PHOSPHODIESTERASE-III INHIBITION OR ADRENOCEPTOR STIMULATION - MILRINONE AS AN ALTERNATIVE TO DOBUTAMINE IN THE TREATMENT OF SEVERE HEART-FAILURE

High levels of endogenous plasma catecholamines in patients with severe congestive heart failure induce a down-regulation of the myocardial beta-adrenoreceptors and thus cause adrenoreceptor agonists, such as dobutamine, to be less effective in the treatment of these patients. Phosphodiesterase III inhibitors work independent of adrenoreceptor activity and plasma catecholamine levels; thus these agents are likely to be more effective in the treatment of severe heart failure. The present study compares both the initial and late hemodynamic effects of dobutamine and milrinone during sequentially administered 24-hour infusions. Twenty patients with severe heart failure (New York Heart Association class III, n = 4; New York Heart Association class IV, n = 16) were investigated. Dobutamine could be administered at the prescribed maximum dose of 15-mu-g/kg/min for 24 hours in only 15 of 20 patients. In three patients the dose was reduced or dobutamine infusion completely stopped because of a drug-related increase in heart rate greater than 140 beats/min. Another 2 of 20 patients showed no hemodynamic improvement over 3 hours at the maximum dose of 15-mu-g/kg/min. Dobutamine administration was also discontinued in these patients on account of the existing unfavorable hemodynamic condition, and therapy with intravenous milrinone was started. All 20 patients responded to milrinone without side effects, although comparison of the hemodynamic effects during a 24-hour infusion was possible in only 15 patients. The 15 patients studied over both observation periods experienced an increase in heart rate from 88.8 to 105.6 beats/min ( + 1 hour; p less-than-or-equal-to 0.001) when receiving dobutamine but had no increase with milrinone. Stroke volume increased during dobutamine infusion from 19.3 to 28.9 ml/m2 (+ 49.6%) after 1 hour and then fell continuously to 25.2 ml/m2 after 12 hours; during milrinone therapy, stroke volume increased from 18.8 to 31.2 ml/m2 (+ 66%; p less-than-or-equal-to 0.001) and remained at this level until the end of the infusion (30.2 ml/m2). Pulmonary capillary wedge pressure (PCWP) decreased (p less-than-or-equal-to 0.001) immediately during milrinone therapy from 26.5 to 16.2 mm Hg after 30 minutes and stabilized at 20.1 mm Hg after 24 hours. During dobutamine infusion PCWP showed a delayed decrease from 27.8 to 19.0 mm Hg after 6 hours and subsequently rose to 22.7 mm Hg after 24 hours. Pulmonary vascular resistance (PVR) fell immediately during milrinone therapy (p less-than-or-equal-to 0.001) from 312.7 to 172.1 dynes . sec . cm-5 after 15 minutes and remained at this level; during dobutamine infusion, PVR fell only slightly and temporarily from 379.8 to 219.3 dynes . sec . cm-5 (p less-than-or-equal-to 0.05). Thus in comparison with dobutamine, sequentially administered milrinone showed more benefit and seemed to be the better medication for treatment of severe heart failure. With an immediate and sustained decrease in PCWP and PVR as well as a marked increased in stroke volume without an increase in heart rate, milrinone leads to a safe and sustained improvement in the hemodynamic condition without clinically symptomatic side effects or tolerance development.