Dispelling Dogma: Milrinone Therapy Is Safe and Effective in Renally-Impaired Patients, and We Knew This!

The use of milrinone in patients with renal insufficiency is controversial because the drug is excreted exclusively by the kidney.1Ayres JK Maani CV Milrinone. StatPearls. StatPearls Publishing, Treasure Island, FL2021Google Scholar As such, anesthesiologists may avoid milrinone in patients experiencing post-cardiotomy shock with renal impairment because of fears about drug accumulation and subsequent tachyarrhythmias, myocardial ischemia, and death—a notion perpetuated in the 2022 American College of Cardiology/American Heart Association guidelines.2Heidenreich PA Bozkurt B Aguilar D et al.2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.Circulation. 2022; 145: e895-1032PubMed Google Scholar,3Chong LYZ Satya K Kim B et al.Milrinone dosing and a culture of caution in clinical practice.Cardiol Rev. 2018; 26: 35-42Crossref PubMed Scopus (20) Google Scholar However, is this practice truly evidence-based? Valkovec et al.4Valkovec AM Kram SJ Henderson JB et al.Renal dysfunction and arrhythmia association in patients receiving milrinone after cardiac surgery.J Cardiothorac Vasc Anes. 2023; 37: 353-359Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar recently investigated whether an association existed between new-onset arrhythmias and renal impairment after cardiac surgery when milrinone was administered for low-cardiac-output syndrome. The primary outcome, the incidence of new-onset sustained or hemodynamically destabilizing arrhythmias, was similar (p = 0.76) between patients with (42.9%) and without (40.35%) renal impairment.4Valkovec AM Kram SJ Henderson JB et al.Renal dysfunction and arrhythmia association in patients receiving milrinone after cardiac surgery.J Cardiothorac Vasc Anes. 2023; 37: 353-359Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar The results contrasted, however, with current dogma and suggested that milrinone may be safe in patients with renal insufficiency. The study's findings are contrary to conventional thinking. Milrinone increases atrioventricular nodal conduction, decreases atrial refractoriness, and increases ventricular response rate.5Tisdale JE Patel R Webb CR et al.Electrophysiologic and proarrhythmic effects of intravenous inotropic agents.Prog Cardiovasc Dis. 1995; 38: 167-180Crossref PubMed Scopus (87) Google Scholar These actions are especially apparent in ischemic myocardium.5Tisdale JE Patel R Webb CR et al.Electrophysiologic and proarrhythmic effects of intravenous inotropic agents.Prog Cardiovasc Dis. 1995; 38: 167-180Crossref PubMed Scopus (87) Google Scholar However, the propensity of milrinone to precipitate arrhythmias has been shown to occur independent of plasma concentrations.6Cuffe MS Califf RM Adams Jr, KF et al.Short-term intravenous milrinone for acute exacerbation of chronic heart failure: A randomized controlled trial.JAMA. 2002; 287: 1541-1547Crossref PubMed Scopus (978) Google Scholar, 7Klein L Massie BM Leimberger JD et al.Admission or changes in renal function during hospitalization for worsening heart failure predict postdischarge survival: Results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF).Circ Heart Fail. 2008; 1: 25-33Crossref PubMed Scopus (221) Google Scholar, 8Woolfrey S Hegbrant J Thysell H et al.Dose regimen adjustment for milrinone in congestive heart failure patients with moderate and severe renal failure.J Pharm Pharmacol. 1995; 47: 651-655Crossref PubMed Scopus (25) Google Scholar Thus, renal function and the excretion of milrinone may be unrelated to the incidence of arrhythmic events. As demonstrated by the present study, the incidence of arrhythmias was unchanged and could not be solely attributable to milrinone alone, even when higher infusion rates were used.4Valkovec AM Kram SJ Henderson JB et al.Renal dysfunction and arrhythmia association in patients receiving milrinone after cardiac surgery.J Cardiothorac Vasc Anes. 2023; 37: 353-359Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar In fact, myocardial dysfunction associated with postcardiotomy shock already predisposes patients to arrhythmias before inotropic drugs are administered. If the practice of withholding milrinone from patients with renal impairment continues, patients who have developed an acute kidney injury secondary to a low-cardiac-output state may be denied a medication that can restore end-organ perfusion.9Kumar N Dorcius D Essandoh M. Renal replacement therapy and mortality in venoarterial extracorporeal membrane oxygenation patients: The devil is in the details.J Cardiothorac Vasc Anes. 2022; 36: 1812-1813Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Nevertheless, the study's findings suggested that there was an association between the duration of milrinone administration and the incidence of arrhythmias.4Valkovec AM Kram SJ Henderson JB et al.Renal dysfunction and arrhythmia association in patients receiving milrinone after cardiac surgery.J Cardiothorac Vasc Anes. 2023; 37: 353-359Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar However, it is highly likely that the duration of milrinone therapy is a function of more severe cardiogenic shock, which is associated with an increased risk of developing arrhythmias. Despite the study's findings, the results must be interpreted with caution. Only 197 of 684 patients who received milrinone were included in the analysis.4Valkovec AM Kram SJ Henderson JB et al.Renal dysfunction and arrhythmia association in patients receiving milrinone after cardiac surgery.J Cardiothorac Vasc Anes. 2023; 37: 353-359Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Half of the patients were excluded because of a history of arrhythmia.4Valkovec AM Kram SJ Henderson JB et al.Renal dysfunction and arrhythmia association in patients receiving milrinone after cardiac surgery.J Cardiothorac Vasc Anes. 2023; 37: 353-359Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar The small sample size also precluded confirmation of the study's neutral results. Another important adverse effect of milrinone is its propensity to cause vasodilation and hypotension, which also affects drug clearance and renal function.6Cuffe MS Califf RM Adams Jr, KF et al.Short-term intravenous milrinone for acute exacerbation of chronic heart failure: A randomized controlled trial.JAMA. 2002; 287: 1541-1547Crossref PubMed Scopus (978) Google Scholar Randomized trials are needed to determine the benefits of milrinone in patients with cardiogenic shock and renal dysfunction to guide their care. None. Renal Dysfunction and Arrhythmia Association in Patients Receiving Milrinone After Cardiac SurgeryJournal of Cardiothoracic and Vascular AnesthesiaVol. 37Issue 3PreviewPATIENTS WHO REQUIRE cardiac surgery are at an increased risk of developing low-cardiac-output syndrome that can continue for days after surgery, potentially leading to critical organ hypoperfusion and cardiogenic shock.1 Treatment options to reverse this acute low-output state include volume expansion, vasopressors, inodilators, and mechanical circulatory support devices.2 Milrinone is a type III phosphodiesterase inhibitor that enhances cardiac output and improves hemodynamics by increasing cyclic adenosine monophosphate, increasing calcium in cardiac myocytes, augmenting contractility, and producing vasodilation in pulmonary and systemic vascular beds. Full-Text PDF