Title

Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS: Plasma IL-1β and IL-6 levels are consistent and efficient predictors of outcome over time

Abstract

Background: Inflammatory cytokines have been related to the development of adult respiratory distress syndrome (ARDS), shock, and multiple organ dysfunction syndrome (MODS). We tested the hypothesis that unfavorable outcome in patients with ARDS is related to the presence of a persistent inflammatory response. For this purpose, we evaluated the behavior of inflammatory cytokines during progression of ARDS and the relationship of plasma inflammatory cytokines with clinical variables and outcome. Methods: We prospectively studied 27 consecutive patients with severe medical ARDS. Plasma levels of tumor necrosis factor alpha (TNF-α) and interleukins (ILs) 1β, 2, 4, 6, and 8 were measured (enzyme-linked immunosorbent assay [ELISA] method) on days 1, 2, 3, 5, 7, 10, and 12 of ARDS and every third day thereafter while patients were receiving mechanical ventilation. Subgroups of patients were identified based on outcome, cause of ARDS, presence or absence of sepsis, shock, and MODS at the time ARDS developed. Subgroups were compared for levels of plasma inflammatory cytokines on day 1 of ARDS and over time. Results: Of the 27 patients, 13 survived ICU admission and 14 died (a mortality rate of 52%). Overall mortality was higher in patients with sepsis (86 vs 38%, p<0.02). The mean initial plasma levels of TNF-α, IL- 1β, IL-6, and IL-8 were significantly higher in nonsurvivors (p<0.0001) and in those patients with sepsis (p<0.0001). Plasma levels of IL-1β (p<0.01) and IL-6 (p=0.03) were more strongly associated with patient outcome than cause of ARDS (p=0.8), lung injury score (LIS), APACHE II score, sepsis (p=0.16), shock, or MODS score. Plasma levels of TNF-α, IL-1β, IL-6, and IL-8 remained significantly elevated over time (p<0.0001) in those who died. Although it was the best early predictor of death (p<0.001), plasma IL-2>200 pg/mL lost its usefulness after the first 48 h. A plasma IL-1β or IL-6 level >400 pg/mL on any day in the first week of ARDS was associated with a low likelihood of survival. Conclusions: Our findings indicate that unfavorable outcome in acute lung injury is related to the degree of inflammatory response at the onset and during the course of ARDS. Patients with higher plasma levels of TNF-α, IL-1β, IL-6, and IL-8 on day 1 of ARDS had persistent elevation of these inflammatory cytokines over time and died. Survivors had lesser elevations of plasma inflammatory cytokines on day 1 of ARDS and a rapid reduction over time. Plasma IL-1β and IL-6 levels were consistent and efficient predictors of outcome.

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