What is the role of milrinone (phosphodiesterase 3 inhibitor) in managing pulmonary hypertension?

From the Guidelines

Milrinone is a valuable agent in managing pulmonary hypertension, particularly in critically ill patients, due to its ability to cause pulmonary vasodilation and improve right ventricular function without significantly decreasing systemic vascular resistance. As a phosphodiesterase-3 inhibitor, milrinone increases intracellular cyclic adenosine monophosphate (cAMP) levels in cardiac and vascular smooth muscle cells, leading to vasodilation in both pulmonary and systemic circulations while enhancing cardiac contractility 1. In the context of pulmonary hypertension, milrinone is often used in intensive care settings, where the management of critically ill patients is challenging due to the risk of right ventricular failure and the potential for treatment to have paradoxically detrimental effects on RV function and the underlying pulmonary vascular disease 1. Some key points to consider when using milrinone in pulmonary hypertension management include:

• Milrinone can be used to maintain systemic vascular resistance (SVR) greater than pulmonary vascular resistance (PVR), which is crucial to prevent right ventricular ischemia 1.
• The selection of inotropes and vasopressors in PAH patients is challenging, but milrinone, along with dobutamine and epinephrine, has neutral or beneficial effects on PVR 1.
• Milrinone is often used in conjunction with other therapies, such as inhaled nitric oxide (iNO), to manage acute pulmonary hypertension, especially in patients who are post-coronary bypass surgery or valve replacement 1.
• When weaning iNO, rebound pulmonary hypertension can occur, and milrinone can be used as replacement therapy to prevent this complication 1.
• Clinicians should monitor for potential side effects, including hypotension, arrhythmias, and thrombocytopenia, and use milrinone cautiously in patients with renal impairment, with dose adjustments recommended as the drug is primarily excreted by the kidneys. Overall, milrinone is a useful agent in the management of pulmonary hypertension, particularly in critically ill patients, due to its ability to improve right ventricular function and reduce pulmonary vascular resistance without significantly decreasing systemic vascular resistance 1.

From the FDA Drug Label

Milrinone lactate is a positive inotrope and vasodilator, with little chronotropic activity different in structure and mode of action from either the digitalis glycosides or catecholamines Milrinone lactate, at relevant inotropic and vasorelaxant concentrations, is a selective inhibitor of peak III cAMP phosphodiesterase isozyme in cardiac and vascular muscle Milrinone lactate also produces dose-related and plasma concentration-related increases in forearm blood flow in patients with congestive heart failure, indicating a direct arterial vasodilator activity of the drug.

The role of milrinone in managing pulmonary hypertension is not directly stated in the provided drug label. However, as a vasodilator, it may help reduce pulmonary vascular resistance, which can be beneficial in patients with pulmonary hypertension.

• Key points:
  • Milrinone has vasodilatory effects.
  • It can increase forearm blood flow.
  • The label does not explicitly mention pulmonary hypertension. 2

From the Research

Role of Milrinone in Pulmonary Hypertension

• Milrinone, a phosphodiesterase 3 inhibitor, has been used as a therapeutic option for managing pulmonary hypertension (PH) 3.
• The use of milrinone in patients with PH may be limited by systemic hypotension, especially in those already receiving prostanoid treatment 3.
• Nebulized milrinone has been used as a novel adjunctive therapy in patients with acute decompensated idiopathic PH, improving symptoms without compromising mean arterial pressure and heart rate 3.

Mechanism of Action

• Milrinone has been shown to improve pulmonary hemodynamics and right ventricular function in chronic pulmonary hypertension by increasing right ventricular function and reducing pulmonary vascular resistance 4.
• The drug has also been found to increase cardiac output and decrease mean pulmonary artery and pulmonary artery wedge pressures in patients with severe left ventricular dysfunction 5.

Clinical Applications

• Milrinone may be a useful therapy for premature infants with echocardiography findings of PH and/or right ventricular dysfunction, as it has been associated with a fall in oxygenation index and inhaled nitric oxide dose 6.
• The use of milrinone as a rapid test for reversibility of pulmonary hypertension in patients with severe left ventricular dysfunction has also been explored, with the drug consistently decreasing pulmonary vascular resistance in these patients 5.

Potential Benefits and Limitations

• The potential benefits of milrinone in managing PH include improved symptoms, reduced pulmonary vascular resistance, and increased right ventricular function 3, 4.
• However, further studies are needed to assess the role of nebulized milrinone in patients with PH and to confirm the efficacy of milrinone in various clinical settings 3, 6.