A response to infection in patients with severe sepsis--do we need a "stage-directed therapy concept"?

Excessive forms of the response of organism to infection play an important role in the pathogenesis of severe sepsis. They may consist of either local pro-inflammatory response with a massive release of cytokines into the systemic circulation, or may be presented as an excessive systemic anti-inflammatory response. In the first case, the result is a systemic pro-inflammatory state, characterised by natural stages of the inflammatory response, in which dysfunction of macrocirculation is followed by microcirculation derangement and mitochondrial alteration at the end. These mechanisms are responsible for the development of remote organs failure. The result in the second case is a deactivation of local immunocompetent cells, which results in the risk of uncontrollable growth of microorganisms, especially in organs with an impaired antimicrobial barrier. This may explain the clinically observed recurrence of septic episodes, when a resolution of infection at one site is later replaced with an outbreak of sepsis from another site. A number of therapeutic interventions aimed on the management of causes and consequences of systemic pro-inflammatory state was clinically tested (e.g. antibiotics, goal directed hemodynamic support and inhibitors of coagulation) with surprisingly different effectiveness. The cause of this difference may lie, apart from the frequently discussed inhomogeneity of the studied patient population, also in an incorrect timing of the therapeutic interventions, which does not respect natural stages of the inflammatory response (Fig. 1, Ref. 40).