clinical investigations in critical care Persistent Elevation of Inflammatory Cytokines Predicts a Poor Outcome in ARDS* Plasma IL-1/1 and IL-6 Levels Are Consistent and Efficient Predictors of Outcome Over Time G. Umberto Meduri, MD, FCCP; Stacey Headley, MD; Gary Kohler, MD; Frankie Stentz, PhD; Elizabeth Tolley, PhD; Reba Umberger, RN, BSN; andKenneth Leeper, MD, FCCP Background: Inflammatory cytokines have been related to the development of adult respiratory distress syn- drome (ARDS), shock, and multiple organ dysfunction syndrome (MODS). We tested the hypothesis that unfa- vorable 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 relation- ship of plasma inflammatory cytokines with clinical variables and outcome. Methods: We prospectively studied 27 consecutive pa- tients with severe medical ARDS. Plasma levels of tumor necrosis factor alpha (TNF-a) and interleukins (ILs) 1{3, 2, 4, 6, and 8 were measured (enzyme-linked immunosor- bent 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. Sub- groups 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). *From the Pulmonary and Critical Care Division (Drs. Meduri, Headley, Kohler, Stentz, Umberger, and Leeper) and Depart- ment of Preventive Medicine (Dr. Tolley), Division of Biosta- tistics and Epidemiology, the University of Tennessee Medical Center, Regional Medical Center, and Veteran Affairs Medical Center, Memphis. This study was supported by Clinical Research Center grant 5M01RR002ll and Mill-Rose Laboratories Grant R07-3340. This study has won the 1993 ACCP Dupont Critical Care Research award (Dr. Stacey Headley). Manuscript received April 5, 1994; revision accepted October 6. Reprint requ es ts: Dr. Meduri, University of Tennessee, Pulmo- nary and Critical Care Div., 956 Court Avenue, Room H314, Memphis, TN 38163 The mean initial plasma levels of TNF-a, IL-1{3, 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-1{3 (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-a, IL-1{3, IL-6, and IL-8 remained signif- icantly elevated over time (p<0.0001) in those who died. Although it was the best early predictor of death (p<O.OOl), plasma IL-2>200 pg/mL lost its usefulness after the first 48 h. A plasma IL-1{3 or IL-6 level >400 pg/mL on any day in the first week of ARDS was associ- ated with a low likelihood of survival. Conclusions: Our findings indicate that unfavorable out- come 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-a, IL-1{3, IL-6, and IL-8 on day 1 of ARDS had persistent el- evation of these inflammatory cytokines over time and died. Survivors had lesser elevations of plasma inflamma- tory cytokines on day 1 of ARDS and a rapid reduction over time. Plasma IL-1{3 and IL-6 levels were consistent and efficient predictors of outcome. (Chest 1995; 107:1062-73) ARDS=adult respiratory distress syndrome; Cst=static pulmonary compliance; ELISA=enzyme-linked immu- nosorbent assay; IL=interleukin; LIS=lung injury score; MODS=multiple organ dysfunction syndrome; ROC=re- ceiver operator characteristic; SBP=systolic blood pres- sure; T:'IIF=tumor necrosis factor Key words: adult respiratory distress syndrome; fibropro- liferation; interleukin-1; interleukin-2; interleukin-4; in- terleukin-6; interleukin-8; multiple organ dysfunction syn- drome; outcome; tumor necrosis factor 1062 Persistent Elevation of Inflammatory Cytokines Predicts Poor Outcome in ARDS (Meduri eta!)