Descriptions of ALI and ARDS have existed since the Civil War. In 1994, a working definition of ALI and ARDS that is now widely used was developed by the American European Consensus Conference (AECC) (8
). This definition depends on evaluation of gas exchange, the chest radiograph, and exclusion of a cardiogenic cause for lung edema. Although facilitating study of comparable patient populations, this definition is open to criticism. For example, conditions under which gas exchange is measured, such as level of positive end-expiratory pressure, are not specified and often significantly influence the measurement (9
). Widespread use of oximetry may replace the use of arterial blood gas measurements (10
). Assessment of cardiac function has evolved as use of Swan-Ganz catheters has diminished and use of serum brain natriuretic peptide levels to assess cardiac function has increased. Interpretation of chest radiographs is inconsistent, although may be made more consistent with training (11
). Use of the AECC definitions results in recruitment of populations of patients with heterogeneous predispositions for development of ALI and with a spectrum of comorbidities that may influence outcome. Furthermore, categorizing patients with ALI by gas exchange impairment into ARDS and non-ARDS groups does not necessarily identify patients with different underlying disease mechanisms, pathophysiology, prognosis, or responsiveness to treatment. A fundamental challenge for investigators is that patients with ALI are likely to have significant heterogeneity in each of these dimensions.
Rather than propose new definitions of ALI or ARDS, the panel advocated flexibility in deciding inclusion criteria. Investigators should consider modifying inclusion and exclusion criteria for individual studies, basing those modifications when possible on results of Phase II studies or application of relevant biomarkers or genetic information. Strategies that would enrich study populations with patients likely to respond to a treatment under study may help define appropriate study populations. For example, study of lung recruitment or use of high positive end-expiratory pressure might require the presence of extensive bilateral opacities on the chest radiograph or CT scan, profound gas exchange abnormalities, and evidence that the lungs are acutely recruitable, whereas studies of pharmacologic interventions with low potential for toxicity might allow enrollment of patients with only modest gas exchange abnormalities and less extensive chest radiographic abnormalities. Exclusion of patients with comorbidities expected to influence the study endpoints but unlikely to respond to the study treatment may be appropriate. Inclusion and exclusion criteria, however, should be reproducibly and feasibly applicable by front-line clinicians. The panel recognized that limiting eligibility may make identification of target populations more challenging, make achievement of target sample size more difficult, and may limit the generalizability of results. Furthermore, the hypotheses underlying exclusion of patients on a genetic or physiologic basis may not, in fact, be valid, and if they are not, their spuriousness may never be discovered. Some exclusion criteria (e.g., those based on genetic testing) may be particularly problematic if there is little prospect of the requisite tests being widely and rapidly available. Additional testing also has the added risk of increasing study costs without benefit. Large, simple trials with broad eligibility criteria may in many instances be worthy of consideration.
Some interventions are appropriately applied across a heterogeneous and large group of patients. These often include process-of-care studies, such as those targeting ventilator or fluid management. Other interventions are better evaluated in groups of patients who share common pathogenetic mechanisms that result in ALI. For example, study of immune modulating therapy for patients with ALI triggered by influenza virus infection would properly be performed in patients demonstrated to be infected with that agent. Both large simple trials and more focused studies targeted at specific subgroups are needed.
Mortality and incidence of ALI differ substantially over the spectrum from infants to aged adults (12
). The incidence and mortality in young adults and children is similar, and is markedly lower than in the elderly. Studies of ALI in adults outnumber pediatric ALI studies, but there have been some recent noted successes in the latter group (13
). It may not be appropriate to include all patients across the entire age range in all trials. To increase the evidence supporting use of ARDS treatments for children, recent recommendations have been published for use of Bayesian and other novel statistical approaches for combining data from children and from adults in ARDS clinical trials (15