Advances in the understanding of acute respiratory

distress syndrome: summarizing a decade of progress

John J. Marini

Department of Medicine, University of Minnesota, Minneapolis/St. Paul, and

Pulmonary/Critical Care Division, Regions Hospital, St. Paul, Minnesota, USA
Correspondence to John J. Marini, Pulmonary/Critical Care Division, Regions
Hospital, 640 Jackson St., St. Paul, MN 55101, USA
Tel: 651 254 3135; fax 651 254 3098; e-mail: john.j.marini@healthpartners.com
Current Opinion in Critical Care 2004, 10:265271
Abbreviations
ALI
ARDS
NAVA
NIH
PEEP

acute lung injury

acute respiratory distress syndrome
neurally adjusted ventilatory assist
National Institutes of Health
positive end-expiratory pressure

2004 Lippincott Williams & Wilkins

1070-5295

Introduction
Over the past decade, unprecedented progress has occurred in the understanding and management of the
clinical problem set that we label as acute lung injury
(ALI) and its more severe variant, the acute respiratory
distress syndrome (ARDS). The scale of improved understanding extends from the microcellular level to the
epidemiologic sciences that underpin the study of our
field. So extensive has the body of recent data become
that adequate treatment would require a thick monograph to detail. Consequently, in this brief and selective
overview, I can only attempt to present the core concepts
of these advances, interpreted within the limited context
of my own perspective.
Certain themes continue to recur: the diversity of
ALI/ARDS; the complexity of the pathogenetic and
therapeutic environments; the time dependence of scientific observations and therapeutic effects; the potential
of fragmentary evidence to give rise to misjudgment and
iatrogenicity; and the ravages of definitional uncertainty
and imprecise classification on clinical research. Over the
span of this decade, we have learned that the entity we
call ARDS varies over time, between patients, and even
regionally within the lungs of an afflicted subject. In
many respects, we are not dealing with one problem but
with many. This variation may help to explain why the
incidence and natural history of this syndrome have been
so difficult to nail down [13]. We have learned that the
pathogenesis and pathoanatomy of ARDS vary markedly
among patients, helping to explain why the therapies we
apply have the potential to damage as well as to heal.

Definitions and epidemiologic issues

Although response and prognosis are acknowledged to
differ with cause, etiologic differences have largely been
ignored when recruiting into clinical trials. The impact of
definitional imprecision on the validity of our clinical
science and on the application of therapeutics to the
individual patient should not be underestimated. Mechanical ventilation provides a good example. Although
not yet confirmed, it has been cogently argued that the
etiology for lung injury helps determine the response to
ventilatory therapy [4]. More importantly, most published trials fail to specify the conditions (eg, positive
end-expiratory pressure [PEEP], ventilation mode, spontaneous vs. controlled conditions) under which gas exchange is measured; the trajectory of illness has often
gone unheeded; and the response to initial treatment has
not been carefully considered prior to enrollment in
clinical trials [5]. Perhaps most disturbing of all, recently
published studies [6,7] indicate that experts often fail to
agree on whether a chest radiograph is compatible with
the most commonly accepted definition of ARDS proposed by the American European Consensus Conference
of 1994 [8]. The rather loose criteria for ALI and ARDS
that were set at that conference serve some purposes
better than others; broad definitions facilitate recruitment into clinical trials and potentially broaden the applicability of the result. Unquestionably, however, this
inclusive approach has had an adverse impact on the
discriminating ability of therapeutic clinical trials. Loose
definitional criteria may also help to account for the
widely varying incidence figures that have emerged from
different epidemiologic surveys. From longitudinal studies conducted in single centers, we have learned that
ARDS mortality has decreased substantially over the
past decade, with major improvement having occurred in
the early 1990s [9]. Consistent data from several sources
indicate that despite the improving prognosis, late
deaths, protracted disability, and lasting psychosocial difficulties are important consequences of the ARDS experience [10].

Pathogenesis
The themes of complexity and time dependence recur in
the literature that addresses the subcellular events associated with pathogenesis of ARDS-related inflammation.
The interplay between pro- and anti-inflammatory mediators has been emphasized by various authors, who
noted that imbalance and dysregulation of these simul265

266 Anniversary issue

taneously activated, antagonistic pathways are key to the

problem. In most instances multiple biologic or biophysical hits may be needed to initiate such an imbalance;
conversely, the complexity of the pathogenesis may dictate that more than one therapeutic pathway needs to be
addressed to evoke a healing response [11]. Even if the
responsible pathways and interactions driving inflammation were well worked out, genetic polymorphism would
introduce wide variation in expression [12]. Furthermore, layered onto the initiating event of ARDS is the
complicating influence of the mechanical forces of ventilatory support that may modify ongoing inflammation,
delay healing, or repeatedly reinitiate the inflammatory
process.

clearance mechanisms are dysfunctional in the injured

lung [35,36]. Encouraging work, however, indicates that
the edema clearance may be accelerated by catecholamine stimulation [3739]. Other novel approaches to
resolving acute lung injury may soon be available. It was
emphasized, for example, that the acutely injured lung
can in some respects be considered a wounded lung, in
that the local environment favors coagulation. Activated
components of the coagulation cascade almost certainly
influence evolution of injury and repair [40]. One or
more of these may be amenable to blockade or acceleration, for example, by activated protein C, a drug reported
to have a beneficial effect on the mortality of some patients [28].

The interplay of cell-cell interactions has been assigned

a potentially important and perhaps pivotal function in
the acute lung injury process. Certain cell lines are
posited to play critical roles in initiating, signaling, mediating, or quelling inflammation. Although the intricate
pathobiology of acute lung injury is still poorly understoodparticularly how the whole process is sequenced
and orchestratedimpressive data assign key roles to
macrophages, neutrophils, endothelial cells, epithelial
cells, and fibroblasts [1318]. A variety of signaling and
effector molecules released from these cells have been
incriminated. Certain of these inflammatory products not
only destroy the normal architecture of the lung but also
disrupt the barrier separating gas and blood [18]. Apoptosis, or programmed cell death of the specific cell types
involved with inflammation and repair, may be crucial to
the resolution of inflammation. This is important, as recent investigations of this biologic process suggest that
apoptosis of neutrophils, fibroblasts, and other cell lines
may be amenable to drug intervention [19,20].

Extrapulmonary organ function

Detailed scientific work conducted over the past decade

has been directed toward oxidant injury and the specific
roles of nitric oxide and PaCO2 in its expression and
modulation [2123]. Evidence for therapeutic benefit
and futility has been presented for antioxidants, corticosteroids, and inhaled nitric oxide [2427]. Considerable
investigational attention has been applied to the changing inflammatory environment over time, to interactions
between the inflammatory process and the coagulation
cascade [28], and to the cross-talk that occurs between
inflammatory events within the lung and within extrapulmonary organs [2931,32]. Surfactant has been
assigned several important roles, not only in reducing
surface tension but also in quelling inflammation and
minimizing alveolar edema [33]. The challenge of detecting and monitoring acute lung injury in this complex
and everchanging environment is widely acknowledged
[34].
Adaptive mechanisms for evacuating exuded liquids are
compromised by alveolar inflammation and epithelial
disruption. It is now evident that several fundamental

Inflammatory events in the lung do not leave peripheral

organs unaffected. Based on data accumulated both in
the laboratory and in the clinical setting, it is plausible
that inflammatory mediators or protein fragments are released from the lung into the bloodstream, with the potential to inflict injury elsewhere [31,32,41,42]. That
the injured lung serves as the primary generator of multiorgan dysfunction, however, is by no means a proven
hypothesis. Whether the nature and concentrations of
such products that enter the bloodstream are sufficient to
initiate or cause injury elsewhere remains an exciting
area of investigation. Conversely, inflammation in the
lung may upregulate anti-inflammatory mechanisms that
may exert their influence at remote sites; some data suggest that anti-inflammatory influences may predominate
in extrapulmonary organs [30].
The influence of mechanical forces on the inflammatory
process now receives considerable attention. Experimental work strongly indicates that cytoskeletal transduction
of mechanical forces upregulates the inflammatory response [16,43]. Repeated cyclical stretch of the endothelium may lead to loss of its integrity or incite biochemical
changes that result in edema formation, leukocyte migration, and other key subcellular events. When cellular
strain is moderate, other noxious influences may synergize to produce the two hits needed to initiate inflammation [14]. Deformation of the alveolar epithelial cells
has been shown to result in altered internal chemistry,
cytokine release, and an intense lipid trafficking to the
site under stress [16,43]. When deformation becomes excessive, overt breaks in the plasma membrane may allow
macromolecules to breach the epithelial membrane barrier, causing catastrophic impairment or death of the affected cell [16]. Such considerations may hold important
clinical implications, as the stresses imposed on the mechanically heterogeneous lung are likely to be severalfold higher than the same pressures applied to a uniformly healthy open lung [44]. A purely mechanical
stimulus applied to healthy lungs of experimental animals has been shown to result in hemorrhagic pulmonary

Acute respiratory distress syndrome Marini 267

edema and neutrophil infiltration within hours of its application [45,46]. Whether this is a result of signaling of
subcellular events and release of inflammatory mediators
with subsequent breakdown of barrier function or
whether the stresses applied by high-pressure mechanical ventilation are sufficient in themselves to disrupt the
barrier (with inflammation as an epiphenomenon) is an
important area of inquiry at the present time.
In summarizing the wealth of new basic information regarding pathogenesis, it is clear that the clinical problem
that we recognize as ALI and ARDS is a complex entity
whose manifestations of abnormality are detectable
along numerous intersecting pathways. Many factors determine the severity of ALI; these are likely to include
genetic predisposition as well as the specific modulating
cofactors of the inflammatory microenvironment. Such
conditioners may include inspired oxygen concentration,
PaCO2 [21], pH, temperature, vascular pressure [47], coagulation status, pharmacologic environment, and other
influences yet to be elucidated.

Clinical strategies
Imaging

Extending previous work, experimental studies published within the past decade have shown that excessive
mechanical stresses developed during mechanical ventilation can inflict injury on both normal and acutely injured lungs [45]. By implication, such forces may also
retard healing. Advances in imaging technology have
contributed greatly to our understanding of the mechanical heterogeneity of ARDS and in so doing have helped
to reshape our ventilatory approach [48,49]. One imaging
technology, positron emission tomography, has proven a
useful investigative tool that can provide information regarding structure, function, and spatial-function relationships [50,51]. Microscanner units are now available that
are suitable for study of small animals. Such advanced
methodologies may be needed as we enter the gene reporting and targeting era of scientific inquiry into the
inflammatory processes of ARDS. More widely available
for clinical use is CT scanning, which has shown the
highly regionalized nature of consolidation and atelectasis in the early stage of ARDS [48,49]. CT scanning has
also shown that cysts and pseudocysts may develop later
in the ventilation process, presumably as a consequence
of uneven stresses or regional variations in tissue
strength [52].
Ventilator-induced lung injury

Repeated application of transalveolar pressures that exceed those corresponding to the inflation capacity of a
healthy lung may disrupt the alveolar/epithelial barrier,
especially in the absence of sufficient end-expiratory
pressure to hold open mechanically unstable lung units.
Although transalveolar pressure is highest in nondependent areas, tissue stresses and shearing forces may be

greatest in the middle and lower zones of the lung most

subject to closure. Closure of small airways and alveolar
units occurs at low end-expiratory pressure, and high
inspiratory pressure repeatedly subjects these tissues to
forces that may be severalfold higher than those experienced in the free wall of alveoli that remain inflated
throughout the tidal cycle [44]. From a theoretical standpoint, shear stresses at the junction of open and closed
tissue will rise to high levels that may mechanically disrupt epithelial or endothelial membranes or incite inflammation.
Reversal of atelectasis, therefore, may not only improve
oxygenation but also reduce damaging tissue stresses.
This is the primary rationale for employing a lungprotective, open lung approach such as the one successfully tested in a clinical trial by Amato et al. [53]. In
that important work, the open lung approach, which emphasized maintained recruitment and avoidance of high
plateau pressures, conferred a 28-day overall survival advantage when compared with a more conventional strategy that sought to minimize the end-expiratory pressure
used to achieve an acceptable PaO2 to FiO2 ratio. High
PEEP is not always required for maximum benefit, however. Indeed, it is likely that unnecessarily high PEEP
can exaggerate ventilation/perfusion mismatching and
increase stresses within tissues that remain uninflated.
Limiting end-inspiratory pressure makes sense whether
or not an open lung approach is attempted. A low tidal
volume approach was associated with reduced mortality
in a large multicenter trial conducted by the National
Institutes of Health (NIH)-sponsored ARDS Network,
further emphasizing the practical importance of reducing
mechanical stresses on the lungs [54]. While it remains
logical to reverse atelectasis whenever possible, high
PEEP is not always needed or desirable. This point was
emphasized in the as yet unpublished results from another ARDS Network clinical trial testing that question.
How PEEP and tidal volume are best selected remains
an important and unresolved clinical management issue.
Data from recent clinical trials suggest that peak tidal
pressures even lower than 30 cmH2O may be associated
with increased mortality [54]; therefore, a safe upper
limit for plateau pressure cannot yet be specified. Moreover, because end-inspiratory pause (plateau) pressures
are influenced by chest wall stiffness as well as by lung
properties, higher pressures are not necessarily associated with injurious transalveolar forces, especially when
plateau pressure rises as a result of increasing endexpiratory alveolar pressure.
Pressure-volume relationships and recruitment

The inspiratory pressurevolume curve has been in use

for many years as a means by which to identify the appropriate PEEP and tidal volume combination [55]. By
this guide, the inflection and deflection zones of the

268 Anniversary issue

inspiratory pressurevolume curve are used to demarcate

a safe region within which tidal pressures may operate.
Yet, the inspiratory pressurevolume curve blends together information coming from all sectors of the lung,
and its undulations are influenced by a variety of factors.
These include the relative proportions of lung units that
are overstretched and recruited [56], the presence of
airway liquids [57], and the compliance of the chest wall
[58]. All may contribute to the shape of the pressure
volume curve. Rarely can one be confident in distinguishing a single pressure or point at which tangential
compliance abruptly transitions from low to high or vice
versa.
The lowest tidal volume that maintains adequate ventilation is not necessarily the least damaging; recent experimental data demonstrate that high tidal volumes may
help to recruit lung units that otherwise would remain
closed at the same level of PEEP [59,60]. Moreover,
when a low tidal volume is used, maintaining minute
ventilation by increasing frequency may not be innocuous, especially at high vascular pressures and flows [61].
Recruitment of unusually adherent alveoli (which tend
to be located in dependent lung zones) may require the
application of pressures that exceed those corresponding
to total lung capacity [60,62]. Sustained applications of
high alveolar pressure, whether by applying an airway
pressure in excess of that which normally achieves total
lung capacity or by brief application of a tidal ventilation
pattern with a high PEEP and plateau pressure, are
known as recruitment maneuvers [6365]. Although of
unproved safety and not always efficacious, such maneuvers often improve oxygenation. When improved oxygenation is observed to result from such maneuvers,
higher end-expiratory pressure is generally required after
tidal ventilation is resumed to sustain the benefit of lung
unit opening [63,65]. Recruitment maneuvers may be
especially important when very small tidal volumes are
in use, as in high-frequency oscillation, a technique with
an excellent physiologic rationale that is gaining advocates in the clinical setting as well [66].
Once the lung is recruited, the problem of selecting the
most efficacious and least harmful PEEP/tidal volume
combination must still be addressed. It has been recently
argued that the decremental compliance value as PEEP
is lowered might be helpful in identifying the least
PEEP value that maintains patency of unstable lung
units, but this attractive theoretical approach requires
clinical confirmation [67]. Limiting plateau pressure
while using relatively high levels of PEEP to maintain
recruitment has a good theoretical rationale but obligates
mild to moderate hypercapnia in many patients. While
higher PaCO2 may be poorly tolerated by patients with
raised intracranial pressure and those intolerant of vasodilation, recent work demonstrates that hypercapnia may
have a salubrious effects on several forms of lung inflam-

mation, including that induced by adverse ventilation

strategies [21,68].
Numerous cofactors and environmental conditions influence the susceptibility of the lung to ventilation-related
damage. In animal experiments, the nature of the underlying lung injury, the vascular pressures used to perfuse
the lung [47,61], the temperature at which reventilation
occurs [69], and body position [46,70] have all been
shown to influence the result of a given PEEP/tidal volume combination. Although adequate sedation must be
given to assure the comfort of the intubated/mechanically ventilated patient, there is theoretical as well as experimental evidence to suggest that preservation of
spontaneous breathing tends to improve oxygen exchange [71,72]. Improved ventilation of dependent regions may indeed be helpful, provided that forceful expiratory effort and increased oxygen consumption are
avoided. Forceful thoracic compression at end expiration
reduces functional residual capacity and could theoretically contribute to the process of tidal closure and reopening [73]. Moreover, innate biologic variability of the
tidal rhythm (whether naturally driven or imposed artificially by a programmed ventilator) appears to serve a
recruitment function when compared with monotonous
ventilation with the same tidal volume and average frequency [74]. Periodic achievement of pressures that amplify the forces of interdependence to achieve opening is
an attractive but unproven explanatory mechanism.
Available data suggest that noninvasive ventilation,
when it can be successfully applied to the care of such
patients, may hold advantages not only for gas exchange
but also for avoidance of complications and ultimate
prognosis [7577]. Unfortunately, because most seriously
affected candidates need high inflation pressures, are comatose, and require lengthy periods of life support, they
are not good candidates for this attractive methodology.
If preservation of spontaneous breathing activity is beneficial and if biologic variation is to be encouraged, techniques that amplify inspiratory muscle activity such as
proportional assist ventilation [78] or neurally adjusted
ventilatory assist (NAVA) [79] hold special promise. The
latter technique adjusts ventilator output in accordance
with a suitably modified and conditioned electromyographic signal. Unlike proportional assist ventilation,
which seeks to monitor inspiratory flow and volume, inferring the required pressure based on knowledge of resistance, compliance, and a simplified equation of motion for the respiratory system, NAVA has a theoretical
advantage of not being subject to errors induced by unopposed auto-PEEP or run-away breathing. NAVA is
still in its earliest phases of development and may or may
not prove applicable to patients with ALI in its current
form.

Acute respiratory distress syndrome Marini 269

Prone positioning

Prone positioning improves secretion drainage from the

airways, relieves lung compression by the heart, and redistributes transalveolar forces so as to allow expansion of
the dorsal regions [80]. Approximately 70% of patients
with ALI respond to prone positioning with clinically
significant increments in oxygen exchange [81]. Experimental data demonstrate that ventilator-induced lung injury is attenuated by prone positioning, primarily by reducing the damage sustained in the supine position by
dependent dorsal areas [43,61]. Proning helps to sustain
the opening achieved by a lung recruitment maneuver
[82]. Despite these benefits, 7 hours of prone positioning
for a 10-day period did not improve survival in the overall
patient sample in a recently published Italian multicenter trial [83]. Subset analysis, however, did suggest
that proning may benefit the most seriously ill patients,
those with improved CO2 exchange after proning, and
those ventilated with the highest tidal volumes. Whether
more prolonged proning carried out for a greater proportion of the intubation period would have culminated differently is also an important question. A well-designed
and executed Spanish multicenter clinical trial of prone
positioning carried out for approximately 20 hours per
day (not yet published) showed an encouraging but nonstatistically significant trend toward lower mortality for
the proned cohort. Unfortunately, as in the Italian trial,
this study was terminated with many fewer patients entered than were targeted by the power analysis.

Discouraging experiences with clinical trials of prone positioning and pharmacologic treatment have taught us
hard lessons. Among the most important are that precise
definitions and careful selection of the study cohort are
needed before a randomized clinical trial can be usefully
translated to clinical practice [89]. Moreover, the complexity of clinical illness, responsiveness to disease and
treatment, and variation of practice environments render
randomized clinical trials very difficult to execute and
limit the relevance of their population-based conclusions
to the bedside management of the individual patient. It
could be cogently argued that randomized clinical trials
are a potentially dangerous methodology when prematurely undertaken, misapplied, or misinterpreted.

Conclusion
The diverse entity identified clinically as the acute respiratory distress syndrome continues to generate observations at the basic and clinical levels that alter prior
understanding of the best approach to management. Discoveries of the past decade have been numerous and
influential, but with molecular, physiologic, and clinical
investigative methodologies steadily improving, there is
little reason to expect that the pace of future insights will
slow.

References and recommended reading

Papers of particular interest, published within the annual period of review,
have been highlighted as:

Of special interest

Of outstanding interest

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