Prednisolone inhibits endotoxin-induced disseminated intravascular coagulation and improves mortality in rats: importance of inflammatory cytokine suppression

In order to determine whether prednisolone has a protective effect against the development of disseminated intravascular coagulation (DIC), we measure d the effect of prednisolone on changes in hemostatic parameters and plasma levels of inflammatory cytokines in endotoxin-treated rats. Decreases in p latelet count and fibrinogen levels, prolongation of prothrombin time, and increases in the plasma fibrin degradation products and levels of thrombin- antithrombin III (TAT) complex following the administration of endotoxin, a ll of which are associated with DIC, were significantly suppressed by the a dministration of prednisolone. Heparin administration significantly suppres sed changes in all these parameters except for the decrease in platelet cou nt. The combination of prednisolone and heparin was more effective than eit her treatment alone. In order to determine whether these effects of prednis olone are correlated with the suppression of inflammatory cytokine producti on, we examined the relationship between changes in plasma levels of cytoki ne, the hemostatic parameters listed above, and mortality using a number of intervention regimens designed to alter events of the experimentally induc ed DIC. Changes in hemostatic parameters associated with DIC following 30 m g/kg per 4 h of endotoxin infusion were significantly suppressed by treatme nt with 1 mg/kg prednisolone 30 min before beginning endotoxin infusion, fo llowed by administration of 250 U/kg heparin 2 h after the start of endotox in infusion (prednisolone-endotoxin-heparin regimen). The heparin and predn isolone were administrated subcutaneously. The administration of prednisolo ne and heparin in the reverse order (i.e. heparin first and prednisolone se cond: heparin-endotoxin-prednisolone regimen) also suppressed changes in he mostatic parameters, albeit to a smaller degree. Cytokine production was al so significantly suppressed by the first treatment, but was not affected by the regimen in which heparin was administered first. Administration of pre dnisolone alone or heparin alone 30 min before endotoxin significantly redu ced the number of renal glomeruli with fibrin thrombi. Plasma levels of cre atinine and alanine transferase were reduced only by prednisolone. Increase d plasma levels of interleukin-1 beta, tissue necrosis factor-alpha and int erleukin-6 were suppressed by prednisolone but not by heparin, and there we re significant correlations between plasma levels of TAT and cytokines. Pre dnisolone was more effective than heparin in reducing mortality at 24 h aft er 100 mg/kg over 4 h of endotoxin infusion (four of 20 versus 15 of 20 dea ths for prednisolone and heparin, respectively). These findings suggest tha t prednisolone inhibits the development of endotoxin-induced DIC and reduce s mortality by a different mechanism than heparin, possibly through suppres sing the production of inflammatory cytokines. Prednisolone may be efficaci ous in preventing DIC and multiple organ dysfunction caused by endotoxin. B lood Coag Fibrinol 10:321-330 (C) 1999 Lippincott Williams & Wilkins.