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

From the Guidelines

Milrinone is a valuable agent in managing vasospasm, particularly cerebral vasospasm following subarachnoid hemorrhage, due to its vasodilatory and cardiac contractility enhancement properties. As a phosphodiesterase-3 inhibitor, milrinone works by increasing intracellular cyclic adenosine monophosphate (cAMP) levels, which leads to vasodilation and improved cardiac contractility 1. For cerebral vasospasm, milrinone is typically administered as an intra-arterial bolus or continuous intravenous infusion. The dual mechanism of action makes milrinone particularly useful as it both dilates constricted vessels and improves cardiac output, enhancing cerebral perfusion. Some key points to consider when using milrinone for vasospasm management include:

• The potential for milrinone to cause hypotension, arrhythmias, and thrombocytopenia, necessitating continuous cardiac monitoring and optimization of fluid status before initiation 1.
• The use of milrinone as part of a multimodal approach to vasospasm management, complementing other treatments such as hypertensive therapy and calcium channel blockers.
• The peak risk for delayed cerebral ischemia (DCI) and cerebral vasospasm is postbleed days 6 to 10 after aneurysmal subarachnoid hemorrhage (aSAH), and prophylactic hemodynamic augmentation with milrinone may be considered during this period 1. Milrinone's role in vasospasm management is supported by its ability to improve cerebral perfusion without significantly increasing cerebral metabolic demands, which is beneficial in the setting of compromised cerebral blood flow 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 vasospasm is as a vasodilator. It works by inhibiting phosphodiesterase, leading to an increase in cAMP and subsequent relaxation of vascular smooth muscle. This results in vasodilation and can help alleviate vasospasm. Key points about milrinone's mechanism of action include:

• Selective inhibition of peak III cAMP phosphodiesterase isozyme in cardiac and vascular muscle
• Direct arterial vasodilator activity
• Increase in forearm blood flow in patients with congestive heart failure 2

From the Research

Role of Milrinone in Managing Vasospasm

• Milrinone, a phosphodiesterase 3 inhibitor, has been proposed as a treatment option for cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH) 3, 4, 5.
• Studies have shown that intravenous milrinone can improve outcomes in patients with cerebral vasospasm, including reduced likelihood of 6-month functional disability and vasospasm-related brain infarction 3.
• Milrinone has also been used to treat cerebral vasospasm following traumatic subarachnoid hemorrhage, with case reports suggesting its safety and potential usefulness in this setting 6.
• The use of milrinone in combination with induced hypertension has been shown to be effective in treating cerebral vasospasm, with improved cerebral perfusion and reduced need for endovascular therapy 7.

Efficacy and Safety of Milrinone

• Studies have reported that milrinone is associated with a lower rate of endovascular angioplasty and a positive impact on long-term neurological and radiological outcomes 3, 5.
• However, milrinone can be prematurely discontinued due to poor tolerance, with common side effects including polyuria, hyponatremia, and hypokalemia 3.
• The safety and efficacy of milrinone in treating cerebral vasospasm have been demonstrated in several studies, with a low incidence of serious adverse events 6, 4, 5.

Clinical Applications of Milrinone

• Milrinone has been used as a first-line therapy for cerebral vasospasm or delayed cerebral ischemia following aSAH, with improved outcomes and reduced need for alternative therapies 5.
• The use of milrinone in combination with norepinephrine-based hyperdynamic hypertensive therapy has been shown to improve cerebral perfusion and outcome in patients with secondary cerebral ischemia after aSAH 7.
• Further studies are needed to confirm the clinical effectiveness of milrinone in treating cerebral vasospasm and to establish its role in clinical practice 3, 6, 4, 5.