Showdown of the Inotropes

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Nishika Patel
Critical care pharmacist with a fondness for cats, wine, and all things vintage. Also an insta-nerd who likes to teach ICU tidbits on her IG page @dr.scriptsndrips.

The Pre-brief

The need for inotropic support with dobutamine or milrinone is common in the management of decompensated heart failure and cardiogenic shock. Neither the European nor American cardiogenic shock guidelines recommend one inotrope over the other. So which inotrope should be selected and are there special circumstances where one inotrope may perform better than the other?

Dobutamine vs. milrinone:

  • Dobutamine is a beta-1 and beta-2 agonist. It’s inotropic properties result from stimulation of the sarcolemmal beta-1 adrenergic receptors of cardiac myocytes. This leads to increased activation of adenylyl cyclase, increased synthesis of cAMP, and increased release of Ca2+ from the sarcoplasmic reticulum. These two mechanisms result in increased contractility albeit with an increase in myocardial oxygen demand. Typical dosing ranges from 2 mcg/kg/min to 20 mcg/kg/min. More hypotension is seen at lower doses (< 5 ng/kg/min) as opposed to higher doses (>10 ng/kg/min).
  • Milrinone is a phosphodiesterase-3 (PDE-3) inhibitor that increases cAMP levels in cardiac myocytes by inhibiting cAMP breakdown by the PDE-3 enzyme. This results in increased release of Ca2+ from the sarcoplasmic reticulum and subsequently an increase in contractility. In addition to this inotropic effect, milrinone also causes peripheral and pulmonary vasodilation resulting in a drop in systemic and pulmonary pressure due to its effects on smooth muscle. Typical dosing ranges from 0.125 mcg/kg/min to 0.75 mcg/kg/min. Renal adjustment is required for patients with a CrCl of 10-50 mL/min; these patients should not receive higher than 0.375 mcg/kg/min. In patients with a CrCl of < 10 mL/min, milrinone is not recommended.

Both inotropes can cause tachyarrhythmias and also some degree of hypotension which may necessitate the need for vasopressor support with norepinephrine.

Preference is often given to milrinone in patients with severe pulmonary hypertension and RV failure due to the purported mechanism of reducing pulmonary-artery pressures and improving RV dysfunction.

Several retrospective studies have been done over the years aiming to put to rest the age-old question of which inotrope is superior in the treatment of cardiogenic shock. In August 2021, the Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock (DOREMI) trial was published in the New England Journal of Medicine. They found that there was no significant difference between the milrinone group and the dobutamine group with regards to the primary composite outcome and other secondary outcomes.

What if patients were previously on beta-blockers? 

Considering the mechanism of action, it is intuitive to believe that the previous long-term use of beta-blockade would hinder the effects of dobutamine, a beta-1 and beta-2 agonist. Along this same line of thinking, it is intuitive to believe that because milrinone exerts its inotropic effects using a different mechanism, milrinone’s effects would be superior to dobutamine’s in patients with prior beta-blockade.

One study by Metra and colleagues examined this very hypothesis. However, rather than use milrinone, they used enoximone, a PDE-3 inhibitor available outside of the US. They found that carvedilol use, and to a lesser extent metoprolol use, significantly blunted the hemodynamic response to dobutamine. However, no such blunting of response was seen in patients receiving carvedilol and metoprolol prior to receiving enoximone.

Debrief:

  • The European and American cardiogenic shock guidelines do not recommend a specific inotrope for the treatment of cardiogenic shock.
  • The DOREMI trial showed that there was no statistically significant difference between milrinone and dobutamine for the primary outcome of in-hospital death from any cause, resuscitated cardiac arrest, receipt of a cardiac transplant or mechanical circulatory support, nonfatal myocardial infarction, transient ischemic attack, stroke, or the initiation of renal replacement therapy.
  • In patients previously on carvedilol, dobutamine may be less effective than milrinone. This is also true for patients previously on metoprolol, although to a lesser extent. Overall, in these patients receiving prior beta-blockade, milrinone may result in a better hemodynamic response than dobutamine.

References:

  1. Thiele H, Ohman E, Waha-Thiele S, et al. Management of cardiogenic shock complicating myocardial infarction: an update 2019. Eur Heart J. 2019; 40(32): 2671-83.
  2. Vahdatpour C, Collins D, Goldberg S. Cardiogenic Shock. J Am Heart Assoc. 2019; 8: e-11991.
  3. Mathew R, Di Santo, P, Jung R, et al. Milrinone as compared with dobutamine in the treatment of cardiogenic shock. NEJM. 2021; 385: 516-25.
  4. Metra M, Nodari S, D’Aloia A, et al. Beta-blocker therapy influences the hemodynamic response to inotropic agents in patients with heart failure. J Am Coll Cardiol. 2002; 40:1248-58.

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