Fig. 7.1
Levosimendan myocardial mechanism of action
7.4 Therapeutic Use
Levosimendan is largely metabolized in the liver and in a smaller proportion in the intestine and is eliminated by renal and fecal excretion. Its clearance is about 3 ml/kg/h, with a half-life of 60 min and with plasma concentration peaking at 2 days. Its main metabolites are OR-1855 and OR-1986. OR-1855 is an intermediate compound, formed in the intestine where it is extracted through the biliary route. OR-1986 is formed by N-acetylation of OR-1855 and is the most clinically relevant metabolite, with a half-life of 80 h that is probably responsible for the prolonged effect of levosimendan, which seems to persist for many days after infusion. Data are derived from animal studies, and it is still unclear whether the effects of this compound are valid in humans.
Levosimendan dosage should be cautious in patients with severe renal and hepatic failure, as data on patients with renal dysfunction suggest that the elimination half-life of OR-1986 (but not of levosimendan half-life) is prolonged in this population, while hepatic failure directly increases levosimendan concentration. Other relative contraindications due to the clinical effects of levosimendan are mechanical obstruction affecting outflow or ventricular filling, severe hypotension, and tachycardia, or history of torsades de pointes.
No risk of tolerance or rebound has been documented after prolonged infusion. Due to its distinct action, levosimendan can be safely used with other cardioactive drugs, including beta-adrenergic inotropes and PDE-3 inhibitors. Moreover, levosimendan action is not antagonized by beta-blockers, enhancing its efficacy in patients treated with beta-blockers and leading to a new, potential therapeutic synergism [18].
Levosimendan is administered through continuous infusion ranging from 0.05 to 0.2 μg/kg/min. A loading dose of 6–12 μg/kg was suggested to anticipate the target concentration, but a significant increase in rate of hypotension has been proven for bolus doses.
7.4.1 Intermittent Administration
Promising results have also been achieved in outpatients with end-stage heart disease, with an intermittent, monthly intravenous administration of levosimendan conferring survival advantage and hemodynamic benefits when compared to controls or dobutamine, along with an improved quality of life [19]. This positive action is probably due to the long-lasting effects of levosimendan and/or of its metabolites.
This new modality of drug administration targets outpatients, increasing the population that might benefit from its unique action and probably reducing hospitalization, morbidity, and mortality in the high-risk population of heart failure patients, thus reducing healthcare expenses.
7.4.2 Possible Future Targets
Diaphragm muscle weakness is a prominent finding in critically ill patients and is due to various conditions, such as mechanical ventilation, chronic obstructive pulmonary disease (COPD), and cachexia. In these patients, specifically in COPD patients, a higher intracellular calcium concentration is needed to obtain normal muscular strength [20]. Moreover, results from animal studies document impaired contractility and efficiency of the diaphragm in congestive heart failure and prolonged, mechanical ventilation in animal models. No therapeutic options have yet proved to improve diaphragm function in these patients. However, levosimendan showed a beneficial effect in isolated diaphragm enhancing contractility, possibly suggesting a new therapeutic approach in patients with respiratory failure and difficult weaning from mechanical ventilation.
7.5 Conclusions
Levosimendan’s exclusive mechanism of action is the cornerstone of its positive clinical effects in various settings. The evidence on its beneficial role in low cardiac output syndrome, in cardiac surgery, in acute heart failure, and in the critically ill patient is solid, making this drug a first choice in these conditions. Promising results in sepsis-related myocardial dysfunction and on intermittent administration in chronic heart failure will probably lead to a wider diffusion of levosimendan in clinical practice.
Summary Table
Drug | Indications | Cautions | Side effects | Dose | Notes |
|---|---|---|---|---|---|
Levosimendan | Low-output syndrome in cardiac surgery | Monitor for hypotension and tachycardia | Hypotension (dose dependent) | Continuous infusion of 0.05–0.1 μg/kg/min, if tolerated, can be increased up to 0.2 μg/kg/min | Hemodynamic effect persists for at least 24 h and has been reported to last for 7–10 days |
Acutely decompensated heart failure
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