Effect of Hyperglycemia in PAI-1 Activity and the Relationship With Outcome in Severe Sepsis and Septic Shock

BACKGROUND

The treatment of the sepsis can be done at three different level:

1. Etiologic therapy. The eradication of the infectious agent is the primary end-point. An appropriate surgical treatment and antibiotic therapy are the key of the etiologic therapy.
2. Symptomatic therapy. It is the traditional approach in the Intensive Care Unit. It involves to correct the symptomatic issues that can lead to the death of the patients, buying the time necessary for the action of the etiologic and the pathogenic therapy. The key point of the symptomatic therapy are: a) an adequate expansion of the volemia and the use of cardiovascular-acting drugs, for the maintenance of an adequate cardiocirculatory homeostasis. Recently it has been demonstrated that an early aggressive haemodynamic therapy direct to maintain a mixed venous Oxygen Saturation above 70% improved the mortality compared with a standard approach (3); b) apply a mechanical ventilation adequate for the maintenance of the respiratory homeostasis. In fact it has been recently shown an increased survival rate in patients treated with low tidal volume ventilation strategy compared to standard strategy.
3. Pathogenic therapy. It consists to block the inflammatory and/or coagulation pathway at different level. In the last 30 years a number of report studied different approach (anti-endotoxin antibodies, anti-TNF antibodies, anti-IL6 antibodies, treatment with high doses of corticosteroid, etc.). While all these approaches showed an efficacy in experimental settings when given preventively, most of them have no effect in phase 3 clinical trial. This discrepancy may be explained considering: 1) the system can be considered chaotic, with riddance and interdependency of the response; 2) in the clinical studies the treatment was applied after the development of the sepsis, when the inflammatory and coagulation systems are still largely activated.

Three study has recently demonstrated a benefit in survival:

1. The treatment with low-dosage corticosteroids in patients non-responders to ACH stimulation test (5). This is a substitutive therapy. It is important to note that the treatment with high dosage corticosteroids to block completely the inflammatory response is not effective (6).
2. The treatment with recombinant activated Protein C (7) did increased the relative survival rate by 20%. Of note the activated Protein C is the only molecule with three main mechanisms of action: anticoagulatory, antiinflammatory and profibrinolytic.
3. In a recent study in post-surgical patients it has been shown a significant improvement in survival in patients treated with a a tight glycemic control within 80 and 110 mg/dL compared to those in which the glycemia was corrected only when reaching higher level (>215 mg/dL) (8).We still lack a definitive explanation for these findings, and the discussion is mainly on the relative roles of glycemia per se versus insulin therapy per se.