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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.
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
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
Prone positioning
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.
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