EXPLANATION


Levosimendan is an inodilator, first gaining European approval in the year 2000 to treat acutely decompensated chronic heart failure. Currently, it is not FDA-approved in the United States. The inotropic effects of levosimendan result from the binding of troponin C, thus stabilizing calcium-induced conformational changes and prolonging the interaction between actin and myosin filaments during systole. The resultant increase in contractility is not associated with significantly increased myocardial oxygen consumption. Levosimendan also produces vasodilation by opening ATP-sensitive potassium channels in vascular smooth muscle, which may have a cardioprotective effect by reducing excessive calcium during ischemic reperfusion injury.


Patients with heart failure receiving levosimendan demonstrate improved hemodynamics and improved symptomatology without the development of drug tolerance. Since its introduction, levosimendan has been used clinically to treat cardiogenic shock, acute stress-induced cardiomyopathy, depressed right ventricular function, and pulmonary hypertension in the post-cardiac surgical and medical patient populations. The most commonly reported adverse events are hypotension, headache, atrial fibrillation, hypokalemia, and tachycardia.


Although levosimendan is used in the pediatric population in locations outside of the United States, the literature supporting its clinical efficacy is rather limited. Lapere et al. conducted a systematic review and meta-analysis of nine randomized controlled trials involving 539 patients who were 18 years and younger that assessed the safety and efficacy of perioperative levosimendan use after cardiac surgery as compared to dobutamine, milrinone, or placebo. The authors concluded that levosimendan reduced the incidence of low cardiac output syndrome and increased cardiac index but did not have any effect on mortality, ICU length of stay (LOS), hospital LOS, duration of mechanical ventilation, serum lactate, central venous oxygen saturation, serum creatine levels, or the incidence of acute kidney injury. Pilia et al. conducted a systematic review of 48 studies, including 1,271 patients investigating the safety profile of levosimendan. Hypotension occurred in 28.9% of patients, and arrhythmias, predominantly tachycardias, occurred in 12.3% of patients. Of note, the reported dosing of levosimendan typically included a loading dose of 12 mcg/kg over 10 to 15 minutes, followed by an infusion of 0.05- 0.2 mcg/kg/min.


The correct answer is A. The inotropic effects of levosimendan are mediated by increasing the sensitivity of cardiac myocytes to calcium. It also promotes vasodilation by opening ATP-sensitive potassium channels in vascular smooth muscle. Catecholamines such as epinephrine and dobutamine act predominantly by beta-receptor activation, while milrinone is a phosphodiesterase-3 inhibitor.


REFERENCES


Nieminen MS, Fruhwald S, Heunks LM, et al. Levosimendan: current data, clinical use, and future development. Heart Lung Vessel. 2013;5(4):227-245.


Papp Z, Agostoni P, Alvarez J, et al. Levosimendan efficacy and safety: 20 years of SIMDAX in clinical use. Card Fail Rev. 2020;6:e19. doi:10.15420/cfr.2020.03


Lapere M, Rega F, Rex S. Levosimendan in pediatric cardiac anaesthesiology: A systematic review and meta-analysis. Eur J Anaesthesiol. 2022;39(8):646-655. doi:10.1097/EJA.0000000000001711


Pilia E, Silvetti S, Bohane SM, Pusceddu E, Belletti A; Safety of levosimendan in pediatric patients: an up-to-date systematic review. J Cardiothorac Vasc Anesth. 2024;38(3):820-828. doi:10.1053/j.jvca.2023.11.020