INFLAMMATORY CYTOKINES IN THE BAL OF PATIENTS WITH ARDS - PERSISTENT ELEVATION OVER TIME PREDICTS POOR OUTCOME

Background: Inflammatory cytokines (ICs) are important modulators of i njury and repair. ICs have been found to be elevated in the BAL of pat ients with both early and late ARDS. We tested the hypothesis that rec urrent injury to the alveolocapillary barrier and amplification of int ra-alveolar fibroproliferation observed in nonresolving ARDS is relate d to a persistent inflammatory response. For this purpose, we obtained serial measurements of BAL IC and correlated these levels with lung i njury score (LIS), BAL indexes of endothelial permeability (albumin, t otal protein [TP]), and outcome. Methods: We prospectively studied 27 consecutive patients with severe medical ARDS. Using enzyme-linked imm unosorbent assay methods, levels of tumor necrosis factor-alpha (TNF-a lpha) and interleukins (IL) 1 beta, 2, 4, 6, and 8 were measured at fr equent intervals in both plasma and BAL. In 22 patients, bilateral BAL was obtained on day 1 of ARDS and at weekly intervals when possible. Right and left BALs were analyzed separately for IC levels, total cell count and differential, albumin, TP, and quantitative bacterial cultu res. Results: On day 1 of ARDS, the 10 nonsurvivors had significantly higher (p=0.0002) BAL TNF-alpha, IL-1 beta, IL-6, and IL-8 levels, whi ch remained persistently elevated over time, indicating a continuous i njury process. In contrast, the 12 survivors had a lesser elevation an d a rapid reduction over time. Initial BAL IL-2 and IL-4 levels were s ignificantly higher in patients with sepsis (p=0.006); both increased over time in survivors and nonsurvivors. BAL levels of TNF-alpha, IL-1 beta, IL-6, and IL-8 correlated with BAL albumin and TP concentration s but not with LIS or ratio of arterial oxygen tension to inspired oxy gen concentration. BAL:plasma ratios were elevated for all measured cy tokines, suggesting a pulmonary origin. On day I of ARDS, nonsurvivors had significantly higher (p=0.04) BAL:plasma ratios for TNF-alpha, IL -1 beta, IL-6, and IL-8. Over time, BAL:plasma ratios for TNF-alpha, I L-1 beta and IL-6 remained elevated in nonsurvivors and decreased in s urvivors. Conclusions: Our findings indicate that an unfavorable outco me in ARDS is associated with an initial, exaggerated, pulmonary infla mmatory response that persists unabated over time. Plasma IC levels pa rallel changes in BAL IC levels. The BAL:plasma ratio results suggest, but do not prove, a pulmonary origin for IC production. BAL TNF-alpha , IL-1 beta, and IL-8 levels correlated with BAL indices of endothelia l permeability. In survivors, reduction in BAL IC levels over time was associated with a decline in BAL albumin and TP levels, suggesting ef fective repair of the endothelial surface. These findings support a ca usal relationship between degree and duration of lung inflammation and progression of fibroproliferation in ARDS.