How is milrinone (phosphodiesterase 3 inhibitor) used to lower pulmonary vascular resistance (PVR)?

Milrinone for Lowering Pulmonary Vascular Resistance (PVR)

Milrinone effectively lowers pulmonary vascular resistance through its phosphodiesterase-3 inhibitory action, which causes pulmonary vasodilation without significantly affecting systemic vascular resistance when properly administered. 1, 2

Mechanism of Action

• Milrinone is a phosphodiesterase-3 (PDE3) inhibitor that inhibits the breakdown of cyclic adenosine monophosphate (cAMP), leading to increased intracellular cAMP levels 1
• The increased cAMP causes pulmonary vasodilation through relaxation of vascular smooth muscle in the pulmonary circulation 2
• Unlike direct β-adrenergic agonists, milrinone works downstream of adrenergic receptors, making it effective even in patients on β-blocker therapy 1
• Milrinone has both inotropic and vasodilatory properties, improving cardiac output while simultaneously reducing pulmonary vascular resistance 2, 3

Clinical Administration

• Intravenous milrinone is typically administered as:
  • Bolus: 25-75 μg/kg over 10-20 minutes (optional in hypotensive patients) 1
  • Continuous infusion: 0.375-0.75 μg/kg/min 1
• For pulmonary hypertension testing before heart transplantation, a single bolus of 50 μg/kg over 1 minute has been shown to effectively lower PVR 3, 4
• Maximum effect on PVR occurs 5-10 minutes after bolus administration and persists for at least 20 minutes 3

Hemodynamic Effects

• Milrinone consistently decreases PVR in patients with pulmonary hypertension by approximately 20-31% 3, 5, 6
• The reduction in PVR is achieved through:
  • Decrease in mean pulmonary artery pressure (12-14%) 3
  • Increase in cardiac output (42%) 3
  • Decrease in pulmonary capillary wedge pressure (16%) 3
• Milrinone can be particularly beneficial in patients with right ventricular failure secondary to pulmonary hypertension 1

Special Considerations

• When using milrinone for PVR reduction, maintaining systemic vascular resistance (SVR) greater than PVR is critical to ensure adequate right ventricular coronary perfusion 1, 7
• Milrinone may cause systemic vasodilation and hypotension, which can be problematic in patients with pre-existing hypotension 1
• To counteract systemic hypotension while preserving the beneficial effects on PVR:
  • Vasopressin at replacement doses can be used to offset the drop in SVR without increasing PVR 1, 7, 8
  • Norepinephrine may also be used but can potentially increase PVR more than vasopressin 8
• In the ICU setting, inhaled nitric oxide (iNO) at 20 parts per million can be used initially for acute pulmonary hypertension, with milrinone started before weaning iNO to prevent rebound pulmonary hypertension 1

Clinical Applications

• Milrinone is indicated for:
  • Acute right ventricular failure with elevated PVR 1
  • Testing reversibility of pulmonary hypertension before heart transplantation 3, 4
  • Management of pulmonary hypertension in cardiac surgical patients 5
  • Treatment of persistent pulmonary hypertension of the newborn (PPHN) with left ventricular dysfunction 1
• In pediatric patients with pulmonary hypertension, intravenous milrinone is reasonable for infants with PPHN and signs of left ventricular dysfunction 1

Combination Therapy

• Milrinone can be combined with other pulmonary vasodilators for enhanced effect:
  • Inhaled prostacyclin (iPGI₂) + inhaled milrinone provides additive pulmonary vasodilation without systemic effects 5
  • When weaning from inhaled nitric oxide, milrinone can be used as replacement therapy to prevent rebound pulmonary hypertension 1
• For patients with hypoxic pulmonary hypertension, milrinone decreases mean pulmonary arterial pressure and PVR without affecting arterial oxygen saturation 6

Potential Adverse Effects

• Systemic hypotension is the most common adverse effect, particularly in patients with pre-existing low blood pressure 1
• Tachycardia and ventricular arrhythmias may occur but are relatively uncommon 6
• In patients with right ventricular failure, the vasodilatory effects of milrinone may require concomitant use of vasopressors to maintain adequate right ventricular perfusion pressure 1, 7
• Terlipressin may be preferred over norepinephrine as a vasopressor when using milrinone, as it has less effect on pulmonary artery pressure 8

Milrinone offers a valuable option for managing pulmonary hypertension and right ventricular dysfunction, with its ability to selectively reduce PVR while improving cardiac output making it particularly useful in critical care settings.