Levosimendan - Short Note for MD Anaesthesiology

Introduction

Mechanism of Action (Triple Action)

1. Calcium Sensitization (Primary mechanism)
   • Binds to troponin C (TnC) in a Ca²+-dependent manner, stabilizing the Ca²+-bound conformation
   • Prolongs actin-myosin interaction → increases rate and extent of myocyte contraction → enhances contractility
   • Binding is Ca²+-dependent: at diastole (low Ca²+), levosimendan detaches from TnC, so relaxation is not impaired - this is a key advantage over other inotropes
2. PDE III Inhibition
   • Potent phosphodiesterase III (PDE III) inhibitor
   • Raises intracellular cAMP → positive inotropic + lusitropic effects
   • Causes systemic, pulmonary, and coronary vasodilation
3. KATP Channel Opening
   • Opens ATP-dependent K+ (KATP) channels in vascular smooth muscle → vasodilation
   • Contributes to myocardial protection against ischemic injury (ischemic preconditioning-like effect)

Pharmacokinetics

Dosing

• Loading dose (optional): 12-24 mcg/kg IV over 10 minutes (often omitted due to hypotension risk)
• Maintenance infusion: Start at 0.05-0.10 mcg/kg/min; titrate up to 0.2 mcg/kg/min
• Usual infusion duration: 24 hours
• Many clinicians skip the bolus and start directly with infusion to avoid hypotension

Hemodynamic Effects

Advantages Over Conventional Inotropes

• Does not significantly increase myocardial oxygen demand (unlike catecholamines)
• Does not impair diastolic relaxation (Ca²+-dependent TnC binding dissociates at diastole)
• Anti-inflammatory and antiapoptotic properties
• Prolonged effect from active metabolite
• Coronary vasodilation (potentially cardioprotective)
• No tachyphylaxis (unlike beta-agonists)

Clinical Indications

1. Acute decompensated HFrEF with low output state, elevated filling pressures
2. Perioperative low cardiac output syndrome (LCOS) in cardiac surgery
3. Cardiogenic shock (as adjunct)
4. Bridge to transplant / mechanical assist devices
5. Patients intolerant to catecholamines or PDE inhibitors
6. Preoperative optimization ("preconditioning") before high-risk cardiac surgery

Key Clinical Trials

Adverse Effects

• Hypotension - most important; risk reduced by maintaining adequate preload
• Atrial fibrillation (seen in REVIVE-II and SURVIVE)
• Ventricular ectopy / arrhythmias
• Headache, dizziness
• Hypokalemia (via KATP channel opening)

Contraindications

• Severe hypotension (SBP <85 mmHg) - relative
• Significant hypovolemia (correct first)
• Severe renal or hepatic impairment (use with caution; active metabolite accumulates)
• Severe mechanical outflow obstruction (HOCM, severe aortic stenosis)
• History of torsades de pointes

Anaesthesia-Specific Relevance

• Used for perioperative management of low EF patients undergoing cardiac/non-cardiac surgery
• Improves cardiac performance and reduces PCWP + SVR in both normal and depressed LV function patients undergoing cardiac surgery
• The Ca²+-dependent mechanism makes it particularly attractive in the OR since it does not cause diastolic dysfunction or increase ischemia risk
• The prolonged hemodynamic effect (from active metabolite) is useful post-bypass - a single intraoperative infusion can support cardiac function into the ICU period
• Watch for hypotension when combined with volatile agents or vasodilators - manage with volume loading +/- vasopressors

Summary Mnemonic - "LEVO TIPS"

• L - Long-acting (active metabolite >80 h)
• E - Europe approved, not USA
• V - Vasodilator (SVR, PVR reduction)
• O - Only Ca²+ sensitizer available
• T - Triple mechanism (TnC binding + PDE III + KATP)
• I - Inotropy without increasing O₂ demand
• P - Prolongs actin-myosin interaction (systole only)
• S - SURVIVE & REVIVE-II (key trials)