A Comparative Study of Glucocorticoids Efficacy in Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a secondary disease that follows-usually within 6-48 h-a primary disease of multifactorial etiology (most frequently pneumonia and extrapulmonary sepsis) associated with severe systemic inflammation. Inflammatory mediators released into the systemic circulation (systemic inflammation) from the site of infection reach the broad pulmonary capillary surface, producing severe and diffuse inflammatory exudate of the pulmonary lobules and resulting in hypoxemic respiratory failure.

In ARDS, systemic inflammation is activated by the nuclear factor-κB (NF-κB) signaling system and downregulated by activated glucocorticoid receptor α (GRα). In these patients, inadequate (endogenous glucocorticoid-activated) GRα-mediated downregulation of proinflammatory transcription factor NF-κB in circulating and tissue cells leads to higher initial levels and persistent elevation over time of plasma and bronchoalveolar lavage markers of inflammation, hemostasis, and tissue repair. Inadequate intracellular GRα-mediated anti-inflammatory activity for the severity of the patient's illness was recently termed critical illness-related corticosteroid insufficiency (CIRCI). Experimental and clinical research shows that CIRCI can be improved with quantitatively and temporally adequate glucocorticoid administration.

Glucocorticoids are commonly used in patients with acute respiratory distress syndrome (ARDS) or at-risk for ARDS with proposed mechanisms including reduction of local lung inflammation and dampening of systemic immune responses.

Clinical trials of glucocorticoids in patients with ARDS or at-risk from a pulmonary infection have had mixed results with some studies suggesting benefit and others showing no beneficial effects. Notably, the glucocorticoid agent, dose, and duration has varied widely between studies increasing the challenge of interpreting discordant findings.

In animal models of ARDS, glucocorticoids decreased the expression of pro-inflammatory mediators in lung tissue, including TNF-a, IL-1a, IL-1b, IL-6 and IL-12 p40, and reduces lung injury through the reduction of oxygen radicals produced by neutrophils. Beyond their anti-inflammatory effects during the acute phase of inflammation, glucocorticoids also contributed to the resolution of inflammation, trough reprogramming effects on macrophages.

Glucocorticoids have been administered during two distinct phases of ARDS, during the early stage of ARDS when inflammation is expected to be most important and during late phase of ARDS, when lung fibrosis predominates. The biological and pathological characteristics of these two entities differ greatly, explaining the observed conflicting results in the effects of glucocorticoids in these two distinct conditions.

The early phase of ARDS is characterized by major alveolar inflammation. Thus, glucocorticoids, potent anti-inflammatory agents, are theoretically expected to be relevant treatment for ARDS.

Late-stage ARDS is characterized histologically by ongoing inflammation with fibroproliferation, presence of hyaline membranes, and persistent diffuse alveolar damage, leading to prolonged mechanical ventilation and a higher risk of death. The largest multicenter placebo-controlled trial, found no evidence for beneficial effects of glucocorticoids initiated for late-stage ARDS.

• The number of patients needing invasive mechanical ventilation [Time frame: From enrollment to the end of treatment at 28 days]
• The Number of ventilator-free days [Time frame: From enrollment to the end of treatment at 28 days]
• Duration of the ICU stay [Time frame: From enrollment to the end of treatment at 28 days]
• Duration of hospitalization [Time frame: From enrollment to the end of treatment at 28 days]
• Incidence of serious adverse events, including secondary infections, hyperglycemia, clinically important gastrointestinal bleeding, and hypertension [Time frame: From enrollment to the end of treatment at 28 days]