Inodilators

Inodilators increase cardiac contractility and also dilate arterial and venous vessels, raising output while lowering afterload and filling pressures. They work independently of beta receptors, so they remain effective in patients taking beta blockers. They are short-term drugs for low-output heart failure, right heart failure and post-cardiac surgery.

Members. Milrinone, enoximone, amrinone (obsolete) and levosimendan.

Mechanism. Phosphodiesterase 3 inhibitors block breakdown of cyclic AMP in myocytes (inotropy and faster relaxation) and vascular smooth muscle (vasodilation). Levosimendan binds troponin C to increase calcium sensitivity and opens ATP-sensitive potassium channels in vessels, causing vasodilation, with little rise in oxygen demand.

Haemodynamics. Cardiac output rises with fall in systemic and pulmonary vascular resistance and wedge pressure. Blood pressure falls modestly.

Pharmacokinetics. Milrinone has a half-life of about 2.3 hours, prolonged in renal failure, and is cleared mainly by the kidney. Levosimendan has an active metabolite (OR-1896) with half-life of about 80 hours, giving haemodynamic effect for up to 7 to 9 days after a 24-hour infusion.

• Milrinone: intravenous, widely used; also given by inhalation for pulmonary hypertension in some units.
• Enoximone: intravenous alternative.
• Levosimendan: intravenous, 24-hour infusion with prolonged effect; licensed in many but not all regions.
• Amrinone: obsolete because of thrombocytopenia.

• Acute heart failure with low output, especially on a beta blocker: milrinone 0.375 to 0.75 micrograms/kg/minute, with a loading dose of 50 micrograms/kg over 10 minutes omitted when blood pressure is low.
• Renal impairment: reduce the milrinone infusion rate when creatinine clearance is under 50 mL/min.
• Enoximone: 5 to 20 micrograms/kg/minute, with optional bolus.
• Levosimendan: 0.05 to 0.2 micrograms/kg/minute for 24 hours, with an optional 6 to 12 micrograms/kg bolus over 10 minutes omitted if systolic pressure is under 100 mmHg. Repeated intermittent infusions are used in some advanced heart failure programmes.
• Right heart failure and pulmonary hypertension: milrinone lowers pulmonary vascular resistance.
• Post-cardiac surgery low output: milrinone or levosimendan, including prophylaxis in children.
• Selection: use when beta blockade blunts dobutamine, or when vasodilation is wanted along with inotropy.

Contraindications. Severe hypotension, uncorrected hypovolaemia, severe outflow obstruction, and for levosimendan severe renal (creatinine clearance under 30 mL/min) or hepatic impairment and history of torsades de pointes.

Adverse effects. Hypotension, atrial and ventricular arrhythmia, headache, hypokalaemia, thrombocytopenia (amrinone more than milrinone), and increased mortality with long-term oral phosphodiesterase 3 inhibitor use.

Compatibility. Milrinone precipitates with furosemide in the same line.

Interactions. Other vasodilators and diuretics add hypotension. Correct potassium and magnesium to reduce arrhythmia.

Monitoring. Continuous electrocardiography and arterial pressure, potassium, magnesium, creatinine, platelets, and cardiac output.

Referral and escalation. Persisting hypotension, arrhythmia or inotrope dependence requires critical care and advanced heart failure input.

Special groups. Renal impairment: reduced milrinone dose. Pregnancy: limited data. Children: milrinone 0.25 to 0.75 micrograms/kg/minute. Older adults: more hypotension.