Effect of Prolonged Methylprednisolone Therapy in Unresolving Acute Respiratory Distress Syndrome

Abstract

Context.-No pharmacological therapeutic protocol has been found effective in modifying the clinical course of acute respiratory distress syndrome (ARDS) and mortality remains greater than 50%. Objective.-To determine the effects of prolonged methylprednisolone therapy on lung function and mortality in patients with unresolving ARDS. Design.-Randomized, double-blind, placebo-controlled trial. Setting.-Medical intensive care units of 4 medical centers. Participants.-Twenty-four patients with severe ARDS who had failed to improve lung injury score (LIS) by the seventh day of respiratory failure. Interventions.-Sixteen patients received methylprednisolone and 8 received placebo. Methylprednisolone dose was initially 2 mg/kg per day and the duration of treatment was 32 days. Four patients whose LIS failed to improve by at least 1 point after 10 days of treatment were blindly crossed over to the alternative treatment. Main Outcome Measures.-Primary outcome measures were improvement in lung function and mortality. Secondary outcome measures were improvement in multiple organ dysfunction syndrome (MODS) and development of nosocomial infections. Results.-Physiological characteristics at the onset of ARDS were similar in both groups. At study entry (day 9 [SD, 3] of ARDS), the 2 groups had similar LIS, ratios of PaO 2 to fraction of inspired oxygen (FIO 2), and MODS scores. Changes observed by study day 10 for methylprednisolone vs placebo were as follows: reduced LIS (mean [SEM], 1.7 [0.1] vs 3.0 [0.2]; PϽ.001); improved ratio of PaO 2 to FIO 2 (mean [SEM], 262 [19] vs 148 [35]; PϽ.001); decreased MODS score (mean [SEM], 0.7 [0.2] vs 1.8 [0.3]; PϽ.001); and successful extubation (7 vs 0; P = .05). For the treatment group vs the placebo group, mortality associated with the intensive care unit was 0 (0%) of 16 vs 5 (62%) of 8 (P = .002) and hospital-associated mortality was 2 (12%) of 16 vs 5 (62%) of 8 (P = .03). The rate of infections per day of treatment was similar in both groups, and pneumonia was frequently detected in the absence of fever. Conclusions.-In this study, prolonged administration of methylprednisolone in patients with unresolving ARDS was associated with improvement in lung injury and MODS scores and reduced mortality.

Oxidative Stress Disrupts Glucocorticoid Hormone-dependent Transcription of the Amiloride-sensitive Epithelial Sodium Channel α-Subunit in Lung Epithelial Cells through ERK-dependent and Thioredoxin-sensitive Pathways

“…The resolution of alveolar pulmonary edema is dependent upon ameliorating the fluid leakage into the distal lung air space coupled with efficient restoration of fluid reabsorption from the alveolar air space. Interestingly, a beneficial effect has been described when corticosteroids were given during the late stage of ARDS (53)(54)(55)(56), whereas a short term high dose treatment with corticosteroids at the onset of ARDS was ineffective to ameliorate ARDS (57,58). We speculate that at the onset of ARDS, the burden of oxidative stress may be overwhelming, resulting in the disruption of corticosteroid-mediated transcriptional activation of ␣-ENaC.…”

Differential Host Inflammatory Responses to Viable Versus Antibiotic-Killed Bacteria in Experimental Microbial Sepsis

“…While the differences in the profiles of TNF-␣ in serum between E. coli-and S. aureus-infected animals correlate with the observed differences in mortality in the D-galactosamine model (40) (Table 1), they also raise the question of whether Finally, there is increasing concern about possibly important differences in host inflammatory responses to sepsis due to gram-positive versus gram-negative bacteria (11,17,32), including recent reexamination of the scope and limitation of glucocorticoids to address such concerns (3,27,39,40,46; D. G. Remick, Editorial, Shock 8:146, 1997). The present findings contribute to our growing knowledge base of differences in host responses to different classes of bacteria and the still further differences resulting from specific antibiotic chemotherapy and, ultimately, should lead to greater harmony between complementary modes of anti-inflammatory and antibiotic intervention strategies.…”

Inflammation – A New Therapeutic Target in Pneumonia

“…In 24 patients with persistent ARDS, glucocorticoid administration improved the lung injury score, PaO 2 :FiO 2 ratio, multiorgan dysfunction score, successful extubation, ICU mortality and hospital mortality [30]. Glucocorticoids induced a reduction in inflammatory cytokines, IL-1β, TNFα, IL-6 and IL-8, and in activation and nuclear translocation of nuclear factor (NF)-ĸB [31].…”