Effects of levosimendan, a novel inotropic calcium-sensitizing drug, in experimental septic shock

Objective: Levosimendan is a novel inodilator that improves cardiac contrac tility by sensitizing troponin C to calcium. This drug has proved to be eff ective in treating advanced congestive heart failure but has not been evalu ated in septic settings. The purpose of the present study was to study the effects of this drug in a porcine model of endotoxemia. Design: Prospective experimental study. Subjects. Fourteen landrace pigs. Interventions. All animals were anesthetized and catheterized for measureme nt of central and pulmonary hemodynamics. Ultrasonic flow probes were place d around the renal artery and portal vein to measure blood flow. A tonomete r was placed in the ileum to measure mucosal pH. Levosimendan was given to six animals as a bolus (200 [mug(.)kg(-1)) followed by a continuous infusio n (200 mug(.)kg(-1.)hr(-1)). Thirty minutes after onset of levosimendan tre atment, all animals received endotoxin (20 mug(.)kg(-1.)hr(-1) for 3 hrs). Measurements and Main Results; At baseline, levosimendan induced a systemic vasodilation with a reduction in blood pressure and an increase in heart r ate. A tendency to an increase in cardiac index did not reach statistical s ignificance (p = .055). Cardiac index and systemic oxygen delivery were markedly improved in the le vosimendan group during endotoxemia. Systemic vascular resistance and blood pressure were reduced in the levosimendan group. The latter parameter, how ever, was only different from the control group during the initial phase of endotoxin shock but not at the late, most pronounced phase of shock. Levos imendan also efficiently attenuated endotoxin-induced pulmonary hypertensio n. Portal venous blood flow and gut oxygen delivery were improved, but no c oncomitant reduction in endotoxin-induced intestinal mucosal acidosis was o bserved. Renal blood flow was unaffected, as was the endotoxin-induced incr ease in plasma endothelin-1-like immunoreactivity. These findings support previous reports of calcium desensitization as a pot ential component in septic myocardial depression. Furthermore, the vasodila tory properties of this drug were well tolerated in the current model of hy podynamic endotoxin shock, and they may have contributed to improved region al blood flow as seen in the gut as well as improved systemic perfusion by means of reduced biventricular afterload. Conclusion. Pretreatment with levosimendan in pigs subjected to endotoxin s hock improved cardiac output and systemic and gut oxygen delivery. In addit ion, pulmonary hypertension largely was attenuated without any adverse effe cts on gas exchange. These results are promising in several aspects, but th e role of levosimendan in the treating circulatory failure in sepsis remain s to be established.