Is Milrinone an Inotrope or Inodilator?

Milrinone is both an inotrope and a vasodilator, which is precisely why the more specific term “inodilator” has become the preferred way to describe it. Calling milrinone simply an inotrope is not wrong, but it tells only half the story. The drug strengthens heart contractions while simultaneously relaxing blood vessels throughout the body, and that combination of effects shapes nearly every clinical decision around its use.

Why the Label Matters

In cardiovascular pharmacology, drugs that make the heart squeeze harder are called inotropes. Drugs that widen blood vessels are called vasodilators. Milrinone does both at once through the same underlying mechanism, so cardiologists and critical care physicians classify it as an inodilator, a portmanteau that captures its dual personality.¹ The distinction is not just academic. A pure inotrope like digoxin boosts the force of the heartbeat but does not meaningfully reduce the resistance the heart pumps against. Milrinone does both, which means it can improve cardiac output while lowering the workload on a struggling heart. That two-for-one profile is why it occupies a distinct niche in the ICU and operating room.

How Milrinone Produces Both Effects

Milrinone works by blocking an enzyme called phosphodiesterase 3, or PDE3. This enzyme normally breaks down a signaling molecule (cyclic AMP, or cAMP) inside cells. When milrinone inhibits PDE3, cAMP levels rise. What happens next depends on the type of cell involved.

In heart muscle cells, the buildup of cAMP leads to increased calcium entry, and calcium is the trigger for muscle contraction. More calcium available to the contractile machinery means each heartbeat generates more force.² At the same time, milrinone speeds up the rate at which calcium is pumped back into storage between beats, which helps the heart relax faster. Faster relaxation means the heart fills more efficiently before its next contraction.³

In the smooth muscle cells that line blood vessels, the same rise in cAMP causes the opposite of contraction: relaxation. The vessel walls loosen, the diameter of arteries and veins increases, and vascular resistance drops.⁴ The result is vasodilation in both the systemic (body-wide) and pulmonary (lung) circulations. So a single molecular action, PDE3 inhibition, produces the two distinct clinical effects that earn milrinone the “inodilator” label.

What the Hemodynamic Numbers Actually Look Like

The combination of stronger contractions and wider vessels shows up clearly in hemodynamic monitoring. In a study of patients with severe left ventricular dysfunction, a single bolus of milrinone increased cardiac output by about 42% within five to ten minutes while simultaneously dropping pulmonary vascular resistance by roughly 31%. Mean pulmonary artery pressure and wedge pressure both fell as well. Heart rate and systemic blood pressure, meanwhile, did not change significantly.⁵

A separate retrospective analysis of 69 patients awaiting heart transplants found that continuous milrinone infusion reduced both left and right ventricular filling pressures and dropped pulmonary and systemic vascular resistance by around 20%.⁶ These numbers illustrate the balanced profile that sets milrinone apart: the heart pumps harder while having less resistance to pump against. That is exactly what you want when a patient’s heart is failing and their vascular beds are clamped down.

Milrinone in Acute Heart Failure and Cardiogenic Shock

Milrinone’s primary territory is the intensive care unit, where it is given intravenously to patients whose hearts cannot generate enough output to sustain organ perfusion. In cardiogenic shock caused by acute decompensated heart failure, a propensity-matched analysis found that milrinone was associated with roughly half the 30-day mortality risk compared with dobutamine, along with improved stroke volume and pulmonary artery compliance.⁷ A meta-analysis pooling data from multiple studies reported a more modest but still statistically meaningful mortality benefit for milrinone over dobutamine in acute heart failure overall, though the absolute difference was small.⁸

Not every study tips in milrinone’s favor. A randomized trial comparing milrinone head-to-head with dobutamine in cardiogenic shock (the DOREMI trial) found no significant difference in the primary composite outcome: roughly half of patients in each group experienced a major event.⁹ The honest read of the evidence is that milrinone and dobutamine are close competitors in cardiogenic shock, with milrinone potentially edging ahead in specific settings, particularly when pulmonary hypertension is part of the picture.

Pediatric Cardiac Surgery

One of milrinone’s strongest evidence bases comes from children recovering from surgery for congenital heart disease. The landmark PRIMACORP trial randomized 238 infants and children to high-dose milrinone, low-dose milrinone, or placebo after corrective cardiac surgery. High-dose milrinone reduced the risk of developing low cardiac output syndrome by 55% compared to placebo, a finding that held up even after patients with major protocol violations were excluded.¹⁰ Follow-up work confirmed that the benefit appears to come from a direct myocardial effect: milrinone improved biventricular function as measured by echocardiographic indices in these young patients.¹¹

Prophylactic milrinone after pediatric cardiac surgery is now widespread practice, with the PRIMACORP trial’s dosing regimen becoming a de facto standard: a loading dose over 60 minutes followed by a continuous infusion for 35 hours.¹² This is one area where milrinone’s inodilator profile is especially valuable. Small children recovering from bypass surgery often develop both poor contractility and elevated pulmonary vascular resistance at the same time, and milrinone addresses both problems simultaneously.

Right Ventricular Failure

The right ventricle is structurally and functionally different from the left. It is thinner-walled and more sensitive to increases in the resistance it pumps against (the pulmonary vascular resistance). When the right ventricle starts to fail, the clinical priority is reducing pulmonary afterload while preserving or improving contractility.¹³ Milrinone fits this requirement well. In an animal model of right ventricular failure from pressure overload, milrinone increased cardiac index by about 11% and improved right ventricular contractility, though stroke volume index actually dipped slightly, likely offset by the rise in heart rate.¹⁴

In clinical practice, milrinone’s ability to drop pulmonary vascular resistance while boosting contractility makes it a go-to agent for right heart failure from pulmonary hypertension, massive pulmonary embolism, or post-cardiac-surgery dysfunction. A pure inotrope would make the right ventricle squeeze harder but would not reduce the elevated pressures in the lung vasculature that caused the problem in the first place. This is perhaps the clearest example of why the inodilator distinction matters clinically.

How Milrinone Compares to Other Inodilators

Milrinone is not the only drug in the inodilator class. Levosimendan, which works through a different mechanism (calcium sensitization rather than PDE3 inhibition), is used widely in Europe and parts of Asia but is not approved in the United States. The two drugs overlap in many clinical scenarios, and comparisons between them are an active area of research.

A narrative review synthesizing surgical and non-surgical data found that levosimendan appears to offer better hemodynamic favorability than milrinone in patients undergoing cardiac surgery.¹⁵ In a three-way comparison after valve replacement surgery, levosimendan and dobutamine were similar in raising cardiac index, while milrinone was somewhat slower and less effective at increasing stroke volume. Dobutamine outperformed both milrinone and levosimendan at raising mean arterial pressure from the 20th minute onward.¹⁶ That last finding highlights a practical trade-off: milrinone’s vasodilatory action lowers blood pressure, which is therapeutic when filling pressures are high but can become a liability if the patient is already hypotensive.

The PROMISE Trial and the Oral Milrinone Cautionary Tale

Any discussion of milrinone must address the PROMISE trial, one of the most sobering results in heart failure pharmacology. In the early 1990s, researchers tested oral milrinone as a long-term therapy for severe chronic heart failure. The trial found that compared to placebo, oral milrinone was associated with a 28% increase in all-cause mortality and a 34% increase in cardiovascular mortality. In the sickest patients (those with the most severe symptoms), mortality rose by 53%. The drug did not show benefit in any subgroup.¹⁷

The PROMISE trial effectively killed oral milrinone. But it also cast a long shadow over intravenous milrinone, which is used for days or weeks rather than months. The mechanisms behind the mortality increase likely relate to chronic cAMP elevation promoting arrhythmias and accelerating myocardial energy depletion over time. Intravenous milrinone used for short-term stabilization in the ICU operates in a fundamentally different clinical context: sicker patients, shorter durations, closer monitoring. Even so, the PROMISE trial is the reason clinicians remain cautious about duration and guard against milrinone creep, where a “temporary” infusion drifts into weeks of use without a clear exit strategy.

Arrhythmia Risk and Other Side Effects

Because milrinone raises intracellular calcium and cAMP, it has inherent proarrhythmic potential. Ventricular arrhythmias are the most clinically significant side effect, occurring in roughly 12% of patients receiving intravenous milrinone, with supraventricular arrhythmias in about 4%.¹⁸ These arrhythmias range from self-limiting runs of non-sustained ventricular tachycardia to sustained rhythms requiring cardioversion.¹⁹ For this reason, milrinone is almost always administered with continuous cardiac monitoring.

Hypotension is the other major concern and flows directly from the vasodilatory half of the inodilator equation. In a patient who is already borderline on blood pressure, the vasodilation from milrinone can push them into frank hypotension. Clinicians sometimes pair milrinone with a vasopressor like norepinephrine to maintain blood pressure while still benefiting from the drug’s inotropic and pulmonary vasodilatory effects. That combination is common in cardiogenic shock management.

Home Infusion for End-Stage Heart Failure

A small but important subset of heart failure patients receive continuous milrinone infusions at home. These are typically patients with end-stage disease who are either waiting for a heart transplant or left ventricular assist device, or who have been deemed ineligible for either. The goal shifts from cure to palliation and keeping the patient out of the hospital.

A study of home inotropic therapy found that patients on continuous milrinone experienced a 16% reduction in overall costs compared with their pre-infusion period, driven mainly by a dramatic drop in hospital days: average length of stay fell from about 21 days to about 5.5 days per admission, and functional status improved significantly.²⁰ However, longer-term analyses suggest the cost picture reverses after about six months, with the ongoing expense of the drug itself outweighing the hospital savings.²¹ Home milrinone remains a bridge or a palliative strategy, not a destination therapy, and the PROMISE trial data hangs over any conversation about prolonged use.

How Milrinone Came To Be

Milrinone was developed as a derivative of amrinone, an earlier PDE3 inhibitor that showed promise in heart failure but had problematic side effects including fever and low platelet counts. Milrinone turned out to be roughly 20 times more potent as an inotrope than amrinone while avoiding those particular toxicities.²² It received FDA approval for intravenous use in 1987 for the short-term treatment of acute heart failure. The oral formulation was never approved after the PROMISE trial results.

An Unexpected Use in the Brain

One of the more intriguing developments in milrinone research has nothing to do with heart failure. After aneurysmal subarachnoid hemorrhage (a type of bleeding stroke), patients often develop delayed narrowing of brain arteries, called cerebral vasospasm, which can cause secondary brain injury. Because milrinone relaxes vascular smooth muscle, some neurocritical care teams have repurposed it to treat this condition.

When delivered directly into brain arteries through a catheter, milrinone increased arterial diameter by an average of about 53% in vasospastic territories, suggesting it can effectively reverse the spasm.²³ Intravenous milrinone has also been studied in this context: a controlled before-after study found that patients receiving IV milrinone had lower odds of long-term functional disability and required far less endovascular intervention, though about 29% of patients needed the drug discontinued because of poor tolerance, mainly hypotension.²⁴ Milrinone has also been identified as having potential anti-inflammatory properties that may address the broader pathology underlying delayed cerebral ischemia, not just the vasospasm component.²⁵ This remains an off-label use without large randomized trials to back it, but the early signal is encouraging enough that confirmatory studies are being pursued.

The PDE3 Subtypes Behind the Scenes

The biology underneath milrinone’s dual action turns out to be more nuanced than it might seem. PDE3 comes in two subtypes, PDE3A and PDE3B, and they are not distributed identically across tissues. In cardiovascular tissues, PDE3A tends to be found in the soluble (cytosolic) portion of cells, while PDE3B is membrane-bound.²⁶ Both subtypes are present in human vascular smooth muscle cells, but only PDE3B expression appears to be regulated by cAMP levels, suggesting a feedback loop that PDE3A lacks.²⁷

Milrinone inhibits both subtypes without much selectivity between them. This lack of subtype selectivity is part of why the drug affects both heart and vessels so broadly. If a more subtype-selective PDE3 inhibitor could be developed, targeting PDE3A predominantly in heart muscle or PDE3B in vascular smooth muscle, it might be possible to dial up the inotropic effect while minimizing the vasodilation, or vice versa. That kind of pharmacological fine-tuning does not exist yet, but the basic science mapping these subtypes is laying the groundwork.