C105-03 Lessons From the Chill Trial: Patterns of Plasma Biomarker Levels Associated With Death and Survival in ARDS

Introduction The Cooling to Help Injured Lungs (CHILL trial) is a multicenter randomized clinical trial of hypothermia and neuromuscular blockade added to usual care vs. usual care alone for 48h in patients newly diagnosed with ARDS. We have randomized 155 patients to date. The objective of this study was to analyze the aggregate plasma biomarker data from the first 138 subjects enrolled to identify expression patterns associated with early and late deaths in patients with moderate to severe ARDS. Methods EDTA-anticoagulated blood was collected at baseline and on study days 1, 2, 3, 4, and 7. Plasma was collected and stored at -80 °C. IL-1ß, IL-6, IL-8, IL-18, ICAM-1, MMP8, RAGE, SPD, and TNF1 were analyzed by ELISA (R&D Systems) and quantified from standard curves. Values for days 1-7 were expressed as change from baseline and area under the curve (AUC) was calculated for study days 1-7. Data are shown as mean ± SEM. Differences in baseline values between subjects dying within 7 days (early deaths) and those surviving > 7 days and differences in AUC values between subjects dying between day 8 and day 60 (late deaths) and subjects surviving for > 60 days (survivors) were tested using a 2-tailed unpaired Student t test. Results Of 138 subjects analyzed, 2 were withdrawn, 12 died ≤7 days, 30 died between day 8 and, and 94 were alive at 60 days. Baseline values of IL-6, IL-8, IL-18, and TNFR1 were higher in the early deaths than in all patients surviving >7 days, but there were no differences in baseline values between the late deaths and survivors (Table). AUC for RAGE was more negative in the survivors than in the late deaths. In contrast, AUC for SPD was substantially higher in survivors than in late deaths (37,774 ±15,680 vs. -58,519±40,129; p = 0.012). Conclusions The 60-day mortality of 30.9% is within the expected range for moderate to severe ARDS. Baseline proinflammatory biomarkers but not markers of alveolar epithelial injury were higher in patients with ARDS who died early. The late deaths exhibited slower decrease in RAGE, a marker of type I alveolar cell injury, than the survivors, suggesting more persistent alveolar injury in the late deaths. SPD, usually considered a marker of Type II alveolar cell injury, was increasing in survivors and decreasing in late deaths, which may reflect greater type II cell proliferation in the survivors, a critical step in lung repair.