Despite the use of effective antibiotics in combination with cardiopulmonary support, the mortality rate from sepsis and septic shock for the last three decades has remained high (29%). Furthermore, the incidence of sepsis and septic shock appear to be increasing. Two new therapeutic approaches of potential value in the treatment of sepsis include stress dose corticosteroids and heparin. Corticosteroids were originally considered for use in sepsis more than 30 years ago. Substantial preclinical data supported their potential benefit. However, in initial clinical studies these agents used in very high doses were not beneficial and in some cases may have been harmful. Subsequent clinical studies however, have suggested that much lower doses (i.e. physiologic stress dose steroids) may be beneficial. A metaanalysis of both earlier and more recent studies support continued investigation of physiologic dose corticosteroids in sepsis. This agent?s mechanism of action is likely multi-fold, including the correction of relative adrenal insufficiency, enhancement of the action of endogenous catecholamine and the inhibition of inflammation via interactions with inflammatory gene expression. Use of heparin in sepsis has also shown early benefit in animal models. Furthermore, review of three recent large phase III trials in sepsis, has shown control patients receiving low dose heparin to have consistently better outcome than control patients who did not receive heparin. Although there are several possible reasons for these effects, one is that low dose heparin may itself be protective in sepsis. Another recent large clinical trial comparing the effects of low molecular weight heparin to placebo in critically ill patients, some of whom presumably presented with sepsis, also showed improved outcome with this type of treatment. The effects of heparin may be two fold at the least. On the one hand, heparin?s anticoagulant effects may be directly beneficial by limiting intravascular thrombin production, inhibit the process of DIC and the end organ injury that would result from an interrupted blood supply. However, thrombin production in sepsis may itself precipitate inflammatory mediator release, suggesting that anti-thrombin agents such as heparin may also have anti-inflammatory effects. Thus, corticosteroids and heparin, while having some actions that are independent, may have others, specifically anti-inflammatory ones, that are overlapping. Both physiologic dose corticosteroids and low dose heparin are increasingly used together in patients with sepsis. Understanding whether their effects interact is important for understanding how best to apply these agents clinically. Furthermore, the combination of these two relatively inexpensive agents with well known side effects may be much more effective than the application of newly developed agents for sepsis such as activated protein C which is proposed to have anticoagulant and anti-inflammatory effects. The present experiment was designed to the first investigate the individual effects of corticosteroids and heparin in a mouse model of E. coli pneumonia and sepsis. If effective individually, then a second purpose was to assess their effects in combination. Experiments have now been performed with both of these agents. Hydrocortisone was effective regardless of the dose of treatment or severity of infection. In contrast, no dose of heparin was effective. In fact, increasing the dose of heparin worsened outcome. Overall these studies appear to support the use of corticosteroids in patients with sepsis. However, these studies also raise concerns regarding the possible use of anti-thrombotic agents in sepsis. Analysis of laboratory data is presently underway to understand the contrasting effects of these two agents.
