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Milrinone is known to have beneficial haemodynamic and clinical effects in patients with congestive heart failure. An investigation into the safety and efficacy of milrinone in patients following heart surgery was undertaken by the European Milrinone Multicentre Trial Group. This paper reports the efficacy, the effects on left heart function, and the adverse events in the study. Ninety-nine adult patients, 61 coronary artery bypass grafting (CABG), 33 valve surgery (VS), and five CABG+VS were studied. Three dosage regimens were investigated sequentially. All patients received a loading dose of intravenous milrinone 50 micrograms kg-1 over 10 min, followed by an infusion of either 0.375 micrograms kg-1 min-1, 0.5 microgram kg-1 min-1, or 0.75 microgram kg-1 min-1 over 12 h. The groups were comparable for age, weight, and surface area; however, in the group receiving 0.5 microgram kg-1 min-1 there were more females and patients undergoing mitral valve surgery. Efficacy criteria of an increase in cardiac index of 30% and/or a decrease in mean pulmonary capillary wedge pressure of 25% were fulfilled by 77 patients at the 60-min measurement. Of the remaining 22 patients, 17 were clinically satisfactory and fulfilled efficacy criteria at some time during the study. At 15 min and 60 min there was a dose-related decrease in systolic and diastolic arterial pressure; however, there was no significant difference in the mean arterial pressure measurements. In all groups there was an improvement in cardiac index at 15 min following the start of milrinone, which was sustained during and up to 4 h after the infusion. This was closely associated with changes in stroke volume index and systemic vascular resistance, and not solely due to a change in heart rate.
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PMID:Milrinone in the treatment of low output states following cardiac surgery. 160 Sep 64

The haemodynamic and biological effects of intravenous milrinone were studied in 24 adult patients with a low cardiac output syndrome following cardiac surgery. The patients received a milrinone bolus of 50 micrograms kg-1 over 10 min followed by a 0.375-0.750 micrograms kg-1 min-1 infusion over 48 h. After the first hour of treatment, an increase in cardiac index, systolic index and left ventricular stroke work index, and a decrease in right and left loading pressures, pulmonary artery pressure, systemic vascular resistance and pulmonary vascular resistance were observed while heart rate and systemic arterial pressure were not modified. These haemodynamic effects were maintained over the 48 h of treatment and persisted 3 h after discontinuation of treatment. Milrinone, which possesses inotropic and vasodilatory effects, increased cardiac performance and corrected the low cardiac output in all patients.
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PMID:Haemodynamic and biological effects of intravenous milrinone in patients with a low cardiac output syndrome following cardiac surgery: multicentre study. 160 Sep 67

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 micrograms/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 less than 0.05 vs. baseline). Patients were subsequently grouped depending on baseline pulmonary wedge pressure greater than or equal to 18 mm Hg (Gr I, n = 9) or less than 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 less than 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 greater than 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.
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PMID:Preload-dependent hemodynamic effects of milrinone in moderate heart failure. 161 32

We have studied the haemodynamic effects of i.v. milrinone, a new phosphodiesterase inhibitor, in patients with low cardiac output after cardiac surgery. Thirty-five patients with a cardiac index (Cl) less than 2.5 litre min-1 m-2 and a pulmonary capillary wedge pressure (PCWP) greater than 8 mm Hg were given a loading dose of milrinone 50 micrograms kg-1 followed by an infusion at one of three rates: 0.375 micrograms kg-1 min-1, 0.5 micrograms kg-1 min-1 or 0.75 micrograms kg-1 min-1 for 12 h. After 1 h there were increases in Cl (35%) (P less than 0.001), heart rate (13%) (P less than 0.01) and stroke volume index (19%) (P less than 0.005). There were decreases in mean arterial pressure (12%) (P less than 0.01), systemic vascular resistance (35%) (P less than 0.001) and PCWP (24%) (P less than 0.05). Pulmonary vascular resistance was unchanged or reduced and left ventricular stroke work index was unchanged or increased. The haemodynamic improvements were sustained throughout the infusion period. Milrinone was tolerated well: three patients developed tachycardia greater than 125 beat min-1, one patient developed atrial fibrillation and one patient had a short run of atrial bigemini. We conclude that milrinone is a useful agent in the treatment of patients with a reduced cardiac output after cardiac surgery.
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PMID:Clinical and haemodynamic effects of milrinone in the treatment of low cardiac output after cardiac surgery. 175 Dec 73

Milrinone is an inotropic agent of the phosphodiesterase inhibitor family. In common with all molecules of this class it has both positive inotropic and vasodilator effects. The haemodynamic effects of 3 dosages of milrinone were studied in 25 patients with low output states after open heart surgery. The low cardiac output was defined as a cardiac index of less than 2.5/min/m2 and pulmonary capillary pressures greater than 8 mmHg. Milrinone was administered as a bolus of 50 micrograms/kg/min over 10 minutes followed by a continuous infusion for at least 12 hours. Six patients were given 0.375 micrograms/kg/min, six patients 0.5 micrograms/kg/min, and 13 patients 0.75 g/kg/min. A significant increase in cardiac index was observed but without any difference between the 3 groups. The heart rate and stroke volumes were increased. There was a mild reduction in systemic blood pressure with a decrease in systemic arterial resistances which returned to almost normal values. Left and right filling pressures did not decrease significantly from the initial values until the end of the bolus injection. Indirect measurements of myocardial oxygen consumption showed an increase in this parameter. There were no changes in blood gas concentrations. The treatment was stopped in only one patient because of peripheral vasodilation. Two patients developed supraventricular tachycardia of no consequence. Milrinone may therefore be proposed as treatment of first intention of low cardiac output states after open heart surgery. It is associated with a mild vasodilatory effect. Improved myocardial function is observed providing attention is paid to vascular filling. None of the maintenance doses used after the bolus injection was shown to be more effective than the others.
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PMID:[Hemodynamic effects of milrinone in the treatment of cardiac insufficiency after heart surgery with extracorporeal circulation]. 176 24

Milrinone is a nonglycoside, nonsympathomimetic bipyridine with positive inotropic and systemic vasodilator properties. In order to evaluate the efficacy and safety of a short term infusion of milrinone, 105 patients with stable New York Heart Association (NYHA) class III or IV heart failure received a loading dose (50 micrograms/kg) and a 48 h continuous infusion (0.5 micrograms/kg/min). Administration of the loading dose resulted in a 28% decrease in pulmonary capillary wedge pressure (PCWP) (P less than 0.001), a 38% increase in cardiac index (P less than 0.001), and a 34% increase in stroke volume index (P less than 0.001) within 15 mins. Milrinone infusion maintained an average 27% and 24% reduction in PCWP during the first and second days, respectively (P less than 0.001). Cardiac index was 32% and 34% above baseline during the same intervals (P less than 0.001). There were no clinically significant changes in heart rate or mean arterial blood pressure during the study period. In a subset of 47 patients who underwent Holter monitoring before and during infusion, a significant increase in ventricular arrhythmias (premature ventricular complexes per hour, ventricular couplets per hour and ventricular runs greater than or equal to three) was demonstrated (P less than 0.0001). In general, milrinone was well tolerated. Of the 105 patients entered, one died of an acute myocardial infarction after premature termination of the infusion, and the infusion rate was decreased in two others because of supraventricular arrhythmias. In patients with severe heart failure, intravenous milrinone has significant beneficial hemodynamic effects. ECG monitoring for arrhythmias is recommended during milrinone infusion.
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PMID:A Canadian multicentre study of a 48 h infusion of milrinone in patients with severe heart failure. 202 94

The response of patients with chronic severe heart failure to extended infusions (greater than or equal to 48 hours) of milrinone was evaluated in a multicenter, baseline-controlled, phase III efficacy and safety trial in 189 patients in the United States. Milrinone was given as loading and maintenance infusions according to one of four dose regimens. An effective response was defined as greater than or equal to 20% increases in cardiac index or decreases in pulmonary wedge pressure. All loading doses (range, 37.5 to 75 micrograms/kg/10 min) were effective short term, and maximum response occurred at 15 minutes. For the three effective regimens, cardiac index increased initially (at 15 minutes) by 24% to 42%, and pulmonary wedge pressure decreased by 24% to 33%. Systemic vascular resistance was reduced by 15% to 31%. The maximal acute response was effective in 99% of individual patients. During maintenance therapy, effective responses were seen at infusion doses of 0.375, 0.50, and 0.75 micrograms/kg/min, whereas an infusion of 0.25 micrograms/kg/min was ineffective. During 2 days of maintenance therapy, cardiac index remained augmented by 34% to 39% for the low and intermediate doses and by 44% to 73% for the high-dose infusion regimen. Pulmonary wedge pressure decreased an average of 18% on day 1 and 30% on day 2. Systemic vascular resistance was reduced by 20% to 25%, and stroke work index was augmented by 21% to 58%. Symptomatic improvement was common during intravenous milrinone therapy for symptoms of dyspnea (61% response), orthopnea (63%), edema (62%), and fatigue (40%). Improvement occurred more frequently in those with worse baseline functional indexes and in those with greater hemodynamic responses to therapy. Safety and tolerance were exceptionally good for these patients with advanced heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hemodynamic and clinical benefits with intravenous milrinone in severe chronic heart failure: results of a multicenter study in the United States. 203 27

Milrinone is a phosphodiesterase inhibitor which combines vasodilating effects with inotropic effects. Hemodynamic improvement after acute administration and increased survival with chronic milrinone therapy in rats with heart failure have been reported before, and suggest long-term hemodynamic improvement. However, no detailed hemodynamic studies are available on prolonged milrinone therapy in rats with heart failure. Therefore, the hemodynamic effects of 2 weeks' milrinone therapy were now investigated in conscious rats with heart failure due to myocardial infarction. The effects were compared to hemodynamic changes after acute administration. Acute milrinone increased the baseline cardiac output in infarcted rats by increasing heart rate rather than stroke volume. However, the maximal cardiac output achieved when the heart was stimulated through a volume load was improved due to increased stroke volume as well as increased heart rate. The increase in maximally stimulated cardiac output after acute milrinone was found to be related to infarct size. Two weeks' milrinone therapy in chronically infarcted rats dose dependently restored the hemodynamic changes which were caused by infarction. In contrast to acute administration, two weeks' milrinone restored cardiac function without an increase in heart rate. The effects were achieved at a rate of administration which presumably has no acute inotropic effects. The data indicate that acute milrinone in infarcted rats has vasodilating effects. Positive inotropic effects, possibly masked by concomitant venodilatation at baseline conditions, became overt after stimulation by volume loading. Long-term milrinone dose dependently restored cardiac function in infarcted rats without effects on heart rate or mean arterial pressure, suggesting that different mechanisms may be involved.
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PMID:Beneficial hemodynamic effects of two weeks' milrinone treatment in conscious rats with heart failure. 222 21

BTS 49465 (flosequinan), a putative selective, balanced arterial and venous vasodilator, displays positive inotropic effects in doses lower than those producing vasodilation. Thus rather than unloading the myocardium, flosequinan may increase myocardial work and oxygen consumption (MVO2), and may adversely affect the patient with myocardial ischemia or compromised coronary blood flow. This study compared the effects of flosequinan with milrinone, a mixed positive inotropic agent and vasodilator, and with nitroprusside (SNP), a standard direct-acting vasodilator, on myocardial dP/dT, MVO2, and myocardial energetics in the normal pentobartital-anesthetized dog. The effect of flosequinan on myocardial work was also evaluated in the dog with propranolol-induced heart failure (PIHF). Fifteen minutes after intraduodenal (id) administration of flosequinan (0.3, 1.0, and 3.0 mg/kg) to seven dogs, mean myocardial dP/dT was increased by 11%, 27%, and 54%, respectively, whereas stroke MVO2 was increased by 10%, 24%, and 47%, respectively. Doses of flosequinan greater than 0.3 mg/kg decreased left ventricular (LV) work but LV efficiency decreased in a dose-related manner. Milrinone (0.1, 0.3, and 1.0 mg/kg, id) increased LV dp/dt by 34%, 68%, and 104% above basal values, while increasing stroke MVO2 by 24%, 106%, and 249%, respectively (n = 7). LV work and LV efficiency decreased after each dose of milrinone. SNP (0.001, 0.003, and 0.01 mg/kg/min, intravenously) did not increase dP/dT but decreased LV work by 28%, 42%, and 46% (n = 5). In animals with PIHF, flosequinan (1 and 3 mg/kg, id) increased LV dP/dT 58% and 87% and increased LV work by 58% and 76% above control values. It was concluded that (1) flosequinan is a positive inotropic agent as well as a vasodilator; (2) in the normal animal the energy cost of positive inotropic activity is less with flosequinan than with milrinone, despite the lesser vasodilating action of the former; and (3) in the animal with a depressed myocardium, flosequinan may adversely affect myocardial work and wall tension.
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PMID:Effect of flosequinan (BTS 49465) on myocardial oxygen consumption. 235 21

This study examined the hemodynamic and regional vascular profile of intravenous (i.v.) milrinone during increasing doses (3, 6, 12 micrograms/kg/min, n = 8) and by intraindividual comparison of milrinone and dobutamine (n = 10) in normal conscious rats. At 3 micrograms/kg/min, Milrinone increased coronary and cerebral blood flow (radioactive microspheres 15 +/- 5 microns) (7.7-9.8 and 1.05-1.27 ml/min/g respectively, both p less than 0.05) without significant changes in systemic hemodynamics. At 6 micrograms/kg/min milrinone increased skeletal muscle blood flow (0.19-0.24 ml/min/g, p less than 0.05) along with increases in cardiac output, stroke volume, and stroke work (all p less than 0.05), while systemic vascular resistance decreased (-51%, p less than 0.05). When compared with dobutamine, milrinone caused a greater increase in cardiac output (+26% vs. +17%) and a greater reduction in systemic vascular resistance. Milrinone and dobutamine increased renal, intestinal, cerebral, and coronary flow to a similar extent, but only milrinone enhanced hepatic arterial blood flow (+26%, p less than 0.05) and tended to increase flow to skeletal muscle (+35%, p = 0.07). We conclude that milrinone exerts significant regional vasodilating effects in a conscious rat model, being most prominent in the coronary and cerebral circulations at a dosage that does not alter central hemodynamics. At higher doses, milrinone causes a balanced increase in regional blood flow including enhanced flow to skeletal muscle. The hemodynamic (particularly as compared with dobutamine) and regional vascular profile of milrinone suggests a predominant vasodilating effect in the rat. Given a similar limited response of rat and diseased human myocardium to milrinone, these findings may have important clinical implications.
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PMID:Central and regional vascular hemodynamics following intravenous milrinone in the conscious rat: comparison with dobutamine. 243 38


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