Many strategies have been proposed for the treatment of
sepsis, and most of the proposed treatment modalities have failed in clinical trials. Many of the previous treatment protocols called for blocking the activity of a single, clearly defined mediator. The underlying hypothesis was that
sepsis induced a specific mediator that then caused organ injury and death. This simple, linear reasoning was frequently based on
cytokines that were defined using
endotoxin models of
sepsis. The
endotoxin models were widely used to study the pathophysiology of
sepsis and were felt to adequately reproduce the full spectrum of inflammatory changes observed in patients with
sepsis. Based on mortality and hematologic changes, these assumptions appeared justified. As the models were examined more closely, and directly compared with focus of
infection models that more accurately portray the changes in
sepsis, it became apparent that the
endotoxin models did not accurately mimic the patient with
sepsis. In the
endotoxin models, the
explosive release of
cytokines into the circulating blood volume was reproducibly found regardless of the species studied (human, primate, pig, rat, or mouse). This lead to a series of anticytokine
sepsis trials, all of which failed. The
cytokine response in focus of
infection models, such as that induced by cecal
ligation and
puncture, was examined and found to be more similar to that observed in patients with
sepsis. When
cytokine inhibitor strategies were used in the cecal
ligation and
puncture model, they were also generally found to lack efficacy. Compounds that have been shown to be effective at reducing mortality in
endotoxin models should be re-evaluated in more clinically relevant models of
sepsis.