Objective: Procalcitonin (PCT) plasma concentrations and its kinetic can be used as a diagnostic tool in critically ill patients and patients with sepsis. Since renal dysfunction is a frequent complication in these patients, and PCT is a protein with a low molecular weight, we have measured the half-life time of PCT after peak concentrations in patients with normal and impaired renal function. We also have analyzed the influence of patients age and gender on PCT elimination kinetic.Design: Prospective clinical study. Renal dysfunction was assessed by plasma creatinine. The half-life time of PCT was evaluated 24 and 48 h after acute induction of PCT, when the focus of PCT induction has rapidly been eliminated.Setting: Intensive care unit of our University hospital, a tertiary health care institution.Patients: 69 patients were included into the study.Interventions: None.Measurements and results: The half-life-time of PCT was not significantly altered during renal dysfunction (26.1–33.1 h, 25–50 percentiles, creatinine clearance < 30 ml/min) when compared with normal renal function (22.3–28.9 h). It neither correlated with creatinine clearance (p = 0.14), nor age (p = 0.99) or gender (p = 0.90, Pearson product-moment correlation).Conclusions: The data of the present study demonstrate that assement of PCT kinetic can also be used for diagnostic and prognostic reasons in patients with renal dysfunction. It may, however, exceed 24 h also in patients with normal renal function. As to the present knowledge, renal secretion does not contribute as a main pathway to PCT elimination.

To analyze the immunomodulatory effect of pyrrolidine dithiocarbamate (PDTC) on the endotoxin (LPS) stimulated inflammatory response, we measured the LPS-stimulated cytokine and NO production in murine peritoneal macrophages, J774A.1 cells and human whole blood in the presence of PDTC (60 microM). PDTC significantly inhibited the production of nitrite, IL-1beta and IL-6 in these cells. TNFalpha release was stimulated in murine cells, but suppressed in human whole blood. We further investigated the influence of PDTC on mortality and cytokine release in mouse endotoxin shock. PDTC was i.p. injected 30 min prior to the induction of endotoxin shock in female NMRI-mice and survival was significantly improved as compared to controls (48% vs 20%, n=25 per group). Plasma concentrations of TNFalpha were slightly augmented while IL-6 levels were decreased in PDTC-treated animals as compared to controls, however, without reaching significance. We conclude that PDTC is a potent immunomodulatory substance that modulates the inflammatory response in vitro and reduces mortality in mouse endotoxin shock. The pathophysiological mechanisms of the protective effect of PDTC in vivo, however, appears to be pluripotent, comprising both antioxidative properties and the inhibition of NF-kB.

During Gram-negative bacterial infections, lipopolysaccharide (LPS) interacts with monocyte/macrophage receptors, resulting in a host defense response. Activation of intracellular signal transduction pathways implicating various protein kinase and phospholipases is crucial in activating the transcription of genes encoding proinflammatory cytokines and inducible nitric oxide synthase (INOS). In this article, we demonstrate that in mouse, endotoxin shock activation of phosphatidylcholine-specific phospholipase C (PC-PLC) plays a major role in controlling the inflammatory response. Inhibition of PC-PLC by the specific inhibitor tricyclodecan-9-yl-xanthogenate (D609) before LPS reduced the release of interleukin-1 beta, interleukin-6 and nitric oxide (NO) in vivo. In contrast, tumor necrosis factor-alpha serum levels were not altered by the pretreatment with D609. Consequently, survival from endotoxin shock of D609-treated animals was significantly improved compared with control animals (45% vs. 20%). Thus, inhibition of PC-PLC can reduce the inflammatory response to LPS and may serve as a novel approach to therapy of sepsis.

In this study we have analysed the influence of temperature and time of storage and of repeated freezing on procalcitonin plasma concentrations ex vivo. We have also analysed the difference of procalcitonin concentrations in arterial or venous blood samples and the influence of different anticoagulation techniques on procalcitonin concentrations (serum, EDTA-, lithium-heparin- or citrate plasma). At room temperature (25 degrees C) a loss of procalcitonin plasma concentrations of 6.4% +/- 2.6% (mean, 2 standard error of the mean) after 3 hours (4.6% +/- 5.2% at 4 degrees C) and 12.3% +/- 3.1% after 24 hours occurred (6.3% +/- 5.0% at 4 degrees C, n = 17 each). Comparing the procalcitonin concentrations of blood samples with different anticoagulants (n = 24 each), there was only a significant difference between procalcitonin concentrations in heparinized plasma and serum (+ 7.6%, difference of the mean). There was no significant influence of the blood sampling technique (arterial or venous line) and of repeated freezing/thawing cycles (up to 3 times) on the procalcitonin concentrations measured. Although the difference of sampling and storage of the blood on procalcitonin concentrations is not significant, multiple factors may act synergistically on the result of procalcitonin measurement. To keep variations of ex vivo conditions as minimal as possible, a standardized technique of anticoagulation, time and temperature of storage is recommended, e.g. the use of EDTA-plasma and storage at room temperature, when samples are measured within 4 hours after blood drawing.