We see that there is a marked temporal change with early up-regulation of these systems, often followed in prolonged sepsis by a down-regulation that may be equally, if not more, injurious. The degree of perturbation of each of these systems has been shown to correlate with poor outcomes, yet we still do not fully understand the additive or mitigating interactions among them.
Better understanding of the complex network of mediators has led to the development of new strategies based on an immunomodulatory therapeutic approach, to be used in conjunction with the still essential hemodynamic resuscitation and eradication of infection.
There have been numerous “false dawns,” as seen with anti-endotoxin antibodies, nitric oxide synthesis inhibition, and cytokine antago-nists. Only activated protein C has produced a statistically significant mortality reduction in patients with severe sepsis and septic shock, leading to the marketing and licensing of the first antisepsis product, drotrecogin alfa (activated). The mode of action of this agent has been only partly uncovered and involves effects other than just its anticoagulation properties. Many discussions have focused on the proper indications of the drug, largely because of the concern about bleeding, the high costs involved, and the lack of benefit in patients with less severe sepsis. Here
The recognition that high doses of steroids were harmful has been replaced by the realization that lower doses of glucocorticoids may be beneficial in patients with septic shock, especially in those with abnormal adrenal function. The importance of aggressive early and complete fluid and vasoactive drug resuscitation has been shown in severe sepsis/ septic shock, although the exact reasons for this observed benefit from multifaceted resuscitation have not yet been determined.