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ORIGINAL ARTICLE

Esophageal Manometry and Regional Transpulmonary Pressure

in Lung Injury
Takeshi Yoshida1,2,3, Marcelo B. P. Amato4, Domenico Luca Grieco1,2,5,6, Lu Chen1,2, Cristhiano A. S. Lima4,
Rollin Roldan4,7, Caio C. A. Morais4, Susimeire Gomes4, Eduardo L. V. Costa4, Paulo F. G. Cardoso8,
Emmanuel Charbonney6,9, Jean-Christophe M. Richard6,10, Laurent Brochard1,3,6, and Brian P. Kavanagh2,3
1
Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada; 2Translational Medicine,
Departments of Critical Care Medicine and Anesthesia, Hospital for Sick Children, and 3Interdepartmental Division of Critical Care Medicine,
University of Toronto, Toronto, Ontario, Canada; 4Divisao de Pneumologia and 8Disciplina de Cirurgia Torácica, Instituto do Coração, Hospital
das Clinicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil; 5Department of Anesthesiology and Intensive Care
Medicine, Catholic University of The Sacred Heart, Fondazione “Policlinico universitario A. Gemelli,” Rome, Italy; 6Cardiac Arrest and Ventilation
International Association for Research, Laboratoire d’anatomie, Université du Québec à Trois-Rivières et Centre Intégré Universitaire de
Santé et de Services Sociaux de la Mauricie-et-du-Centre-du-Québec, Trois-Rivières, Canada; 7Unidad de Cuidados Intensivos, Hospital
Rebagliati, Lima, Perú; 9Centre de Recherche de l’Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada; and 10Department of
Pre-Hospital and Emergency Medicine, General Hospital of Annecy, Annecy, France
ORCID ID: 0000-0002-7512-1865 (L.C.).

Abstract
Rationale: Esophageal manometry is the clinically available
method to estimate pleural pressure, thus enabling calculation of
transpulmonary pressure (PL). However, many concerns make it
uncertain in which lung region esophageal manometry reflects local PL.
Objectives: To determine the accuracy of esophageal pressure (Pes)
and in which regions esophageal manometry reflects pleural pressure
(Ppl) and PL; to assess whether lung stress in nondependent regions
can be estimated at end-inspiration from PL.
Methods: In lung-injured pigs (n = 6) and human cadavers (n = 3),
Pes was measured across a range of positive end-expiratory pressure,
together with directly measured Ppl in nondependent and dependent
pleural regions. All measurements were obtained with minimal
nonstressed volumes in the pleural sensors and esophageal balloons.
Expiratory and inspiratory PL was calculated by subtracting local Ppl
or Pes from airway pressure; inspiratory PL was also estimated by
subtracting Ppl (calculated from chest wall and respiratory system
elastance) from the airway plateau pressure.
Measurements and Main Results: In pigs and human cadavers,
expiratory and inspiratory PL using Pes closely reflected values in
dependent to middle lung (adjacent to the esophagus). Inspiratory PL
estimated from elastance ratio reflected the directly measured
nondependent values.
Conclusions: These data support the use of esophageal manometry
in acute respiratory distress syndrome. Assuming correct calibration,
expiratory PL derived from Pes reflects PL in dependent to middle
lung, where atelectasis usually predominates; inspiratory PL
estimated from elastance ratio may indicate the highest level of lung
stress in nondependent “baby” lung, where it is vulnerable to
ventilator-induced lung injury.
Keywords: esophageal manometry; transpulmonary pressure;
acute respiratory distress syndrome

( Received in original form September 5, 2017; accepted in final form January 9, 2018 )
Supported by a RESTRACOMP (Research Training Competition) training award from the Research Institute of the Hospital for Sick Children, Toronto, Ontario,
Canada; São Paulo Research Foundation grant FAPESP #2014/02030-7, São Paulo, Brazil; National Council for Scientific and Technological Development,
Brazil; and Coordination for the Improvement of Higher Level Personnel, Brazil.
Author Contributions: T.Y. designed the study (pigs and cadavers), conducted the study (pigs), analyzed the data (pigs), wrote the manuscript, and revised the manuscript.
M.B.P.A. designed the pleural sensors (pigs and cadavers), designed the study (pigs and cadavers), analyzed data (pigs), revised the manuscript, and organized the
study as a supervisor (pigs). D.L.G. conducted the study (cadavers) and analyzed the data (cadavers). L.C. designed the study (cadavers) and revised the manuscript.
C.A.S.L. prepared the pleural sensors (pigs and cadavers) and conducted the study (pigs). R.R., C.C.A.M., and S.G. conducted the study (pigs). E.L.V.C. analyzed
the data (pigs) and revised the manuscript. P.F.G.C. performed surgical procedures (pigs). E.C. designed the study (cadavers), conducted the study (cadavers), and
revised the manuscript. J.-C.M.R. designed the study (cadavers), conducted the study (cadavers), analyzed the data (cadavers), revised the manuscript, and organized
the study as a supervisor (cadavers). L.B. designed the study (cadavers) and revised the manuscript. B.P.K. designed the study (pigs) and revised the manuscript.
Correspondence and requests for reprints should be addressed to Takeshi Yoshida, M.D., Ph.D., Keenan Research Centre, Li Ka Shing Knowledge Institute,
St. Michael’s Hospital, 30 Bond Street, Toronto, ON, M5B 1W8 Canada. E-mail: takeshiyoshida@hp-icu.med.osaka-u.ac.jp.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.
Am J Respir Crit Care Med Vol 197, Iss 8, pp 1018–1026, Apr 15, 2018
Copyright © 2018 by the American Thoracic Society
Originally Published in Press as DOI: 10.1164/rccm.201709-1806OC on January 11, 2018
Internet address: www.atsjournals.org

1018 American Journal of Respiratory and Critical Care Medicine Volume 197 Number 8 | April 15 2018
ORIGINAL ARTICLE
At a Glance Commentary
Scientific Knowledge on the
Subject: Esophageal manometry—
the only clinically available method to
estimate pleural pressure—enables
calculation of transpulmonary
pressure. However, concerns about the
technique include: 1) a large vertical
gradient of pleural pressure (especially
in acute respiratory distress
syndrome), 2) two different formulas
for calculating transpulmonary
pressure (one calculating from
esophageal pressure, the other
calculating from the elastance of the
chest wall and respiratory system), and
3) the validity of the esophageal
pressure measurement itself. Thus, it is
uncertain in which region
transpulmonary pressure is
represented by esophageal
manometry.
What this Study Adds to the
Field: We directly measured pleural
pressure in pigs and human cadavers.
Esophageal pressure (inspiratory or
expiratory) accurately reflected pleural
pressure in lung adjacent to the
esophageal balloon (i.e., dependent
to middle lung). Inspiratory
transpulmonary pressure calculated
from elastance ratio was close to the
measured value in the nondependent
lung. These data support the validity of
esophageal manometry. First,
expiratory esophageal pressure is
potentially useful to guide positive end-
expiratory pressure settings to counter
dorsal atelectasis. Second, because
inspiratory transpulmonary pressure
estimated from elastance ratio
indicates the highest level of lung
stress, this represents a novel and
testable clinical target to reduce
ventilator-induced lung injury.
In acute respiratory distress syndrome
(ARDS), ventilator-induced lung injury is
known to occur in nondependent “baby”
lung regions (1–4), as the ventilation is
shifted to nondependent lung regions
because of dependent atelectasis. To
protect this nondependent “baby” lung,
the clinician targets and limits global
parameters such as VT (5, 6) and plateau
Yoshida, Amato, Grieco, et al.: Esophageal Pressure and Regional PL
pressure (Pplat) (6). In addition, positive
end-expiratory pressure (PEEP) is used
to prevent dependent atelectasis and, if
successful, increases the size of the “baby”
lung and lessens its susceptibility to injury
from inspiratory stretch (4). The mortality
rate of patients with ARDS, however, has
remained high over the last two decades,
despite lung-protective ventilation. One
explanation may be that such global
parameters reflect distension of the whole
lung and the chest wall and not the
transpulmonary pressure (PL) distending
any specific lung region, thereby causing
overdistention of nondependent lung and
underrecruitment of dependent lung
(7–10).
Esophageal manometry is the only
clinically available method to separate
airway pressure (Paw) applied to the
respiratory system into the component
distending the chest wall (i.e., pleural
pressure [Ppl]), and that distending the lung
(PL, the difference between Paw and Ppl)
(11). Esophageal manometry has the
potential to optimize PEEP and to prevent
excessive inspiratory stretch, rather than
targeting pressures applied to the whole
respiratory system (i.e., global parameters).
To prevent atelectasis, it has been proposed
to adjust PEEP such that expiratory PL is
slightly positive, and this is assumed to
ensure that the lung (if recruitable) is
maintained open (8). To prevent injury
from inspiratory stretch, attempts are also
made to limit end-inspiratory lung stress
(i.e., inspiratory PL).
However, the validity of esophageal
manometry has been questioned. First, the
accuracy of the absolute value of esophageal
pressure (Pes) to estimate Ppl has been
questioned. Second, two different estimates
of Ppl (and thus PL) have been proposed,
and although both are derived from
esophageal manometry, they yield very
different estimates of PL (12, 13). One is
based on measured (or “absolute”) value of
Pes (termed PL,es) (8), and the other is
based on elastance ratio of chest wall to
respiratory system (termed PL,ER) (14–16).
Third, it is known that Ppl (and therefore
PL) increases along the vertical axis (higher
in dependent, lower in nondependent) in
the supine position, and this gradient is
greater in the presence of ARDS (17, 18).
These concerns make uncertain in
which lung regions esophageal manometry,
if accurate, reflects local distending
pressure.
We examined the inspiratory and
expiratory estimates of PL derived from
esophageal manometry and compared each
with the actual values of local PL in
dependent and nondependent lung. To
accomplish this, we directly measured Ppl
in dependent (Ppl,D) and nondependent
lung (Ppl,ND), in addition to Pes, in
anesthetized pigs and in human cadavers.
Methods
The animal study (pigs) was approved by the
ethics committee for experimental studies at
Faculdade de Medicina da Universidade de
São Paulo. The human cadavers came from
a specific donation program of the anatomy
laboratory of Université de Quebec à Trois-
Rivieres, and experiments were conducted
in accordance with Canadian regulations
after ethics committee approval. Detailed
methods are described in the online
supplement.
Animal Experiments
Preparation. Six Landrace pigs were
anesthetized and paralyzed. An esophageal
balloon catheter (NutriVent; Sidam) was
inflated with minimal nonstress volume
(see Figure E6 in the online supplement) to
measure Pes and its position validated as
previously described (11, 19). Acute lung
injury was established by surfactant
depletion (20).
Pleural pressure measurement.
Regional Ppl was measured using surgically
inserted pleural sensors (wafer type, flat-
balloon) in nondependent and dependent
pleural spaces (Ppl,ND, Ppl,D, respectively);
Ppl was recorded simultaneously with Pes,
across a range of PEEP levels (decreasing
from 24 to 4 cm H2O) before and after
induction of lung injury. During this
procedure, low VT ventilation used assisted
volume-controlled ventilation (VT 5 ml/kg,
respiratory rate of 25/min, pause 0.3 s).
Electrical impedance tomography.
Electrical impedance tomography (EIT)
data were recorded (Enlight1800; Timpel
SA) at the sixth intercostal space. The
amount of lung collapse was estimated
by the number of pixel units in which
compliance decreased after passing best
compliance, as PEEP was lowered in
decremental steps from 24 to 4 cm H2O, as
previously described (21).
1019
 ORIGINAL ARTICLE

Computed tomography. Computed
tomography (CT) scans were used to
estimate the superimposed pressure
between two pleural sensors, as previously
described (18).
Human Cadaver Study
Preparation. Cadavers were immersed in
evaluated by a one-way ANOVA followed
by Tukey pairwise multiple comparisons.
PL,es or PL,ER and PL,ND or PL,D were
compared using regression analysis and
Bland-Altman analysis. Differences were
considered significant if P , 0.05.
Results
approaching midway between nondependent
and dependent Ppl at higher levels of
PEEP (Figure E2A). At lower levels of
PEEP, PL,es approximated to PL,D: PL,D 
PL,es , PL,ND, whereas at higher levels of
PEEP, PL,es was intermediate between PL,ND
and PL,D: PL,D , PL,es , PL,ND (Figure 2A).
There was a good correlation between PL,
D and PL,es (R = 0.94, P , 0.01, slope =
2

the special fluid to preserve their elasticity,
according to the Thiel method (22).
Cadavers were intubated, suctioned, and
connected to a mechanical ventilator. An
esophageal balloon catheter (NutriVent)
was inflated with minimal nonstressed
volume (Figure E6) and its position
validated (as above). The respiratory
mechanics in these cadavers are
comparable to the values in patients with
lung injury (23).
Ppl measurements. Regional Ppl was
measured using surgically inserted pleural
sensors (as above) in nondependent and
dependent pleural spaces; pressures were
recorded simultaneously with Pes, across a
range of PEEP levels (decreasing from 15 to
5 cm H2O). PEEP levels were lower here to
avoid barotrauma in cadavers; they are a
scarce resource. During this procedure, low
VT ventilation used volume-controlled
ventilation (VT 6 ml/kg, respiratory rate of
10/min, pause 0.3 s).
Definitions and Calculations
1. Superimposed pressure (18) = lung
density 3 lung height, where lung
density = 1 2 (CT numbers/21,000),
compared before and after lung injury.
2. Vertical Ppl gradient = Ppl,D 2 Ppl,ND.
3. PL = Paw 2 Ppl, which was calculated at
end-inspiration, and at end-expiration,
as follows:
d Using esophageal pressure (8), PL,es =
Paw 2 Pes.
d Using direct measurement of Ppl in
Pleural Pressure Gradient in Normal
and Injured Lungs
In pigs, the vertical Ppl gradient was
significantly greater (at all PEEP levels) in
injured versus normal lungs (Figure E1); at
PEEP of 10 cm H2O, the vertical gradient
was 1.8-fold greater in injured versus normal
lungs (Figure 1). This is similar to the values
of superimposed pressure (1.7-fold) from
nondependent to dependent lung estimated
using CT images (Figure 1). The vertical Ppl
gradient was correlated with superimposed
pressure between two sensors (R2 = 0.81,
P , 0.01, slope = 1.37, y-intercept = 21.07
cm H2O). The baseline characteristics
(before thoracotomy) of the human cadavers
(n = 3) are described in Table E1, and (at
PEEP 10 cm H2O) the vertical Ppl gradient
was 10.0 6 3.1 cm H2O (Figure 1).
Expiratory Transpulmonary Pressure
Calculated from Pes
In pigs with injured lungs, the end-expiratory
Pes, nondependent Ppl, and dependent
Ppl all decreased in parallel as PEEP
was decreased. End-expiratory Pes closely
reflected dependent Ppl; it was always
slightly less than dependent Ppl,
14
Vertical pleural pressure gradient
Superimposed pressure
12
10
(cmH2O)
1.13, y-intercept = 0.55 cm H2O; Figure E3,
left panel). Bland-Altman analysis revealed
that PL,es served a good surrogate for
expiratory PL in the dependent lung regions
(i.e., mean difference, 0.9 cm H2O), but PL,
es was systematically higher than PL,D as
PEEP was increased (Figure E3, right
panel).
In human cadavers, Pes at end-
expiration was approximately midway
between actual (measured) Ppl in
nondependent and dependent lung; this
relationship was consistent at all levels of
PEEP (from 5–15 cm H2O; Figure E2B).
The PL,es was midrange between PL,ND and
PL,D, and this relationship was maintained
at all values of PEEP (Figure 2B).
Representative (serial) CT images in
a pig confirmed that the position of the
esophagus was close to the dependent sensor
at lower levels of PEEP (Figure 2A), whereas
at higher levels of PEEP it was in the
midzone (i.e., distant from the dependent
sensor) (Figure 2A). In contrast to the pigs,
the position of the esophagus is closer to
midthorax (in the anterior-posterior
dimension) in a patient with ARDS
(Figure 2B).
*

nondependent lung, PL,ND = Paw 2 8

*
Ppl,ND.
d Using direct measurement of Ppl in
6

dependent lung, PL,D = Paw 2 Ppl,D. 4

4. Inspiratory PL = Pplat 2 Ppl was also
calculated from elastance ratio of chest
wall to respiratory system (PL,ER), as
described previously (10, 14–16): PL,ER =
Pplat 2 [Pplat 3 (ECW/ERS)].
Statistics
Intergroup differences were evaluated by a
two-way repeated ANOVA followed by
Dunnett test. Intragroup differences were
2
0
Normal Lung Injured Lung Cadaver
Figure 1. The vertical gradient of pleural pressure at positive end-expiratory pressure (PEEP) of
10 cm H2O in pigs and human cadavers. The vertical gradient of pleural pressure (Ppl) at PEEP of
10 cm H2O was described in normal pigs, lung-injured pigs, and human cadavers, respectively. The
vertical gradient of Ppl was significantly greater in injured versus normal lungs (1.8 times), which was
similar to that determined using computed tomography (i.e., superimposed pressure) (1.7 times). The
vertical gradient of Ppl in human cadavers was z10 cm H2O. *P , 0.01 compared with normal lung.

1020 American Journal of Respiratory and Critical Care Medicine Volume 197 Number 8 | April 15 2018
ORIGINAL ARTICLE

A PEEP4 PEEP24 prevent almost any atelectasis (i.e., ,1%

collapse as measured by EIT) was 4.6 6 2.2
cm H2O (necessary to apply PEEP level of 16
cm H2O) (Figure 3). A value of PL,es just
20
above zero was not enough to maintain
injured lungs open (i.e., 17.2 6 7.3%
atelectasis at PEEP level of 8 cm H2O,
Expiratory Transpulmonary

15 ‡
*+ corresponding to PL,es just above 0 cm H2O).
*+‡
Pressure (cmH2O)

+‡
*
* +‡
10 +‡ * +‡ ‡
‡
Inspiratory Transpulmonary Pressure
‡ *
+ * +‡ *+ ‡
Calculated from Esophageal Pressure
+ *+ * ‡ ‡
5
* ‡
‡
‡ In the pig model with injured lungs, Pes at
‡
‡ ‡ end-inspiration closely reflected dependent
‡ ‡
‡ ‡ Ppl at lower levels of PEEP (Figure E4A). At
‡ ‡
0 ‡ Non-dependent sensor higher levels of PEEP, Pes was midway
‡
Esophageal between nondependent Ppl and dependent
Dependent sensor Ppl (Figure E4A). At lower levels of PEEP,
–5 PL,es approached PL,D, such that: PL,D  PL,
4 6 8 10 12 14 16 18 20 22 24
es , PL,ND, whereas at higher levels of PEEP,
PEEP (cmH2O)
PL,es was intermediate: PL,D , PL,es , PL,ND
(Figure 4A).
B PEEP12 In human cadavers, Pes at end-
inspiration was approximately midway
between Ppl in nondependent and
dependent lung (at PEEP ranging from
15
5–15 cm H 2 O; Figure E4B). The P L,es
was midrange between PL, ND and P L, D,
and this relationship, PL, D , P L,es , P L,
10
ND , was maintained at all values of PEEP
Expiratory Transpulmonary

(Figure 4B).
Pressure (cmH2O)

5 In pigs and human cadavers, there was

good correlation between PL,ND, PL,D, and
0 PL,es (Figures 5A and 6A, left panel). PL
calculated from Pes underestimated
–5 inspiratory PL in the nondependent lung
regions (Figure 5A, right panel). PL
–10 Non-dependent sensor calculated from Pes (either inspiratory or
Esophageal expiratory) had the same spatial relationship
Dependent sensor (i.e., reflected PL in the lung regions
–15
adjacent to the esophageal balloon;
5 10 15
i.e., dependent to middle lung) (Figures 2
PEEP (cmH2O)
and 4).
Figure 2. The spatial relationship of expiratory transpulmonary pressures calculated from esophageal
pressure in lung-injured pigs and human cadavers. (A) In lung-injured pigs, expiratory transpulmonary Inspiratory Transpulmonary Pressure
pressure, calculated using esophageal pressure (Pes) (i.e., positive end-expiratory pressure [PEEP] Calculated from Elastance Ratio
minus expiratory Pes), reflected the directly measured values in mid (at higher PEEP values) and Inspiratory Ppl calculated from the elastance
dependent lung regions (at lower PEEP values). Static computed tomography (CT) images in a ratio ([ECW/ERS], in contrast to Pes at end-
representative pig confirmed that the position of the esophagus was close to the dependent sensor at
inspiration) closely reflected nondependent
PEEP of 4 cm H2O but was closer to midzone (i.e., more distant from the dependent sensor) at PEEP
of 24 cm H2O. (B) In human cadavers, expiratory transpulmonary pressure, calculated using Pes,
inspiratory Ppl in pigs and human cadavers
reflected the directly measured values in midlung regions. A representative CT image was presented (Figures E4A and E4B). In pigs and human
from the acute respiratory distress syndrome (ARDS) registry. The position of the esophagus was cadavers, inspiratory PL calculated from
observed to be located midthorax in a patient with ARDS. Taken together, these CT images indicate elastance ratio (PL,ER) closely reflected the
that Pes reflected the local pleural pressure that was adjacent to the esophageal balloon. *P , 0.05 nondependent actual (measured) values:
compared with Pes; 1P , 0.05 compared with dependent sensor; ‡P , 0.05 compared with PEEP 4. PL,D , PL,ER  PL,ND (Figures 4A and 4B).
PL calculated from elastance ratio served a
Taken together, these CT images and Expiratory Esophageal Pressure and good surrogate for inspiratory PL in the
the comparative Ppl measurements indicate Prevention of Atelectasis nondependent lung regions (i.e., mean
that Pes reflected the Ppl that was adjacent In pigs with lung injury, the minimum PL difference, 0.8 cm H2O) (Figure 5B, right
to the esophageal balloon. (calculated using Pes, i.e., PL,es) needed to panel) but not for inspiratory PL in the

Yoshida, Amato, Grieco, et al.: Esophageal Pressure and Regional PL 1021

 ORIGINAL ARTICLE

consistent with previous results (18) and

Expiratory Transpulmonary Pressure (cmH2O)

15 60
Esophageal
corroborates the CT findings that
Atelectasis 50 distribution of aeration follows this
gradient (i.e., more atelectasis at more

Atelectasis (%)
10 40
dependent lung) after injury. In injured
30
lungs with an increased vertical Ppl
gradient, lung-protective strategy
5 20 targeting global parameters (e.g., the
limitation of VT, Pplat, and PEEP) cannot
10 protect each region at the same time
(7–10).
0 0 Previous studies reflect these limitations.
24 22 20 18 16 14 12 10 8 6 4 For example, a lung-protective strategy
PEEP (cmH2O) (i.e., Pplat , 30 cm H2O; VT, 6 ml/kg) was
–5 not sufficient to limit tidal hyperinflation—
and inflammation—in nondependent
Figure 3. The relationship of expiratory transpulmonary pressures calculated from esophageal
“baby” lung regions (7). Also, setting PEEP
pressure (Pes) and the amount of lung collapse in lung-injured pigs. Lung collapse (estimated by
electrical impedance tomography) was progressively increased as positive end-expiratory pressure in the absence of understanding the impact
(PEEP) was decreased. Expiratory transpulmonary pressure was calculated using absolute Pes on local distension, such as with use of a
(i.e., PEEP minus expiratory Pes). The minimum transpulmonary pressure needed to prevent PEEP/FIO2 table, may increase the risk of
atelectasis (i.e., maintain ,1% collapse as measured by electrical impedance tomography) was under recruiting dependent “atelectatic”
4.6 6 2.2 cm H2O (at PEEP 16 cm H2O). lung (8, 9). Thus, to reduce inspiratory
stress and minimize atelectasis, clinicians
might separately target inspiratory PL
dependent lung regions (i.e., mean difference, esophageal manometry was used in less measured in nondependent “baby” lung
7.3 cm H2O) (Figure 6B , right panel). than 1% of patients with ARDS (25); a and expiratory PL measured in dependent
major reason may be that its validity has “atelectatic” lung. These hypothetical aims
been questioned, as follows. would be especially important in the setting
Discussion First, in the supine position, a gradient of lung injury, where the vertical Ppl
of Ppl exists (higher in dorsal, lower in gradient is increased.
Our study confirmed the accuracy of the ventral), and this gradient is far greater in
absolute values of Pes, if calibrated properly. injured lungs (17, 18); thus, it is not Application of the Findings
Also, the two different estimates of PL possible for any single reading of Pes to It has been recognized that two different
(calculated from Pes or from the elastance simultaneously represent Ppl in dependent methods (i.e., calculation from directly
ratio) can reasonably reflect PL for clinical lung and in nondependent lung. measured Pes [8] or elastance ratio of chest
purposes but not in the same lung regions. Second, local factors may be important. wall to respiratory system [10, 14–16])
First, PL calculated from Pes (either For example, the mass of the mediastinum allow the estimation of PL, which we named
inspiratory or expiratory) accurately appears to increase—and falsely elevate— PL,es and PL,ER, respectively. The differences
reflected PL in the lung regions adjacent to Pes by direct compression (26, 27). Also, obtained by these two methods were
the esophageal balloon (i.e., dependent to incorrect volumes of air in the esophageal believed to indicate the inaccuracy
middle lung), if correctly calibrated. Thus, balloon can result in over- or underestimation (unreliability) of either (or both) as
Pes at end-expiration is potentially useful to of the surrounding Ppl (28). measures of PL. Our findings suggest
guide PEEP settings to counter atelectasis in Third, two different estimates of Ppl instead that the two values, PL,es and PL,ER,
dependent to middle lung regions. Second, (and thus PL)—both derived from accurately represent the local PL in
inspiratory PL calculated from the elastance esophageal manometry—are widely used. different locations: the dependent to
ratio (PL,ER) reasonably reflects local PL One estimate of PL is based on measured middle and the nondependent lung,
in the nondependent “baby” lung. PL,ER Pes (termed PL,es) (8), and the other is respectively. Far from diminishing the
indicates the highest level of inspiratory based on elastance ratio of chest wall to utility of esophageal manometry because
lung stress and may represent a novel and respiratory system (termed PL,ER) (14–16). of potential inaccuracy, this raises the
testable clinical target to reduce ventilator- These two estimates of PL have been shown possibility of “individualizing” lung
induced lung injury. to yield quite different results (12, 13), and protection by using expiratory PL, as well
this discrepancy raised concerns about as inspiratory PL, both derived from
Use of Pes in Patients with ARDS the validity of esophageal manometry in esophageal manometry.
Pes is a surrogate for Ppl, and its reflecting local distending pressure. Pes at end-expiration accurately
measurement has enhanced our knowledge reflects Ppl in the lung regions adjacent
about the mechanical properties of the lung Pleural Pressure Gradient to the esophageal balloon (i.e., middle to
and chest wall (11, 24). Although widely The current data demonstrate that the dependent lung) in which atelectasis usually
used in research, a large epidemiologic vertical gradient of Ppl increased (1.7 times) predominates. Our findings are compatible
study covering 50 countries reported that after induction of lung injury; this is with previous pioneering findings showing

1022 American Journal of Respiratory and Critical Care Medicine Volume 197 Number 8 | April 15 2018
ORIGINAL ARTICLE

A considered to be at functional residual

25 capacity (Ppl in nondependent lung vs.
Non-dependent sensor Elastance ratio
* +‡
dependent lung: 20.8 6 1.4 cm H2O vs.
Inspiratory Transpulmonary

20
Esophageal Dependent sensor
* +‡ 6.2 6 1.3 cm H2O at PEEP of 4 cm H2O,
+‡
pigs; 2.2 6 1.8 cm H2O vs. 13.1 6 5.0 cm
Pressure (cmH2O)

*+‡
*+ ‡ +‡
* +‡
‡ H2O at PEEP of 5 cm H2O, cadavers; Figure
15 *+‡
+‡ ‡
*+ +‡
+‡ ‡ E2) This explains why the estimate of Ppl
*+ *+ *+ ‡
+
+
‡ calculated from elastance ratio reflects the
10 *+ *+ ‡
+ ‡ value in nondependent lung but not other
‡ ‡
lung regions.
5 Because nondependent “baby” lung
regions will be the region most susceptible
0 to stress during inspiration when the
4 6 8 10 12 14 16 18 20 22 24 ventilation is shifted to nondependent lung
PEEP (cmH2O) regions because of dependent atelectasis
(1–3), its local PL (i.e., PL,ER) may be a
B more specific marker of risk from
30 Non-dependent sensor Elastance ratio
ventilation-induced lung injury than local
PL in the middle to dependent lung regions
Inspiratory Transpulmonary

25 Esophageal Dependent sensor

(i.e., PL,es).
Pressure (cmH2O)

20 In summary, individualizing lung

15 protection may be possible using esophageal
manometry to calculate expiratory PL,es (to
10 + minimize atelectasis in dependent lung)
5 and to separately calculate inspiratory
0 PL,ER (to minimize overdistension in
–5
nondependent lung).
–10 Limitations
5 10 15
There are several limitations to the current
PEEP (cmH2O)
work. First, the assumptions (mentioned
Figure 4. The spatial relationship of inspiratory transpulmonary pressures calculated from above) for the method calculated from
esophageal pressure versus elastance ratio in lung-injured pigs and human cadavers. In lung-injured elastance ratio may be not true in all patients
pigs (A) and human cadavers (B), inspiratory transpulmonary pressure, calculated using elastance with ARDS. In obese patients or the patient
ratio (published equations in References 10, 14–16), closely matched the directly measured value who has air trapping, Ppl in nondependent
in nondependent lung. However, note that inspiratory transpulmonary pressure, calculated lung might be significantly greater than zero.
using esophageal pressure (Pes) (i.e., plateau pressure minus inspiratory Pes [8]), reflected the
Indeed, body mass index in each cadaver
directly measured values in mid and dependent lung regions adjacent to the esophageal balloon.
was low in this study. Also, the numbers
*P , 0.05 compared with Pes; 1P , 0.05 compared with dependent sensor; ‡P , 0.05 compared
with PEEP 4. PEEP = positive end-expiratory pressure. in the cadaver protocol are small (n = 3),
because we considered the cadaver protocol
to be primarily a proof of concept. Therefore,
that absolute Pes was a good surrogate for mediastinum corroborates this theory further studies may be needed to determine
Ppl in the middle lung regions in dogs (29). (Figure 2). whether PL,ER reflects the local PL in
Taken together, thus, setting PEEP using Inspiratory PL calculated from nondependent lung in patients with ARDS
expiratory Pes to prevent dorsal (i.e., elastance ratio (PL,ER) is a reasonable from a range of causes
middle to dependent) atelectasis makes estimate of the local PL in nondependent Second, several issues related to
sense. A previous clinical trial showed that lung (Figure 4). This estimation, PL,ER, is methodology, including small numbers of
a ventilatory strategy using Pes at end- based on two assumptions: first, Ppl is zero this study, nonrandomized PEEP order, and
expiration to maintain a positive value of at functional residual capacity (Paw is the use of recruitable lung injury model,
PL,es had physiological benefits in patients zero); second, the elastance ratio of should be addressed. With low balloon
with ARDS (8). The location of the chest wall to respiratory system can be volume, the Pes may underestimate
esophageal balloon below the mediastinum extrapolated from tidal breaths (from each surrounding pressure and, conversely,
(Figure 2) may suggest compression and a PEEP level to Pplat) to the whole range may overestimate pressure if the volume is
falsely elevated Pes. However, the current from zero PEEP to Pplat (10, 14–16). We high (28). Thus, it is important to stress
data do not suggest any impact by the mass evaluated the first assumption in the that all our results were obtained with
of the mediastinum (Figure 2), potentially current study and found that Ppl in minimal nonstressed volumes in the
because of suspension of the heart by the nondependent lung (but not in other lung pleural sensors and esophageal balloons
pericardial ligaments (30); that atelectasis is regions) was the closest to zero at low PEEP (i.e., calibrated properly; Figure E6), to
not limited to lung regions underlying the levels, at which the lung volume is optimally estimate Ppl.

Yoshida, Amato, Grieco, et al.: Esophageal Pressure and Regional PL 1023

 ORIGINAL ARTICLE

A
30 5

Esophageal - Nondependent sensor (cmH2O)

2
R = 0.61, p<0.01
y = 0.78x – 1.47 0

Difference in Inspiratory PL
(Esophageal) (cmH2O)

20
Inspiratory PL

–5

–10
10

–15

0 –20
0 10 20 30 –10 0 10 20 30
Inspiratory PL Mean Inspiratory PL
(Nondependent sensor) (cmH2O) (Esophageal + Nondependent sensor)/2 (cmH2O)

B Elastance Ratio - Nondependent sensor (cmH2O)

30 2 10
R = 0.67, p<0.01
y = 0.69x + 4.91

5
Difference in Inspiratory PL
(Elastance Ratio) (cmH2O)

20
Inspiratory PL

–5
10

–10

0 –15
0 10 20 30 –10 0 10 20 30
Inspiratory PL Mean Inspiratory PL
(Nondependent sensor) (cmH2O) (Elastance Ratio + Nondependent sensor)/2 (cmH2O)
Figure 5. The correlation between inspiratory transpulmonary pressure calculated from nondependent sensor versus (A) esophageal pressure and
(B) elastance ratio. Each correlation between inspiratory transpulmonary pressure (PL) calculated from nondependent sensor versus (A) esophageal
pressure (Pes) and (B) elastance ratio was shown in the left panel. The black dots represent the data from lung-injured pigs and the white dots
represent the data from human cadavers. Black lines represent the linear regression line. The corresponding Bland-Altman analyses are shown in the
right panel. Black lines and thin gray lines represent the mean 6 2 SD of the differences between inspiratory PL calculated from Pes (A) and elastance
ratio (B) versus nondependent sensor. (A) There was a good correlation between inspiratory PL calculated from nondependent sensor versus Pes.
However, PL calculated from Pes underestimated (z4.4 cm H2O) inspiratory PL in the nondependent lung regions. (B) There was a good correlation
between inspiratory PL calculated from nondependent sensor versus elastance ratio. Also PL calculated from elastance ratio served a good surrogate
for inspiratory PL in the nondependent lung regions (i.e., mean difference, 0.8 cm H2O).

Third, the accuracy of direct Ppl
measurements is key. We confirmed that
there were no major pneumothoraces using
EIT (six of six pigs), CT scans (four of six
pigs), and ultrasound and X-ray (all
cadavers). We used several approaches to
ensure that the pleural sensors were not
associated with measurement artifact
(online supplement). Successful occlusion
testing indicated that the “dynamic” injured (porcine) lungs open, using pixel
changes in Ppl and Pes were reliable, and compliance-based collapse in EIT. Thus, we
confirmation that the vertical Ppl gradient need to confirm how much PL,es will be
(from our pleural sensors) was equal to necessary to keep injured lungs open in
superimposed pressure between two patients with ARDS in CT.
sensors (estimated from CT scan) suggested Fifth, it is important to stress that PL,ER
validity of the “static” Ppl. reflects the highest level of static lung stress
Fourth, we found that a value of PL,es but cannot predict the amount of cyclic
just above zero was not enough to keep parenchymal deformation at the ventilated

1024 American Journal of Respiratory and Critical Care Medicine Volume 197 Number 8 | April 15 2018
ORIGINAL ARTICLE

A
30 10

Esophageal - Dependent sensor (cmH2O)

2
R = 0.78, p<0.01
y = 0.90x + 2.77

Difference in Inspiratory PL
20
(Esophageal) (cmH2O)
Inspiratory PL

0
10
–5

0
–10

–10 –15
–10 0 10 20 30 –10 0 10 20 30
Inspiratory PL Mean Inspiratory PL
(Dependent sensor) (cmH2O) (Esophageal + Dependent sensor)/2 (cmH2O)

B Elastance Ratio - Dependent sensor (cmH2O)

30 15
2
R = 0.66, p<0.01
y = 0.71x + 9.24

10
Difference in Inspiratory PL
(Elastance Ratio) (cmH2O)

20
Inspiratory PL

5
10
0

0
–5

–10 –10
–10 0 10 20 30 –10 0 10 20 30
Inspiratory PL Mean Inspiratory PL
(Dependent sensor) (cmH2O) (Elastance Ratio + Dependent sensor)/2 (cmH2O)
Figure 6. The correlation between inspiratory transpulmonary pressure calculated from dependent sensor versus (A) esophageal pressure and (B)
elastance ratio. Each correlation between inspiratory transpulmonary pressure (PL) calculated from dependent sensor versus (A) esophageal pressure
(Pes) and (B) elastance ratio was shown in the left panel. The solid dots represent the data from lung-injured pigs, and the open dots represent the
data from human cadavers. Black lines represent the linear regression line. The corresponding Bland-Altman analyses were shown in the right panel.
Black lines and thin gray lines represent the mean 6 2 SD of the differences between inspiratory PL calculated from Pes (A) and elastance ratio (B) versus
dependent sensor. (A) There was a good correlation between inspiratory PL calculated from dependent sensor versus Pes. PL calculated from Pes
reflected values nearby the dependent lung regions (i.e., mean difference, 2.1 cm H2O). (B) There was a good correlation between inspiratory PL calculated
from dependent sensor versus elastance ratio. However, PL calculated from elastance ratio overestimated (z7.3 cm H2O) inspiratory PL in the dependent
lung regions.

“baby” lung like driving pressure does,
which is considered as a major determinant
of ventilator-induced lung injury (31). Thus,
we need to confirm that the ventilatory
strategy incorporating the limitation of PL,
ER at end-inspiration and maintenance
of positive PL,es at end-expiration
would help to limit dynamic lung stress.
Furthermore, we evaluated this concept
under passive conditions but not under atelectasis and improve survival
active condition. (NCT01681225). In addition, it suggests
that estimation of “local” PL in nondependent
Future Directions (i.e., vulnerable) lung might be possible;
These data add strong evidence for the this would represent a novel and testable
potential utility of esophageal manometry target to reduce ventilator-induced lung
in ARDS. The current study supports injury, and prospective study is needed
the rationale for an ongoing trial targeting to assess the plausibility of this
Pes at the end-expiration to reduce concept.

Yoshida, Amato, Grieco, et al.: Esophageal Pressure and Regional PL 1025

 ORIGINAL ARTICLE

Conclusions
These data further support the validity of
esophageal manometry. Pes accurately
reflected Ppl in the lung regions adjacent to
the esophageal balloon (i.e., dependent and
middle lung) in expiration and inspiration.
In addition, inspiratory PL calculated
from elastance ratio (PL,ER) corresponds
to the local PL in nondependent lung, the
region most vulnerable to ventilator-
induced lung injury. n
Author disclosures are available with the text
of this article at www.atsjournals.org.
Acknowledgment: The authors thank Fabiana
Madotto, Ph.D., School of Medicine and Surgery,
University of Milan-Bicocca, Manza, Italy, for
statistical advice; Gilles Bronchti, M.D., Ph.D.,
and Cardiac Arrest and Ventilation International
Association for Research, Anatomy Laboratory,
Université du Québec à Trois-Rivières, for the
support of Dr. Bronchti’s laboratory and making
Thiel cadavers available for this protocol; and Mr.
Almir Ferrer and Mrs. Diana Rosales, Research &
Development Department, Medtronic, São
Paulo, Brazil, for the development and design of
pleural sensors using three-dimensional printers.

References 15. Staffieri F, Stripoli T, De Monte V, Crovace A, Sacchi M, De Michele M,

1. Tsuchida S, Engelberts D, Peltekova V, Hopkins N, Frndova H, Babyn P,
et al. Atelectasis causes alveolar injury in nonatelectatic lung regions.
Am J Respir Crit Care Med 2006;174:279–289.
2. Bellani G, Guerra L, Musch G, Zanella A, Patroniti N, Mauri T, et al. Lung
regional metabolic activity and gas volume changes induced by tidal
ventilation in patients with acute lung injury. Am J Respir Crit Care
Med 2011;183:1193–1199.
3. Borges JB, Costa EL, Bergquist M, Lucchetta L, Widström C, Maripuu E,
et al. Lung inflammation persists after 27 hours of protective Acute
Respiratory Distress Syndrome Network Strategy and is concentrated
in the nondependent lung. Crit Care Med 2015;43:e123–e132.
4. Gattinoni L, Marini JJ, Pesenti A, Quintel M, Mancebo J, Brochard L. The
“baby lung” became an adult. Intensive Care Med 2016;42:663–673.
5. Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP,
Lorenzi-Filho G, et al. Effect of a protective-ventilation strategy on
mortality in the acute respiratory distress syndrome. N Engl J Med
1998;338:347–354.
6. Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT,
Wheeler A; Acute Respiratory Distress Syndrome Network. Ventilation
with lower tidal volumes as compared with traditional tidal volumes for
acute lung injury and the acute respiratory distress syndrome. N Engl
J Med 2000;342:1301–1308.
7. Terragni PP, Rosboch G, Tealdi A, Corno E, Menaldo E, Davini O, et al.
Tidal hyperinflation during low tidal volume ventilation in acute
respiratory distress syndrome. Am J Respir Crit Care Med 2007;175:
160–166.
8. Talmor D, Sarge T, Malhotra A, O’Donnell CR, Ritz R, Lisbon A, et al.
Mechanical ventilation guided by esophageal pressure in acute lung
injury. N Engl J Med 2008;359:2095–2104.
9. Loring SH, Pecchiari M, Della Valle P, Monaco A, Gentile G, D’Angelo E.
Maintaining end-expiratory transpulmonary pressure prevents
worsening of ventilator-induced lung injury caused by chest wall
constriction in surfactant-depleted rats. Crit Care Med 2010;38:
2358–2364.
10. Grasso S, Terragni P, Birocco A, Urbino R, Del Sorbo L, Filippini C,
et al. ECMO criteria for influenza A (H1N1)-associated ARDS: role of
transpulmonary pressure. Intensive Care Med 2012;38:395–403.
11. Akoumianaki E, Maggiore SM, Valenza F, Bellani G, Jubran A, Loring SH,
et al.; PLUG Working Group (Acute Respiratory Failure Section of the
European Society of Intensive Care Medicine). The application of
esophageal pressure measurement in patients with respiratory failure.
Am J Respir Crit Care Med 2014;189:520–531.
12. Loring SH, O’Donnell CR, Behazin N, Malhotra A, Sarge T, Ritz R, et al.
Esophageal pressures in acute lung injury: do they represent artifact
or useful information about transpulmonary pressure, chest wall
mechanics, and lung stress? J Appl Physiol (1985) 2010;108:
515–522.
13. Gulati G, Novero A, Loring SH, Talmor D. Pleural pressure and optimal
positive end-expiratory pressure based on esophageal pressure
versus chest wall elastance: incompatible results. Crit Care Med
2013;41:1951–1957.
14. Gattinoni L, Chiumello D, Carlesso E, Valenza F. Bench-to-bedside
review: chest wall elastance in acute lung injury/acute respiratory
distress syndrome patients. Crit Care 2004;8:350–355.
et al. Physiological effects of an open lung ventilatory strategy
titrated on elastance-derived end-inspiratory transpulmonary
pressure: study in a pig model. Crit Care Med 2012;40:2124–2131.
16. Chiumello D, Cressoni M, Colombo A, Babini G, Brioni M, Crimella F,
et al. The assessment of transpulmonary pressure in mechanically
ventilated ARDS patients. Intensive Care Med 2014;40:1670–1678.
17. Agostoni E. Mechanics of the pleural space. Physiol Rev 1972;52:
57–128.
18. Pelosi P, D’Andrea L, Vitale G, Pesenti A, Gattinoni L. Vertical gradient
of regional lung inflation in adult respiratory distress syndrome.
Am J Respir Crit Care Med 1994;149:8–13.
19. Baydur A, Behrakis PK, Zin WA, Jaeger M, Milic-Emili J. A simple
method for assessing the validity of the esophageal balloon
technique. Am Rev Respir Dis 1982;126:788–791.
20. Lachmann B, Robertson B, Vogel J. In vivo lung lavage as an
experimental model of the respiratory distress syndrome. Acta
Anaesthesiol Scand 1980;24:231–236.
21. Costa EL, Borges JB, Melo A, Suarez-Sipmann F, Toufen C Jr, Bohm SH,
et al. Bedside estimation of recruitable alveolar collapse and
hyperdistension by electrical impedance tomography. Intensive
Care Med 2009;35:1132–1137.
22. Hunter A, Eisma R, Lamb C. Thiel embalming fluid–a new way to revive
formalin-fixed cadaveric specimens. Clin Anat 2014;27:853–855.
23. Delisle S, Charbonney E, Gosselin P, Ouellet P, Rigollot M, Bronchti G,
et al. Study of ventilation during cardio pulmonary resuscitation
(CPR): a new model using Thiel cadavers [abstract]. Am J Respir Crit
Care Med 2016;193:A7030.
24. Mauri T, Yoshida T, Bellani G, Goligher EC, Carteaux G, Rittayamai N,
et al.; PLeUral pressure working Group (PLUG—Acute Respiratory
Failure section of the European Society of Intensive Care Medicine).
Esophageal and transpulmonary pressure in the clinical setting:
meaning, usefulness and perspectives. Intensive Care Med 2016;42:
1360–1373.
25. Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al.;
LUNG SAFE Investigators; ESICM Trials Group. Epidemiology,
patterns of care, and mortality for patients with acute respiratory
distress syndrome in intensive care units in 50 countries. JAMA
2016;315:788–800.
26. Knowles JH, Hong SK, Rahn H. Possible errors using esophageal
balloon in determination of pressure-volume characteristics of the
lung and thoracic cage. J Appl Physiol 1959;14:525–530.
27. Washko GR, O’Donnell CR, Loring SH. Volume-related and
volume-independent effects of posture on esophageal and
transpulmonary pressures in healthy subjects. J Appl Physiol (1985)
2006;100:753–758.
28. Mojoli F, Iotti GA, Torriglia F, Pozzi M, Volta CA, Bianzina S, et al. In vivo
calibration of esophageal pressure in the mechanically ventilated
patient makes measurements reliable. Crit Care 2016;20:98.
29. Pelosi P, Goldner M, McKibben A, Adams A, Eccher G, Caironi P, et al.
Recruitment and derecruitment during acute respiratory failure: an
experimental study. Am J Respir Crit Care Med 2001;164:122–130.
30. Rodriguez ER, Tan CD. Structure and anatomy of the human
pericardium. Prog Cardiovasc Dis 2017;59:327–340.
31. Amato MB, Meade MO, Slutsky AS, Brochard L, Costa EL, Schoenfeld DA,
et al. Driving pressure and survival in the acute respiratory distress
syndrome. N Engl J Med 2015;372:747–755.

1026 American Journal of Respiratory and Critical Care Medicine Volume 197 Number 8 | April 15 2018