ORIGINAL ARTICLE

Effect of Lowering VT on Mortality in Acute Respiratory Distress

Syndrome Varies with Respiratory System Elastance
Ewan C. Goligher1,2,3*, Eduardo L. V. Costa4,5*, Christopher J. Yarnell1,2,6, Laurent J. Brochard1,7‡,
Thomas E. Stewart8, George Tomlinson2, Roy G. Brower9, Arthur S. Slutsky1,7, and Marcelo P. B. Amato4
1
Interdepartmental Division of Critical Care Medicine and 6Institute of Health Policy, Management, and Evaluation, University of
Toronto, Toronto, Ontario, Canada; 2Division of Respirology, Department of Medicine, University Health Network and Sinai Health
System, Toronto, Ontario, Canada; 3Toronto General Hospital Research Institute, Toronto General Hospital, Toronto, Ontario, Canada;
4
Laborato
rio de Pneumologia LIM-09, Disciplina de Pneumologia, Instituto do Coraça ~o, Hospital das Cl
ınicas, Faculdade de Medicina,
Universidade de Sa ~o Paulo, Brazil; 5Research and Education Institute, Hospital S
ırio-Libanes, Sa
~o Paulo, Brazil; 7Keenan Research
8
Centre, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada; St. Joseph’s Hospital, Hamilton, Ontario,
Canada; and 9Pulmonary and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland
ORCID ID: 0000-0002-0990-6701 (E.C.G.).

Abstract that the mortality benefit from lower-VT ventilation strategies

Rationale: If the risk of ventilator-induced lung injury in acute
respiratory distress syndrome (ARDS) is causally determined by
driving pressure rather than by VT, then the effect of ventilation
with lower VT on mortality would be predicted to vary according
to respiratory system elastance (Ers).
Objectives: To determine whether the mortality benefit of
ventilation with lower VT varies according to Ers.
Methods: In a secondary analysis of patients from five
randomized trials of lower- versus higher-VT ventilation
strategies in ARDS and acute hypoxemic respiratory failure, the
posterior probability of an interaction between the randomized
VT strategy and Ers on 60-day mortality was computed using
Bayesian multivariable logistic regression.
Measurements and Main Results: Of 1,096 patients available
for analysis, 416 (38%) died by Day 60. The posterior probability
varied with Ers was 93% (posterior median interaction odds ratio,
0.80 per cm H2O/[ml/kg]; 90% credible interval, 0.63–1.02). Ers
was classified as low (,2 cm H2O/[ml/kg], n 5 321, 32%),
intermediate (2–3 cm H2O/[ml/kg], n 5 475, 46%), and high (.3
cm H2O/[ml/kg], n 5 224, 22%). In these groups, the posterior
probabilities of an absolute risk reduction in mortality > 1% were
55%, 82%, and 92%, respectively. The posterior probabilities of
an absolute risk reduction > 5% were 29%, 58%, and 82%,
respectively.
Conclusions: The mortality benefit of ventilation with lower VT
in ARDS varies according to elastance, suggesting that lung-
protective ventilation strategies should primarily target driving
pressure rather than VT.
Keywords: acute respiratory distress syndrome; lung-protective
ventilation; driving pressure

(Received in original form September 16, 2020; accepted in final form January 12, 2021.
*These authors are equally contributing first authors.
‡
L.J.B. is Deputy Editor of AJRCCM. His participation complies with American Thoracic Society requirements for recusal from review and
decisions for authored works.
Supported by the Canadian Institutes of Health Research Early Career Investigator award AR7-162822 (E.C.G.), the Eliot Phillipson Clinician
Scientist Training Program (C.J.Y.), and the Clinician Investigator Program of the University of Toronto (C.J.Y.).
Author Contributions: E.C.G., E.L.V.C., and M.P.B.A. conceived the study. E.C.G., E.L.V.C., and C.J.Y. designed and conducted the analysis. All
authors provided interpretations of the data. E.C.G. and E.L.V.C. drafted the manuscript. All authors critically revised the manuscript for
intellectually important content.
Correspondence and requests for reprints should be addressed to Ewan C. Goligher, M.D., Ph.D., Toronto General Hospital, 585 University
Avenue, 11-PMB Room 192, Toronto, ON, M5G 2N2 Canada. E-mail: ewan.goligher@utoronto.ca.
This article has a related editorial.
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 203, Iss 11, pp 1378–1385, June 1, 2021
Copyright © 2021 by the American Thoracic Society
Originally Published in Press as DOI: 10.1164/rccm.202009-3536OC on January 12, 2021
Internet address: www:atsjournals:org

1378 American Journal of Respiratory and Critical Care Medicine Volume 203 Number 11 | June 1 2021
ORIGINAL ARTICLE
At a Glance Commentary
Scientific Knowledge on the
Subject: Low-VT ventilation is
recommended for all patients with
acute respiratory distress syndrome
(ARDS). The driving pressure hypoth-
esis predicts that lowering VT will be
of greatest benefit when respiratory
system elastance (Ers) is high and less
beneficial when Ers is low.
What This Study Adds to the
Field: In this secondary analysis of
previous VT-ventilation strategy trials
(n 5 1,096 patients), the mortality
benefit of ventilation with lower VT
in ARDS varied according to Ers and
driving pressure: mortality benefit
was greater in patients with high
elastance and comparatively low in
patients with low elastance. This
finding suggests that the adequacy of
lung protection during mechanical
ventilation should be assessed primar-
ily in terms of driving pressure rather
than VT. Modest increases in VT may
be safe in patients with low Ers
provided that driving pressure
remains acceptably low.
The use of lower VT (i.e., 4–8 ml/kg of
predicted body weight [PBW]) prevents
ventilator-induced lung injury (VILI) and
reduces mortality in acute respiratory distress
syndrome (ARDS) (1). The driving pressure
hypothesis holds that the benefit of lowering
VT depends on the resulting reduction in
driving pressure—the distending pressure
applied to the lung during tidal inflation
(computed as inspiratory plateau pressure
minus the positive end-expiratory pressure
[PEEP])—rather than the reduction in VT
per se. This is highly plausible from a
mechanistic standpoint because the
mechanical stress and strain leading to VILI
are determined both by VT and by end-
expiratory lung volume (as reflected by
higher respiratory system elastance [Ers]) (2);
driving pressure reflects both parameters (see
Figure E1 in the online supplement).
Previous studies have demonstrated that
driving pressure is independently associated
with mortality (3, 4). However, this
association remains susceptible to residual
confounding because driving pressure is
Goligher, Costa, Yarnell, et al.: Low-VT Ventilation and Elastance in ARDS
physiologically and mathematically coupled
with VT, the severity of illness, and elastance
(5, 6). It remains unknown whether the
benefit of lowering VT differs between
patients with high elastance (and high
driving pressure) and patients with low
elastance (and low driving pressure).
The driving pressure hypothesis has
important implications for the management
of ARDS. If driving pressure is causally
responsible for death from VILI, then
patients in whom driving pressure remains
elevated when a low “protective” VT is
applied (i.e., those with high elastance) would
benefit from further reductions in VT.
Conversely, it would not be beneficial or
necessary to require low VT when driving
pressure is low (i.e., in patients with low
elastance).
Previous attempts to propose differing
strategies for titrating VT on the basis of
elastance have proven controversial (7, 8),
and low-VT ventilation is recommended for
all patients with ARDS (9). Yet the
requirement for low VT is not without
potential harm; heavy sedation and/or
neuromuscular blockade may be required to
suppress respiratory drive and breath-
stacking dyssynchrony in some patients (10,
11). This limits spontaneous breathing and
early mobilization and increases the risk of
diaphragm-disuse atrophy and prolonged
mechanical ventilation (12). A ventilation
strategy primarily targeting driving pressure
might avoid these harms to some extent by
permitting spontaneous breathing with a
modestly larger VT in appropriately selected
patients with low elastance. Importantly, the
upper limit of safe driving pressure for a
driving pressure–targeted ventilation strategy
has not been established.
We undertook this study to establish
whether the causal effect of lowering the VT of
ventilation on mortality in randomized trials
varied according to elastance. In accordance
with the driving pressure hypothesis, we
hypothesized that lowering VT would be
associated with a relatively greater mortality
benefit in patients with high elastance and a
relatively lower reduction in mortality (or
possible harm) in patients with low elastance.
Methods
Study Population
Data for this analysis were drawn from five
previously published randomized clinical
trials of lower versus higher VT in patients
with ARDS (13–17). These data were
employed in a previous analysis of the
association between driving pressure and
mortality in ARDS (3). The inclusion criteria,
sample size, and intervention versus control
strategies tested in each trial are listed in
Table E1. Patients in this data set were
ventilated in the supine position in a
controlled mode with a total respiratory rate
equal to the set respiratory rate.
Measurements
The following variables were extracted from
the trial databases for each patient: the trial in
which each patient was enrolled, randomized
treatment assignment (lower- vs. higher-VT
strategy), mortality at Day 60, Ers (computed
as the quotient of driving pressure and VT)
(15) on study Day 1 after randomization, the
PaO2/FIO2 ratio, and the severity-of-illness
score (Simplified Acute Physiology Score
[18] or Acute Physiology and Chronic
Health Evaluation [APACHE] score [19]).
Ers was normalized to PBW (cm H2O/[ml/
kg]) as in previous studies (15, 20–22) to
account for variation in lung volume and
elastance associated with height; actual body
weight was used for patients enrolled in trials
published before 2000, as height was not
available. In anesthetized healthy humans,
normalized Ers is generally below 1 cm H2O/
(ml/kg) (23, 24).
Statistical Analysis
The analysis was designed on the basis of a
causal model hypothesizing that the effect of
lowering VT on mortality varies according to
Ers (Figure E1). In the primary analysis, a
Bayesian logistic regression model was
constructed to quantify the posterior
probability of an interaction between
intervention (lower- vs. higher-VT strategy)
and Ers (see online supplement for details)
on 60-day mortality. The model was adjusted
for markers of illness severity, including the
PaO2/FIO2 ratio, predicted risk of death
computed from illness severity scores (either
APACHE or Simplified Acute Physiology
Score, depending on the trial), and the
mortality rate of the control group in each
study. Ers values were available on Day 1
after randomization. Informative priors were
used for variables known to be associated
with mortality (Ers, PaO2/FIO2 ratio, predicted
risk of death); otherwise, neutral priors were
used (see online supplement for a detailed
rationale for prior construction and Table E2
for the specification of priors). The effect of
the intervention was modeled as a random
1379
 ORIGINAL ARTICLE

effect because of differences in intervention
between trials. The median and 90% credible
interval (CrI) were reported for each
parameter of interest.
To account for the systematic influence
of the randomly assigned VT ventilation
strategy on Ers (measured on Day 1 after
randomization, not at baseline), the mean
difference in elastance between the lower-
and higher-VT groups within each trial was
subtracted from the elastance values for
patients receiving the higher-VT ventilation
strategy to obtain similar distributions of
elastance between groups. Simulations
suggested that this correction would
mitigate potential bias introduced by using
postrandomization measurements of
elastance; furthermore, simulations also
demonstrated that this potential bias tends
to shift the estimated interaction coefficient
toward the null (see Figure E2). The
sensitivity of the results to varying priors
and data restrictions was assessed (see
online supplement for details). We assessed
the evidence against the null hypothesis of
no interaction (odds ratio [OR], 1) under
the skeptical prior with a one-sided
alternate hypothesis (OR , 1) using the
Bayes factor (25).
To control for the possibility that
variations in treatment effect associated with
Ers reflected differences in the underlying
severity of ARDS, the potential interactions
between other markers of illness severity
(PaO2/FIO2 ratio, the severity-of-illness score)
and randomized treatment assignment on
mortality were evaluated.
In a separate analysis of heterogeneity of
treatment effect, the Subpopulation
Treatment Effect Pattern Plot (STEPP)
technique was employed for a frequentist
hypothesis test of the interaction between VT
strategy and Ers and the absolute risk
difference in mortality (26). Subgroups were
sized at 250 patients, with an overlap of up to
30 patients between subgroups.
The analyses were conducted using the
rethinking and STEPP packages and Stan in
RStudio version 1.1.456 (RStudio) and R
version 3.6.2 (R Foundation for Statistical
Computing), respectively. Bayesian models
were run using two chains and 5,000
iterations including a burn-in of 1,000
iterations. Convergence was assessed by
inspection of trace plots and R-hat statistics.
Posterior estimates of parameters were
reported with 90% CrIs by convention.
Results
Of 1,202 patients enrolled in the five trials,
106 were unavailable for analysis because of
missing data on Ers (n 5 91), the risk of
death predicted using the illness severity
score (n 5 10), or the PaO2/FIO2 ratio (n 5 5),
leaving a total of 1,096 patients for analysis.
The trial characteristics are summarized in
Table 1. Baseline characteristics for the
patients according to randomized treatment
assignment are shown in Table E1. The
distribution of Ers on Day 1 after
randomization (before and after adjustment
for differences between groups) is shown in
Figure E3. The difference in VT between
groups tended to be lower in patients with
higher elastance, whereas the difference in
driving pressure between groups was higher
in patients with higher elastance (Figure 1).
A total of 416 patients (38%) died on or
before Day 60.
In the primary analysis, the posterior
probability that the mortality benefit of
ventilation with lower VT varied according to
elastance was 93% (posterior median
interaction OR, 0.80 per cm H2O/[ml/kg];
90% CrI, 0.63 to 1.02) (Figure E4). The
absolute risk reduction (ARR) associated
with a lower-VT ventilation strategy
increased progressively with increasing
elastance (Figure 2). The posterior
probability of meaningful clinical benefit
from lower-VT ventilation varied
substantially with elastance (Figure 3).
In patients with low elastance (defined as
,2 cm H2O/[ml/kg]; n 5 321, 32%), the
posterior probability of an ARR of at least 1%
was 55% (posterior median ARR, 1.6%; 90%
CrI, 29.1% to 12.5%). In patients with
intermediate elastance (defined as 2–3 cm
H2O/(ml/kg); n 5 475, 46%), the posterior
probability of an ARR . 1% was 82%
(posterior median ARR, 6.2%; 90% CrI,
24% to 17%). In patients with high elastance
(defined as .3 cm H2O/[ml/kg]; n 5 224,

Table 1. Characteristics of Trials from which Individual Patient Data Were Drawn

Sample Size (% Female) Ventilation Strategy

Lower VT Higher VT Inclusion Lower VT Higher VT
Trial Arm Arm Criteria Arm Arm

Amato et al., 1998 (17) 29 (NA) 24 (NA) ARDS with LIS > 2.5 VT , 6 ml/kg of actual VT of 12 ml/kg
BW, DP , 20 cm
H2O
Brochard et al., 1998 (14) 58 (43) 58 (43) ARDS with Murray VT of 6–10 ml/kg of VT . 10 ml/kg
LIS . 2.5 actual BW,
Pplat , 25 cm H2O
Stewart et al., 1998 (13) 60 (22) 60 (38) P/F < 250 mm Hg or VT , 8 ml/kg of actual VT of 10–15 ml/kg of
severe sepsis BW, Ppeak , 30 cm actual BW,
or severe burns H2O Ppeak < 50 cm H2O
Brower et al., 1999 (16) 26 (58) 26 (31) ARDS with P/F VT of 8 ml/kg of VT of 10–12 ml/kg,
< 200 mm Hg predicted BW, Pplat , 55 cm H2O
Pplat , 30 cm H2O
ARDSNet, 2000 (15) 432 (40) 429 (41) ARDS with P/F VT of 4–8 ml/kg of VT of 12 ml/kg
< 300 mm Hg predicted BW, Pplat
of 25–30 cm H2O

Definition of abbreviations: ARDS 5 acute respiratory distress syndrome; ARDSNet 5 ARDS Network; BW 5 body weight; DP 5 driving pressure;
LIS 5 lung injury score; NA 5 not available; P/F 5 PaO2/FIO2; Ppeak 5 peak pressure; Pplat 5 plateau pressure.

1380 American Journal of Respiratory and Critical Care Medicine Volume 203 Number 11 | June 1 2021
ORIGINAL ARTICLE
12
Tidal volume (ml/kg)
10
6
4
1 2
Normalized elastance (cm H2O/(ml/kg))
Figure 1. VT and driving pressure according to respiratory system elastance and higher- versus lower-VT strategy. The shaded regions represent
the standard errors.
22%), the posterior probability of an
ARR . 1% was 92% (posterior median ARR,
12.1%; 90% CrI, 21% to 27%). The posterior
probabilities of an ARR . 5% were 29%,
58%, and 82%, respectively.
The posterior probability of an
ARR . 1% exceeded 50% when elastance
exceeded approximately 1.5 cm H2O/(ml/kg)
(Figure 3). In patients with elastance , 1.5
cm H2O/(ml/kg), the median driving
pressures were 14.6 cm H2O (interquartile
range, 13.4–16.6 cm H2O) in the higher-VT
arm and 8.2 cm H2O (interquartile range,
6.0–10.0 cm H2O) in the lower-VT arm.
By comparison, the mortality benefit of
lower-VT ventilation did not vary according
to the PaO2/FIO2 ratio (posterior median OR
for interaction, 0.98 per 25–mm Hg increase;
90% CrI, 0.89–1.08) or predicted risk of
death (posterior median interaction OR, 0.99
per 10% increase; 90% CrI, 0.90–1.10)
(Figure E4).
In sensitivity analyses of the primary
model, the posterior probability that the
mortality benefit of a lower-VT ventilation
strategy varied according to elastance was
similar when the model was computed using
minimally informative priors for all
covariates (posterior median OR, 0.79 per
cm H2O/[ml/kg]; 90% CrI, 0.58–1.08;
posterior probability of OR , 1, 93%), under
an informative prior reflecting
physiologically based confidence that the risk
of death from VILI is higher with increasing
Goligher, Costa, Yarnell, et al.: Low-VT Ventilation and Elastance in ARDS
Driving pressure (cm H2O)
3 4 5 6
Tidal volume strategy
elastance (posterior median OR, 0.80 per cm
H2O/[ml/kg]; 90% CrI, 0.66–0.98; posterior
probability of OR , 1, 96%), and under a
skeptical prior expressing the belief that the
effect of VT is unlikely to vary meaningfully
with Ers (posterior median OR, 0.90 per cm
H2O/[ml/kg]; 90% CrI, 0.75–1.07; posterior
probability of OR , 1, 85%). The Bayes
factor for the one-sided null-hypothesis test
of no interaction under the skeptical prior
was 3.6, indicating substantial evidence
against the null hypothesis (equivalent to
P , 0.01 under conventional frequentist
testing) (25). Additional sensitivity analyses
are reported in the online supplement.
In the STEPP analysis, the effect of
lower-VT ventilation on mortality also varied
according to elastance (interaction,
P 5 0.02); the difference in the absolute risk
of death between higher- versus lower-VT
ventilation was large only at high elastance
(Figure 4). Similar results were obtained
when varying the size of the subgroups and
the degree of overlap between subgroups.
Discussion
The driving pressure hypothesis predicts that
the effect of lowering VT on mortality in
ARDS will vary according to respiratory
system elastance because the reduction in
mechanical stress and strain (and hence the
mortality benefit) obtained by lowering VT
50
40
30
20
10
0
1 2 3 4 5 6
Normalized elastance (cm H2O/(ml/kg))
Higher Lower
depends on the volume of lung available for
tidal ventilation (as reflected by Ers; lower
lung volume results in higher elastance). The
findings of the present analysis corroborate
this prediction by demonstrating a high
probability that the mortality benefit of
lowering VT varies with Ers. We found
substantial evidence against the null
hypothesis of no interaction using both
Bayesian and frequentist methods. These
results imply that VT can be individualized
according to Ers and that the adequacy of
lung protection should be assessed by the
resulting driving pressure (which reflects
mechanical stress and strain) rather than by
VT per se.
Previous studies have shown that
driving pressure is strongly associated with
mortality (4, 27). This observed association,
however, does not necessarily entail that
driving pressure is the causal determinant of
benefit from lower-VT ventilation,
particularly because of potential residual
confounding and mathematical coupling
among VT, driving pressure, and elastance.
Mediation analysis (3) cannot confirm
causality because the relation between
mediator and outcome is not randomized
(6). By contrast, the present analysis retains
the randomly assigned treatment effect in the
model; therefore, differences in outcome
between patients randomized to lower VT
and patients randomized to higher VT can be
attributed to a causal effect of the ventilation
1381
 ORIGINAL ARTICLE

1.00
Lower Tidal Volume
Higher Tidal Volume

Posterior mean absolute risk reduction (%)

40

0.75
Posterior probability of death

20

0.50

0
0.25

0.00 -20

1 2 3 4 5 6 1 2 3 4 5 6
Normalized elastance (cm H2O/(mL/kg)) Normalized elastance (cm H2O/(mL/kg))

Figure 2. The left graph shows the probability of death according to respiratory system elastance and randomized treatment assignment to
lower- versus higher-VT ventilation strategy. The right graph shows the median and 90% prediction interval for absolute risk reduction in
mortality from randomization to a lower-VT ventilation strategy according to respiratory system elastance. A rug-plot density of patients at each
elastance value is represented above the x-axis. The shaded regions represent the 90% prediction intervals for the mean.

1.00 strategy. Rather than linking driving pressure

Posterior probability of treatment effect

to the risk of death, the present analysis

demonstrates that the effect of treatment
0.75 Effect of lower VT (lowering VT) on the risk of death varies with
ventilation strategy on elastance (and hence driving pressure). This
absolute risk of death
analytical approach therefore more strongly
t5% decrease (benefit)
0.50 warrants the conclusion that the effect of
t1% decrease (benefit)
lowering VT on mortality is greater in
t1% increase (harm)
patients with higher driving pressures (i.e.,
t5% increase (harm)
0.25 higher elastance values) and lower in patients
with lower driving pressures (i.e., lower
elastance values). These results support the
0.00 validity of driving pressure as a predictive
1 2 3 4 5 6 marker for the mortality benefit of lowering
Normalized elastance (cm H2O/(mL/kg)) VT in ARDS and suggest that lung-
protective ventilation strategies should
primarily target driving pressure rather
Driving pressure (cm H2O)

55
45
than VT.
Since the driving pressure concept was
35
Higher tidal volume strategy first proposed, the threshold value of driving
25 pressure to be targeted for lung-protective
Lower tidal volume strategy
15 ventilation has been debated. We found that
5 the posterior probability of even a small
mortality benefit (ARR . 1%) from the
1 2 3 4 5 6
lower-VT strategies was low (<50%) in
Normalized elastance (cm H2O/(mL/kg))
patients with Ers < 1.5 cm H2O/(ml/kg). In
Figure 3. Posterior probabilities of various values of the treatment effect of a lower-VT these patients, driving pressure was
ventilation strategy on mortality according to respiratory system elastance. The lower panel approximately 15 cm H2O in the higher-VT
shows the driving pressures correlated with these probabilities of benefit or harm at varying group. Accordingly, we may infer that when
elastance. The error bars represent the SEM. driving pressure is at or below 15 cm H2O,

1382 American Journal of Respiratory and Critical Care Medicine Volume 203 Number 11 | June 1 2021
ORIGINAL ARTICLE

0.7 driving pressure does not necessarily imply

a high risk of VILI. In a classic paper,
Dreyfuss and colleagues convincingly
demonstrated that VILI results from high
0.6 transpulmonary driving pressure and lung
distention (whether from positive-pressure
ventilation or negative-pressure ventilation)
Risk of death at day 60

rather than from high airway pressures per

0.5 Intervention se (38). Because chest wall elastance is
Higher tidal volume strategy elevated in many patients with ARDS (35),
Lower tidal volume strategy transpulmonary driving pressure may
provide more direct information about lung
0.4
stress and strain than airway driving
pressure (39).
Our findings also have important
implications for research in ARDS. First,
0.3
future clinical trials of very-low-VT
ventilation facilitated by extracorporeal CO2
removal may consider focusing on an
1.5 2.0 2.5 3.0 3.5 enriched patient population with higher
Subgroup median elastance (cm H2O/(ml/kg))
elastance, as previously proposed (40, 41).
Second, although the severity of hypoxemia
Figure 4. Subpopulation Treatment Effect Pattern Plot analysis of the mortality benefit of a is the primary means by which ARDS
lower-VT ventilation strategy according to respiratory system elastance. The error bars represent severity is classified (42), we found that the
95% confidence intervals. Subgroups are plotted according to the median elastance value in PaO2/FIO2 ratio had no meaningful influence
each subgroup. The gray dashed lines represent a linear smooth fit onto the relationship on the association between lower-VT
between respiratory system elastance and mortality for the higher- and lower-VT strategy arms.
ventilation and mortality. Ers may provide
more information than either severity of
the probability of mortality benefit from analysis (Figure 1). Clinicians should hypoxemia or severity of illness about the
lowering the VT of ventilation is low. therefore consider lowering VT below 6 ml/ risk of VILI and the potential benefit of lung-
This finding also implies that the risk of kg of PBW when driving pressure remains protective interventions, as also suggested by
harm from a modest increase in VT is low higher than 15 cm H2O, appreciating that a recent study demonstrating that the change
provided that the resulting driving pressure further reductions in the VT provided may in driving pressure after randomization and
does not exceed this threshold. Permitting a sometimes—but not always—be adjustments in VT and PEEP is a better
modest increase in VT may sometimes complicated by severe hypercapnic acidosis predictor of survival than the change in
reduce atelectasis, attenuate hypercapnia and with potential harm (33). Very low VT oxygenation (43). Future studies of lung-
respiratory drive, unload the respiratory might be achieved by marked increases in protective interventions may consider
muscles, relieve dyspnea, reduce sedation the respiratory rate (34). determining the risk of VILI and the
requirements, and facilitate early Ers reflects the elastances of both the potential for a benefit on this basis. Third,
mobilization (11, 28, 29). It might reduce the lung and the chest wall. The elastance of the lung elastance (as opposed to Ers) and
risk of breath-stacking dyssynchrony and/or lung within the baby lung (“specific transpulmonary driving pressure may
the need for sedation given to reduce elastance” approximated by the ratio of provide even more useful information to
dyssynchrony (11). Our analysis suggests measured elastance to the aerated lung predict the risk of VILI. The potential role
that clinicians can use the measurement of volume) is approximately normal in ARDS, for transpulmonary driving pressure
elastance and driving pressure to weigh the suggesting that increased lung elastance measurements to guide lung-protective
relative benefit and harm of lowering or primarily results from a loss of aerated ventilation, particularly during assisted
raising VT targets in individual patients. volume due to atelectasis and consolidation ventilation, requires evaluation in future
Recent work has shown that driving pressure (35). Elastance is also influenced by PEEP; clinical trials.
can also be measured with acceptable increasing PEEP may increase elastance Our analysis suggests a conclusion
accuracy during assisted mechanical (reflecting overdistention) or decrease that is potentially different from that of a
ventilation (30–32). elastance (reflecting lung recruitment) (36). previous report of the benefit of a lower-VT
Conversely, clinicians should not In the trials included in this analysis, ventilation strategy in patients with lower
regard ventilation with a VT of 6 ml/kg of elastance measurements were obtained at plateau pressures (44). Examining the
PBW as adequately lung protective when approximately 10 cm H2O of PEEP, which effect of lower versus higher VT on
driving pressure remains elevated. It is is similar to levels of PEEP applied in mortality according to quartiles of Ers in
important to note that many patients with contemporary clinical practice (37), and the data used for this analysis appears to
high Ers randomized to a lower-VT strategy PEEP levels were very similar in the higher- yield qualitatively similar results (Figure
were ventilated with a VT of 4–5 ml/kg or lower-VT groups. When chest wall E5). However, several considerations
PBW in the clinical trials included in this elastance is increased, elevated airway should be borne in mind when comparing

Goligher, Costa, Yarnell, et al.: Low-VT Ventilation and Elastance in ARDS 1383
 ORIGINAL ARTICLE

these studies. First, plateau pressure varies
according to VT, Ers, and PEEP; plateau
pressure could be low even when elastance
and driving pressure are high if a low PEEP
is applied. Plateau pressure is therefore an
imperfect surrogate for compliance or
elastance, as suggested by the fact that the
result described by Hager and colleagues
appears to differ from the result reported
in the original ARDS Network (ARDSNet)
trial, in which mortality rates appeared to
be very similar between lower- and higher-
VT strategies in patients with the highest
respiratory-system compliance (15).
Analysis by Amato and colleagues suggests
that driving pressure is more strongly
associated with the outcome than is plateau
pressure (3). Second, rather than treating
patients with different values of elastance
as completely independent subgroups, we
used analytical approaches (regression on
elastance as a continuous variable, STEPP
technique) that borrow strength from
neighboring patients with higher or lower
values of elastance and more faithfully
reflect the underlying continuous
physiology. This minimizes the possible
influence of outliers in the data (see Figure
E5). It is possible that differences in the
ventilation strategies employed in the
ARDSNet trial and other trials included in
this analysis (e.g., respiratory rate, PaCO2,
and pH targets) could account for
differences between the present findings
and those of Hager and colleagues,
although we found a similar magnitude of
interaction in a sensitivity analysis
restricted to the ARDSNet trial.
Several limitations in this work must be
appreciated. First, it would be ideal to use
prerandomization baseline elastance for this
analysis because lowering VT modifies Ers;
elastance may increase because of lung
derecruitment, or it may decrease because of
the relief of hyperdistention from high VT.
The higher average Ers in patients in the
high-VT arm could also reflect VILI from
higher VT. To address this problem, we
systematically shifted the distribution of Ers
for the higher-VT group to match that of the
lower-VT group by subtracting the mean
difference in each trial. We used simulation
to determine how both systematic and
random changes in Ers after randomization
would affect estimates of the interaction
coefficient: reassuringly, these changes
seemed to bias the results toward the null if
an interaction was present and did not
appear to give rise to a false interaction
(Figure E2).
Second, it is theoretically possible that
patients with lower Ers are less likely to
benefit from lowering VT because they have a
comparatively shorter duration of ARDS and
therefore have comparatively less time at risk
for injury. A relatively high prevalence of
rapidly improving ARDS has been
documented in the most recent ARDSNet
trials (45). However, the prevalence of
rapidly resolving ARDS was very low in the
ARDSNet trial included in this analysis.
Moreover, multiple studies have shown that
even relatively brief exposure to higher VT
and driving pressure during early ARDS is
associated with increased mortality (4, 46).
Third, this is a post hoc secondary
analysis of clinical trials. However, the
analytic design was conceived on an a priori
basis and specified in advance of data
analysis. The use of a Bayesian approach with
neutral priors also mitigates the risk of
overestimating effects associated with post
hoc analysis. Fourth, not all published
randomized trials of lower versus higher VT
(1) were included in our data set, as we used
data from a previous individual patient data
metanalysis. Our data set includes the largest
and most influential clinical trial in this field
(15) and comprises over 1,000 patients,
suggesting that the results are likely
generalizable to the broad population of
patients with ARDS. Patient-level data from
other data sets with more complete baseline
data and data on elastance and VT over time
would provide additional insights. Fifth, the
included trials were completed over two
decades ago but remain the empirical basis
for guidelines recommending lower-VT
ventilation in ARDS. Finally, other
physiological characteristics (respiratory rate,
mechanical power, hypercapnia) may modify
the risk of VILI; these factors were not
considered in this analysis.
Conclusions
The probability that the mortality benefit
associated with a lower-VT ventilation
strategy in patients with ARDS varies
according to Ers is high. Patients with higher
elastance (and hence higher driving
pressures) are likely to accrue a greater
mortality benefit, whereas patients with
lower elastance (and hence lower driving
pressures) are likely to accrue less mortality
benefit. Lung-protective ventilation strategies
should primarily target driving pressure
rather than VT. 䊏
Author disclosures are available with the
text of this article at www.atsjournals.org.

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