Multicenter, double-blind study of intravenous milrinone for patients with acute heart failure in Japan. Japan Intravenous Milrinone Investigators

Y Seino, S Momomura, T Takano, H Hayakawa, K Katoh
Critical Care Medicine 1996, 24 (9): 1490-7

OBJECTIVES: Milrinone is a phosphodiesterase F-III inhibitor with positive inotropic and vasodilating activities. We investigated the hemodynamic response and pharmacokinetics of intravenous milrinone in patients with acute heart failure.

DESIGN: Double-blind studies: a prospective, multicenter, double-blind, dose-finding study and a placebo-controlled, double-blind, comparative study.

SETTING: Patients with acute heart failure (pulmonary artery occlusion pressure of > or = 18 mm Hg), who were hospitalized in the cardiac care units of 33 institutes in Japan, were entered into the study.

PATIENTS: Fifty-four patients with acute or decompensated heart failure in the dose-finding study and 52 patients in the placebo-controlled, double-blind, comparative study.

INTERVENTIONS: The present multicenter study consisted of a double-blind, dose-finding study (50-micrograms/kg intravenous loading dose, followed by 0.25, 0.5, or 0.75 microgram/kg/min of a continuous infusion of milrinone for 6 hrs, n = 54), and a placebo-controlled, double-blind, comparative study (50-micrograms/kg loading dose, followed by 0.5 microgram/kg/min of a continuous infusion of milrinone vs. placebo treatment, n = 52). We investigated the effects on cardiovascular hemodynamics, subjective symptoms, physical findings, and the pharmacokinetics of intravenous milrinone in a total of 106 patients with acute heart failure.

MEASUREMENTS AND MAIN RESULTS: In the double-blind, dose-finding study, dose-dependent inotropic/vasodilating hemodynamic effects were documented for percent changes in cardiac index (+21.2%, +25.8%, and +30.9%, respectively) and pulmonary artery occlusion pressure (-12.8%, -17.0%, -41.3%, respectively) vs. plasma drug concentration at the equilibrium state (6 hrs after starting continuous infusion; 97 +/- 13, 197 +/- 22, and 284 +/- 28 ng/mL, respectively). Throughout the 6-hr infusion period, subjective symptoms were improved in 40%, 46.2%, and 70% of patients, respectively, for the three continuous infusion rates (0.25, 0.5, and 0.75 microgram/kg/min). In the placebo-controlled, double-blind, comparative study, the milrinone group exhibited marked improvement in cardiovascular hemodynamics (pulmonary artery occlusion pressure: from 26 +/- 6 to 15 +/- 3 mm Hg; cardiac index: from 2.6 +/- 0.9 to 3.3 +/- 1.1 L/min/m2) within 15 mins after starting drug administration. However, the placebo group showed no significant hemodynamic changes. Subjective symptoms and physical findings of acute heart failure improved in 47.6% and 40%, respectively, of patients within 60 mins after starting milrinone. The placebo group, however, showed no improvement providing inotropic/vasodilating (both 0%).

CONCLUSION: Continuous infusion of milrinone (0.25 to 0.75 microgram/kg/min) after a 50-micrograms/kg loading dose is effective for inotropic/vasodilating hemodynamic support in patients with acute or decompensated heart failure.

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