trained operators (competence in
advanced critical care echocardiography) , using a
standard procedure . Briefly, the following
echocardiographic views were examined: long-axis M-mode view of
the superior vena cava (SVC) to assess its collapsibility;
four-chamber long-axis view to assess the end-diastolic
right ventricle/left ventricle (RV/LV) area ratio and LV
ejection fraction; short-axis view of the LV via the
transgastric approach to evaluate the kinetics of the
interventricular septum. Pulsed-wave Doppler aortic flow was
obtained at the level of the aortic annulus, and the
velocitytime integral was automatically processed by tracing the
envelope of aortic flow for cardiac index calculation.
Cor pulmonale was defined as a dilated right ventricle
(end-diastolic RV/LV area ratio >0.6) associated with
paradoxical septal motion on the short-axis view .
Echocardiographic images were recorded, and a
computerassisted evaluation was performed off-line by two trained
senior sonographers (FB, AMD). When possible,
transthoracic echocardiography was also performed to assess
pulmonary artery systolic pressure (PASP), using the
tricuspid regurgitation continuous-wave Doppler
technique. Undetectable values of tricuspid regurgitation
were assigned a PASP value lower than any actually
measured during the study (20 mmHg). A longitudinal
view of the fossa ovalis was obtained to evaluate
right-toleft shunting by injecting 9.5 mL of sterile-modified
fluid gelatine solution (Plasmion [Fresenius-Kabi, Sevres,
France] or Gelofusine 4% [B-Braun Medical,
BoulogneBillancourt, France]) aerated with 0.5 mL of room air via
two syringes connected with a three-way stopcock, as
previously described [2,11]. The injection was considered
successful if the entire right atrium was opacified with
microbubble-induced contrast. Up to three successful
contrast studies were performed on each patient. Patent
foramen ovale (PFO) shunting was defined as right-to-left
passage of bubbles through a valve-like structure within
three cardiac cycles after complete opacification of the
right atrium [2,17]. TPBT was defined as right-to-left
passage of bubbles through a pulmonary vein more than
three cardiac cycles after complete opacification of the
right atrium . TPBT was considered minor, moderate,
or large for the passage of one to ten bubbles, ten to 30
bubbles, or more than 30 bubbles, respectively. When
the clinical condition and plateau pressure allowed,
contrast TEE was repeated after decreasing or increasing
the PEEP level.
The data were analysed using the SPSS Base 13.0
statistical software package (SPSS Inc., Chicago, IL, USA).
Continuous data were expressed as mean standard
deviation, unless otherwise specified and were compared
using the Mann-Whitney test for two groups comparison.
For subgroups analysis, continuous data were compared
using the Kruskal-Walis test followed by pairwise
Mann-Whitney test with Benjamini-Hochberg
correction. Categorical variables, expressed as percentages, were
evaluated using the chi-square test or Fisher exact test.
Two-tailed p values <0.05 were considered significant.
A total of 265 ARDS patients underwent contrast TEE.
Forty-nine patients were excluded because of inconclusive
contrast study (n = 7) or patent foramen ovale (n = 42).
Thus, the present study includes 216 patients (150 men
and 66 women), with a median age of 63 (50 to 76) years.
Moderate-to-large TPBT was detected in 57 patients
(prevalence of 26%; 95% confidence interval 20% to 32%).
Among the 159 patients without significant TPBT, 120
had no TPBT and 39 had a minor TPBT.
Clinical and echocardiographic findings
Patients with moderate-to-large TPBT were not
significantly different from others regarding clinical
characteristics (Table 1). The time elapsed between ARDS onset
and TEE was similar in patients with moderate-to-large
TPBT as compared to others (0.9 0.9 vs. 0.8 1.0 days,
p = 0.30). Respiratory settings and arterial blood gases at
TEE day were not different between groups except for a
lower tidal volume. Prevalence of septic shock was higher
in the group with moderate-to-large TPBT (Table 1).
Hemodynamic and echocardiographic variables were
similar between groups except for lower values of E/A
ratio and higher values of cardiac index, heart rate, and
superior vena cava collapsibility in patients with
moderateto-large TPBT as compared to others (Table 2). In a
subgroup analysis scrutinizing patients with moderate vs.
large TPBT, cirrhosis was more prevalent in patients with
large TPBT, and PaCO2 values were higher in those with
moderate TPBT as compared to others (Table 3).
Effect of PEEP level on TPBT
We studied the effect of PEEP-level changes (7 [5-10]
cmH2O vs. 15  cmH2O) in 80 patients. TPBT was
similar with lower and higher PEEP in the majority (n = 74,
93%) of patients (including 57 with absent-or-minor TPBT,
and 17 with moderate-to-large TPBT). TPBT was moderate
at lower PEEP but minor at higher PEEP in one patient;
conversely, TPBT was moderate at lower PEEP but large at
higher PEEP in one patient and minor at lower PEEP but
moderate at higher PEEP in four patients.
The outcome of patients according to TPBT is displayed
in Table 4. The proportion of patients managed during
the ICU stay with prone positioning and/or nitric oxide
as adjunctive therapy for severe hypoxemia was similar
between the groups. The pneumothorax rate during the
ICU stay was not different between the groups. There was
a trend towards increased ICU mortality rates and a
significant increase in hospital mortality rates in patients with
moderate-to-large TPBT. Among ICU survivors,
mechanical ventilation (MV) duration and ICU duration were
longer in patients with moderate-to-large TPBT (Table 4).
The main finding of our study was that moderate-to-large
TPBT was detected with contrast echocardiography in
26% of patients with ARDS. TPBT was associated with
higher cardiac index, longer mechanical ventilation
duration and intensive care unit stay, and higher hospital
mortality. There was no obvious relation with end-expiratory
pressure level nor oxygenation.
Choice of contrast solution
Studies evaluating TPBT with contrast echocardiography
mainly used saline  or gelatine [11,21] contrast
solution. We chose gelatine solution because it is superior to
saline for the opacification of cardiac chambers .
However, the size of colloid micro-bubbles is smaller (12 10
m) than those of saline contrast (24 to 180 m) .
Because the normal size of pulmonary capillaries is estimated
around 8 m, some gelatine bubbles could theoretically
transit through non-dilated pulmonary capillaries . A
suspension of soluble monosaccaride micro-particles with
a median bubble size of 3 m was used to detect TPBT in
20% of stroke patients . This confirms the fact that
even bubbles smaller than non-dilated pulmonary
capillaries may not cross the pulmonary circulation in all patients.
Applying the classification of gelatine-bubble transit
proposed by Vedrinne et al.  (grade 0, no microbubble in
the left atrium; grade 1, a few bubbles in the left atrium;
grade 2, moderate bubbles without complete filing of the
left atrium; grade 3, many bubbles filing the left atrium
completely; and grade 4, extensive bubbles as dense as in
the right atrium) to our cohort would result in no grade 3
or 4 TPBT. Other studies have used the threshold of 3
saline bubbles transit to detect intrapulmonary shunt in
healthy humans during exercise . As we detected
TPBT with gelatin contrast solution, our conclusions may
not be transposable with the use of saline. Whether the
Table 1 Clinical and respiratory characteristics of patients with acute respiratory distress syndrome according to
transpulmonary bubble transit
use of both contrast solutions could help distinguish
between intrapulmonary shunt due to pulmonary capillary
distention versus intrapulmonary arteriovenous shunts
needs further studies.
Mechanisms of TPBT
Detection of transpulmonary transit of small-sized bubbles
may result from several mechanisms, including transit
through perfused but non-aerated lung areas, transit
through dilated capillaries, or opening of dynamic
intrapulmonary arteriovenous anastomosis.
Non-aerated lung areas as a result of lung edema are a
hallmark of ARDS. In our study, patients with large TPBT
tended to have a more severe ARDS, as attested by a trend
towards a lower compliance and a higher plateau and
driving pressure despite lower tidal volumes. Because of
Table 2 Hemodynamic and echocardiographic variables in patients with acute respiratory distress syndrome according
to transpulmonary bubble transit
Heart rate/respiratory rate ratio
Systolic arterial pressure, mmHg
Mean arterial pressure, mmHg
Superior vena cava respiratory collapsibility, %
Maximum atrial septal excursion, mm
LV systolic function
Cardiac index, L/min/m2
Systolic pulmonary artery pressure, mmHg
Acute cor pulmonale, n (%)
aN, number of patients in which the parameter could be assessed; bhemodynamic variables were recorded at the time of transesophageal echocardiography;
PEEP, positive end-expiratory pressure; E/A ratio, ratio of early (E) over late (A) peak velocities at the mitral valve; LV, left ventricle.
their small size, we cannot exclude that bubbles may
have transited through normal-sized capillaries,
especially in perfused but non-ventilated areas. Patients with
moderate-to large TPBT had a lower tidal volume as
compared to others. One hypothesis could be a lesser
compression of intra-alveolar capillaries leading to greater
The size distribution of pulmonary capillaries during
ARDS is not precisely known, but nests of dilated
capillaries that abnormally admitted contrast medium into
the pulmonary veins were reported in post-mortem
arteriogram studies . Sepsis may enhance pulmonary
vessels vasodilatation through prostanoids  or the
nitric oxide pathway . In healthy humans, exercise and
hypoxia may induce opening of intrapulmonary
arteriovenous anastomosis (IPAV) . IPAV opening is also
enhanced by supine position , and catecholamine
infusion . To date, the precise magnitude of IPAV during
ARDS is unknown, and the importance of blood flow
through these anastomoses to the efficiency of pulmonary
gas exchange remains controversial .
In subgroup analysis, cirrhosis was more prevalent in
patients with large TPBT. Cirrhotic patients exhibit
vasodilatation of pulmonary pre-capillary and capillary
vessels (possibly triggered by enhanced pulmonary
production of nitric oxide ), leading to arteriovenous
communications, intrapulmonary shunt, and the
hepatopulmonary syndrome. Increased blood flow through these
dilated capillaries is further enhanced by the impairment
of hypoxic vasoconstriction.
Role of cardiac index
Septic shock was more frequent in patients with
moderateto-large TPBT in our study and probably explains the
association with higher values of heart rate, cardiac index,
and features of hypovolemia (collapsibility of superior
vena cava and lower E/A ratio). These latest features were
not associated with lower cardiac index, probably
because heart rate was also higher. Tachycardia may
increase TPBT via a decrease in pulmonary capillary transit
time . Previous reports in experimental models of
acute lung injury , healthy humans , and ARDS
patients [35-37] showed an increase in intrapulmonary
shunt with increased cardiac output via capillary
distension  and/or recruitment [39,40], especially in
nonventilated lung regions. It is, however, difficult to conclude
whether higher cardiac output is a cause or a
consequence of intrapulmonary shunt, because severe
dilatation or arteriovenous anastomosis could theoretically
lead to higher cardiac index via an alleviation of
pulmonary vascular resistances. In subgroup analysis,
moderate TPBT was associated with hypercapnia. Hypercapnia
Plateau pressure, cmH2O
Driving pressure, cmH2O
Arterial blood gases$
PaO2/FiO2 ratio, mmHg
ARDS, acute respiratory distress syndrome; *44; #respiratory settings were recorded at the time of transesophageal echocardiography; PEEP, positive end-expiratory
pressure; $blood gases were recorded on the day of transesophageal echocardiography (latest available before echocardiography) and the proportion of patients
receiving nitric oxide and prone position on the TEE day was similar in the groups with large, moderate, or absent to minor TPBT (2 [13.3%] vs. 9 [21.4%] vs. 22 [13.9%],
p = 0.48; and 1 [6.7%] vs. 7 [16.7%] vs. 22 [13.8%], p = 0.63, respectively); ap value <0.05 (corrected Mann-Whitney test after Kruskal-Wallis test) as compared to absent to
minor transpulmonary bubble transit; bP value <0.05 (corrected Mann-Whitney test after Kruskal-Wallis test) as compared to moderate transpulmonary bubble transit.
has been previously shown to exert a vasoconstrictive
effect on pulmonary circulation, but may also increase
cardiac output (through peripheral arterial vasodilation) and
intrapulmonary shunt .
Contrary to our expectations, PaO2/FiO2 ratio did not
differ between groups with or without TPBT. Numerous
factors influence oxygenation during ARDS, including
intrapulmonary shunt, but also effect of low PvO2 on
PaO2 , intra-cardiac right-to-left shunt (patients with
patent foramen ovale shunting were excluded from the
study) , and low ventilation-perfusion ratio . Higher
cardiac index increases intrapulmonary shunt, but also
PvO2, and the net effect on PaO2 may vary from one
patient to another. Moreover, PaO2/FiO2 ratio depends on
Table 4 Outcome of patients with acute respiratory distress syndrome according to transpulmonary bubble transit
(n = 86)
Pneumothorax, n (%)
Adjunctive therapy, n (%)
ICU mortality, n (%)
Hospital mortality, n (%)
28-day ventilator-free days, mean SD
28-day ICU-free days, mean SD
ICU survivors (n = 109)
MV duration, mean days SD
ICU duration, mean days SD
ICU, intensive care unit; MV, mechanical ventilation; SD, standard deviation.
FiO2 in a non-linear relationship which is influenced by
the severity of shunt . Increased PEEP levels did not
alter TPBT magnitude in the vast majority of patients
tested (92.5%), whereas TPBT was lessened or enhanced
in rare cases. Higher PEEP levels may decrease shunt via
improved lung recruitment and/or decreased cardiac
output. However, these two mechanisms may be
inversely related during ARDS . In addition, higher
PEEP levels could act differently on the size of
pulmonary capillaries depending on their location, with collapse
of intra-alveolar vessels and dilation of extra-alveolar
capillaries , leading to opposite effects on
intrapulmonary shunt. Last, alteration of oxygenation may require
more severe intrapulmonary shunts than those observed
in the present study.
TPBT was associated with longer duration of
mechanical ventilation and ICU stay. No significant difference in
ICU mortality was found, but hospital mortality was
higher in the group of patients with moderate-to-large
TPBT. The latter finding could be explained by a poorer
condition after longer mechanical ventilation and ICU
stay. Septic shock, which was more frequent in patients
with moderate-to-large TPBT in our study, could also
explain these findings.
Limitations of this study include its mono-centric design
and the seven-year period inclusion. However, our
mechanical ventilation strategy did not vary during the study
period. Second, we only report on a single TEE within
three days of ARDS start. Third, we did not measure
cardiac output and lung recruitment during PEEP changes.
Fourth, we did not compare contrast TEE with other
methods of measurement of shunt, such as measurement
of venous admixture using a pulmonary arterial catheter,
(n = 23)
and as previously stated, detection of TPBT cannot be
used as a direct surrogate of intrapulmonary shunt. Fifth,
we did not explore TPBT in other ICU patients without
ARDS and could not report on its general prevalence in
critically ill patients and during mechanical ventilation or
sepsis. In physiological studies performed in healthy
humans, TPBT could be detected during exercise but not
at rest [9,10].
In conclusion, we report the first evaluation of contrast
echocardiography to detect TPBT in the setting of
ARDS. Although moderate-to-large TPBT was identified
in 26% of patients, we did not detect any massive TPBT
in this setting. TPBT did not influence oxygenation, and
may not be used as a direct surrogate of intrapulmonary
shunt during ARDS. TPBT was mainly associated with a
hyperdynamic hemodynamic status and septic shock.
Whether TPBT is present in ventilated patients with
septic shock but not ARDS requires further studies.
ARDS: acute respiratory distress syndrome; ICU: intensive care unit;
IPAV: intrapulmonary arteriovenous anastomosis; LV: left ventricle;
MV: mechanical ventilation; PASP: pulmonary artery systolic pressure;
PEEP: positive end-expiratory pressure; PFO: patent foramen ovale;
Pplat: plateau pressure; RV: right ventricle; SVC: superior vena cava;
TEE: transesophageal echocardiography; TPBT: transpulmonary bubble transit;
Vt: tidal volume.
The authors declare that they have no competing interests.
AMD designed the study. FB, AMD, KR, AWT, FRC, RL, and EV performed TEE
and collected data. FB and AMD evaluated echocardiographic images off-line,
analysed the data, and wrote the article. LB and CBB supervised the study and
revised the manuscript. All authors read and approved the final manuscript.
1. Kelman GR , Nunn JF , Prys-Roberts C , Greenbaum R. The influence of cardiac output on arterial oxygenation: a theoretical study . Br J Anaesth . 1967 ; 39 ( 6 ): 450 - 8 .
2. Mekontso Dessap A , Boissier F , Leon R , Carreira S , Campo FR , Lemaire F , et al. Prevalence and prognosis of shunting across patent foramen ovale during acute respiratory distress syndrome . Crit Care Med . 2010 ; 38 ( 9 ): 1786 - 92 .
3. Dantzker DR , Brook CJ , Dehart P , Lynch JP , Weg JG . Ventilation-perfusion distributions in the adult respiratory distress syndrome . Am Rev Respir Dis . 1979 ; 120 ( 5 ): 1039 - 52 .
4. Matamis D , Lemaire F , Harf A , Teisseire B , Brun-Buisson C. Redistribution of pulmonary blood flow induced by positive end-expiratory pressure and dopamine infusion in acute respiratory failure . Am Rev Respir Dis . 1984 ; 129 ( 1 ): 39 - 44 .
5. Ralph DD , Robertson HT , Weaver LJ , Hlastala MP , Carrico CJ , Hudson LD . Distribution of ventilation and perfusion during positive end-expiratory pressure in the adult respiratory distress syndrome . Am Rev Respir Dis . 1985 ; 131 ( 1 ): 54 - 60 .
6. Riley RL , Cournand A. Ideal alveolar air and the analysis of ventilation-perfusion relationships in the lungs . J Appl Physiol . 1949 ; 1 ( 12 ): 825 - 47 .
7. Wagner PD , Saltzman HA , West JB . Measurement of continuous distributions of ventilation-perfusion ratios: theory . J Appl Physiol . 1974 ; 36 ( 5 ): 588 - 99 .
8. Cressoni M , Caironi P , Polli F , Carlesso E , Chiumello D , Cadringher P , et al. Anatomical and functional intrapulmonary shunt in acute respiratory distress syndrome . Crit Care Med . 2008 ; 36 ( 3 ): 669 - 75 .
9. Laurie SS , Yang X , Elliott JE , Beasley KM , Lovering AT. Hypoxia-induced intrapulmonary arteriovenous shunting at rest in healthy humans . J Appl Physiol ( 1985 ). 2010 ; 109 ( 4 ): 1072 - 9 .
10. Lovering AT , Romer LM , Haverkamp HC , Pegelow DF , Hokanson JS , Eldridge MW . Intrapulmonary shunting and pulmonary gas exchange during normoxic and hypoxic exercise in healthy humans . J Appl Physiol ( 1985 ). 2008 ; 104 ( 5 ): 1418 - 25 .
11. Vedrinne JM , Duperret S , Bizollon T , Magnin C , Motin J , Trepo C , et al. Comparison of transesophageal and transthoracic contrast echocardiography for detection of an intrapulmonary shunt in liver disease . Chest . 1997 ; 111 ( 5 ): 1236 - 40 .
12. Boissier F , Katsahian S , Razazi K , Thille AW , Roche-Campo F , Leon R , et al. Prevalence and prognosis of cor pulmonale during protective ventilation for acute respiratory distress syndrome . Intensive Care Med . 2013 ; 39 ( 10 ): 1725 - 33 .
13. Ranieri VM , Rubenfeld GD , Thompson BT , Ferguson ND , Caldwell E , Fan E , et al. Acute respiratory distress syndrome: the Berlin definition . JAMA . 2012 ; 307 ( 23 ): 2526 - 33 .
14. Mercat A , Richard JC , Vielle B , Jaber S , Osman D , Diehl JL , et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial . JAMA . 2008 ; 299 ( 6 ): 646 - 55 .
15. Mekontso Dessap A , Charron C , Devaquet J , Aboab J , Jardin F , Brochard L , et al. Impact of acute hypercapnia and augmented positive end-expiratory pressure on right ventricle function in severe acute respiratory distress syndrome . Intensive Care Med . 2009 ; 35 ( 11 ): 1850 - 8 .
16. Trachsel D , McCrindle BW , Nakagawa S , Bohn D. Oxygenation index predicts outcome in children with acute hypoxemic respiratory failure . Am J Respir Crit Care Med . 2005 ; 172 ( 2 ): 206 - 11 .
17. Mayo PH , Beaulieu Y , Doelken P , Feller-Kopman D , Harrod C , Kaplan A , et al. American college of chest physicians/La Societe de reanimation de langue Francaise statement on competence in critical care ultrasonography . Chest . 2009 ; 135 ( 4 ): 1050 - 60 .
18. Vieillard-Baron A , Charron C , Chergui K , Peyrouset O , Jardin F. Bedside echocardiographic evaluation of hemodynamics in sepsis: is a qualitative evaluation sufficient? Intensive Care Med . 2006 ; 32 ( 10 ): 1547 - 52 .
19. Jardin F , Dubourg O , Bourdarias JP . Echocardiographic pattern of acute cor pulmonale . Chest . 1997 ; 111 ( 1 ): 209 - 17 .
20. Fischer CH , Campos O , Fernandes WB , Kondo M , Souza FL , De Andrade JL , et al. Role of contrast-enhanced transesophageal echocardiography for detection of and scoring intrapulmonary vascular dilatation . Echocardiography . 2010 ; 27 ( 10 ): 1233 - 7 .
21. Siostrzonek P , Zangeneh M , Gossinger H , Lang W , Rosenmayr G , Heinz G , et al. Comparison of transesophageal and transthoracic contrast echocardiography for detection of a patent foramen ovale . Am J Cardiol . 1991 ; 68 ( 11 ): 1247 - 9 .
22. Tan HC , Fung KC , Kritharides L. Agitated colloid is superior to saline and equivalent to levovist in enhancing tricuspid regurgitation Doppler envelope and in the opacification of right heart chambers: a quantitative, qualitative, and cost-effectiveness study . J Am Soc Echocardiogr . 2002 ; 15 ( 4 ): 309 - 15 .
23. Nemec JJ , Marwick TH , Lorig RJ , Davison MB , Chimowitz MI , Litowitz H , et al. Comparison of transcranial Doppler ultrasound and transesophageal contrast echocardiography in the detection of interatrial right-to-left shunts . Am J Cardiol . 1991 ; 68 ( 15 ): 1498 - 502 .
24. Butler BD , Hills BA . The lung as a filter for microbubbles . J Appl Physiol Respir Environ Exerc Physiol . 1979 ; 47 ( 3 ): 537 - 43 .
25. Horner S , Ni XS , Weihs W , Harb S , Augustin M , Duft M , et al. Simultaneous bilateral contrast transcranial doppler monitoring in patients with intracardiac and intrapulmonary shunts . J Neurol Sci . 1997 ; 150 ( 1 ): 49 - 57 .
26. Tomashefski Jr JF , Davies P , Boggis C , Greene R , Zapol WM , Reid LM . The pulmonary vascular lesions of the adult respiratory distress syndrome . Am J Pathol . 1983 ; 112 ( 1 ): 112 - 26 .
27. Myers TP , Myers PR , Adams HR , Parker JL . Enhanced prostanoid-mediated vasorelaxation in pulmonary arteries isolated during experimental endotoxemia . Shock . 1999 ; 11 ( 6 ): 436 - 42 .
28. Spohr F , Cornelissen AJ , Busch C , Gebhard MM , Motsch J , Martin EO , et al. Role of endogenous nitric oxide in endotoxin-induced alteration of hypoxic pulmonary vasoconstriction in mice . Am J Physiol Heart Circ Physiol . 2005 ; 289 ( 2 ): H823 - 31 .
29. Stickland MK , Welsh RC , Haykowsky MJ , Petersen SR , Anderson WD , Taylor DA , et al. Intra-pulmonary shunt and pulmonary gas exchange during exercise in humans . J Physiol . 2004 ; 561 (Pt 1): 321 - 9 .
30. Lovering AT , Riemer RK , Thebaud B. Intrapulmonary arteriovenous anastomoses: physiol , pathophysiol both? Ann Am Thorac Soc . 2013 ; 10 ( 5 ): 504 - 8 .
31. Rodriguez-Roisin R , Krowka MJ . Hepatopulmonary syndrome-a liver-induced lung vascular disorder . N Engl J Med . 2008 ; 358 ( 22 ): 2378 - 87 .
32. Lindstedt SL . Pulmonary transit time and diffusing capacity in mammals . Am J Physiol . 1984 ; 246 ( 3 Pt 2 ): R384 - 8 .
33. Freden F , Cigarini I , Mannting F , Hagberg A , Lemaire F , Hedenstierna G. Dependence of shunt on cardiac output in unilobar oleic acid edema: distribution of ventilation and perfusion . Intensive Care Med . 1993 ; 19 ( 4 ): 185 - 90 .
34. Bryan TL , van Diepen S , Bhutani M , Shanks M , Welsh RC , Stickland MK . The effects of dobutamine and dopamine on intrapulmonary shunt and gas exchange in healthy humans . J Appl Physiol ( 1985 ). 2012 ; 113 ( 4 ): 541 - 8 .
35. Lemaire F , Gastine H , Regnier B , Teisseire B , Rapin M. Perfusion changes modify intrapulmonary shunting in patients with adult respiratory distress syndrome . Am Rev Respir Dis . 1978 ;Suppl: 117 - 44 .
36. Lynch JP , Mhyre JG , Dantzker DR . Influence of cardiac output on intrapulmonary shunt . J Appl Physiol Respir Environ Exerc Physiol . 1979 ; 46 ( 2 ): 315 - 21 .
37. Payen DM , Carli PA , Brun-Buisson CJ , Huet YJ , Teisseire BP , Chiron-Payen B , et al. Lower body positive pressure vs. dopamine during PEEP in humans . J Appl Physiol ( 1985 ). 1985 ; 58 ( 1 ): 77 - 82 .
38. Glazier JB , Hughes JM , Maloney JE , West JB . Measurements of capillary dimensions and blood volume in rapidly frozen lungs . J Appl Physiol . 1969 ; 26 ( 1 ): 65 - 76 .
39. Fougeres E , Teboul JL , Richard C , Osman D , Chemla D , Monnet X. Hemodynamic impact of a positive end-expiratory pressure setting in acute respiratory distress syndrome: importance of the volume status . Crit Care Med . 2010 ; 38 ( 3 ): 802 - 7 .
40. Warrell DA , Evans JW , Clarke RO , Kingaby GP , West JB . Pattern of filling in the pulmonary capillary bed . J Appl Physiol . 1972 ; 32 ( 3 ): 346 - 56 .
41. Pfeiffer B , Hachenberg T , Wendt M , Marshall B. Mechanical ventilation with permissive hypercapnia increases intrapulmonary shunt in septic and nonseptic patients with acute respiratory distress syndrome . Crit Care Med . 2002 ; 30 ( 2 ): 285 - 9 .
42. Aboab J , Jonson B , Kouatchet A , Taille S , Niklason L , Brochard L. Effect of inspired oxygen fraction on alveolar derecruitment in acute respiratory distress syndrome . Intensive Care Med . 2006 ; 32 ( 12 ): 1979 - 86 .
43. Permutt S WR , Brower RG . How changes in pleural and alveolar pressure cause changes in afterload and preload . In: Marcel Dekker, editor. Heart-lung interaction in Health and Disease . New York; 1989 . p. 243 - 50 .
44. McCabe WR . Jackson , GC Gram negative bacteriemia: etiology and ecology . Arch Intern Med . 1962 ; 110 ( 6 ): 847 - 55 .