Hyaluronan in sepsis : A clinical and experimental study

Sammanfattning: Sepsis and septic shock are important causes of morbidity and mortality in the intensive care unit (ICU). Mortality rates in septic shock are estimated to be 40-50%, in spite of modem intensive care. Death is commonly caused by cardiovascular collapse and multiple organ dysfunction syndrome (MODS). Hepatic dysfunction is a common component of MODS, and can have a major impact on prognosis and survival. Sepsis is, among other derangements, also accompanied by disturbed tissue water homeostasis with increased extravasation of water resulting in tissue edema.Hyaluronan is an interstitial macromolecule that participates in the regulation of tissue hydration. It is normally present in small concentrations in the blood, and is rapidly cleared from the blood by the liver endothelial cells. The synthesis of hyaluronan can be stimulated by inflammatory mediators. Thus sepsis and hyaluronan turnover could interact in many ways. The aim of the present investigations was to study possible changes in circulating hyaluronan concentrations in relation to sepsis and septic shock.Plasma levels of hyaluronan were studied in 44 patients with infections and septic shock. Increased plasma concentrations were found, and the increase correlated to disease severity and outcome. In experimentally induced sepsis in pigs, an increase in circulating concentrations was found, and a relation to hemodynamic instability and outcome was seen. A moderate increase in blood hyaluronan concentrations was seen after surgical trauma in both humans and pigs. Crystalloid infusion therapy also caused a small increase in plasma hyaluronan concentrations in healthy volunteers, probably through an increased washout of interstitial hyaluronan. The hepatic turnover of hyaluronan was studied in septic shock patients. Low extraction ratios at high circulating concentrations were found, suggesting a reduced capacity of hepatic uptake and an increased inflow to the circulation. The kinetics of plasma turnover of hyaluronan were studied in septic and non-septic ICU patients. A prolonged half-life was seen among the septic patients, suggesting a reduced clearance capacity.In conclusion, sepsis is accompanied by increased circulating hyaluronan concentrations. The magnitude of the increase seems to correlate to disease severity and outcome. The cause of this increase is suggested to be both reduced hepatic uptake function, and increased input to the circulation. The relative contributions of these mechanisms, and the possible clinical utility of plasma hyaluronan measurements, remain to be determined.