Levosimendan restores both systolic and diastolic cardiac performance in lipopolysaccharide-treated rabbits: comparison with dobutamine and milrinone.
OBJECTIVE
Current treatment strategies for severe septic conditions (i.e., intravenous fluids, vasopressors, and cardiac inotropes) reestablish fluid balance and improve cardiac systole but do not address diastolic dysfunction. Our study aimed to fully characterize both systolic and diastolic abnormalities of sepsis-associated heart failure and to identify treatment that would support full-cycle cardiac improvement.


METHODS
Endotoxin-injected rabbits, an animal model of abnormal cardiac function in human sepsis, were used to delineate cardiac abnormalities and to examine effects of drug treatments on heart systolic and diastolic function (n = 30); saline-injected animals served as comparators (n = 17). As treatment, three inotropes commonly used for treatment of cardiac failure were infused for 45 mins in separate animal groups-milrinone, dobutamine, and levosimendan.


METHODS
Variables of left ventricular systolic and diastolic function were assessed with a pressure conductance catheter. Measurements were made before and after endotoxin/saline injection and before and after inotrope treatment.


RESULTS
Pressure-volume analyses of the left ventricle showed marked impairment in systolic function and in all indices of diastolic function (isovolumic relaxation time constant, left ventricular end-diastolic pressure, and end-diastolic pressure-volume relationship) in endotoxin-treated rabbits. The inotropes, milrinone, dobutamine, and levosimendan, could each partially or completely restore systolic function in the lipopolysaccharide-treated rabbits. However, only levosimendan therapy led to additional beneficial effects on left ventricular relaxation and diastolic function.


CONCLUSIONS
Cardiac failure in severe sepsis results from impairments in both systolic and diastolic functions. Treatment with the calcium sensitizer levosimendan improved both systolic and diastolic cardiac functions in septic animals, but cyclic adenosine monophosphate-dependent inotropes milrinone and dobutamine only improved systolic function.
Barraud
Damien
D
Equipe d'Accueil 322, Université, Paris, France.
Faivre
Valérie
V
Damy
Thibault
T
Welschbillig
Stéphane
S
Gayat
Etienne
E
Heymes
Christophe
C
Payen
Didier
D
Shah
Ajay M
AM
Mebazaa
Alexandre
A
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003971:Diastole / Q000187:drug effects*; D004195:Disease Models, Animal; D004280:Dobutamine / Q000494:pharmacology / Q000627:therapeutic use; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D006835:Hydrazones / Q000494:pharmacology* / Q000627:therapeutic use; D008070:Lipopolysaccharides; D020105:Milrinone / Q000494:pharmacology / Q000627:therapeutic use; D011724:Pyridazines / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D018805:Sepsis / Q000150:complications*; D000077464:Simendan; D013599:Systole / Q000187:drug effects*; D016277:Ventricular Function, Left / Q000187:drug effects*
D002316:Cardiotonic Agents; D006835:Hydrazones; D008070:Lipopolysaccharides; D011724:Pyridazines; D000077464:Simendan; D004280:Dobutamine; D020105:Milrinone