Milrinone


Article Author:
Jack Ayres


Article Editor:
Christopher Maani


Editors In Chief:
Marie Amma
Jennifer Barrow
Darcy Duncan


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
5/15/2019 9:29:52 PM

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 is used 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 is often used 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

The use of Milrinone in the outpatient setting in adults is directed to patients who have severe symptoms of congestive heart failure (CHF) refractory to optimal medical therapy. Previously, an oral version was used 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 are able to undergo cardiac transplantation, initiate mechanical circulatory support, or it may be employed for 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 resulting 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: 2-2.5 Hrs

Volume of distribution: 0.13-0.14 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 used in the ICU and perioperative setting. Prior to initiation of this medication, a right heart catheterization may be considered for obtaining hemodynamic measurements to establish the patient’s baseline parameters and to gauge patient response to continuous infusion. Repeat or dosing monitoring is not routinely performed 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 obtained 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 was previously used 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 and pharmacists should be familiar with the dosing of the drug.


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Milrinone - Questions

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A 65-year-old male has a past medical history of type II diabetes mellitus, liver cirrhosis, chronic obstructive pulmonary disease (COPD), end-stage renal disease, and NYHA (New York Heart Association) class 4 heart failure. He is being treated with milrinone in the cardiac unit for cardiac support during an acute heart failure exacerbation. Which of the patient's comorbid conditions will have the greatest effect on the duration of action of milrinone?



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During morning rounds your team is reviewing the discharge medications for a patient who was admitted 1 week ago for CHF exacerbation and is now stable following 1 week of diuresis. An ambitious medical student on the team suggests initiating outpatient Milrinone, as this was used during his pediatric rotation and helped improve patient symptoms and decreased the frequency of hospitalizations. What is a major concern about initiating Milrinone as an outpatient in this patient?



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A 36-year old female with severe pulmonary artery hypertension is scheduled to undergo laparoscopic cholecystectomy. In addition to preventing and actively treating intraoperative hypoxia, hypercarbia, and acidosis, the patient is initiated on a medication that decreases pulmonary artery pressures and improves cardiac output. What is the second messenger involved in the vasodilatory effects of this medication?



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What enzyme does milrinone inhibit?



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What is the mechanism of action of milrinone?



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A 74-year-old male with NYHA class IV heart failure presents to the emergency department for worsening shortness of breath, orthopnea and 10 kg weight gain. On physical examination, he is dyspneic at rest, has bilateral lower extremity pitting edema, and also bilateral fluffy infiltrates on chest X-ray. He is admitted to the cardiac unit; however, he does not tolerate diuresis due to low blood pressures and is initiated on a phosphodiesterase III inhibitor to improve cardiac output. Which of the following is the least likely physiologic effect of this medication?



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You are planning for the care of a 74-year-old male with NYHA (New York Heart Association) stage IV heart failure who is scheduled to undergo heart transplantation. You plan for the patient to recover in the cardiac unit and are considering using a PDE III inhibitor to enhance inotropy and lusitropy in the immediate postoperative period. Which of the following is true regarding adverse effects among this drug class?



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Milrinone - References

References

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]
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]
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]
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]

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