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Stability of milrinone lactate in the presence of 29 critical care drugs and 4 i.v. solutions.

The stability of milrinone lactate in the presence of 29 critical care drugs during simulated Y-site injection and in 4 i.v. solutions was studied. Ten milliliters of milrinone 400 microg/mL (as the lactate salt) was combined with 10 mL of each of 29 commonly used critical care drugs in 5% dextrose injection. Also, mixtures containing milrinone 400 microg/ mL in lactated Ringer's injection, 5% dextrose injection, 0.45% sodium chloride injection, and 0.9% sodium chloride injection were prepared. All mixtures were prepared in triplicate and stored at 22-23 degrees C in glass containers or polyvinyl chloride bags under fluorescent light. Samples were withdrawn zero, one, two, and four hours after mixing for each milrinone-secondary drug mixture and at intervals up to seven days for each milrinone-i.v. diluent mixture. Samples were examined visually and analyzed by high-performance liquid chromatography, enzymatic assay, or fluorescence polarization immunoassay. No precipitation or substantial pH change was observed in any of the mixtures. In all the mixtures, milrinone retained more than 96% of its initial concentration, and the other drugs retained more than 97% of their initial concentrations. Milrinone 400 microg/mL in 5% dextrose injection and 29 critical care drugs were stable for four hours at 22-23 degrees C during simulated Y-site administration. Milrinone 400 microg/mL was stable in lactated Ringer's injection, 5% dextrose injection, 0.45% sodium chloride injection, and 0.9% sodium chloride injection for seven days at 22-23 degrees C.

Cardiotonic Agents↗

Treatment with phosphodiesterase inhibitors type III and V: milrinone and sildenafil is an effective combination during thromboxane-induced acute pulmonary hypertension.

OBJECTIVES: To evaluate the effects of phosphodiesterase type III and V (PDEIII and PDEV) inhibition on pulmonary and systemic haemodynamics in a porcine model of acute pulmonary hypertension. METHODS: Twenty-four adult swine were anaesthetized with 1 MAC isoflurane and mechanically ventilated with an FI(O(2)) of 100%. Micromanometer-tipped catheters were placed in the ascending aorta, pulmonary artery and right ventricle. Pulmonary flow was measured with a perivascular probe using transit time ultrasound. Pulmonary hypertension was induced with a continuous infusion of the thromboxane analogue, U46619. The animals were then randomized to four groups: Group 1 (n=6) received 50 mg of sildenafil (PDEV inhibitor) diluted in water via an orogastric tube; Group 2 (n=6) received 50 microg kg(-1) of i.v. milrinone (PDEIII inhibitor); Group 3 (n=6) received sildenafil followed by milrinone; and Group 4 (n=6) received placebo via an orogastric tube. RESULTS: Pulmonary hypertension was achieved in all animals. Calculated pulmonary vascular resistance decreased by an average of 36% after sildenafil (P<0.05), 41% after milrinone (P<0.05), and 61% with both drugs combined (P<0.05). Systemic vascular resistance decreased by 37% (P<0.05) with milrinone alone, and 36% (P<0.05) with milrinone and sildenafil combined but it was preserved in the sildenafil group. Cardiac output and right ventricular dP/dT were significantly improved after milrinone or both drugs combined, but not with sildenafil. CONCLUSION: Milrinone and sildenafil are effective pulmonary vasodilators, with independent action and additive effect. Both drugs combined achieved a better haemodynamic profile, with greater pulmonary vasodilatation and increased contractility but without additional systemic vasodilatation. The systemic haemodynamic profile (systemic vasodilation, cardiac output, right ventricular dP/dT) is improved with milrinone but not with sildenafil.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

Effects of milrinone treatment in cardiomyopathic hamsters (CHF 147) with severe congestive heart failure.

The effects of oral milrinone treatment in cardiomyopathic hamsters with severe congestive heart failure (CHF) were evaluated. Strict criteria based on increase in body weight were established to define day no 1 of treatment. Survival rate of non-treated hamsters (group 1) ranged between 9 and 16 d, mean 12.9 (SEM 0.8) d, after entering the study. Hamsters treated with milrinone in drinking water (group 2a: 0.3 mg.ml-1, or group 2b: 0.6 mg.ml-1) survived between 6 and 36 d, mean 15.0(2.1) d, NS, for group 2a, and between 6 and 47 d, mean 19.6(4.0) d, NS, for group 2b. There was a significant difference between the number of hamsters that survived longer than 16 d between untreated hamsters (group 1, n = 0/12) and hamsters treated with milrinone (groups 2a, b, n = 7/24). There was no significant correlation between survival duration and milrinone daily dose nor between survival and milrinone plasma concentration at death. Milrinone treatment also significantly decreased pulmonary congestion as measured by the number of pigment containing macrophages per alveolus. No other pathological findings were modified by milrinone. It was concluded that, in addition to exerting a beneficial effect on pulmonary congestion, milrinone improved survival in some CHF hamsters. However, more studies are needed to evaluate the possibility of an arrythmogenic potential that might explain why some treated hamsters died earlier than non-treated hamsters.

Animals↗

The effect of milrinone on hemodynamics and left ventricular function after emergence from cardiopulmonary bypass.

Although milrinone effectively increases cardiac function, few studies have specifically evaluated its efficacy during cardiac surgery. We investigated the effects of milrinone on hemodynamics and left ventricular function in cardiac surgical patients who were already treated with catecholamines. Thirty-seven patients undergoing cardiac surgery were studied. Immediately after emergence from cardiopulmonary bypass (CPB), patients were randomly assigned to a control group (n = 10) or to one of these milrinone groups: milrinone 50 microg/kg intravenously (n = 8), 50 microg/kg + 0.5 microg x kg(-1) x min(-1) (n = 10), or 75 microg/kg + 0.75 microg x kg(-1) x min(-1) (n = 9). Hemodynamics and transesophageal echocardiogram were recorded while constant filling pressures were maintained by volume reinfusion from the CPB reservoir. Arterial blood samples were obtained for the measurement of milrinone plasma concentrations and to determine the dose response curve. In all three milrinone groups, cardiac index and velocity of circumferential fiber shortening (Vcfc) significantly increased from the baseline, and both were significantly higher at 5 and 10 min than those in the control group. The plasma concentration of milrinone with half of maximum increase in Vcfc was 139.3 ng/mL based on the dose-response curve. Thus, milrinone improves hemodynamics and left ventricular function when constant loading conditions are maintained.

Cardiac Surgical Procedures↗

The effects of milrinone and its mechanism in the fatigued diaphragm in dogs.

UNLABELLED: We studied the effects of milrinone and its mechanism in nonfatigued and fatigued diaphragms in dogs. In Group Ia (n = 5), animals without fatigue, defined as the inability to sustain muscle force, received only maintenance fluids. In Group Ib (n = 5), dogs without fatigue were given a bolus injection (50 microg/kg) followed by continuous infusion (0.5 microg x kg(-1) x min(-1)) of milrinone. In Groups IIa, IIb, and IIc (n = 8 in each), diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. After producing fatigue, only maintenance fluids were administered (Group IIa); milrinone (50 microg/kg loading dose plus 0.5 microg x kg(-1) x min(-1) maintenance dose) was administered (Group IIb); or nicardipine 5 microg x kg(-1) x min(-1) was infused simultaneously with milrinone (Group IIc). Diaphragmatic contractility was assessed with transdiaphragmatic pressure (Pdi). No differences in Pdi were observed in Groups Ia and Ib. After the fatigue-producing period, Pdi at low-frequency (20-Hz) stimulation decreased from the prefatigued values in Groups IIa, IIb, and IIc (P < 0.05), whereas the decrease was minimal at high-frequency (100-Hz) stimulation. Compared with Group IIa, Pdi to each stimulus increased during milrinone infusion in Group IIb (P < 0.05). In Group IIc, the augmentation of Pdi in the fatigued diaphragm by milrinone was not abolished with an administration of nicardipine. In conclusion, milrinone improves contractility in the fatigued canine diaphragm but not via its effect on transmembrane calcium movement. IMPLICATIONS: Diaphragmatic fatigue may contribute to the development of respiratory failure. Milrinone increases contractility in the fatigued diaphragm and thereby may have an inotropic action on the improvement of diaphragmatic fatigue.

Animals↗

The efficacy of preemptive Milrinone or Amrinone therapy in patients undergoing coronary artery bypass grafting.

UNLABELLED: Acute deterioration in ventricular function and oxygen transport is common after cardiac surgery. We hypothesized that milrinone or amrinone may reduce their occurrence and catecholamine requirements and increase cellular enzyme levels in patients undergoing coronary artery bypass. In 45 patients, we randomly administered milrinone 50 microg/kg plus 0.5 microg x kg(-1) x min(-1) infusion for 10 h, amrinone 1.5 mg/kg plus 10 microg x kg(-1) x min(-1) infusion for 10 h, or placebo at release of aortic cross-clamp. Hemodynamic variables, dopamine requirement, and laboratory values were recorded. At the postoperative nadir, stroke volume index was higher in the Milrinone and Amrinone groups (mean +/- SD, 27.8 +/- 4.0 and 26.1 +/- 3.2 vs. 20.4 +/- 5.1 mL x min (-1) x m(-2) per beat, P < 0.0001), and oxygen transport index was higher (354.7 +/- 57.8 and 353.7 +/- 91.2 vs 283.0 +/- 83.9 mL. min(-1) x m(-2), P = 0.009). The postoperative dopamine requirement was less (6.6 +/- 2.7 and 6.8 +/- 2.6 vs 10.4 +/- 2.0 mg/kg, P < 0.008), and postoperative serum lactate, alanine and aspartate aminotransferase, lactate dehydrogenase, creatinine kinase, C-reactive protein, and glucose levels were less (P < 0.01). The mean postoperative heart rate was faster in the Milrinone group than in the Amrinone and Placebo groups (96.8 +/- 10.3 vs. 86.9 +/- 9.5 and 87.8 +/- 10.8 bpm, P < 0.01). Milrinone and amrinone administered preemptively reduce postoperative deterioration in cardiac function and oxygen transport, dopamine requirement, and increases in serum lactate, glucose, and enzyme levels, although milrinone may increase heart rate. IMPLICATIONS: Preemptive milrinone or amrinone administration before separation from cardiopulmonary bypass in cardiac surgical patients not only ameliorates postoperative deterioration in cardiac function and oxygen transport, but also reduces dopamine requirement and increases serum lactate, glucose, and cellular enzyme levels, although milrinone may increase heart rate.

Aged↗

Pharmacokinetics of intravenous milrinone in patients undergoing cardiac surgery.

BACKGROUND: Milrinone is a phosphodiesterase inhibitor with positive inotropic and vasodilator effects that are useful in the treatment of ventricular dysfunction after cardiac surgery. However, the pharmacokinetics of the drug have been investigated only in healthy volunteers and in patients with chronic congestive heart failure. This study investigates the pharmacokinetics of milrinone in adult cardiac surgical patients after cardiopulmonary bypass. METHODS: Milrinone was administered to 25 patients just before or immediately after separation from cardiopulmonary bypass. Arterial blood was sampled over the next 16 h and milrinone plasma concentrations were determined by high-performance liquid chromatography. Data were analyzed by extended nonlinear least-squares regression. The relation between milrinone plasma concentration and hemodynamic effect was examined in an additional 11 patients who had cardiac indices less than 2.5 l.min-1.m-2 immediately after separation from cardiopulmonary bypass. Milrinone was administered and plasma concentrations were related to changes in cardiac index during the next 10 min. RESULTS: A milrinone dose of 50 micrograms/kg in conjunction with an infusion of 0.5 micrograms.kg-1.min-1 consistently maintained plasma concentrations in excess of 100 ng/ml. A triexponential equation describing the plasma concentration as a function of time was used to describe the data. Central-compartment volume was 102 ml/kg, volume of distribution was 1,698 ml/kg, and elimination clearance was 1.88 ml.kg-1.min-1. Pharmacokinetic parameters were independent of dose. The relation between plasma concentration and percentage increase in cardiac index could be described by a sigmoidal curve with the plasma concentration associated with a 50% increase in cardiac index equal to 167 ng/ml. CONCLUSIONS: A milrinone dose of 50 micrograms/kg with an infusion at 0.5 micrograms.kg-1.min-1 maintains plasma concentrations at or above the threshold of therapeutic effects.

Aged↗

Influence of acidosis on cardiotonic effects of milrinone.

BACKGROUND: The present study was designed to determine whether augmentation of cardiac performance by milrinone is affected by acidosis in in vivo canine and in vitro guinea pig preparations, and to elucidate a mechanism in relation to the cyclic adenosine monophosphate (cAMP) formation. METHODS: Halothane-anesthetized, ventilated dogs were randomly assigned to a control group (arterial pH [pHa] approximately 7.4, base excess [BE] > -2 mM; n = 7), mild acidosis group (pHa approximately 7.2, BE < -9 mM; n = 7); or severe acidosis group (pHa < 7, BE < -20 mM; n = 6). Arterial blood pressure, left ventricular pressure (including maximum rate of increase, LV dP/dtmax), and pulmonary blood flow (PBF) were measured. Acidosis was induced by transient hypoxia and maintained with hydrogen chloride infusion. Hemodynamic responses to milrinone infusions at 2 and 5 microg x kg(-1) x min(-1) were then studied. In addition, left atria and right ventricular strips were dissected from guinea pig hearts and suspended in HEPES-Tyrode solution, with pH values adjusted to 7.4, 7, or 6.6. The concentration-response relation of isometric contractions for milrinone (10(-7) to 10(-4) M) and 8-bromo-cAMP (10(-4) to 10(-3) M) were determined. RESULTS: In the control group of dogs, significant increases in LV dP/dtmax (2,674 +/- 822 to 3,999 +/- 1,016 mmHg/s [means +/- SD]) and PBF (2.04 +/- 0.98 to 2.44 +/- 0.96 l/min [means +/- SD]) were seen with a milrinone infusion of 5 microg x kg(-1) x min(-1). In the mild acidosis group, 5 microg x kg(-1) x min(-1) milrinone also increased LV dP/dtmax and PBF. However, neither LV dP/dtmax nor PBF changed in the severe acidosis group. In in vitro experiments, milrinone exerted a positive inotropic effect in a concentration-dependent manner on the right ventricular preparations at pH 7.4, but not at pH 7 and 6.6, whereas no significant difference was observed in inotropic responses to 8-bromo-cAMP at pH values of 6.6, 7, and 7.4 on the right ventricular strips. In the right ventricular in vitro preparation, 10(-4) M milrinone was accompanied by a significant increase in intracellular cAMP content at apH of 7.4 but not 7. CONCLUSIONS: These results indicate that the inotropic effect of milrinone is attenuated by acidosis due, at least in part, to decreased cAMP formation in acidotic muscle.

8-Bromo Cyclic Adenosine Monophosphate↗

Characterization of the cardiotonic effects of milrinone, a new and potent cardiac bipyridine, on isolated tissues from several animal species.

The cardiotonic activity of milrinone (Win 47203), a potent analogue of amrinone, was demonstrated in isolated guinea pig, cat, rabbit, rat, and hamster atria and papillary muscles. Milrinone, in concentrations of 0.1-300 micrograms/ml, caused concentration-dependent increases in guinea pig papillary muscle and atrial developed tension with minimal increases in atrial rate. Compared with the in vitro inotropic activity of amrinone, milrinone was approximately 30 times more potent. The inotropic and chronotropic effects of milrinone do not appear to be mediated by the release of endogenous norepinephrine, by the direct stimulation of beta-adrenergic or histaminergic receptors, or through the stimulation of prostaglandin synthesis. The inotropic response of the guinea pig papillary muscles to isoproterenol was potentiated when isoproterenol was given at the peak effect of a minimally effective concentration of milrinone or after prolonged incubation with milrinone. No potentiation was observed when isoproterenol was administered at the peak effect of a high concentration of milrinone, which suggests that the positive inotropic action of milrinone may not be solely attributable to cyclic AMP phosphodiesterase inhibition.

Aminopyridines↗

Comparison of the effects of cilostazol and milrinone on intracellular cAMP levels and cellular function in platelets and cardiac cells.

Cilostazol is a potent cyclic nucleotide phosphodiesterase (PDE) type 3 (PDE3) inhibitor that was recently approved by the Food and Drug Administration (FDA) for the treatment of intermittent claudication. Its efficacy is presumed to be due to its vasodilatory and platelet activation inhibitory activities. Compared with those treated with placebo, patients treated with cilostazol showed a minimal increase in cardiac adverse events. Because of its PDE3 inhibitory activity, however, the possibility that cilostazol exerts positive cardiac inotropic effects is a safety concern. Therefore we compared the effects of cilostazol with those of milrinone, a selective PDE3 inhibitor, on intracellular cyclic adenosine monophosphate (cAMP) levels in platelets, cardiac ventricular myocytes, and coronary smooth muscle cells. We also compared the corresponding functional changes in these cells. Cilostazol and milrinone both caused a concentration-dependent increase in the cAMP level in rabbit and human platelets with similar potency. Furthermore, cilostazol and milrinone were equally effective in inhibiting human platelet aggregation with a median inhibitory concentration (IC50) of 0.9 and 2 microM, respectively. In rabbit ventricular myocytes, however, cilostazol elevated cAMP levels to a significantly lesser extent (p < 0.05 vs. milrinone). By using isolated rabbit hearts with a Langendorff preparation, we showed that milrinone is a very potent cardiotonic agent; it concentration-dependently increased left ventricular developed pressure (LVDP) and contractility. Cilostazol was less effective in increasing LVDP and contractility (p < 0.05 vs. milrinone), which is consistent with the cardiac cAMP levels. The cardiac effect of OPC-13015, a metabolite of cilostazol with about sevenfold higher PDE3 inhibition, was similar to cilostazol. Whereas milrinone concentration-dependently increased cAMP in rabbit coronary smooth muscle cells, cilostazol did not have such an effect. However, both compounds increased coronary flow equally in rabbit hearts. Our results show that although cilostazol and milrinone both inhibit PDE3, cilostazol preferentially acts on vascular elements (platelets and flow). This unique profile of cilostazol is consistent with its beneficial and safe clinical outcomes in patients with intermittent claudication.

Animals↗

Milrinone improves arterial oxygenation in dogs with acute lung injury induced by oleic acid.

The aim of the study was to investigate effects of milrinone on pulmonary permeability in dogs with acute lung injury induced by oleic acid. To induce acute lung injury, we administered 0.08 mg/kg of oleic acid to 19 adult mongrel dogs and then measured hemodynamic parameters and performed blood gas analysis. An injection of oleic acid depressed the mean arterial pressure, cardiac index, and arterial oxygenation. Dogs were divided into three groups: six received a bolus of milrinone (50 microg/kg) followed by a continuous (0.5 microg/kg/min, low-dose), seven received a bolus (100 microg/kg) followed by a continuous (1.0 microg/kg/min; i.e., a low-dose twice; high-dose), and six no milrinone (control). Milrinone administration improved the cardiac index and arterial oxygenation and simultaneously depressed the intrapulmonary shunt fraction and the extravascular thermal lung water as extravascular water content of the lung. These changes produced by milrinone are different according to the doses. In conclusion, milrinone acts on the capillary endothelium and inhibits an accumulation in the extravascular water content of the lung, which may induce an improvement in arterial oxygenation. Milrinone may also improve arterial oxygenation through an inhibition of platelet aggregation and chemical mediators that are released from platelets. The latter mechanism also may improve arterial oxygenation, and the exact property responsible for causing the effect of milrinone has not yet been identified.

Animals↗

Population pharmacokinetics and dosing regimen design of milrinone in preterm infants.

AIMS: To define the pharmacokinetics of milrinone in very preterm infants and determine an optimal dose regimen to prevent low systemic blood flow in the first 12 h after birth. METHODS: A prospective open-labelled, dose-escalation pharmacokinetic study was undertaken in two stages. In stage one, infants received milrinone at 0.25 microg/kg/min (n = 8) and 0.5 microg/kg/min (n = 11) infused from 3 to 24 h of age. Infants contributed 4-5 blood samples for concentration-time data which were analysed using a population modelling approach. A simulation study was used to explore the optimal dosing regimen to achieve target milrinone concentrations (180-300 ng/ml). This milrinone regimen was evaluated in stage two (n = 10). RESULTS: Infants (n = 29) born before 29 weeks gestation were enrolled. Milrinone pharmacokinetics were described using a one-compartment model with first-order elimination rate, with a population mean clearance (CV%) of 35 ml/h (24%) and volume of distribution of 512 ml (21%) and estimated half-life of 10 h. The 0.25 and 0.5 microg/kg/min dosage regimens did not achieve optimal milrinone concentration-time profiles to prevent early low systemic blood flow. Simulation studies predicted a loading infusion (0.75 microg/kg/min for 3 h) followed by maintenance infusion (0.2 microg/kg/min until 18 h of age) would provide an optimal milrinone concentration profile. This was confirmed in stage two of the study. CONCLUSION: Population pharmacokinetic modelling in the preterm infant has established an optimal dose regimen for milrinone that increases the likelihood of achieving therapeutic aims and highlights the importance of pharmacokinetic studies in neonatal clinical pharmacology.

Cardiovascular Diseases↗

Effect of milrinone on left ventricular relaxation and Ca(2+) uptake function of cardiac sarcoplasmic reticulum.

Milrinone, a phosphodiesterase 3 (PDE3) inhibitor, is known to enhance left ventricular (LV) contractility by an inhibition of the breakdown of cAMP through the mechanism inhibiting PDE3. However, it is unclear whether milrinone also exerts positive lusitropy, like dobutamine. Here, we assessed the effects of milrinone on in vivo LV relaxation, as well as the Ca(2+)-ATPase activity and the Ca(2+) uptake function of the cardiac sarcoplasmic reticulum (SR), compared with the effect of dobutamine on those functions. After dobutamine (3 microg x kg(-1) x min(-1)) was administered, the peak value of the first derivative of LV pressure (+dP/dt) increased by 46%, whereas the time constant (tau) of LV pressure decay decreased by 6.9%, respectively. After milrinone (10 microg/kg) was administered, the peak +dP/dt increased to a similar extent as dobutamine (46%), whereas tau decreased much more than dobutamine (19.9%; P < 0.05). In LV crude homogenate, the thapsigargin-sensitive, Ca(2+)-ATPase activity-cAMP relationships was significantly less increased by milrinone compared with dobutamine (P < 0.05), indicating the higher sensitivity of the SR Ca(2+)-ATPase activity on cAMP by milrinone than by dobutamine. In the SR vesicles purified from LV muscles, the addition of cAMP increased the SR Ca(2+) uptake in a dose-dependent fashion, and the PDE3 inhibitors (milrinone and cGMP) significantly augmented this response (P < 0.05). Hence, milrinone substantially improved LV relaxation in association with an acceleration of the SR Ca(2+)-ATPase activity and the SR Ca(2+) uptake. This acceleration might be due to an inhibition of the membrane-bound PDE3 in the SR, leading to a local elevation of cAMP.

Adrenergic beta-Agonists↗

Cardiotonic agent milrinone stimulates resorption in rodent bone organ culture.

The cardiotonic agent amrinone inhibits bone resorption in vitro. Milrinone, an amrinone analog, is a more potent cardiotonic agent with lower toxicity. In contrast to amrinone, milrinone stimulated resorption in cultures of neonatal mouse calvaria and fetal rat limb bones. Threshold doses were 0.1 microM in calvaria and 0.1 mM in limb bones; maximal stimulation occurred in calvaria at 0.1 mM. Maximal responses to milrinone and parathyroid hormone were comparable. Milrinone concentrations below 0.1 mM did not affect calvarial cyclic AMP. 0.5 microM indomethacin inhibited milrinone effects in calvaria but usually not in limb bones. 3 nM calcitonin inhibited milrinone-stimulated resorption and there was no escape from this inhibition. Structural homology between milrinone and thyroxine has been reported. We find similarities between milrinone and thyroxine actions on bone, because prostaglandin production was crucial for the effects of both agents in calvaria but not in limb bones, and neither agent exhibited escape from calcitonin inhibition.

Animals↗

Enhanced vasodilatory responses to milrinone in catecholamine-precontracted small pulmonary arteries.

UNLABELLED: Beta-adrenergic agonists (e.g., epinephrine [E] and norepinephrine [NE]) and phosphodiesterase-III inhibitors (e.g., milrinone) are often used in combination to augment ventricular function in the perioperative period. In the myocardium, milrinone acts synergistically with beta-adrenergic agonists to increase contractility. However, the potential interaction between catecholamines with combined alpha- and beta-adrenergic activity and milrinone in the pulmonary circulation has not been determined. We evaluated the vasodilatory effects of milrinone and nitroglycerine on large elastic and small muscular porcine pulmonary vascular rings precontracted with catecholamines with beta-adrenergic agonist activity (E and NE), the alpha-adrenergic agonist phenylephrine, and a nonadrenergic agonist, the thromboxane analog U46619. In small pulmonary arteries, the vasorelaxation with milrinone was significantly enhanced in rings precontracted with E or NE compared with those precontracted with phenylephrine or U46619. However, in large pulmonary arteries, the vasorelaxation with milrinone was similar in all vessel rings and was not influenced by the agonist used to induce precontraction. In marked contrast, the vasorelaxant responses to nitroglycerine were not altered by the specific agonist used for precontraction in either small or large pulmonary vascular rings. Thus, the pulmonary vascular effects of milrinone are enhanced when combined with drugs with beta-adrenoreceptor agonist activity. The vasodilatory interactions exhibited by phosphodiesterase-III inhibitors and the catecholamines NE and E suggest that their combined use might be beneficial in circumstances in which ventricular dysfunction and increased pulmonary vascular resistance occur. IMPLICATIONS: This study demonstrated that milrinone had enhanced vasodilator effects when combined with drugs with beta-adrenoreceptor agonist activity in small pulmonary artery segments removed from pigs.

Animals↗

The effect of milrinone on the right ventricular function in patients with reduced right ventricular function undergoing off-pump coronary artery bypass graft surgery.

This investigation evaluated the effect of continuous milrinone infusion on right ventricular (RV) function during off-pump coronary artery bypass graft (OPCAB) surgery in patients with reduced RV function. Fifty patients scheduled for OPCAB, with thermodilution RV ejection fraction (RVEF) <35% after anesthesia induction, were randomly allocated to either milrinone (0.5 microg/kg/min) or control (saline) group. Hemodynamic variables and RV volumetric data measured by thermodilution method were collected as follows: after anesthesia induction (T1); 10 min after heart displacement for obtuse marginal artery anastomosis (T2); after pericardial closure (T3). Cardiac index and heart rate increased and systemic vascular resistance significantly decreased in milrinone group at T2. Initially lower RVEF of milrinone group was eventually comparable to control group after milrinone infusion. RVEF did not significantly change at T2 and T3 in both groups. RV end-diastolic volume in milrinone group consistently decreased from the baseline at T2 and T3. Continuous infusion of milrinone without a bolus demonstrated potentially beneficial effect on cardiac output and RV afterload in patients with reduced RV function during OPCAB. However, aggressive augmentation of intravascular volume seems to be necessary to maximize the effect of the milrinone in these patients.

Aged↗

[Effective milrinone therapy to a Duchenne muscular dystrophy patient with advanced congestive heart failure].

We experienced a Duchenne muscular dystrophy (DMD) patient with severe congestive heart failure (CHF) successfully treated with milrinone. He had been diagnosed as having CHF since 24 years of age when he began to have mechanical ventilation with a nasal mask at home. Although angiotensin converting enzyme (ACE) inhibitor was effective for his CHF, cardiac function worsened year by year. Respiratory infection triggered the exacerbation of CHF at the end of 1997 (27 years old). On admission to our hospital on January 7, 1998, PaO2 was 48 mmHg and cardiothoracic ratio (CTR) was 62%. Both ventricles were dilated and ventricular wall motility was markedly reduced on ultrasonocardiography. Ejection fraction of the left ventricle (LVEF) was 5%. Serum brain natriuretic peptide (BNP) was 760 pg/ml. Continuous intravenous infusion of milrinone was started on January 8 at the rate of 0.25-0.35 microgram/kg/min. His general condition improved and LVEF increased up to 15% on January 27. No serious side effects were observed. Even after milrinone withdrawal, his cardiac condition remained stable until the end of February 1998. Temporary deteriorated CHF due to urinary tract infection was successfully treated by chemotherapy and milrinone. Subsequently he was discharged on March 13 and could stay in his home for 7 weeks uneventfully with milrinone infusion therapy. When he was readmitted to the hospital for evaluation of CHF on April 30, CTR was 44%, LVEF was 20% and BNP was 44 pg/ml. CHF is one of the life threatening complications for DMD. Although catecholamine is a well utilized agent for advanced CHF, it has limited effect in DMD, because beta receptors are down-regulated due to long-lasting cardiac dysfunction. Increased heart rate and arrhytmia are also serious problems during catecholamine therapy. Milrinone is a type III phosphodiesterase inhibitor having inotropic and vasodilatic actions with modest increase of heart rate and little torelance. Milrinone is probably effective in improving CHF of DMD and has less side effects as compared to catecholamine. We concluded that milrinone might improve quality of lives of DMD patients with advanced CHF, although further cumultative studies are necessary to confirm its effectiveness and safety.

Adult↗

Slow induction of milrinone after coronary artery bypass grafting.

The aim of this study was to evaluate the hemodynamic effects of a slow induction of milrinone after open heart surgery. Twenty patients who underwent elective coronary artery bypass grafting were randomized into two groups, with 10 patients receiving a continuous infusion of milrinone (5 microg/kg/min) (group M), and 10 patients undergoing treatment without milrinone (group C). This is a preliminary study for evaluating the efficacy of a slow induction of milrinone, so patients in low cardiac output state were excluded. A continuous infusion without an initial loading dose was initiated in the intensive care unit. Hemodynamic parameters and the concentration of milrinone were measured 90 minutes and 3 hours after initiation of the milrinone infusion. A significant decrease in arterial pressure occurred at 3 hours in group M, and both the systemic vascular resistant indices decreased significantly (p<0.05) at 90 minutes. No significant changes occurred in group C. Cardiac index and heart rate increased significantly (p<0.05) in group M, but were unchanged in group C. No significant change in double product was observed in either group. Hypotension (systolic blood pressure less than 100 mmHg) or arrhythmia did not occur in group M. The concentration of milrinone at 90 minutes and 3 hours was 97+/-22 and 124+/-27 ng/ml, respectively. A slow induction of milrinone is safe and effective in patients following cardiac surgery.

Aged↗