PHARMACODYNAMICS AND PHARMACOKINETICS OF MILRINONE ADMINISTRATION TO INCREASE OXYGEN DELIVERY IN CRITICALLY ILL PATIENTS

Objectives: The positive inotropic and vasodilator actions of phosphod iesterase (PDE) inhibitor drugs may offer therapeutic alternatives to beta-agonists in critically ill patients. We hypothesized that milrino ne administration would increase cardiac index (CI) and oxygen deliver y (Do(2)) in ICU patients, and that a pharmacokinetic model previously developed in cardiac surgery patients may be used to predict milrinon e plasma concentrations in a medical-surgical ICU population. Setting: ICU in two tertiary-care, university medical centers. Design and inte rventions: A prospective, open-label, multicenter, dose-escalating stu dy in three successive groups of eight ICU patients who received a 10- min loading dose of milrinone (25 mu g/kg [LOW], 50 mu g/kg [MED], and 75 mu g/kg [HIGH]). In addition, all patients then received a milrino ne infusion of 0.5 mu g/kg/min for 1 h. Measurements: Hemodynamic meas urements included heart rate (KR); mean arterial, pulmonary artery, ce ntral venous, and pulmonary artery occlusion pressures; and thermodilu tion cardiac output. Oxygen transport indexes included arterial and ve nous blood oxygen tensions to determine Do(2) and oxygen consumption ( Vo(2)). Data were analyzed by univariate repeated measures analysis of covariance, with baseline values utilized as covariate regressors. Re sults: Twenty-four adult ICU patients 20 to 84 years of age completed the study. The three groups did not differ, except that the patients i n the MED group were significantly older (67+/-4 years, mean+/-SEM) co mpared with either the patients in the LOW (48+/-7 years) or HIGH (47/-6 years) group. While HR did not change in the LOW group (90+/-4 to 93+/-3 beats/min), HR increased significantly in the HIGH group (94+/- 5 to 112+/-8 beats/min) (baseline to 60 min infusion time points). All milrinone doses increased both CI and Do(2). At the end of the 10-min lending dose, CI increased 0.3 L/min/m(2) in the LOW group, 1.1 L/min /m(2) in the MED group, and 0.9 L/min/m(2) in the HIGH group. Do(2) in creased 8% in the LOW group, 33% in the MED group, and 23% in the HIGH group, similar to the changes in CI. Mixed venous oxygen saturation i ncreased 3 to 5% during the 10-min loading dose of milrinone. During t his same time period, mean arterial pressure decreased 6 to 16% and pu lmonary artery pressures decreased 9 to 15%. Peak plasma milrinone con centrations increased as a function of the loading dose (159+/-9 ng/mL in the LOW group, 302+/-33 ng/mL in the MED group, and 411+/-45 ng/mL in the HIGH group). However, milrinone concentrations were similar in all three groups after the 1-h infusion; 113+/-14 ng/mL (LOW), 147+/- 22 ng/mL (MED), and 119+/-14 ng/mL (HIGH). In all patients with final plasma milrinone concentrations greater than 100 ng/mL (15/23), the CI increased by at least 0.4 L/min/m(2) (range, 0.4 to 1.8 L/min/m(2)). Conclusions: Our study confirms that a milrinone loading dose of 50 mu g/kg/min followed by an infusion of 0.5 mu g/kg/min achieves adequate plasma concentrations of 100 ng/mL or greater, which significantly in creases both CI and Do(2). In addition, a previously established pharm acokinetic model of milrinone disposition is confirmed in this mixed I CU population.