Milrinone

Article Author:
Jack Ayres
Article Editor:
Christopher Maani
Updated:
9/2/2019 8:27:43 PM
PubMed Link:
Milrinone

Indications

Milrinone is a medication indicated for cardiac support in patients with acute heart failure, pulmonary hypertension, or chronic heart failure. It functions by improving cardiac contractility (inotropy), cardiac relaxation (lusitropy) and inducing vasodilation and has the overall effect of increased cardiac output, improvement of left ventricle-arterial coupling, and enhanced cardiac mechanical efficiency. Its use is primarily in the perioperative and ICU settings, although it also has utility for outpatient therapy in select patient populations.

Use in the Perioperative Setting

Milrinone is often used during various cardiac surgeries, including coronary artery bypass graft surgery, cardiac transplantation, and other cardiac surgeries that require cardiac support. Likewise, it has utility in non-cardiac surgeries for patients with acute decompensated left ventricular heart failure, acute right ventricular heart failure, or pulmonary artery hypertension. 

Cardiac Units and the ICU

Milrinone use is mostly in the ICU and the cardiac unit for cardiac support in patients in acute heart failure, for weaning patients with pre-existing left ventricular dysfunction from cardiopulmonary bypass, or as a temporizing agent for patients with plans to undergo cardiac surgery or transplantation. In the neonate population, it is indicated to treat persistent pulmonary hypertension (i.e., neonates with a congenital diaphragmatic hernia).

Outpatient Use of Milrinone

Clinicians direct the use of milrinone in the outpatient setting to patients who have severe symptoms of congestive heart failure (CHF) refractory to optimal medical therapy. Previously, an oral version was in use in the outpatient setting for symptomatic treatment of New York Heart Association (NYHA) class III/IV CHF; however, this fell out of favor due to increased patient mortality secondary to ventricular arrhythmia and sudden cardiac death.[1] (see Toxicity section)

In pediatric patients with congenital heart failure, outpatient milrinone infusion regimens are a means of bridging patients until they can undergo cardiac transplantation, initiate mechanical circulatory support, or it may work palliatively in those that are not eligible for transplant/mechanical intervention. This method of treatment is effective for improving patient symptoms and decreasing the number of hospitalizations.[2]

Mechanism of Action

Phosphodiesterase Inhibitors

Milrinone is the phosphodiesterase inhibitor drug class. Phosphodiesterase is an enzyme that hydrolyzes the second messenger cyclic adenosine monophosphate (cAMP) and guanosine monophosphate (cGMP), terminating their effects in various tissues. There are several variants of phosphodiesterase inhibitors throughout the body; milrinone is selective for phosphodiesterase III at low doses and nonselective at high doses. Phosphodiesterase III is located primarily in the cardiac sarcoplasmic reticulum and in the smooth muscle in arteries and veins. 

Cardiac Effects of Milrinone

In the myocardium, PDE III inhibitors lead to increased contractility (inotropy) and improved relaxation (lusitropy), which improves systolic and diastolic function, thereby optimizing cardiac output. Increased heart rate (chronotropy) also occurs but is less pronounced than the increases in heart rate seen with medications in the catecholamine class.

Inhibition of phosphodiesterase III prevents the breakdown of cAMP with downstream effects of increasing protein kinase A activity, which causes phosphorylation of calcium ion channels in the sarcoplasmic reticulum and ultimately increases calcium availability to the myocyte sarcomere. This increased calcium availability manifests in increased cardiac inotropy and chronotropy.

PDE III inhibition causes increased calcium reuptake into the sarcoplasmic reticulum, which results in enhanced myocardial relaxation (lusitropy) with producing improved diastolic function. 

Vasoactive Effects of Milrinone

In the vasculature, PDE III inhibition prevents cGMP metabolism in the smooth musculature and results in vasodilation in both arteries and veins. The vasodilatory effects seen with milrinone are more potent than those seen with beta-2 agonists, including dobutamine and isoproterenol. Milrinone is available in an inhalational formula for directed vasodilation of the pulmonary vasculature for treatment of pulmonary hypertension.

Administration

Intravenous Dosing

Loading doses: 25 to 50 mcg/kg (loading dose given over 10 minutes)

Infusion rates: ranging between 0.375 and 0.75 mcg/kg/min

Inhalation Administration

Not an FDA approved use; there is no consensus on the dosing via this route[3]

Pediatric Home Dosing

Infusion rate:  0.3mcg/kg/min to 1mcg/kg/min

Pharmacokinetics

T1/2: 2 to 2.5 Hrs

Volume of distribution: 0.13 to 0.14 L/kg/hr

Elimination: via urine, renal clearance 0.3 L/min (90% recovered in urine in 8 hrs)

Adverse Effects

The most feared adverse effect of milrinone is its potential to induce hemodynamic changes and arrhythmias. Milrinone may cause ventricular tachyarrhythmia, which may lead to cardiac ischemia or sudden cardiac death. These changes are not shown to follow a dose-dependent relationship. Milrinone can cause an increase in venous vessel capacitance, leading to decreased preload and manifesting as headaches, syncope, and severe hypotension. Unlike tachyarrhythmias, hypotension occurs in a dose-dependent relationship.[4]

Besides its hemodynamic and arrhythmogenic effects, milrinone may also affect platelet function and inflammatory pathways. It may block platelet aggregation, suppress neointimal hyperplasia associated with endothelial injury, and attenuate the proinflammatory effects of cardiopulmonary bypass.

Contraindications

Milrinone is contraindicated in patients with hypersensitivity to any of its components. It is relatively contraindicated in patients with severe heart failure or severe pulmonary hypertension. In severe pulmonary hypertension, generalized vasodilation of pulmonary vasculature may worsen VQ mismatch and lead to worsened hypoxemia. When considering the use of milrinone in these populations, it is advisable to consult a specialist for expert guidance. Use of milrinone is generally contraindicated in patients with acute renal failure and end-stage renal disease, as it primarily undergoes renal excretion, although studies demonstrate that the dose-dependent relationship of adverse events is scarce and there is no clear guidance for milrinone use or dosing in chronic renal disease.[3][4]

Monitoring

Milrinone is primarily for use in the ICU and perioperative setting. Before initiation of this medication, a right heart catheterization may be a consideration for obtaining hemodynamic measurements to establish the patient’s baseline parameters and to gauge the patient response to continuous infusion. Repeat or dosing monitoring is not routine due to the risks associated with repeat vascular access or risks related to continuous indwelling catheters. Pulmonary artery catheterization for monitoring of pulmonary pressures should be done with discretion and only after considering a risk-benefit analysis on a case-by-case basis. 

Serum milrinone levels are not routinely necessary as the arrhythmogenic toxic effects have not shown a dose-dependent linear relationship.[4]

Toxicity

Cardiovascular toxicity is primarily seen in patients receiving milrinone chronically and manifests as tachyarrhythmias and sudden cardiac death. At high dosing, patients may also experience hypotension and syncope. 

Milrinone had a previous use as an oral formulation for outpatient use in patients with NYHA class III and IV chronic heart failure (CHF) to improve symptoms and decrease the frequency of hospital admissions. However, this practice was discontinued following the PROMISE trial in 1991 due to safety concerns. This double-blinded clinical trial assessed patients with CHF class III/IV that were placed on milrinone or placebo and was ended early due increased mortality in the milrinone group secondary to ventricular tachyarrhythmias and sudden cardiac death.[3][1]

Enhancing Healthcare Team Outcomes

Milrinone can be a useful medication for providing cardiac support in patients with acute and chronic heart failure, for providing intraoperative cardiac support and for acting as a bridge to definitive surgical or mechanical support or for palliative support in specific patient populations. However, due to this medication’s toxicity and the risks associated with invasive monitoring, ICU providers should carefully perform a risk-benefit analysis before initiating patients on this medication. Nurses should be familiar with the dosing of the drug, and provide additional monitoring for adverse effects as well as patient compliance. Pharmacists should work closely with the prescriber and verify dosing and perform medication reconciliation to preclude any drug-drug interactions. Given the toxicity and potential adverse event profile of milrinone, an interprofessional, collaborative, team effort is the best means by which to drive patient outcomes optimally. [Level V]


References

[1] Packer M,Carver JR,Rodeheffer RJ,Ivanhoe RJ,DiBianco R,Zeldis SM,Hendrix GH,Bommer WJ,Elkayam U,Kukin ML, Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. The New England journal of medicine. 1991 Nov 21     [PubMed PMID: 1944425]
[2] Curley M,Liebers J,Maynard R, Continuous Intravenous Milrinone Therapy in Pediatric Outpatients. Journal of infusion nursing : the official publication of the Infusion Nurses Society. 2017 Mar/Apr     [PubMed PMID: 28248808]
[3] Mladěnka P,Applová L,Patočka J,Costa VM,Remiao F,Pourová J,Mladěnka A,Karlíčková J,Jahodář L,Vopršalová M,Varner KJ,Štěrba M, Comprehensive review of cardiovascular toxicity of drugs and related agents. Medicinal research reviews. 2018 Jul     [PubMed PMID: 29315692]
[4] Chong LYZ,Satya K,Kim B,Berkowitz R, Milrinone Dosing and a Culture of Caution in Clinical Practice. Cardiology in review. 2018 Jan/Feb     [PubMed PMID: 29045285]