Levosimendan

Levosimendan - is a unique, currently unlicensed, agent which is used in some centres for patients with acute decompensated congestive heart failure (CHF). Levosimendan enhances myocardial contractility without increasing oxygen requirements, and causes coronary and systemic vasodilation. Studies have shown that levosimendan increases cardiac output and lowers cardiac filling pressures and is associated with a reduction of cardiac symptoms, risk of death and hospitalisation. Its action is independent of interactions with β-adrenergic receptors. Compared with dobutamine in the LIDO trial (Follath, et al. Lancet 2002; 360: 196–202), levosimendan exerted superior haemodynamic effects and in secondary and post hoc analyses was associated with a lower risk of death after 31 and 180 days. However, in the SURVIVE trial (Mebazaa, et al. JAMA 2007; 297: 1883–91), levosimendan versus dobutamine in patients with acute decompensated heart failure who required inotropic support, long-term survival was no different between the groups, though there was a trend towards early survival improvement with levosimendan. The REVIVE II study (currently
unpublished) showed that patients who received levosimendan in addition to standard therapy were more likely to show clinical improvement and less likely to deteriorate than patients on standard therapy alone. The role of levosimendan in clinical practice remains unclear; some centres use it in a variety of scenarios listed below, though trials have not been conclusively conducted to establish benefit. Although the infusion is for 24 hours only, the haemodynamic effects persist
beyond 48 hours.

Uses
Acute decompensation of severe chronic heart failure despite maximal standard therapy
Left ventricular failure post-acute myocardial infarction necessitating inotropic therapy despite optimal therapy
Low cardiac output syndrome or cardiogenic shock post-coronary artery bypass grafting or heart valve repair/replacement
Cardiogenic shock refractory to inotropes
Undesirable side effects from standard inotropes, e.g. arrhythmias
Contraindications
Right heart failure
High-output failure
Congenital heart disease
Isolated diastolic dysfunction
Hypertrophic cardiomyopathy
Uncorrected stenotic valve disease
Endocarditis

Administration
• Ready-diluted vial containing 12.5 mg levosimendan in 5-ml vial (2.5 mg/ml)
• Withdraw 5 ml from a 250-ml bag of sodium chloride 0.9% or glucose 5% and replace with 5 ml (12.5 mg) levosimendan
• Final concentration of infusion is 50 μg/ml.Administer peripherally or centrally

The trials have used a loading dose plus a 24 hour infusion.However, in practice many units omit the loading dose as it is associated with a transient hypotension and tachycardia and a risk of arrhythmia.The loading dose should be omitted if patient is hypotensive or treated with inotropes.

• Loading dose (most users omit this in the ICU): 6–12 (trials used 24) μg/kg given over 10 min
• Followed by a continuous infusion of 0.1 μg/kg/min for a further 24 hours only. One vial is adequate for the majority of cases

Dosage chart (ml/h):

Weight (kg)	Infusion rate at 0.1 ug/kg/min (ml/h)
50	6
60	7.2
70	8.4
80	9.6
90	10.8
100	12
110	13.2
120	14.4

Adverse effects

Headache

Hypotension (<15%)

Arrhythmias (<10%)

Myocardial ischaemia

Cautions

Hypotension (exacerbation)

Use with milronone or enoximone as levosimendan may also have phosphodiesterase inhibitory effects

Hepatic failure (reduced clearance)

Organ failure

Renal: unknown, but in practice the dose is not adjusted. Active metabolite (ORG 1896) is renally cleared and has a long half-life of ~80 hours

Acknowledgement: Critical Care Pharmacy Team, Guy’s and St Thomas’

NHS Foundation Trust