REVIEW

CURRENT
OPINION Stress and strain within the lung
Luciano Gattinoni a,b, Eleonora Carlesso a, and Pietro Caironi a,b

Purpose of review
To describe the physiological meaning and the clinical application of the lung stress and strain concepts.
Recent findings
The end-inspiratory plateau pressure and ratio of tidal volume/ideal body weight are inadequate
surrogates for the end-inspiratory stress (equal to the transpulmonary pressure) and the end-inspiratory strain
(change in lung volume relative to the resting volume). For a given plateau pressure or tidal volume/ideal
body weight, stress and strain may vary largely due to the variability of chest wall elastance and the
resting lung volume. The injurious limits of stress and strain in healthy lungs are reached when stress and
strain reach the total lung capacity. This occurs when the resting lung volume (the baby lung in case of
acute respiratory distress syndrome) is increased by two-fold to three-fold. As these limits are rarely reached
in clinical practice and damage has been reported with stress and strain well below this upper limit, this
implies the presence in the lung parenchyma of regions which act as stress raisers or pressure multipliers.
These are primarily linked to the inhomogeneous distribution of local stress and strain.
Summary
End-inspiratory stress and strain, as well as the lung inhomogeneity and the stress raisers, must be taken in
account when setting mechanical ventilation.
Keywords
airway plateau pressure, lung stress and strain, lung volume, stress raisers

INTRODUCTION considering these concepts as applied to the lung

Stress and strain are basic concepts primarily defined
by pulmonary physiologists in the 1960s [1]. In the
following 50 years, however, these concepts were
almost passed over in critical care literature until
Lachmann [2] resumed them in his seminal editorial
on ‘open the lung and keep it open’, a sort of
‘manifesto’ of the lung protective strategy. In the
last few years, these concepts have gained further
popularity, although their application in intensive
care is still scanty and even debated. In this brief
review, we will discuss the lung stress and strain
focusing on their anatomical basis, their physiologi-
cal meaning and the conceptual framework in
which they should be inserted to acquire a definitive
clinical meaning.
MEASUREMENT OF END-INSPIRATORY
LUNG STRESS AND STRAIN
In bioengineering parlance, stress is defined as the
distribution of internal forces per unit of area
induced by an external force applied onto a specific
material. Strain is defined as the consequent change
in linear dimension over the initial shape or refer-
ence value of that specific material. When
parenchyma during ventilation, stress and strain are
usually measured within a micro-scale range with
methods which are unfeasible in clinical practice.
Several studies, over the years, have been conducted
trying to define on the micro-scale the stress
strain
characteristics occurring at alveolar level. The avail-
able knowledge on this issue has been recently
reviewed [3]. On a macro-scale level, we may define
lung strain as the ratio of the change in lung volume
to the resting lung volume during respiration
(dV/V0), whereas lung stress is defined as the pres-
sure developed within the lung structures onto
a
Dipartimento di Anestesiologia, Terapia Intensiva e Scienze Dermato-
logiche, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policli-
nico, Università degli Studi di Milano and bDipartimento di Anestesia,
Rianimazione (Intensiva e Subintensiva) e Terapia del Dolore, Fondazione
IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy
Correspondence to Professor Luciano Gattinoni, Dipartimento di Anes-
tesiologia, Terapia Intensiva e Scienze Dermatologiche, Fondazione
IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Via Francesco
Sforza 35, 20122 Milan, Italy. Tel: +39 02 55033232; fax: +39 02
55033230; e-mail: gattinon@policlinico.mi.it
Curr Opin Crit Care 2012, 18:42–47
DOI:10.1097/MCC.0b013e32834f17d9

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KEY POINTS
 Global stress and strain are inadequately estimated by
plateau pressure and tidal volume/ideal body weight
and must be measured.
 Twenty to 50 h of mechanical ventilation may induce
lung injury up to death when stress and strain reach the
total lung capacity.
 Lung inhomogeneity (presence of regions of collapse/
consolidation close to open lung regions) may act as
stress raisers multiplying locally the applied global
stress and strain.
which the distending force is applied. Such distend-
ing force corresponds to the transpulmonary pres-
sure (PL), that is, the difference between airway
(PAW) and pleural pressures (Ppl):
PL ¼ PAW
Ppl
Stress and strain are mathematically linked by
a proportionality constant corresponding to the
Young’s modulus in engineering parlance. In pul-
monary physiology, such constant is called specific
lung elastance. Accordingly
stress ðPL Þ ¼ Kðspecific lung eleastanceÞ
 strainðdV=V 0 Þ
Therefore, to estimate lung stress and strain in
clinical practice, we must know values of both pleu-
ral pressure and resting lung volume, that is, the
reference volume.
The only possibility of estimating pleural pres-
sure in humans is to measure esophageal pressure. In
experimental studies, we found that the absolute
values of esophageal pressure reflect values of pleu-
ral pressure of the middle region of the lung, that is,
half distance between the ventral and the dorsal
lung surfaces. In contrast, it overestimates pleural
pressure of the nondependent lung regions and
underestimates pleural pressure of the dependent
lung regions [4]. However, variations in esophageal
pressure may accurately reflect the corresponding
variations in pleural pressure [4]. Talmor et al. [5], in
a proof-of-concept study, employed the absolute
values of esophageal pressures (considered as equal
to the absolute values of pleural pressure) as a tool to
set positive end expiratory pressure (PEEP) in a series
of acute respiratory distress syndrome (ARDS)
patients, thereby promoting the use of transpulmo-
nary pressure in clinical practice. In subsequent
studies, the same group of investigators showed a
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Stress and strain within the lung Gattinoni et al.
correlation between measurements of esophageal
pressure, gastric and bladder pressures, claiming
that this was the proof of the adequacy of esoph-
ageal pressure to estimate the pleural pressure and
the transpulmonary pressure [6,7]. The idea, how-
ever, was refused or challenged in a series of
editorials [8–10]. With this regard, our personal
opinion is that esophageal pressure represents just
the pressure inside the esophagus; therefore, the
best we can expect from its measurement is an
estimate of the variations in pleural pressure. In
the last few years, we have been measuring in almost
all mechanically ventilated patients esophageal
pressure with a modified nasogastric tube, which
avoids the need for supplemental catheters into the
esophagus [11]. On the basis of this experience, we
have found that values of esophageal pressure are in
general too high to represent the true pleural pres-
sure. Nonetheless, if our aim is to estimate lung
stress, what matters are the variations in esophageal
pressure, and not its absolute values.
(1)
Regarding lung strain, its measurement requires
the measurement of lung volume, which can be
done automatically by several ventilators. Nonethe-
less, the reference volume for lung strain compu-
tation has recently been an object of controversy.
We usually employed as reference volume the func-
tional residual capacity (FRC), that is, the resting
lung volume at 0 cmH2O end-expiratory pressure
[12]. It must be noted that what we defined here
(2) as ‘resting position’ of the lung is in reality the
equilibrium point of the respiratory system in which
the outward forces of the chest wall are equal and
opposite to the inward forces of the lung. Therefore,
at FRC, the ‘resting lung’ is actually in a prestressed
condition, as the transpulmonary pressure, in
supine position, equals 1–3 cmH2O (and decreases
along the gravitational axis). For practical purposes,
however, such prestress, at least during mechanical
ventilation, may be considered negligible as com-
pared with the order of magnitude of the stress to
which a lung tissue with acute inflammatory edema
is subjected during mechanical ventilation. This
scenario is completely different if we consider as
reference volume the end-expiratory lung volume
as during the application of PEEP as reported by
Mentzelopoulos and Brunner [13,14]. In this case,
the increase in PEEP for the same tidal volume
applied will unavoidably induce a decrease in strain.
We believe that the volume due to the PEEP applied,
which may be considered as a continuous strain (as
opposed to the tidal strain due to the tidal volume
application), should be considered as an inflated
volume fully inducing a strain of the lung, and thus
included in the calculation of lung strain. Therefore,
when judging the literature, the definition of strain
www.co-criticalcare.com 43
 Respiratory system
must be carefully considered and evaluated. In fact,
lung strain may be calculated as either
strain ¼ V T =ðFRC þ PEEP volumeÞ (3)
or
strain ¼ ðV T þ PEEP volumeÞ=FRC (4)
From Eq. (2), the meaning of the proportionality
constant of the stress
strain relationship, that is,
the specific lung elastance, may appear immediately
evident, as it equals the lung stress developed when
the lung strain is equal to 1. Accordingly, the specific
lung elastance equals the transpulmonary pressure
required to double the resting lung volume (i.e.,
FRC). We have recently observed that the specific
lung elastance is remarkably similar in patients with
normal or ARDS lungs, being the stress
strain
relationship linear up to about the total lung
capacity [12]. Therefore, knowing the transpulmo-
nary pressure resulted and the tidal volume applied,
it is possible to estimate the reference lung volume.
Actually, in a recent study, dynamic FRC was suc-
cessfully estimated in humans using a stress and
strain approach at any PEEP level without discon-
necting the patients from the ventilators [15]. It
must be noted, however, that specific lung elastance
differs among mammalians (mice, rats, pigs, etc.)
(unpublished data).
STRUCTURES OF THE LUNG BEARING
STRESS AND STRAIN
The structure to which stress is applied is the lung
extracellular matrix, which may be defined as a
network of proteins and carbohydrates, which pro-
vides the lung skeleton. The mechanical properties
of such skeleton are related to the presence of elastin
and the fibrillar collagen (type I and III), whereas the
nonfibrillar macromolecules (such as hyaluronic
acid and proteoglycans) fill the spaces within the
fiber network, thereby stabilizing the three-dimen-
sional architecture of the lung skeleton. In this
review, we will focus on the mechanical roles of this
structure avoiding its important physiological,
metabolic and regulatory activities. For an excellent
review on extracellular matrix function, see Pelosi
and Negrini [16]. The macrostructure of the lung
skeleton has been fully described by Weibel [17].
According to his description, two major fiber sys-
tems are present within the lung. One originates
from the lung periphery (visceral pleura) and goes
deeply down into the lung, whereas the second one
originates from the hilum and goes centripetally
into the lung, wherein the two systems connect
to each other at the alveolar level. The elastin, which
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forms a fiber network linked together with amo-
phorfous elastin, is particularly present at the alveoli
mouth, and is responsible for the elastic character-
istics of the lung. Elastin may elongate up to 1.5
times its original length. The collagen fibers, in
contrast, are inextensible and work as a stop-length
structure, thus affecting the total lung capacity. In
the resting position, the collagen fibers are folded
within the extracellular matrix and they progress-
ively unfold up to their full extension during
inspiration. The images of the three-dimensional
architecture of elastin and collagen networks are
reported both for rat and human lung by Toshima
et al. [18]. From a mechanical point of view, the
proteoglycans and the glycosaminoglycans act in
part as lubricants and are putatively responsible for
the viscous behavior of the lung, that is, the resist-
ance of the lung to the shear flow and the linear
strain during tidal breath when a stress is applied.
The fiber network is the structure directly bearing
the applied load, whereas epithelial and endothelial
cells are anchored via integrins to the extracellular
matrix. Therefore, the cells are in parallel with the
load-bearing structure and are deformed during
the lung distension up to the unphysiological stress
and strain. The participation of the cells in bearing
the load through their tight connections is still a
matter of discussion, as recently reviewed [3].
It is well known that when the lung stress and
strain are unphysiological (and we will discuss
below the meaning of this adjective), the lung
reacts by producing inflammatory cytokines and
mediators, thereby commencing an inflammatory
process within the lung parenchyma. The direct
transduction of the mechanical stimulus to a bio-
logical reaction, however, is not a well defined
process, and it is generally attributed to not well
defined mechano-receptors. It is known, however,
that both epithelial and endothelial cells may react
to mechanical deformation by producing inflamma-
tory cytokines [19]. More recently, the importance
of the extracellular matrix in triggering the inflam-
matory response has been pointed out [20]. In fact,
when the extracellular matrix loses its integrity, as
likely during the application of an excessive stress
and strain, fragments of hyaluronan activate an
inflammatory response through Toll-like receptors.
In contrast, the hyaluronan, when not fragmented,
prevents epithelial cells apoptosis. Moreover, the
possible important role of coupling between mech-
anical forces and enzyme activity in the breakdown
of the extracellular matrix and in its remodeling has
been recently emphasized [21]. In conclusion, there
is increasing evidence that an excessive stress
and strain may induce inflammatory responses
within the lung parenchyma through a variety of
Volume 18  Number 1  February 2012

biochemical pathways likely triggered by alterations
of the extracellular matrix, that is, the potential
injury to the structure in which stress and strain
are directly applied [22].
UNPHYSIOLOGICAL LUNG STRESS AND
STRAIN
Although the mechanisms of lung inflammation
associated with mechanical ventilation have been
increasingly elucidated, the clear definition of
unphysiological lung stress and strain is lacking.
We know, in general, that greater is the lung strain
applied, worse is the lung damage developed and the
outcome derived, as shown in the first ARDS net-
work study [23]. However, which are the anatomical
and physiological boundaries that make the stress
and strain applied to the lung unphysiological?
&&
Protti et al. [24 ] in a series of experiments on
healthy pigs undergoing long-term mechanical
ventilation at 0 cmH2O PEEP and strain ranging
from below 1 to greater than 3, found that all
animals ventilated with a strain below 1.5 (i.e.,
1.5 times their resting lung volume) survived for
54 h of mechanical ventilation without any func-
tional or anatomical lung damage, whereas all
animals ventilated with a strain greater than 2.5
died with respiratory failure and marked lung
edema. A ‘grey’ and unclear zone was identified
between these two limits, with some animals dying
and some others surviving with perfectly healthy
lungs. From this study, it has been clearly shown
that in healthy lungs, mechanical ventilation
becomes injurious and lethal when the stress and
strain reached are around the total lung capacity.
Therefore, it is quite obvious to consider that unphy-
siological stress and strain occur around this area,
which, in humans, should be equal to a tidal trans-
pulmonary pressure greater than 22–23 cmH2O and
a volume variation more than double the resting
lung volume. This condition, however, is likely to be
extremely rare in clinical practice, even considering
the small dimensions of the ‘baby lung’ [25]. There-
fore, in order to explain the clinical results clearly
documenting the advantages of a low tidal venti-
lation as compared with higher tidal volume even in
patients with a relatively good compliance (and a
greater baby lung) [26], factors other than the global
end-inspiratory stress and strain must be taken into
account such as a lung inhomogeneity and the
possible presence of stress raisers during ventilation.
THE CONCEPT OF LUNG STRESS RAISERS
In an ideal isotropic lung, when a force is applied to
the lung fiber network, the stress and strain
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Stress and strain within the lung Gattinoni et al.
generated are equal in any lung region, that is, each
fiber bears the same load and undergoes the same
deformation. In contrast, if an inhomogeneity is
present in the network, such as for instance lung
collapse (reversible lung closure) or lung consolida-
tion (nonreversible lung closure), the applied force
will be inhomogeneously distributed within the
lung parenchyma, and, therefore, will be concen-
trated in the regions around the collapse or consol-
idation. Thus, the fibers connected to the lesions
will have to bear the load previously born by the
consolidated/collapsed regions, thereby resulting in
a locally increased stress and strain. This model was
extensively described years ago by Mead et al. [27] in
a theoretical study. In particular, they considered
two neighbor lung regions fully expanded at
30 cmH2O transpulmonary pressure. If one of the
two regions loses its elasticity (i.e., during consol-
idation or collapse), the applied force will concen-
trate in the other one, thereby increasing its strain
and stress. Mead et al. computed that if the volume
ratio of the two regions had gone from 10/10 (both
regions distended) to 10/1 (one region distended
and the other one collapsed/consolidated), the
stress of the open regions would have increased from
30 to about 140 cmH2O. The mathematical basis of
this computation relies on the fact that the stress
being expressed as a force/area ratio, a volume ratio
of 10/1 should be transformed into a ratio of areas.
As area is volume at a power of 0.66, a volume ratio
of 10/1 will be equal to an area ratio of (10/1)0.66,
that is, 4.57. The initial force applied to the two lung
regions, therefore, should be multiplied almost five
fold, thus increasing the stress of the open unit up to
30  4.57 cmH2O, that is, 132.13 cmH2O. This quite
complicated description was used to describe a
phenomenon which is intuitively easy to under-
stand and potentially important in clinical practice.
Regions of inhomogeneity, that is, either lung col-
lapsed or consolidated, actually act as stress raisers
or pressure multipliers in the neighbor regions. This
phenomenon should have a maximum effect at the
interface between regions always open and regions
always closed, but should be also present at a lower
degree within lung regions undergoing opening and
closing during tidal ventilation. Overall, the basic
concept is that in an inhomogeneous lung the pres-
ence of areas of stress raisers may make dangerous
transpulmonary pressures, which normally are
‘innocent’ in healthy or even in less inhomo-
geneous lungs. That acute lung injury or ARDS
induce a huge inhomogeneity within the diseased
lung parenchyma is knowledge acquired by com-
puted tomography (CT) scan and, more recently, by
&
respiratory input impedance [28 ]. The presence of
regions acting as stress raisers may explain why even
www.co-criticalcare.com 45
 Respiratory system
low transpulmonary pressure may be dangerous in a
very inhomogeneous lung and the decrease of the
stress raisers (and inhomogeneity) is the only
rational explanation why PEEP should improve
mortality in ARDS patients. The multiplying factor
reported by Mead et al. was derived experimentally
in a recent work by employing synchrotron-
based radiograph tomographic microscopy (which
generates detailed three-dimensional alveolar geo-
metries). In fact, in isolated rat lungs, the investi-
gators showed that the local strain developed in the
alveolar wall carries a multiple of the value of the
global strain up to four times, a value impressively
similar to computations by Mead et al. [29].
END-INSPIRATORY LUNG STRESS AND
STRAIN AND STRESS RAISERS IN
CLINICAL PRACTICE
On the basis of what we have presented above, as far
as clinical practice is concerned, we believe that
two main issues have to be considered: the global
stress and strain applied or developed into the over-
all lung parenchyma, and the possible management
of areas of stress raisers. The current surrogates for
lung stress and strain are the plateau airway pressure
and the tidal volume as standardized on ideal body
weight. Chiumello et al. [12] showed that these
surrogates are clearly inadequate. As an example,
the same plateau pressure of 30 cmH2O, depending
on the chest wall elastance, may result in a lung
stress ranging from 8 to 26 cmH2O. In the first case,
the lung volume increases at end-inspiration by
about 66%, considering the specific lung elastance
equal to 12 cmH2O, 8 cmH2O transpulmonary pres-
sure results in a strain of 0.66 – see Eq. (2). Such
increase in lung volume is perfectly tolerable by
the overall respiratory system. In the second case,
the original volume will increase by about 200%,
thereby reaching a volume zone close to total lung
capacity. The application of concepts on lung vol-
umes and lung strain to tailor mechanical venti-
lation (integrated with the evaluation of the BMI)
has been recently pointed out by Mattingley et al.
[30]. Their results have been also re-analyzed and
elegantly emphasized under the light of lung stress
and strain by Fanelli and Ranieri [31]. It appears,
therefore, that there is an increasing trend to con-
sider lung stress and strain, at least in their global
expression, as a meaningful tool to tailor a well
tolerated mechanical ventilation instead of employ-
ing plateau airway pressures and tidal volume as
standardized on ideal body weight. In this light, it
is interesting to note that, in patients with severe
respiratory failure due to H1N1 pandemia, there has
been an increasing use of extracorporeal membrane
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lung oxygenation [32,33], which allows a complete
control and limitation of lung stress and strain [34].
Although the global lung strain is relatively easy
to assess, to date the potential presence, intensity and
extent of areas of stress raisers may only be inferred by
lung inhomogeneity, which usually parallels the
lung CT severity. In the presence of stress raisers,
techniques such as recruitment maneuvers are not
without risks, as shown in experimental settings [35].
In patients with acute lung injury/ARDS, Caironi et al.
&&
[36 ] found that increasing PEEP markedly reduced
lung areas of intra-tidal opening and closing
phenomenon in patients with a high lung recruit-
ability, thereby likely decreasing areas of stress raisers
while increasing the continuous strain. The
beneficial effects of reducing areas of stress raisers
appeared to be greater than the potential disadvan-
tages of increasing the continuous strain while
increasing PEEP. This observation raises a question
on the nature of the lung strain applied, that is, static
vs. dynamic. It is very likely that continuous strain is
far less dangerous than tidal strain, at least in cell
cultures and in experimental animals. The findings of
Caironi et al. go toward this direction. Moreover,
there is increasing evidence that all the maneuvers
aimed at decreasing lung inhomogeneity, when it is
severe, such as higher PEEP [37–39] and prone pos-
ition [13,40,41], tend to improve outcome, as shown
in recent meta-analyses [42,43].
CONCLUSION
In conclusion, there is increasing interest in measur-
ing lung stress and strain as a possible tool to guide a
well tolerated mechanical ventilation. This
approach has a solid physiological background
and, undoubtedly, allows measuring the real forces
distending the lung. Several issues, however, need to
be elucidated, which are equally or even more
important than what has been already elucidated,
such as the difference between tidal stress and strain
(as a function of tidal volume) and continuous stress
and strain (as a function of PEEP). Finally, an esti-
mate of the stress raisers and lung inhomogeneity
will allow inferences on local phenomena of stress
and strain, which are probably of major importance
in ventilator management of severe respiratory
failure.
Acknowledgements
This study was supported in part by an Italian grant
provided by Fondazione Fiera di Milano for Transla-
tional and Competitive Research (2007, L.G.).
Conflicts of interest
There are no conflicts of interest.
Volume 18  Number 1  February 2012

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