Prolonged glucocorticoid treatment in ARDS: Pathobiological rationale and pharmacological principles

• Exogenous glucocorticoids (GCs) are agonist compounds that bind to the GC receptor (GRα), producing a rapid pharmacological response. • The view of GCs’ actions as solely antiinflammatory and immunosuppressive is obsolete, impacting the design of randomized controlled trials (RCTs) in critical illness and clinical practice. • GC treatment should be guided by a clear understanding of (i) newly identified GC-GRα regulatory and coregulatory actions, (ii) GC-GRα temporal involvement in disease pathobiology, and (iii) GC pharmacological principles relevant to critical illness. • Acute respiratory distress syndrome (ARDS) is an acute multifactorial interstitial lung disease leading to acute hypoxemic respiratory failure requiring mechanical ventilation (MV) for life support. • ARDS progresses through three temporal phases: (i) acute (respiratory failure), (ii) subacute (after ventilatory support removal), and (iii) chronic (following hospital discharge). • Translational clinical research has constructed a pathophysiological model of ARDS that fits pathogenesis (biology—core stratum) with morphological (histology—intermediate stratum) and clinical (physiology—outer stratum) findings observed during the disease. • The activated GC-GRα plays a central role in every phase of homeostatic recovery, leading to ARDS resolution. For this reason, exogenous GC administration should be extended beyond the phase of ventilatory dependence to support disease resolution and restoration of anatomical function. • Multiple components of GC treatment protocol profoundly affect the response, while interindividual variability remains an unpredictable and uncontrollable factor. • The dosage, timing of initiation, mode of administration, duration, tapering, and cointerventions to support the GRα and mitochondrial functions are all essential elements to achieving optimal response to therapy. • Implementation of pharmacodynamic and pharmacokinetic principles impact clinical efficacy, while pathobiological understanding optimizes treatment administration and monitoring response. • The substantial between-patient variability in plasma concentrations and intracellular response provides the rationale for RCTs investigating adjusting dose and duration, targeting clinical and laboratory improvements.