Abstract
Based on molecular mechanisms and physiologic data, a strong association has been established between dysregulated systemic inflammation and progression of acute respiratory distress syndrome (ARDS). In ARDS patients, glucocorticoid receptor-mediated downregulation of systemic inflammation is essential to restore homeostasis, decrease morbidity and improve survival and can be significantly enhanced with prolonged low-to-moderate dose glucocorticoid treatment. A large body of evidence supports a strong association between prolonged glucocorticoid treatment-induced downregulation of the inflammatory response and improvement in pulmonary and extrapulmonary physiology. The balance of the available data from eight controlled trials (n = 622) provides consistent strong level of evidence for improving patient-centered outcomes and hospital survival. The sizable increase in mechanical ventilation-free days (weighted mean difference, 6.48 days; CI 95% 2.57–10.38, p < 0.0001) and intensive care unit-free days (weighted mean difference, 7.7 days; 95% CI, 3.13–12.20, p < 0.0001) by day 28 is superior to any investigated intervention in ARDS. For treatment initiated before day 14 of ARDS, the increased in hospital survival (70 vs. 52%, OR 2.41, CI 95% 1.50–3.87, p = 0.0003) translates into a number needed to treat to save one life of 5.5. Importantly, prolonged glucocorticoid treatment is not associated with increased risk for nosocomial infections (22 vs. 27%, OR 0.61, CI 95% 0.35–1.04, p = 0.07). Treatment decisions involve a tradeoff between benefits and risks, as well as costs. This low-cost, highly effective therapy is familiar to every physician and has a low risk profile when secondary prevention measures are implemented.
Highlights
Reviewed by: Vijay Srinivasan, Children’s Hospital of Philadelphia, USA Satoshi Nakagawa, National Center for Child Health and Development, Japan
The sizable increase in mechanical ventilation-free days and intensive care unit-free days by day 28 is superior to any investigated intervention in acute respiratory distress syndrome (ARDS)
For treatment initiated before day 14 of ARDS, the increased in hospital survival (70 vs. 52%, OR 2.41, CI 95% 1.50–3.87, p = 0.0003) translates into a number needed to treat to save one life of 5.5
Summary
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. In sepsis and ARDS, systemic inflammation is activated by the nuclear factor-κB (NF-κB) signaling system and downregulated by the activated glucocorticoid receptor-α (GRα) [1] (Figure 1) In these patients, inadequate (endogenous glucocorticoid activated) GRα-mediated downregulation of pro-inflammatory NF-κB in circulating and tissue cells leads to higher initial levels and persistent elevation over time in plasma and bronchoalveolar lavage (BAL) markers of inflammation, hemostasis, and tissue repair [1]. Experimental ARDS is associated with a significant reduction in lung tissue GRα expression [20,21,22] and increase in GRβ mRNA [21], leading to decreased GRα nuclear translocation [21] In these experiments, lowdose glucocorticoid treatment – contrary to placebo – restored GRα number and function, leading to resolution of pulmonary inflammation [22, 23]. ARDS patients randomized to prolonged methylprednisolone treatment, contrary to placebo, demonstrated a sustained reduction in plasma and/or BAL levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 [1], IL-8, soluble intercellular adhesion molecule-1 [1], procollagen aminoterminal propeptide type I and III [1], indices of alveolar-capillary membrane permeability (BAL albumin, total protein, and percentage neutrophils) [26], and an increase in IL-10 [1], protein C [27], and surfactant [28]
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