Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia

Abstract

The present study was undertaken to evaluate the extent to which an endogenous interleukin-1 (IL-1) response contributes to the hemodynamic and metabolic consequences of sublethal endotoxemia or lethal Gram-negative septic shock. Young, healthy baboons received either a sublethal dose of lipopolysaccharide (LPS) or an LD100 of live Escherichia coli bacteria, and one half of the animals in each group were continuously infused with IL-1 receptor antagonist (IL-1ra). Plasma IL-1β was not detected in this model of endotoxemia. Administration of IL1ra had only minimal effects on the modest hemodynamic and metabolic responses to sublethal endotoxemia, and did not attenuate the plasma cytokine response. In contrast, high circulating levels of IL-1β (range 300-800 pg/ml) were seen during lethal E. coli septic shock. IL-1ra treatment significantly attenuated the decrease in mean arterial blood pressure (MAP) (from -72±8 to -43±6 mm Hg; P < 0.05) and cardiac output (from 0.81±0.17 to -0.48±0.15 liter/min; P < 0.05), and significantly improved survival from 43 to 100% at 24 h (P < 0.05). The plasma IL-1β and IL-6 responses to lethal E. coli septic shock were also significantly diminished by IL-1ra treatment (P < 0.05), whereas tumor necrosis factor-α (TNFα) concentrations were unaffected. We conclude that an exaggerated systemic IL-1β response is characteristic of lethal E. coli septic shock, and contributes significantly to the hemodynamic and metabolic consequences of E. coli septic shock. IL-1ra can significantly attenuate the cytokine cascade and improve survival.