THE SYSTEMIC INFLAMMATORY RESPONSE - PERSPECTIVE OF HUMAN ENDOTOXEMIA

Improvements in detection of cytokines and other intermediary substanc es has allowed a new wave of investigations to determine the role that endotoxin plays in initiating these mediators. We have reviewed all s tudies of endotoxin administration (Escherichia coli, Lot EC-5, 4 ng/k g) to healthy humans in an effort to collate the currently available d ata that describes mediator elaboration and therapy directed against t hem. More than 60 studies included descriptions of the effects of admi nistering endotoxin alone and with pretreatments, such as antiendotoxi n molecules (n = 8), mediator receptor antagonist (n = 9), antimediato r therapy (n = 5), and anti-inflammatory agents (n = 49), which were g iven in an attempt to modify the inflammatory response, Endpoints that were monitored included vital signs and symptoms, leukocyte and plate let patterns, alterations in coagulation, hormonal secretion, plasma e nzyme activities, plasma cytokine and anticytokine concentrations, pla sma metabolic substrates, and ex vivo mononuclear cell responses. Anal ysis of investigations of human endotoxemia with and without pretreatm ents suggests that such trials a) are safe, b) are unable to achieve t he success of small animal studies using pretreatments of endotoxemia, and c) have results similar to antimediator therapy administered rece ntly to patients with Gram-negative bacteremia. Establishment of endot oxemia in humans may provide a valuable screening method to determine which antimediator treatments should be submitted to carefully constru cted clinical trials.