Acute respiratory distress syndrome, the critical care

paradigm: what we learned and what we forgot

Luciano Gattinoni, Eleonora Carlesso, Franco Valenza, Davide Chiumello and
Maria Luisa Caspani

In the last several years, we definitely learned that the acute

respiratory distress syndrome lung is small, nonhomogeneous,
and that mechanical ventilation in this baby lung may cause
physical damage as well as inflammatory reaction. The clinical
benefit of the gentle lung treatment, based on a decrease of
global/regional stress and strain into the lung, has been finally
proved. However, we forgot the importance of lung perfusion
and its distribution in this syndrome and, besides a low tidal
volume, we still do not know how to handle the other variables
of mechanical ventilation. Measurements of variables as
transpulmonary pressure and end expiratory lung volume, for a
rational setting of mechanical ventilation, should be introduced
in routine clinical practice.
Keywords
ALI/ARDS, ventilator-induced lung injury, randomized trials,
lung mechanics, gas exchange
Curr Opin Crit Care 10:272278. 2004 Lippincott Williams & Wilkins.

Istituto di Anestesia e Rianimazione, Universita degli Studi di Milano, Ospedale

Policlinico IRCCS, Milano, Italy
Correspondence to Prof. Luciano Gattinoni, Istituto di Anestesia e Rianimazione,
Ospedale Maggiore Policlinico-IRCCS, Via Francesco Sforza, 35 20122 Milano,
Italy
Tel: 39 02 55033232/3231; fax: 39 02 55033230;
e-mail: gattinon@policlinico.mi.it
Current Opinion in Critical Care 2004, 10:272278
Abbreviations
ARDS
EELV
PEEP
PV

acute respiratory distress syndrome

end expiratory lung volume
positive end expiratory pressure
pressure-volume

2004 Lippincott Williams & Wilkins

1070-5295

Introduction
The acute respiratory distress syndrome (ARDS) was described more than 30 years ago as adult distress syndrome, and became acute respiratory distress syndrome
years later. Although data about its incidence are somewhat conflicting, depending on the criteria used for its
definition, they are in the range of what the World
Health Organization classifies as rare disease. We may
then wonder why so much interest, clinical passion,
and scientific work has been devoted to this syndrome.
We believe for two main reasons. First, ARDS is our
disease because it was born together with critical care.
Second, it is a scenario where most of the clinical problems of the critically ill patients and critical care technology are maximally exploited. Derangements of respiration, circulation, metabolism, coagulation, and
inflammation are all present in this syndrome, which is
then a perfect paradigm to study the underlying physiology, the complex interactions between organ systems,
and their interaction with treatment. In the last few
years, several advances had been made in the understanding of this syndrome and its treatment. We would
like to comment on them from a physiologic perspective,
rather than to provide a formal review.

History
The ARDS was first described by Ashbaugh et al. [1],
and the key features of the syndrome, as well as of its
treatment, were already clearly defined in this first report. The underlying pathology was clearly recognized as
heavy lung, that is, pulmonary edema of noncardiac origin, and the key functional impairment were low compliance of respiratory system and hypoxemia despite
high FiO2 (refractory hypoxemia). The cornerstone of
the treatment was the use of positive end expiratory
pressure (PEEP) which, since the beginning, was inseparably linked with the ARDS concept.
Interestingly, the main concern for the potential damages of mechanical ventilation was the high FiO2, and it
was not unusual to ventilate patients with plateau pressure up to 100 cm H2O, or even higher. That PEEP
worked by increasing the end expiratory lung volume
was realized very early [2], and a typical treatment included modest PEEP, 5 to 10 cm H2O, FiO2 as low as
possible, and VT 1215 mL/kg, to keep the PaCO2 in
normal range [3].

272

ARDS, critical care paradigm Gattinoni et al. 273

In 1972, Hill et al. [4] reported a case in which a patient

was treated with long-term venoarterial membrane oxygenation, and most of us thought that the solution of the
problem was very close. This report lead to the NIHsponsored multicenter ECMO trial [5]. The entry criteria were based on oxygenation defects (short or medium
term), which were expected to result in a mortality of
about 50%. Actually, the mortality in both groups
(ECMO and treated) was about 90%. Approximately at
the same time, Suter et al. [6] introduced the concept
of the best PEEP. This was a landmark paper because,
for the first time, the interactions of gas exchange, lung
mechanics, and hemodynamics were considered together
in a structured analysis, clearly indicating that the respiratory treatment for ARDS is not simply the care of PO2.
In the same period, we were studying the possibility of
decreasing the ventilation in experimental animals down
to zero, maintaining the normal PO2 by apneic oxygenation and removing the CO2 by extracorporeal means
[7,8], and we introduced explicitly the concept of lung
rest [9]. The clinical application of the lung rest was the
extracorporeal CO2 removal [10,11], which was later
translated in the permissive hypercapnia [12]. However, the concept was, at that time, a hopeful hypothesis,
because the damages of mechanical ventilation, with the
exception of gross barotrauma [13,14], were not recognized.
Only many years after the ARDS description, we recognized that ARDS lungs are deeply inhomogeneous
[15,16], that they are small instead of stiff [17], and
that the baby lung accounts for the damages of mechanical ventilation. A great deal of research was then devoted
to ventilator-induced lung injury, and in the last 10 years
further progress has been made in understanding ARDS
physiopathology and redefining treatment.

Physiopathology
CT lung anatomy

The CT scan dramatically improved our understanding

of the ARDS lung [18]. The most important findings
were that the lung densities are gravity dependent both
in supine and in prone position [19]. As the edema is
evenly distributed throughout the lung this led to the
concept of sponge lung [20]. The increased lung mass
and increased superimposed pressure squeeze out the
gas of the most dependent regions, leading to the CT
appearance of gasless dependent regions. A further support to this model was provided by the analysis of a
gas/tissue pressure curve at end expiration, which
showed that the pressure at which the lung collapses,
along the sterno-vertebral axis, is equal to the superimposed pressure [21]. Animal studies, with oleic acid
induced ARDS, further supported this hypothesis [22].
The sponge model has been challenged recently. Wilson
et al. [23,24] proposed an alternative model: in the

edematous lung, the pressure causes the airfluid interface to penetrate the mouth of the alveoli, then the air
fluid interface is inside the alveoli and the lung becomes
compliant. The basic difference between the two views
is that in the sponge model, the edema is believed to be
primarily in the interstitium, whereas in the airfluid
interface, model the edema is predominantly in the alveoli.
Lung structure and function

The CT scan allowed detection of the structural changes

occurring in ALI/ARDS with time [25]. In early ARDS,
the lung structure is usually preserved and the predominant lesion is the tissue edema. With time, the lung
remodels with the appearance of fibrosis, pseudocysts,
and blebs, likely due to the mechanical ventilation [26].
These lesions have been found by different authors to be
predominant either in the nondependent [2729] or in
the dependent lung regions [25]. This is likely due to the
setting used for mechanical ventilation. Interestingly, in
the ARDS survivors, an increased reticular pattern
(likely fibrosis) has been found in the nondependent
lung regions, which are more exposed to the mechanical
insults [3032].
Although great advances have been obtained in understanding the inflation and ventilation distribution by the
CT scan, we still need a reliable method to investigate
the regional perfusion. The pulmonary circulation during
ARDS has been carefully studied several years ago, and
the main characteristics were a diffuse pulmonary vasoconstriction associated with microthrombosis or capillary
disruption [33,34]. In our opinion, no significant advances have been made in this field in the last 10 years.
Unfortunately, the lack of information on regional pulmonary perfusion prevents full understanding of the alteration of the gas exchange. We hope that the introduction of new technologies such as MRI or the combination
of PET and CT scan may allow significant advances in
this fundamental field in the future.
Tidal volume distribution

The importance of tidal volume distribution has been

fully recognized in the last few years. At ZEEP, both in
experimental animals and in humans, it has been found
the prevalent distribution of the inflated volume in the
non-dependent lung regions [3537]. This is associated
with a tidal opening of the intermediate-dependent lung
regions that collapse at the end of expiration. This phenomenon has been found to be associated with biologic
reactions, leading to an increased inflammatory response
in the lung parenchyma [3840]. The application of
PEEP adequate to prevent end-expiratory collapse may
prevent such a phenomenon, but its importance in improving outcome is still debated.

274 Anniversary issue

Positive end expiratory pressure

That PEEP is an expiratory phenomenon preventing

end-expiratory collapse has been described more than 30
years ago [2]; however, this has been fully appreciated
only with the definition of the open-lung concept [41].
The relation between PEEP and plateau pressure has
been investigated in the last few years. As PEEP is an
end-expiratory phenomenon it may keep open at endexpiration only the lung regions which have been
opened by the previous plateau pressures [42]. The
opening pressures are widely distributed throughout the
lung and may be as high as 4050 cm H2O. The interaction between plateau pressure and PEEP is the physiologic basis of the recruitment maneuver. This technique, which is in principle similar to the sigh [43,44], is
just a provision of high opening inspiratory pressures.
After opening is achieved, PEEP is usually increased to
maintain the airway patency [45,46].
Three issues, however, should be considered. First, for a
rational approach to the PEEP setting we should know,
in any given patient, the potential for recruitment. Second, we should realize that the opening pressure is the
transpulmonary pressure and not the airway pressure;
indeed, the chest/lung compliance should be considered.
Third, we do not know the answer to the most fundamental question: is always keeping the lung open the
best strategy? We know that avoiding intratidal collapse
is beneficial, at least in experimental animals, but we do
not know whether always keeping some lung regions
closed is detrimental. No one attempts to open a lobar
pneumonia, and a closed region is theoretically best
protected. We need to clarify these issues in the future.
Lung mechanics

In the last few years, we fully appreciated that the chest

wall elastance may be deeply altered, as observed in
ARDS of extrapulmonary origin [47] and in surgical patients [48]. However, we believe that what matters most
is the abdominal pressure, which is the most relevant
variable affecting the chest wall elastance. Unfortunately, chest wall elastance and abdominal pressure are
not routinely assessed in ALI/ARDS. This sharply contrasts with a rational setting of mechanical ventilation,
because the transpulmonary pressure (which requires the
knowledge of chest elastance) and not the airway pressure is the distending force of the lung and the potential
damaging factor of the mechanical ventilation.
In recent years, we observed a decline of enthusiasm for
the pressure-volume (PV) curve of the respiratory system, although for years it has been advocated as a fundamental tool to understand recruitment or setting
PEEP [49]. Because the PV curve has been mainly investigated in the inspiratory limb, whereas PEEP is an
end-expiratory phenomenon, the rational for setting
PEEP according to the lower inspiratory inflection point

is questionable. Very recently, more attention has been

paid to the expiratory limb of the PV curve [50]. This, at
least, seems a more physiologic approach, but its value is
far from being proved.
Gas exchange

In the last few years, there has been a greater appreciation of the importance of CO2. It is worth remembering
that, if we consider the gas transport, 1 mmHg of PCO2
change is equivalent to 8 to 10 mmHg PO2 change, because of the different shapes of CO2 and O2 dissociation
curves. That PCO2 is more related to the structural
changes of the lung than PO2 has been known for many
years; in fact, the appearance of pseudocysts and blebs in
late ARDS is associated with an increased PCO2 [25].
Most recently it has been shown that an increased dead
space is an independent prognostic factor in ALI/ARDS
patients [51]. Moreover, the PCO2 decrease from prone
to supine is associated with survival [52]. It is possible
that, in the next few years, we will rediscover the importance of CO2 in several fields. However, as previously
discussed, the full understanding of the gas exchange
alteration requires the measurement of the regional ventilation and perfusion, and, unfortunately, we lack techniques to do so.
Hemodynamics

In our opinion, no great progress has been made in the

last 10 years. However, not only what we learn is important, but also what we forget, and our impression is that
the importance of hemodynamics is actually underevaluated. The enthusiasm for the pulmonary artery catheter
also declined. Are we moving in the right direction? The
greatest example of this oblivion is the assessment of the
effectiveness of recruitment [53,54]. This is done by observing the oxygenation increase. Unfortunately, we forgot that PO2 may greatly rise without any recruitment,
simply because of blood flow decrease or diversion, or
both. This phenomenon was fully appreciated several
years ago [55,56], and has been progressively forgotten.
Equating the recruitment with a PO2 increase, without
considering the hemodynamics, both during recruitment
maneuver or PEEP setting is misleading. Indeed, we
believe that progress could be made in this area just by
rediscovering what has been described many years ago.

Ventilator-induced lung injury

This subject has been largely investigated in recent years
both in experimental and in clinical settings and likely
represents the greatest advance made in the ALI/ARDS
field. Two main controversies, however, require some
comments. The first is the debate (more emotional than
rational) about the importance of the inflammatory reactions [5760]; the second concerns the concept of volotrauma and barotrauma [61].
We believe that there is much evidence, both in the
experimental [38,62] and clinical settings [63], that me-

ARDS, critical care paradigm Gattinoni et al. 275

chanical ventilation may lead to lung inflammation.

However, if the mechanical ventilation is too injurious,
the lung is just destroyed, without time for developing
inflammation. Contradictory findings may be explained
by different experimental settings.
Discussing barotrauma and volotrauma is not only of academic interest but may be clinically relevant. In fact, if
the problem is the volotrauma, the attention should
focus on the tidal volume setting. If it is barotrauma, the
attention should focus on airway pressure. In our opinion
this is a false problem, because pressure and volume are
two faces of the same coin.
The key question is understanding which are the first
triggers of VILI. It is quite evident that the initial trigger
is a physical one (mechanical ventilation), whereas the
consequences may be both physical and biochemical
[64]. Mead et al. elegantly approached this problem on a
theoretical background [65]. When a force (pressure) or a
volume (tidal volume) is applied to the lung, this undergoes a stress (that is, a tension in the fiber system of the
lung skeleton), and a strain (that is, the elongation of the
fibers), until the collagen is fully distended at total lung
capacity. The alveolar and the capillary cells are anchored to the fiber cytoskeleton and have to accommodate their surface when the structure is strained. It is
evident that what matters is not the airway pressure per
se, but the pressure applied to the lung fiber skeleton,
which is the transpulmonary pressure. It is also evident
that what is really important is not the tidal volume per
kilogram but the tidal volume relative to the end expiratory lung volume (EELV). Indeed, the rough equivalent of stress is the transpulmonary pressure and the
rough equivalent of strain is tidal volume/EELV. These
are linked in the following equation [64]:
Transpulmonary pressure (stress)
= Lung specific elastance
* [Tidal volume/EELV] (strain)
where the lung specific elastance, that is, elastance*EELV,
reflects the intrinsic elastic characteristics of the lung
tissue. Indeed, if we take into account the transpulmonary pressure and the VT/EELV, the difference between barotrauma and volotrauma vanishes.
We may then hypothesize the following sequence of
VILI: when a pressure is applied to the fiber cytoskeleton each fiber carries an equal amount of mechanical
load. If the system is not homogeneous, as in ALI/ARDS,
the mechanical load is unevenly distributed and fibers
may reach the stress at rupture. The strain is associated
with stress. If the stress is not so high as to cause mechanical disruption but is nevertheless excessive, the associated strain is unphysiological. The cells anchored to
the cytoskeleton have to accommodate their shape. This
change of shape activates a series of mechanical sensors,

which in turn results in an inflammatory cascade [6672].

It is possible that the first biologic trigger is caused by
the activation of macrophages followed by production of
IL8 and metalloproteinases, which in turn activate the
neutrophils with full-blown inflammation [73]. On the
other hand, the mechanical strain of the lung capillaries,
through a variety of mechanisms, produces an increase of
lung edema [7477,7880].
Unfortunately, both the stress (transpulmonary pressure)
and strain (tidal volume/EELV) are not measured in
clinical practice. We believe that approaching VILI as a
problem of stress and strain distribution may provide a
better understanding of apparently contradictory phenomena and may be crucial for future settings of mechanical ventilation.

Clinical advances
Randomized trials

Several outcome trials have been performed in ALI/

ARDS field during the last few years, dealing with mechanical ventilation [8185], nitric oxide supply [8688],
surfactant therapy [8991], and prone position [92]. The
greatest advances have been made in mechanical ventilation. The Brazilian trial tested a lung-protective strategy (low PEEP high VT vs high PEEP low VT) in a
relatively small series of patients and found impressive
differences in mortality [81]. This study was criticized for
the high mortality found in the control group, but represented a strong impetus for further work. Other trials
[8284] compared different tidal volume in a range between 8 and 10 mL/kg and failed to show differences in
outcome. The largest NIH trial [85], comparing a wider
gap of tidal volume (6 vs 12 mL/kg) found a significant
difference in mortality in favor of the low tidal volume
group. Considering all these results together, we believe
that, after 30 years, the concept of gentle treatment of
the lung has been finally documented. However, we also
believe that the real comparison should be made between different strain and stress instead of different tidal
volume/kg and airway pressure.
Both the nitric oxide trials [8688] and surfactant trials
[8991] were unsuccessful, and the use of these forms of
therapy should be devoted to selected cases.
The prone position is largely used in ALI/ARDS [93]. Its
effectiveness for improving oxygenation is unquestionable but, unfortunately, we and others were not able to
find differences in outcome. The largest study on prone
position [92], however, has several limitations, such as
the shortness of time in prone position (6 hours), the total
length time of study (10 days), and, perhaps more important, the uncontrolled mechanical ventilation in both
treatment arms. If the rationale of using the prone position is not the gas exchange but the reduction of stress
and strain maldistribution while prone [94,95], it is evi-

276 Anniversary issue

dent that the study design should be modified [64]. A

new trial allowing prone position for 20 hours with strict
control of mechanical ventilation is actually ongoing.

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The last important trial, still unpublished, is the ALVEOLI study, which compared two different PEEP
strategies (high and low). The trial was interrupted for
lack of treatment effectiveness. It is difficult to comment
on these results in the absence of data. However, if we
accept the concept that PEEP may affect the outcome
by decreasing the stress and strain maldistribution
through its action of keeping the lung open, it is possible
that a random allocation of patients with low or high
potential for recruitment in the two treatment arms may
obscure the real effectiveness of PEEP. It is in fact possible that high PEEP is effective in patients with high
potential for recruitment, decreasing their stress and
strain maldistribution, whereas it may be harmful in patients with low potential for recruitment in which PEEP
just increases the total stress and strain. Further work is
needed in the field.

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If we have to summarize what we have learned in the last

few years in the management of the ARDS, the answer
is straightforward: the gentle treatment of the lung by
low tidal volume. To reach this goal, permissive hypercapnia may be tolerated while its role on lung protection
is still debated. Gentle lung treatment results in less
stress and strain of the lung parenchyma, less VILI, and
decreased inflammatory reaction.
The setting of the other variables of mechanical ventilation is still not defined. However, if we accept a physiologic perspective [96], it is possible that high PEEP
should be limited to patients with high potential for recruitment. Other potential important variables as FiO2
and respiratory rate have not been sufficiently studied.
We may also expect further advances if new technology
will allow us to understand the regional pulmonary perfusion. We still believe, but we cannot prove yet, that
prone position is an important tool for decreasing the
danger of mechanical ventilation and we expect that, in
the future, a rational setting of mechanical ventilation
will imply measurements of transpulmonary pressures
and baseline end-expiratory lung volumes.

References and recommended reading

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Of special interest
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