Limitations of the AECC Definition of ARDS
The AECC definition of ARDS has critical limitations that contributed to decades of failed therapeutic trials, primarily due to its lack of standardized ventilatory parameters for assessing oxygenation, absence of severity stratification, and failure to capture the profound heterogeneity of the syndrome across aetiological, physiological, and biological domains. 1, 2
Major Definitional Flaws
Lack of Standardized Ventilatory Assessment
The AECC definition did not require standardized ventilatory support when evaluating oxygenation defects, allowing PaO2/FiO2 ratios to be calculated under varying PEEP levels, which fundamentally undermines the reliability and comparability of the hypoxemia criterion. 2, 3
This absence of a minimum PEEP requirement meant that patients could meet ARDS criteria under vastly different ventilatory conditions, making the diagnosis inconsistent and unreliable across centers. 2, 4
Inadequate Severity Stratification
The AECC definition used only two categories (ALI and ARDS) based solely on PaO2/FiO2 thresholds, which failed to adequately stratify patients by mortality risk or identify those who might benefit from specific interventions like prone positioning or ECMO. 2, 4
The binary classification system (PaO2/FiO2 ≤300 for ALI, ≤200 for ARDS) did not capture the spectrum of disease severity, limiting its utility for both clinical decision-making and research trial enrollment. 2
Heterogeneity Not Addressed
Aetiological Heterogeneity
The AECC definition required no specific aetiological criteria, lumping together patients with fundamentally different underlying causes—from direct pulmonary infections to indirect sepsis, from aspiration to transfusion-related injury—all under one umbrella diagnosis. 1
This inclusive approach meant that ARDS-mimics (such as acute interstitial pneumonias, drug-induced lung injury, or diffuse alveolar hemorrhage) could be misclassified as ARDS, despite requiring entirely different treatments like immunosuppression rather than supportive care alone. 1
Only a minority of patients meeting AECC criteria for ARDS actually demonstrated diffuse alveolar damage on post-mortem pathological evaluation, revealing a fundamental disconnect between clinical diagnosis and underlying pathology. 1
Physiological and Biological Heterogeneity
The definition included no physiological criteria beyond gas exchange, ignoring critical variables like respiratory system compliance, dead space fraction, or lung recruitability that profoundly affect treatment response and prognosis. 1, 4
No biological markers or endotypes were incorporated, despite growing evidence that ARDS encompasses distinct inflammatory and molecular phenotypes that respond differently to therapies. 1
Clinical and Research Consequences
Failed Therapeutic Trials
The heterogeneity inherent in the AECC definition likely contributed to the failure of multiple interventional studies targeting inflammation, coagulation, oxidative stress, and endothelial injury, as treatments effective for specific subphenotypes were diluted across heterogeneous populations. 1
Without phenotype-aware trial design, beneficial treatments may have been discarded because they helped some patients while harming or providing no benefit to others within the same diagnostic category. 1
Lack of Precision Medicine Framework
- The AECC definition provided no framework for identifying which patients would benefit from specific interventions, making it impossible to apply precision medicine approaches that target treatments to those most likely to respond. 1
Cardiac Failure Exclusion Ambiguity
The criterion requiring that pulmonary edema not be "fully explained by cardiac failure" was vague and subjective, with no standardized approach for ruling out hydrostatic causes, leading to inconsistent application across clinicians and centers. 2, 4
The reliance on pulmonary artery wedge pressure measurements was impractical in many settings and did not account for mixed cardiogenic and non-cardiogenic causes of edema. 2, 4
Radiographic Interpretation Variability
The requirement for "bilateral infiltrates" on chest radiography lacked standardized interpretation criteria, leading to significant inter-observer variability in diagnosis. 2, 4
No reference imaging standards existed to guide clinicians in distinguishing ARDS from other causes of bilateral opacities. 4
Common Pitfalls in Clinical Application
Clinicians often diagnosed ARDS based on PaO2/FiO2 ratios obtained at widely varying PEEP levels (or even without PEEP), making severity assessments meaningless for guiding therapy. 3
The lack of timing criteria meant that chronic conditions could be misclassified as acute ARDS. 2
The absence of re-evaluation requirements under standardized conditions meant that transient hypoxemia could lead to ARDS diagnosis even when oxygenation rapidly improved. 3