Inhaled levosimendan reduces mortality and release of proinflammatory mediators in a rat model of experimental ventilator-induced lung injury

Objectives: Mechanical ventilation during critical care can cause structural and functional disturbances in the lung with subsequent release of proinflammatory mediators, termed ventilator-induced lung injury (VILI). VILI progressively provokes decreased efficiency of gas exchange with subsequent hypoxic pulmonary vasoconstriction leading to cardiopulmonary alterations, such as pulmonary hypertension and right heart failure. We therefore aimed to evaluate whether inhalation therapy with levosimendan, a calcium-sensitizer with pulmonary vasodilating properties, could attenuate VILI and improve shortterm survival in a rat experimental model. Design: Experimental animal model. Setting. University hospital. Subjects. Forty male Sprague-Dawley rats. Interventions: Rats were randomly treated as follows (n = 8, each group): 1) inhalation of the solvent only before induction of VILI, no further intervention; 2) inhalation of 240 mu g of levosimendan before VILI induction; 3) inhalation of 24 mu g of levosimendan before VILI induction; 4) intravenous administration of 24 mu g/kg levosimendan before VILI induction; 5) control group with surgical preparation only. All groups were observed for 4 hrs. Measurements and Main Results: After 4 hrs following induction of VILI, levels of interleukin-1 beta and macrophage inflammatory protein-2 in plasma and bronchoalveolar lavage fluid were analyzed by enzyme-linked immunosorbent assay. Nitric oxide release from alveolar macrophages was measured by Griess assay. Content of matrix metalloproteinase-2 and matrix metalloproteinase-9 in bronchoalveolar lavage fluid was analyzed by gelatin zymography. Inhalation of 240 mu g of levosimendan significantly improved survival after 4 hrs and mean arterial blood pressure compared with VILI only. Additionally, inhalation of 240 mu g and infusion of 24 mu g/kg levosimendan significantly reduced the release of interleukin-1 beta, the nitric oxide release from alveolar macrophages, macrophage inflammatory protein-2 in plasma, and the macrophage inflammatory protein-2 and matrix metalloproteinase-9 content in bronchoalveolar lavage fluid compared with VILI only. Conclusions: Our study demonstrates that prophylactic inhalation of 240 mu g of levosimendan improves survival and reduces release of inflammatory mediators in our experimental model of VILI This might affect the clinical prophylaxis and treatment of VILI.