Can milrinone (phosphodiesterase 3 inhibitor) and dobutamine (beta-adrenergic agonist) be used concomitantly?

From the Guidelines

Milrinone and dobutamine can be used together in certain clinical situations, particularly in patients with severe heart failure or cardiogenic shock, as evidenced by the most recent guidelines 1. This combination therapy, sometimes called "dual inotropic therapy," leverages the complementary mechanisms of these medications to improve cardiac function. Milrinone works as a phosphodiesterase-3 inhibitor that increases cardiac contractility and causes vasodilation, while dobutamine primarily stimulates beta-1 adrenergic receptors to increase heart rate and contractility. Some key points to consider when using this combination include:

• Typical dosing might include milrinone at 0.125-0.75 mcg/kg/min and dobutamine at 2.5-20 mcg/kg/min, with both medications requiring continuous intravenous infusion and careful titration based on hemodynamic response, as outlined in the 2022 AHA/ACC/HFSA guideline 1.
• This combination can provide more robust hemodynamic support than either agent alone because they work through different cellular pathways, potentially allowing for lower doses of each medication which may reduce side effects.
• However, this dual therapy requires close monitoring for arrhythmias, hypotension, and tachycardia in an intensive care setting with continuous cardiac monitoring, frequent blood pressure checks, and possibly invasive hemodynamic monitoring.
• The combination should be used cautiously and typically as a temporary bridge to more definitive therapy or cardiac recovery. It's also important to note that the choice of inotropic agent may need to be changed during longer periods of support, and the ongoing need for inotropic support and the possibility of discontinuation should be regularly assessed, as suggested by the guidelines 1. Additionally, the development of tachyphylaxis should be acknowledged, and lower doses of parenteral inotropic drugs are preferred to minimize adverse effects 1. Overall, the use of milrinone and dobutamine together should be guided by the most recent and highest quality evidence, and should prioritize the patient's morbidity, mortality, and quality of life outcomes.

From the Research

Combination Therapy with Milrinone and Dobutamine

• The use of milrinone and dobutamine together has been studied in various clinical settings, including cardiogenic shock and severe heart failure 2, 3, 4, 5, 6.
• A study published in 1992 found that the combination of milrinone and dobutamine induced beneficial hemodynamic effects, including a significant increase in stroke volume index and a reduction in pulmonary capillary wedge pressure 3.
• However, other studies have found that the combination of milrinone and dobutamine may not provide additional benefits compared to using either drug alone 2, 4, 5.
• A systematic review and meta-analysis published in 2023 found that there was no significant difference in all-cause mortality, length of ICU stay, or length of hospital stay between patients treated with milrinone or dobutamine 5.
• Another study published in 2024 found that both milrinone and dobutamine can trigger arrhythmias, including ventricular and supraventricular tachyarrhythmias, and emphasized the need for a tailored approach to managing these iatrogenic arrhythmias 6.

Safety and Efficacy

• The safety and efficacy of milrinone and dobutamine have been compared in several studies, with mixed results 2, 4, 5.
• A study published in 2019 found that milrinone and dobutamine demonstrated similar effectiveness and safety profiles, but with differences in adverse events 2.
• Another study published in 2021 found that there was no significant difference in the primary composite outcome or important secondary outcomes between patients treated with milrinone or dobutamine 4.
• A systematic review and meta-analysis published in 2023 found that dobutamine may be associated with a shorter hospital length of stay, but also with an increased risk of all-cause mortality 5.

Clinical Implications

• The choice of milrinone or dobutamine as initial inotrope therapy for cardiogenic shock may depend on the individual patient's characteristics and the specific clinical setting 2, 4, 5.
• Clinicians should be aware of the potential risks and benefits of using milrinone and dobutamine, including the risk of arrhythmias and other adverse events 3, 6.
• Further studies are needed to determine the optimal use of milrinone and dobutamine in clinical practice, including the potential benefits and risks of combination therapy 5.