title: Effects of levosimendan, a novel inotropic calcium-sensitizing drug, in experimental septic shock.
abstract: OBJECTIVE
  Levosimendan is a novel inodilator that improves cardiac contractility by sensitizing troponin C to calcium. This drug has proved to be effective in treating advanced congestive heart failure but has not been evaluated in septic settings. The purpose of the present study was to study the effects of this drug in a porcine model of endotoxemia.
  
  
  METHODS
  Prospective experimental study.
  
  
  METHODS
  Fourteen landrace pigs.
  
  
  METHODS
  All animals were anesthetized and catheterized for measurement of central and pulmonary hemodynamics. Ultrasonic flow probes were placed around the renal artery and portal vein to measure blood flow. A tonometer was placed in the ileum to measure mucosal pH. Levosimendan was given to six animals as a bolus (200 microg x kg(-1)) followed by a continuous infusion (200 microg x kg(-1) x hr(-1)). Thirty minutes after onset of levosimendan treatment, all animals received endotoxin (20 microg x kg(-1) x hr(-1) for 3 hrs).
  
  
  RESULTS
  At baseline, levosimendan induced a systemic vasodilation with a reduction in blood pressure and an increase in heart rate. A tendency to an increase in cardiac index did not reach statistical significance (p =.055). Cardiac index and systemic oxygen delivery were markedly improved in the levosimendan group during endotoxemia. Systemic vascular resistance and blood pressure were reduced in the levosimendan group. The latter parameter, however, was only different from the control group during the initial phase of endotoxin shock but not at the late, most pronounced phase of shock. Levosimendan also efficiently attenuated endotoxin-induced pulmonary hypertension. Portal venous blood flow and gut oxygen delivery were improved, but no concomitant reduction in endotoxin-induced intestinal mucosal acidosis was observed. Renal blood flow was unaffected, as was the endotoxin-induced increase in plasma endothelin-1-like immunoreactivity. These findings support previous reports of calcium desensitization as a potential component in septic myocardial depression. Furthermore, the vasodilatory properties of this drug were well tolerated in the current model of hypodynamic endotoxin shock, and they may have contributed to improved regional blood flow as seen in the gut as well as improved systemic perfusion by means of reduced biventricular afterload.
  
  
  CONCLUSIONS
  Pretreatment with levosimendan in pigs subjected to endotoxin shock improved cardiac output and systemic and gut oxygen delivery. In addition, pulmonary hypertension largely was attenuated without any adverse effects on gas exchange. These results are promising in several aspects, but the role of levosimendan in the treating circulatory failure in sepsis remains to be established.
authors.affiliation: Department of Surgical Sciences, Section of Anaesthesiology and Intensive Care Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Oldner
authors.forename: D
authors.initials: D
authors.lastname: Konrad
authors.forename: E
authors.initials: E
authors.lastname: Weitzberg
authors.forename: A
authors.initials: A
authors.lastname: Rudehill
authors.forename: P
authors.initials: P
authors.lastname: Rossi
authors.forename: M
authors.initials: M
authors.lastname: Wanecek
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D004927:Escherichia coli Infections / Q000188:drug therapy; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006835:Hydrazones / Q000627:therapeutic use*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D011724:Pyridazines / Q000627:therapeutic use*; D012772:Shock, Septic / Q000188:drug therapy*; D000077464:Simendan; D013552:Swine
chemical_list: D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan; D002118:Calcium