Two-stage response to endotoxin infusion into normal human subjects: Correlation of blood phagocyte luminescence with clinical and laboratory markers of the inflammatory, hemostatic response

Abstract

Objective To characterize a two-stage response of normal human subjects to an intravenous bolus infusion of endotoxin by using phagocyte luminescence and molecular markers of hemostatic and inflammatory system, phagocyte, and endothelial cell perturbation. Design Prospective evaluation of the response of normal subjects to endotoxin. Setting Medical intensive care unit, university laboratories. Subjects Normal healthy male subjects ranging in age from 24 to 37 yrs. Measurements Luminescence measurements of phagocyte oxidase, oxidase-myeloperoxidase, opsonin receptor expression, clinical chemical and molecular markers of hemostatic and inflammatory system activation, phagocyte activation, and endothelial cell injury. Results Response to intravenous bolus endotoxin includes two stages. The symptomatic first stage (time [T]-0 to T + 8 hrs) included sharp rises in phagocyte oxidase, oxidase-myeloperoxidase, and opsonin receptor expression with the appearance of morphologic and molecular markers of hemostatic and inflammatory system activation, phagocyte activation, and endothelial cell injury. All variables with the exception of soluble thrombomodulin, soluble fibrin monomer, lactate, white cell count, and opsonin receptor expression returned to baseline by T + 8 hrs, by which time all acute clinical symptoms had disappeared. The asymptomatic second stage (T + 8–48 hrs) included a second peak of oxidase activity at T + 24 hrs with an elevated but declining lactate and opsonin receptor expression. This coincided with a second high peak of soluble fibrin monomer, sustained elevated concentrations of soluble thrombomodulin and plasma soluble tissue factor antigen, a decrease in factor VIIa concentration to 50% of baseline at T + 12–24 hrs, and an increase in C-reactive protein/C3d and C4d complexes, which peaked at T + 24 hrs. Conclusions The results suggest that the human response to endotoxin consists of a previously well-characterized, symptomatic, first stage acute inflammatory response followed by an asymptomatic second stage that is marked by a second peak of oxidase activity, a continued increase and sustained elevation of markers of hemostatic and complement system activation, and endothelial cell injury. We conclude that this second stage represents a recovery or reperfusion phase of a compensated response to endotoxin in which contact of the microvasculature perturbed during the first stage is reestablished with blood in a second asymptomatic stage.