Glucocorticosteroids as Adjunctive Therapy for Acute Respiratory Distress Syndrome and Sepsis? Yes, But Not as Monotherapy*
Acute respiratory distress syndrome (ARDS), sepsis, burns, polytrauma as well as many other conditions treated in the ICU are characterized by “immune dysregulation” (1, 2). Glucocorticoids have been postulated to restore “immunologic balance” in these disorders (1, 2). However, it is likely that several factors influence the clinical response to glucocorticoid therapy and the risk-to-benefit ratio of these agents in this setting. These include the hosts immune status, the disorder being treated, the timing, the dose, the dosing strategy, and the specific glucocorticoid that is prescribed as well as glucocorticoid receptor (GR) polymorphisms, the sex of the patient, and tissue glucocorticoid resistance. Since 1969 (3), approximately 125 randomized controlled trials (mean, n = 315) have been performed in patients with severe sepsis and septic shock, ARDS, community-acquired pneumonia, Pneumocystis pneumonia, bacterial meningitis, polytrauma, cardiac surgery, burns, traumatic brain injury, spinal cord injury, and following cardiac arrest. Many of these studies, however, are limited by small sample size and major methodological issues. A critical analysis limited to those high-quality studies suggests that bacterial meningitis is the only condition which unequivocally improves patient-centered outcomes (reduced risk of hearing loss and other neurologic sequelae but not mortality) (4). The use of “low-dose” glucocorticoids in patients with septic shock reduces the duration of vasopressor dependency and length of ICU stay; however, the effect on mortality is less clear. The ongoing Adjunctive Corticosteroid Treatment in Critically ill patients with septic shock study should help resolve this issue (5). Similarly, in patients with ARDS, glucocorticoids increase the number of ventilator-free days (VFDs) and reduce ICU length of stay (LOS) without a clearcut survival benefit. In this issue of Critical Care Medicine, McKown et al (6) investigated the association between preadmission oral glucocorticosteroid receipt and the development of ARDS in a cohort of critically ill patients admitted to the ICU with sepsis. The “hypothesis” of this study was that the use of glucocorticoids at the time of the development of sepsis would prevent an excessive proinflammatory response and thereby reduce the risk of developing ARDS. In a multivariate analysis, the authors demonstrated that preadmission glucocorticoids were associated with a lower prevalence of ARDS in the 96 hours after ICU admission (OR, 0.53; 95% CI, 0.33–0.84; p = 0.008); however, there was no difference in ICU LOS, VFD, or hospital mortality. This study has several important implications, namely, that glucocorticoids do indeed modulate the immune dysfunction in sepsis (lower risk of ARDS) and that this effect may be time dependent (the earlier the better) (7, 8); however, this seemingly beneficial effect may not translate into improved patient-centered outcomes.
Patients with acute inflammatory diseases such as ARDS and sepsis may develop tissue resistance to glucocorticoids (2), limiting the efficacy of glucocorticoids. Several mechanisms may explain this phenomenon including decreased expression of the alpha isoform of the GR (α-GR) and decreased nuclear translocation of the GR-complex (9). Importantly, oxidation of cysteine thiol groups of the GR may occur in patients with ARDS and sepsis, reducing ligand and DNA binding resulting in decreased glucocorticoid activity (10). In addition, the failure of glucocorticoids to improve the outcome of critically ill patients may be related to the fact that adjunctive glucocorticoids alone are unable to reverse the pathologic features of uncontrolled inflammation. We have recently demonstrated that the combination of hydrocortisone and IV vitamin C improves the outcome of patients with severe sepsis and septic shock (11). This finding is supported by an in-vitro model where we have demonstrated that hydrocortisone together with vitamin C protects the vascular endothelium from damage by endotoxin while neither agent alone had this effect (12).
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