title: Inhaled levosimendan reduces mortality and release of proinflammatory mediators in a rat model of experimental ventilator-induced lung injury.
abstract: OBJECTIVE
  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 short-term survival in a rat experimental model.
  
  
  METHODS
  Experimental animal model.
  
  
  METHODS
  University hospital.
  
  
  METHODS
  Forty male Sprague-Dawley rats.
  
  
  METHODS
  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 microg of levosimendan before VILI induction; 3) inhalation of 24 microg of levosimendan before VILI induction; 4) intravenous administration of 24 microg/kg levosimendan before VILI induction; 5) control group with surgical preparation only. All groups were observed for 4 hrs.
  
  
  RESULTS
  After 4 hrs following induction of VILI, levels of interleukin-1beta 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 microg of levosimendan significantly improved survival after 4 hrs and mean arterial blood pressure compared with VILI only. Additionally, inhalation of 240 microg and infusion of 24 microg/kg levosimendan significantly reduced the release of interleukin-1beta, 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 microg 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.
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Therapy, University Hospital of Johann Wolfgang Goethe-University, Frankfurt am Main, Germany. k.boost@med.uni-frankfurt.de
authors.forename: Kim A
authors.initials: KA
authors.lastname: Boost
authors.forename: Sandra
authors.initials: S
authors.lastname: Hoegl
authors.forename: Andrea
authors.initials: A
authors.lastname: Dolfen
authors.forename: Holger
authors.initials: H
authors.lastname: Czerwonka
authors.forename: Patrick
authors.initials: P
authors.lastname: Scheiermann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zwissler
authors.forename: Christian
authors.initials: C
authors.lastname: Hofstetter
mesh_terms: D000136:Acid-Base Equilibrium / Q000187:drug effects; D000280:Administration, Inhalation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002245:Carbon Dioxide / Q000097:blood; D002316:Cardiotonic Agents / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006835:Hydrazones / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000097:blood*; D007275:Injections, Intravenous; D053583:Interleukin-1beta / Q000097:blood; D008168:Lung / Q000098:blood supply; D019402:Macrophage Inflammatory Proteins / Q000097:blood; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D010100:Oxygen / Q000097:blood; D053717:Pneumonia, Ventilator-Associated / Q000276:immunology* / Q000401:mortality; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012121:Respiration, Artificial / Q000009:adverse effects*; D000077464:Simendan; D015996:Survival Rate; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D016207:Cytokines; D006835:Hydrazones; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D019402:Macrophage Inflammatory Proteins; D011724:Pyridazines; D014665:Vasodilator Agents; D002245:Carbon Dioxide; D000077464:Simendan; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D010100:Oxygen