Clinical Sepsis Trials

¹ The Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver.

Despite the impressive experimental findings of improved survival when bacteremic or endotoxemic animals are treated with anticytokine therapies, endotoxin-binding compounds, or other agents directed against important mediators of organ system dysfunction in sepsis, clinical trial results to the present have shown no clearcut benefit for the use of these agents, with reductions in mortality suggested only in patient subgroups, which were defined retrospectively. The only exception to this retrospective identification of subgroups was the anti-TNF monoclonal antibody study where patients with septic shock were identified prospectively. Unfortunately, as mentioned above, although a trend towards benefit was seen with anti-TNF therapy in patients with septic shock, this did not achieve statistical significance. Clearly, animal models for sepsis, which generally use acute endotoxin or bacterial insults in a previously healthy animal, differ markedly from the clinical situation, where infection usually has no well-defined starting time and occurs in patients with pre-existent medical problems. In addition to these differences in models, the results from the clinical sepsis trials force a rethinking of the paradigm that a single mediator can play a central role contributing to organ system dysfunction and mortality in sepsis. Rather, the relatively modest improvement in outcome, even in subgroups of patients, achieved with monoclonal anti-TNF antibodies or IL-lra demonstrates the necessity of defining biochemical and clinical markers albeit to better identify patients who may benefit from these therapies. Such an approach was suggested in the initial phase I/II monoclonal anti-TNF antibody study, where patients with elevated serum TNF levels appeared to have a better response to the antibody, as defined by survival from their septic episode. Additionally, results from the recently completed clinical studies, showing evidence for increased circulating levels of additional proinflammatory cytokines, despite the blockade of IL-l or TNF-, indicate that combination therapy may be useful in achieving further decreases in mortality among patients with sepsis, organ system dysfunction, and shock.