The effects of steroids on the outcome of sepsis are dose dependent. Low doses appear to be beneficial, but high doses do not improve outcome for reasons that are insufficiently understood. The effects of steroids on systemic inflammation as a function of dose have not previously been studied in humans. To determine the effects of increasing doses of prednisolone on inflammation and coagulation in humans exposed to LPS, 32 healthy males received prednisolone orally at doses of 0, 3, 10, or 30 mg (n = 8 per group) at 2 h before i.v. injection of Escherichia coli LPS (4 ng/kg). Prednisolone dose-dependently inhibited the LPS-induced release of cytokines (TNF-α and IL-6) and chemokines (IL-8 and MCP-1), while enhancing the release of the anti-inflammatory cytokine IL-10. Prednisolone attenuated neutrophil activation (plasma elastase levels) and endothelial cell activation (von Willebrand factor). Most remarkably, prednisolone did not inhibit LPS-induced coagulation activation, measured by plasma concentrations of thrombin-antithrombin complexes, prothrombin fragment F1+2, and soluble tissue factor. In addition, activation of the fibrinolytic pathway (tissue-type plasminogen activator and plasmin-α2-antiplasmin complexes) was dose-dependently enhanced by prednisolone. These data indicate that prednisolone dose-dependently and differentially influences the systemic activation of different host response pathways during human endotoxemia.

Objective: Sepsis intervention studies need better patient stratification methods, and one way to realize this is the introduction of stable biomarkers. A set of recently developed novel biomarkers, based upon precursor-fragments of short-lived hormones, was previously shown to be increased during sepsis. However, it is not known whether these biomarkers are influenced by sepsis intervention strategies. Therefore we investigated the markers in a model of human endotoxemia intervened by increasing doses of prednisolone. Design and setting:Prospective, open-label study in a specialized clinical research unit of a university hospital. Subjects: Thirty-two healthy male volunteers. Interventions: Subjects received prednisolone orally at doses of 0, 3, 10 or 30 mg (n = 8 per group) at 2 h before intravenous injection of Escherichia coli lipopolysaccharide (LPS) (4 ng/kg). Blood samples were drawn during 24 h after LPS injection. Measurements and results: LPS injection caused an increase in levels of midregional pro-adrenomedullin (MR-proADM), midregional pro-atrial natriuretic peptide (MR-proANP), C-terminal proarginine-vasopressin (CT-proAVP) and procalcitonin (PCT). Prednisolone caused a dose dependent inhibition of MR-proADM, MR-proANP and CT-proAVP levels. Conclusions: These results show that a set of novel, highly stable sepsis biomarkers was increased during human endotoxemia and was dose-dependently inhibited by corticosteroid pre-treatment.

Convincing evidence exists that bacterial translocation can occur in humans during various disease processes. However, it remains to be determined whether a causal relationship between bacterial translocation and MOF exists. MOF is probably multifactorial and not uniform in origin; when evaluating translocation as a causative factor in the absence of an infective focus, the type of initiating event and the period of time after which MOF develops should be taken into account. The origin of early MOF is probably a non-bacterial, extensive, inflammatory response resulting in massive generalized endothelial cell activation. Late MOF may be caused primarily by bacterial translocation inducing an imbalance between proinflammatory and anti-inflammatory cytokines.

In the SIRS/MOF patients, the changes in lipoprotein composition in lymph are a reflection of those in plasma, except for the triglyceride levels. In comparison with the non-SIRS/MOF patients, the SIRS/MOF patients show a shifted LPS binding capacity of high-density lipoproteins toward low-density lipoproteins in plasma and in lymph. Moreover, in plasma and lymph, novel cholesterol-containing particles, resembling high-density lipoprotein, were identified in the SIRS/MOF patient group.

Convincing evidence exists that bacterial translocation can occur in humans during various disease processes. However, it remains to be determined whether a causal relationship between bacterial translocation and MOF exists. MOF is probably multifactorial and not uniform in origin; when evaluating translocation as a causative factor in the absence of an infective focus, the type of initiating event and the period of time after which MOF develops should be taken into account. The origin of early MOF is probably a non-bacterial, extensive, inflammatory response resulting in massive generalized endothelial cell activation. Late MOF may be caused primarily by bacterial translocation inducing an imbalance between proinflammatory and anti-inflammatory cytokines.