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Levosimendan

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Levosimendan studies

 

Claudia Cheng & Anna Lee

Updated February 2006

Drug class

  • Calcium sensitizer
  • Indicated for short term treatment of acutely decompensated severe chronic heart failure

Mode of action

  • Dual:
    1. calcium sensitization for positive inotrope effect
    2. activation of ATP-dependent potassium channels  for vasodilation and cardioprotective effect
  • Calcium sensitization by 3 postulated mechanisms:

  1. increasing affinity of cardiac Troponin C  for calcium

  2. direct stabilization of the calcium-induced conformation of cardiac Troponin C

  3.  action on other target proteins in the molecular cascade of myocardial contraction

  • Resultant increase in tension development, myocardial contractility. Does not affect total intracellular calcium concentration. Therefore, enhanced  myocardial performance achieved without increasing myocardial oxygen consumption and without provoking fatal arrhythmias
  • Activation of potassium channels in vascular smooth muscle producing venous, arterial and coronary vasodilation

Clinical effects

  1. Increase in cardiac index
  2. Decrease in pulmonary capillary wedge pressure
  3. Others: reduce preload and afterload, improve coronary blood flow, no adverse effect on diastolic function, decreased potential for arrhythmia, improved cardiac function in stunned myocardium

Studies

Clinical uses

  • Decompensated low-output heart failure (cardiac index <2.5/l/min/m2 or PCWP >16mmHg or LVEF <0.4)

  • Best documented indication

  • Bolus injection followed by infusion 0.05-0.2 ug/kg/min for 24 hours

  • Outcome benefits included regression of dyspnoea, improved hemodynamic index, increased urine output, shortened hospital and ICU stay, and lower 180-day mortality

  • Effects last for 3-4 days due to long acting metabolite (half-life 80 hours)

  • Repetitive administration at intervals of 4-8 weeks maintained clinical improvement in 6 out of 9 patients in a small study

  •  Left ventricular failure in acute coronary artery disease

    • Reduced 180-day mortality

    • Reduce infarct size in animal studies

    • Prevent myocardial stunning after coronary reperfusion in a case series of 18 patients

  • Cardiogenic shock

    • No formal controlled studies

    • In several clinical observations, improved hemodynamics if combined with noradrenaline to maintain adequate perfusion pressure

    • Infusion 0.05-0.2ug/kg/min for 24 hours without bolus

  • Perioperative treatment in patients undergoing cardiac surgery

    • No formal controlled studies

    • In several clinical observations, improved hemodynamics, improved/prevented postoperative ischemic cardiac depression

    • Given as bolus 12ug/kg or as infusion 0.2ug/kg/min for 6 hours

Dose

  • Avoid an infusion rate >0.2ug/kg/min

  • Avoid prolong infusion >24 hours for dose dependent adverse effects

  • Treatment of decompensated cardiac failure (level of evidence:B)

Adverse effects

  • Most common adverse reaction is headache and hypotension (both 5%)
  • Well tolerated in sick patient population
  • No increase risk of hypotension and ischaemia in patients with heart failure due to acute myocardial infarction
  • No increase risk for arrhythmias
  • No attenuated effects with beta-blockers
  • Caution in renal, hepatic impairment, severe hypotension, severe tachycardia, history or torsades de pointes. Correct hypovolemia

Further reading

Ferenc Follath et al. European Experience on the Practical Use of Levosimendan in Patients with Acute Heart Failure Syndromes. The American Journal of Cardiology Vol 96 (6A) Sept 19, 2005

G. Delle Karth et al. Hemodynamic effects of a continuous infusion of levosimendan in critically ill patients with cardiogenic shock requiring catecholamines.  Acta Anaesthesiol Scand 2003; 47: 1251—1256

Martín J. García-González et al.,Utility of Levosimendan, a New Calcium Sensitizing Agent, in the Treatment of Cardiogenic Shock Due to Myocardial Stunning in Patients With ST-Elevation Myocardial Infarction: A Series of Cases. Journal of Clinical Pharmacology, 2005;45:704-708

© Claudia Cheng and Anna Lee February 2006

©Charles Gomersall, October, 2009 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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