A lipid A analog, E5531, blocks the endotoxin response in human volunteerswith experimental endotoxemia

Background: Endotoxin (lipopolysaccharide [LPS]) has been associated with s epsis and the high mortality rate seen in septic shock. The administration of a small amount of LPS to healthy subjects produces a mild syndrome quali tatively similar to that seen in clinical sepsis. We used this model to tes t the efficacy of an endotoxin antagonist, E5531, in blocking this LPS-indu ced syndrome. Methods In a placebo-controlled, double-blind study, we randomly assigned 3 2 healthy volunteers to four sequential groups (100, 250, 500, or 1000 mu g of E5531). Each group of eight subjects (six assigned to E5531, two assign ed to placebo) received a 30-min intravenous infusion of study drug. LPS (4 ng/kg) was administered to all subjects as an intravenous bolus in the con tralateral arm at the midpoint of the infusion. Symptoms, signs, laboratory values, and hemodynamics (by echocardiogram) were evaluated at prospective ly defined times. Results: In subjects receiving placebo, LPS caused headache, nausea, chills , and myalgias. E5531 led to a dose-dependent decrease in these symptoms th at was statistically significant (p < .05) except for myalgias. The signs o f endotoxemia (fever, tachycardia, and hypotension) were consistently inhib ited at the three higher doses (250, 500, and 1000 mu g, p < .05). Tumor ne crosis factor-alpha and interleukin-6 blood levels were both lower in those who received E5531 (p <.0001). The C-reactive protein level and white bloo d cell count response were decreased at all doses (p <.0001). The hyperdyna mic cardiovascular state (high cardiac index and low systemic vascular resi stance) associated with endotoxin challenge was significantly inhibited at the higher doses of E5531. Conclusions: E5531 blocks the symptoms and signs and cytokine, white blood cell count, C-reactive protein, and cardiovascular response seen in experim ental endotoxemia. This agent is a potent inhibitor of endotoxin challenge in humans and may be of benefit in the prevention or treatment of sepsis an d septic shock. (Grit Care Med 2000; 28:2713-2720).