Preload-Dependent Hemodynamic Effects of Milrinone in Moderate Heart Failure

Abstract

Milrinone, a bipyridine derivative with positive inotropic and balanced type vasodilating properties, acutely improves cardiac pump function in patients with severe and moderate to severe heart failure. Whether it has similar effects in patients with mild to moderate heart failure is unknown. A hemodynamic evaluation of oral milrinone in dosage of 2.5, 5 and 10 mg was carried out on 3 consecutive days in 18 patients with NYHA class 2.7 heart failure. Patients continued with diuretics and digitalis, administered 15 h before each hemodynamic study. Peak milrinone plasma levels ranged from 77 to 252 µg/ml and were attained at 60-90 min following administration. Concomitantly, milrinone significantly reduced pulmonary wedge and right atrial pressures with 24, 47 and 44, and 25, 42 and 38 % with the 2.5-, 5- and 10-mg doses, respectively. Milrinone had no effect on cardiac or stroke indices with either dose. Moreover, systemic vascular resistance only decreased by 12% with the highest dose, together with a 7 % fall in mean arterial pressure and a 13 % rise in heart rate (all p < 0.05 vs. baseline). Patients were subsequently grouped depending on baseline pulmonary wedge pressure ≧ 18 mm Hg (Gr I, n = 9) or < 18 mm Hg (Gr II, n = 9). Changes in pulmonary wedge, pulmonary artery and right atrial pressure were similar in both groups following each dose. In contrast, the effect on cardiac pump function clearly differed in patients with high versus normal baseline wedge pressure. In Gr I, cardiac index increased significantly by 16 % (5 and 10 mg). In Gr II, cardiac index decreased with 13% following the 10-mg dose (p < 0.05 vs. baseline). When maximal individual changes in cardiac index were compared, 10 mg milrinone resulted in an improvement of cardiac index in all patients with baseline wedge pressures > 15 mm Hg, but in a decrease in cardiac index in patients with lower wedge pressures. It is concluded that milrinone induces contrasting effects on cardiac pump function in patients with mild to moderate heart failure, which may negatively affect its early and, possibly, also late efficacy in this patient group.

The relationship between simulated milrinone exposure and hypotension in children

“…14 Nevertheless, particularly in populations with cardiac dysfunction, the interplay between milrinone therapeutic effect, adverse effects, and underlying systemic and cardiovascular physiology, including fluid status and preload, are complex. 11,23,26,27 Since milrinone is both a positive inotrope and systemic vasodilator, it may improve cardiac output and subsequent blood pressure in subjects with abnormally high systemic vascular resistance or abnormal myocardial contractility. [28][29][30] As a result, large interpatient variability in milrinone exposure, including plasma concentrations greater than 500 ng/ml, has been found in paediatric pharmacokinetic trials without a demonstrable effect on safety profiles.…”

The Effect of Milrinone on the Right Ventriclular Function in Patients with Reduced Right Ventricular Function Undergoing Off-pump Coronary Artery Bypass Graft Surgery

“…Given normal or near-normal RV afterload, preload is the determinant for the RV performance (17). Milrinone has been demonstrated to have beneficial hemodynamic effects only in heart failure patients with an adequate preload (18). Therefore, maintenance of sufficient intravascular volume seems to be crucial for beneficial effect of milrinone on RV function during OPCAB.…”

Clinical practice

“…The central hemodynamic benefits of this drug appear to be well maintained, and, importantly, its use in children has been proven to be effective in the setting of postoperative low cardiac output syndrome [25]. Milrinone has however also been associated with arrhythmias [12] and adverse hemodynamic effects [46], but we have found this to be the best first choice of therapy in patients with moderate to severe ventricular dysfunction with respiratory or underperfusion symptoms.…”