Effects of levosimendan on mitochondrial function in patients with septic shock: a randomized trial

Mitochondrial dysfunction is key feature of septic shock and contributes to the development of sepsis related organ dysfunction. It is characterized by a variable reduction of the respiratory chain (RC) activities, altered mitochondrial morphology and reactive oxygen species production. Recent data have reported the efficacy of levosimendan, a calcium sensitizer, in improving heart performance and organ perfusion in critically ill patients. Moreover, it has been demonstrated that Levosimendan has antioxidant properties. Nevertheless, the effects of levosimendan on mitochondrial function are not fully elucidated. The objective of this study was therefore to evaluate the effect of levosimendan on mitochondria performance. Five mitochondrial parameters were screened: the redox status; the amount of scavenging enzymes; the activities of the RC complexes; the mitochondrial content; the steady state levels of the RC subunits; the mitochondrial biogenesis. Our results show that patients treated with levosimendan had a significant reduction of glutathionylated proteins and an increase in the amount of the antioxidant enzyme MnSOD, underlining its antioxidant properties. The activities of the RC complexes I, II and III were unchanged in the mitochondria of patients treated with levosimendan compared to controls whereas the mitochondrial content was significantly higher in levosimendan vs. control patients. Finally, evaluation of mitochondrial biogenesis did not show any significant difference in the two groups, although an overall increase in the amount of the RC subunits was observed in the levosimendan group. In conclusion, our study demonstrated that in septic shock patients, Levosimendan exerts antioxidant action by increasing antioxidant defense and lowering oxidative damage.