Levosimendan is a calcium-sensitizing inotrope with vasodilatory properties (“inodilator”). It increases myocardial contractility without (at clinically used doses) significantly increasing oxygen consumption. Vasodilation occurs via opening ATP-sensitive potassium channels in vascular smooth muscle, reducing afterload (and preload).

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Levosimendan may be considered as an alternative or adjunct to dobutamine. Use with milrinone and other PDE-III inhibitors should generally be avoided because of synergistic vasodilatory effects. Some data suggest phosphodiesterase inhibitor (PDEI/PDE-3) activity, and care should be exercised when using levosimendan together with milrinone or enoximone.

 

Mechanism of action

Calcium sensitization (primary “calcium sensitizer” concept)

Levosimendan binds to cardiac troponin C in a calcium-dependent manner. This increases myofilament responsiveness to the existing intracellular Ca²⁺ signal, producing more force without necessarily increasing intracellular Ca²⁺ to the same extent as traditional inotropes.

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Vasodilation (inodilator effect)

Levosimendan opens ATP-sensitive potassium channels in vascular smooth muscle, causing vasodilation. This leads to reduced systemic vascular resistance/afterload (and reduced filling pressures).

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PDE-3 signaling (proposed/partial effect)

PDE-3 normally degrades cAMP inside cardiomyocytes. When PDE-3 is inhibited, intracellular cAMP increases, which activates protein kinase A (PKA). PKA then phosphorylates several key proteins that strengthen contraction: it enhances L-type calcium channel activity to increase Ca²⁺ influx, increases ryanodine receptor activity to promote greater Ca²⁺ release from the sarcoplasmic reticulum, and phosphorylates phospholamban to accelerate Ca²⁺ reuptake into the sarcoplasmic reticulum (improving lusitropy) and optimize Ca²⁺ cycling for the next heartbeat.

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Some argue PDEI activity explains part of levosimendan’s inotropic effect in patients. This pathway commonly increases MVO₂, especially if it also causes tachycardia.

 

Hemodynamic effects and pharmacology

In clinical trials, levosimendan has:

• Increased cardiac output (increase of 10-40%)

• Reduced PCWP

• Reduced afterload

• Improved dyspnea/clinical status in some trial designs
   

The vasodilatory component can cause significant hypotension; risk may be reduced by maintaining adequate filling pressures/preload.

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Levosimendan has an active acetylated metabolite with a half-life >80 hours, allowing hemodynamic effects to persist days after discontinuation.

 

Indications

Levosimendan is indicated for:

• Acute decompensation of severe chronic heart failure (NYHA III/IV) despite standard oral therapy (ACEi/A2RA/β-blockers/aldosterone antagonists as tolerated) plus IV vasodilators/diuretics.

• Left ventricular failure post–acute MI necessitating inotropic therapy despite optimal therapy.

• Low cardiac output syndrome or cardiogenic shock post–CABG or post heart valve repair/replacement.

• Cardiogenic shock refractory to dobutamine (≥5 mcg/kg/min for >24 hours).

• Undesirable adverse effects with dobutamine, e.g., arrhythmias.

• Reduced LV systolic function and hypoperfusion in the absence of severe hypotension (despite norepinephrine).

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Use with norepinephrine in hypotensive low-output states

Norepinephrine is commonly used alongside levosimendan in hypotensive low-output states to maintain blood pressure while levosimendan improves contractility (and may lower afterload). A contemporary review of cardiogenic shock pharmacotherapy (Riccardi M, Pagnesi M, Chioncel O, et al.) notes that concomitant norepinephrine may be advised to prevent/avoid hypotension when using an inodilator like levosimendan.

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If there is profound hypotension despite norepinephrine (especially escalating doses), levosimendan should be avoided.

 

Practical precautions when BP is borderline

• Skip the loading bolus

• Start low infusion rate and titrate carefully with invasive monitoring

• Ensure adequate preload and correct hypovolemia

• Remember effects can persist due to metabolite, thus hypotension/benefit may outlast infusion

• Also in patients with marked tachycardia/arrhythmia burden levosimendan should be used with caution (can increase HR and provoke AF)
   

Dosing and administration

Standard infusion (common approach)

• 0.1 microgram/kg/min for 24 hours

• If excessive hypotension or tachycardia reduce to 0.05 microgram/kg/min

• May be increased to 0.2 microgram/kg/min. Uptitration may be considered when the patient is tolerating the current rate (no significant hypotension, tachycardia/AF, or ischemic symptoms) and you still need more haemodynamic effect (ongoing low output or hypoperfusion). Reassess within 30–60(-120) minutes of any dose change and titrate accordingly.
   

Duration: infuse for no more than 24 hours.

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Persistence of effect: hemodynamic effects persist for at least 48 hours and may be seen up to 9 days after discontinuation.

 

Loading dose (bolus)

Loading dose is not generally used in practice.

 

SPC/label approach: 6–12 microgram/kg over 10 minutes
Another bolus approach: 12–24 μg/kg over 10 minutes
 

Higher exposure (higher infusion rates and/or bolus) can increase risk of hypotension and atrial fibrillation, which is one reason many clinicians avoid boluses even though boluses appear in some trial protocols and labels.

 

Vial usage / repeat dosing

One vial (one 5 mL vial contains 12.5 mg of levosimendan) is adequate for treatment in the majority of cases.

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In patients >90 kg, infusion may last <24 hours; benefit of a second vial is uncertain and should be considered only in exceptional circumstances.

 

If the patient still meets inclusion criteria, there may occasionally be justification for repeating infusion after 7 days.

 

Reviews conclude that consecutive infusions (leading to longer than 24h infusions) are not recommended because metabolite accumulation during prolonged infusions was linked to more adverse events.

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Time course of effect (practical expectations)

Minutes to 1 hour

• CO/CI can begin to rise early after starting infusion (especially if bolus is used)

• BP can fall early (vasodilation), sometimes before perfusion gains are obvious

• Product label concept: assess response within 30–60 minutes after starting or after dose change

• With continuous infusion, peak levosimendan plasma concentrations are reached within ~4 hours

• CO/CI: earliest trend within 30–60 min; clearer 2–6 h; often strongest by 24 h and sometimes further over next 1–3 days via metabolite

• LVEF: may appear to change early but is noisy and load-dependent in acute setting; trials/reviews tend to report changes at ~24 h to days rather than minute-to-minute
   

2 to 6 hours

• By end of a 6-hour infusion in invasive studies: reductions in filling pressures/SVR and increases in stroke volume/CI

• Practical “signal” often apparent in CI, PAWP/PCWP, ScvO₂/SvO₂, urine output, lactate trend, etc.

• Dyspnea/clinical status: symptom/clinical improvement signals can appear as early as 6 hours, with persistence at 24 h and 5 days
   

24 hours

• Hemodynamic improvements commonly assessed at 24 hours; 6-hour effects are sustained or augmented by 24 hours in classic hemodynamic work.

1 to 3 days and beyond (post-infusion peak effect)

• Active metabolites may reach maximal plasma concentrations 48-60 hours after infusion has been stopped

• Maximal hemodynamic effects described 1–3 days after starting infusion.

• Continued improvement the day after a 24-hour infusion is normal

 

Major adverse effects and cautions

Common/major side effects

• Hypotension

• Tachycardia

• Enhanced AV conduction (may increase heart rate unpredictably especially in atrial fibrillation, atrial flutter, atrial tachycardia)
   

Arrhythmias and trial safety signals

• REVIVE-II: more episodes of hypotension, AF, and ventricular ectopy

• SURVIVE: higher incidence of AF, lower incidence of worsening HF vs dobutamine; early mortality reduction not sustained through 180 days
   

Dose-related harms

• Higher exposure (bolus and/or higher infusion rates) increases risk of hypotension and atrial fibrillation

• In RUSSLAN (post-MI LV failure dose-ranging), the highest-dose group had more hypotension/ischemia
   

Trial dosing regimens

• LIDO (levosimendan vs dobutamine; hemodynamic trial)

  • Loading: 24 μg/kg over 10 min

  • Infusion: 0.1 μg/kg/min for 24 h

  • The infusions were continued for 24 h and titrated every 2 hours toward the hemodynamic goal (CI ↑30% and/or PCWP ↓25%). So it wasn’t a fixed 0.1 for everyone the whole time.
     

• SURVIVE (mortality through 180 days; levosimendan vs dobutamine)

  • Loading: 12 μg/kg over 10 min

  • Infusion: 0.1 μg/kg/min for 50 min, then 0.2 μg/kg/min for 23 h as tolerated
     

• REVIVE II (levosimendan vs placebo; symptom/clinical course)

  • Bolus: 6–12 μg/kg

  • Infusion: 0.1–0.2 μg/kg/min for 24 h

  • start was 0.1 μg/kg/min, and if tolerated infusion was titrated after ~50 min to 0.2 μg/kg/min for the remainder; if not tolerated, reduced or stopped.
     

• RUSSLAN (post–MI LV failure; dose-ranging; 6-hour infusion regimens). Loading dose over 10 min, infusion 6 h.

  • 6 μg/kg + 0.1 μg/kg/min

  • 12 μg/kg + 0.2 μg/kg/min

  • 24 μg/kg + 0.2 μg/kg/min

  • 24 μg/kg + 0.4 μg/kg/min (highest-dose group: more hypotension/ischemia)​​

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