Prolonged glucocorticoid treatment in ARDS: Pathobiological rationale and pharmacological principles

Glucocorticoids (GCs) are agonist compounds that bind to the GC receptor (GRα), producing a rapid pharmacological response. Clinical efficacy depends on the magnitude and duration of exposure to GRα; the effect is systemic, including lung tissue and circulating cells. The extraordinary research advancements of the last decade have radically reshaped our understanding of the GRα's multifaceted actions, the effector of GC actions. In this chapter, we first examine the pathogenetic rationale for GC treatment by (i) placing ARDS in the context of the general adaptation to critical illness and (ii) as an acute multifactorial interstitial lung disease (not a syndrome). We examine the progression of each integrated stratum of this disease—pathogenesis—morphology—physiology—in patients with adaptive versus maladaptive responses. During the three phases of disease progression, the GC-GRα operates as the central homeostatic rheostat regulating cellular, tissue-specific, and systemic responses with fine-tuning of every process in every organ, adapting responses to constantly changing surrounding signals. We synthesize the current literature on the role of the GRα as the effector of GC therapy, including genomic and nongenomic effects, and examine pharmacological principles to guide GC administration. This review addresses the role dosage, timing of initiation, mode of administration, duration, and tapering play in achieving an optimal response to GC therapy in ARDS. An updated metaanalysis of randomized controlled trials (RCTs) investigating GC treatment in ARDS includes evaluating treatment protocols’ components. Based on RCT data, GC plasma concentration-time profiles, and pharmacodynamic studies, optimal results are most likely achievable with early intervention, an initial bolus dose to achieve close to maximal GRα saturation, followed by a continuous infusion to maintain high levels of response throughout the treatment period, and slow tapering. We finally address the substantial between-patient variability in plasma concentrations and intracellular response, a rationale for adjusting dose and duration targeting clinical and laboratory improvements. These findings have practical clinical relevance and should be incorporated into the design of future trials.