PURPOSE: Cytokines have been associated with the development of sepsis and diffuse tissue injury following septic or endotoxic challenges in humans. Furthermore, relative organ-system dysfunction, not specific organ dysfunction, appears to predict outcome from critical illness. We hypothesized that persistence of inflammatory cytokines within the circulation, reflecting a generalized systemic inflammatory response, is associated with multiple-system organ failure (MSOF) and death from critical illness. In addition, since hepatic function is central to host-defense homeostasis, we further reasoned that critically ill patients with hepatic cirrhosis would have an increased incidence of MSOF and death following sepsis associated with a persistence of cytokines in the blood. PATIENTS AND METHODS: We measured serum levels of tumor necrosis factor (TNF), interleukin (IL) 1, IL-2, IL-6, and interferon gamma (IFG) serially for the first 48 h following the onset of hypotension (systolic blood pressure < 90 mm Hg) thought likely to be due to sepsis in all patients presenting to one ICU. These data were correlated with initial severity of shock and retrospective determination of septic or nonseptic origin, preexistent hepatic cirrhosis, subsequent development of MSOF, and outcome. RESULTS: Fifty-three specific episodes of shock in 52 patients were recorded (35 septic and 18 nonseptic episodes). Mortality was higher in septic patients (41 vs 17 percent, p < 0.01), as was the development of MSOF (29 vs 6 percent, p < 0.001), incidence of cirrhosis (21 vs 0 percent, p < 0.01), and TNF levels over the study interval (p < 0.01). Nonseptic patients also had an initial elevation in TNF over 48-h levels (p < 0.05) that were higher than serum levels reported for normal subjects (chi 2, p < 0.05). There was no relation between peak TNF level and outcome. Sixty-seven percent of the cirrhotic patients had development of MSOF and died, while only 30 percent of the noncirrhotic patients had development of MSOF or died (p < 0.05). The TNF and IL-6 levels in patients who had MSOF or who died were both elevated and did not decrease over time independent of presence or absence of sepsis (p < 0.01). Similarly, IL-6 levels after 12 h were higher in cirrhotic patients than in noncirrhotic septic patients (p < 0.05). No elevation in IL-1, IL-2, or IFG was seen in any patient subpopulation. CONCLUSIONS: TNF and IL-6 serum levels are higher in septic than in nonseptic shock, but the persistence of TNF and IL-6 in the serum rather than peak levels of cytokines predicts a poor outcome in patients with shock.