The systemic inflammatory response: perspective of human endotoxemia.

Improvements in detection of cytokines and other intermediary substances has allowed a new wave of investigations to determine the role that endotoxin plays in initiating these mediators. We have reviewed all studies of endotoxin administration (Escherichia coli, Lot EC-5, 4 ng/kg) to healthy humans in an effort to collate the currently available data that describes mediator elaboration and therapy directed against them. More than 60 studies included descriptions of the effects of administering endotoxin alone and with pretreatments, such as antiendotoxin molecules (n = 8), mediator receptor antagonist (n = 9), antimediator therapy (n = 5), and anti-inflammatory agents (n = 49), which were given in an attempt to modify the inflammatory response. Endpoints that were monitored included vital signs and symptoms, leukocyte and platelet patterns, alterations in coagulation, hormonal secretion, plasma enzyme activities, plasma cytokine and anticytokine concentrations, plasma metabolic substrates, and ex vivo mononuclear cell responses. Analysis of investigations of human endotoxemia with and without pretreatments suggests that such trials a) are safe, b) are unable to achieve the success of small animal studies using pretreatments of endotoxemia, and c) have results similar to antimediator therapy administered recently to patients with Gram-negative bacteremia. Establishment of endotoxemia in humans may provide a valuable screening method to determine which antimediator treatments should be submitted to carefully constructed clinical trials.