Seino Y, Momomura S, Takano T, Hayakawa H, Katoh K
First Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
Crit Care Med. 1996 Sep;24(9):1490-7. doi: 10.1097/00003246-199609000-00010.
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.
Double-blind studies: a prospective, multicenter, double-blind, dose-finding study and a placebo-controlled, double-blind, comparative study.
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.
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.
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.
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%).
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.
米力农是一种具有正性肌力和血管舒张活性的磷酸二酯酶Ⅲ抑制剂。我们研究了静脉注射米力农对急性心力衰竭患者的血流动力学反应和药代动力学。
双盲研究：一项前瞻性、多中心、双盲、剂量探索研究和一项安慰剂对照、双盲、对比研究。
日本33家机构心脏监护病房收治的急性心力衰竭患者（肺动脉闭塞压≥18 mmHg）纳入本研究。
剂量探索研究中有54例急性或失代偿性心力衰竭患者，安慰剂对照、双盲、对比研究中有52例患者。
本多中心研究包括一项双盲、剂量探索研究（静脉注射负荷剂量50μg/kg，随后以0.25、0.5或0.75μg/kg/min持续输注米力农6小时，n = 54）和一项安慰剂对照、双盲、对比研究（负荷剂量50μg/kg，随后以0.5μg/kg/min持续输注米力农与安慰剂治疗，n = 52）。我们在总共106例急性心力衰竭患者中研究了静脉注射米力农对心血管血流动力学、主观症状、体格检查结果和药代动力学的影响。
在双盲、剂量探索研究中，记录到心脏指数（分别为+21.2%、+25.8%和+3%）和肺动脉闭塞压（分别为-12.8%、-17.0%、-41.3%）相对于平衡状态（持续输注开始6小时后；分别为97±1 μg/mL、197±22 μg/mL和284±28 μg/mL）时血浆药物浓度的剂量依赖性正性肌力/血管舒张血流动力学效应。在整个6小时输注期间，对于三种持续输注速率（0.25、0.5和0.75μg/kg/min），分别有40%、46.2%和70%的患者主观症状得到改善。在安慰剂对照、双盲、对比研究中，米力农组在开始给药后15分钟内心血管血流动力学有显著改善（肺动脉闭塞压：从26±6降至15±3 mmHg；心脏指数：从2.6±0.9升至3.3±1.1 L/min/m²）。然而，安慰剂组未显示出显著的血流动力学变化。开始米力农治疗后60分钟内，分别有47.6%和40%的急性心力衰竭患者主观症状和体格检查结果得到改善。然而，安慰剂组未显示出正性肌力/血管舒张改善（两者均为0%）。
50μg/kg负荷剂量后持续输注米力农（0.25至0.75μg/kg/min）对急性或失代偿性心力衰竭患者的正性肌力/血管舒张血流动力学支持有效。
