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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Venodilatation may be an important property in drugs used to treat heart failure. Deductions about venous tone from standard hemodynamic studies may be misleading since filling pressures may be reduced by improved left ventricular function. To study the venodilator properties of drugs, we have modified a radionuclide blood pool method and shown that venous volume is increased by 10% after glyceryl trinitrate but is unchanged after the arteriolar dilator hydralazine. In patients with congestive cardiac failure, the calcium channel blocker, felodipine, causes a marked reduction in systemic vascular resistance and left ventricular filling pressures, but venous volume remains unchanged. In a similar group of patients comparable arterial and central effects are seen after the administration of captopril, but venous volume increases by 16%, and this increased venous volume is sustained after 3 months of long-term treatment. Milrinone has been used to treat both acute and chronic heart failure. As expected of a phosphodiesterase inhibitor, it exhibits inotropic properties in animals and humans and also causes arterial vasodilatation. We have studied its effects on venous tone in 10 patients with severe heart failure (New York Heart Association classes III to IV). Milrinone was given intravenously at a loading dose of 50 micrograms/kg followed by an infusion of 0.5 micrograms/kg/min. After treatment, cardiac index, which was measured by thermodilution, increased from 1.8 +/- 0.48 to 2.3 +/- 0.65 L/min/m2 (p less than 0.001); pulmonary artery wedge pressure fell from 23 +/- 6 to 11 +/- 5 mm Hg (p less than 0.001); and systemic vascular resistance index decreased from 4296 to 3168 dynes.sec.cm-5/m2 (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of venous tone in heart failure. 203 25

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

Milrinone and enalapril, which inhibit PDE-III and ACE, respectively, are able to prolong survival of myocardially infarcted (MI) rats. This study sought to identify oral hemodynamic effects of these agents which could underlie such efficacy in this heart failure model. Four weeks after ligation of the left main coronary artery, basal left ventricular (LV) systolic pressure and dP/dtmax, heart rate and mean blood pressure of the MI rats were significantly less than that of sham-operated controls, and LV end-diastolic pressure (LVEDP) was markedly elevated. Milrinone, at 2.0 mg/kg, reduced LVEDP and renal blood flow of these 4-week MI rats by an average of 39 and 18%, respectively (P less than 0.05) within 1 h. At 4.0 mg/kg, it reduced LVEDP by 46% and raised heart rate by 16% (P less than 0.05). Enalapril (1.0 mg/kg) increased small intestine blood flow of these compromised rats by 16% (P less than 0.05), and tended to reduce LVEDP (-28%) within 1.5 h. Treatment with milrinone (2.0 mg/kg) plus enalapril (1.0 mg/kg) promoted LV dP/dtmax, coronary blood flow, and heart rate by 48, 40 and 13%, and reduced LVEDP by 40% (P less than 0.05 for all effects). Thus these agents can reduce LVEDP and redistribute cardiac output of MI rats. Furthermore, the combination of enalapril and milrinone can restore LVEDP and LV dP/dtmax of MI rats to near normal and promote coronary blood flow without compromising cardiac output or renal blood flow. Such effects, it timely or sustained, may prolong survival.
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PMID:Beneficial hemodynamic effects of milrinone and enalapril in conscious rats with healed myocardial infarction. 255 83

Prognosis of heart failure patients remains poor and stimulates research of new active drugs and therapeutic improvements. Besides diuretic and vasodilating agents, the place of positive inotropic drugs remains to be defined. Long term benefit remains to be demonstrated for Milrinone, Enoximone and Digitalis. However, absence of benefit has been established with Amrinone and beta adrenoceptor agonists. Too many uncontrolled studies have complicated the accurate evaluation of efficacy of these positive inotropic drugs. Purpose of heart failure treatment remains to improve functional status without deterioration of myocardial fibers contractility. The respective roles of cAMP, gAMP and intracellular calcium concerning myocardial fiber longevity remains to be clarified.
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PMID:[Treatment of chronic heart failure with positive inotropic agents]. 257 55

Controlled and uncontrolled hemodynamic and clinical studies have noted that the long-term treatment of patients with chronic heart failure with phosphodiesterase (PDE) inhibitors, such as amrinone, milrinone, enoximone and imazodan, may accelerate progression of the underlying disease and provoke serious ventricular arrhythmias. However, in an experimental model of chronic progressive left ventricular dysfunction, milrinone has been reported to reduce mortality to a degree comparable to that seen with the converting-enzyme inhibitors. These discordant observations suggest that either the deleterious hemodynamic and electrophysiologic effects of the PDE inhibitors are not translated into an adverse effect on mortality, or the animal model used to evaluate the effects of milrinone cannot be used to investigate the action of these drugs in human heart failure. Unfortunately, no trial has prospectively evaluated the effect of PDE inhibition on the survival of patients with heart failure. To address this need, the Prospective Randomized Milrinone Survival Evaluation (PROMISE Trial) has been launched in 75 to 90 clinical research centers in the United States and Canada. This study will enroll 750 patients with severe (class IV) heart failure, who have symptoms refractory to conventional therapy with digitalis, diuretics, converting-enzyme inhibitor and direct-acting vasodilators. Patients will be randomly assigned to additional treatment with either oral milrinone or placebo, and followed until death or to the conclusion of the study. The primary end point will be all-cause mortality, but the effect of milrinone on functional capacity will also be evaluated. The results of the study should define the place of PDE inhibitors in the treatment of chronic heart failure.
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PMID:Effect of phosphodiesterase inhibitors on survival of patients with chronic congestive heart failure. 264 29

Milrinone exerts positive inotropic and dose-dependent vasodilatory effects that promote haemodynamic improvement after intravenous administration to patients with heart failure. Bolus doses of 12.5-75 micrograms kg-1 markedly increase cardiac output and cause a substantial reduction in cardiac filling pressure and in systemic vascular and pulmonary vascular resistance. There is no evidence of tolerance to these effects which are maintained during continuous infusion for up to 48 h. In contrast, there are minimal effects on heart rate or systemic blood pressure, except at very high doses. At lower filling pressures, milrinone increases cardiac output more markedly than equally hypotensive doses of pure vasodilators. This response is accompanied by an increased left ventricular dP/dtmax and a shift in the left ventricular performance is associated with a lower myocardial energy requirement. Despite a fall in mean arterial pressure and transcoronary driving pressure, coronary venous flow is increased and there is a reduction in the arterio-coronary venous oxygen difference. This reflects a global improvement in left ventricular diastolic function, characterized by accelerated early relaxation and greater chamber distensibility. Improved performance of the right ventricle is due primarily to reduced right ventricular afterload as milrinone produces minimal inotropic effects on the right ventricle.
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PMID:Acute effects of intravenous milrinone in heart failure. 268 Apr 96

Clinical evaluation of oral milrinone in moderate to severe heart failure has demonstrated pronounced beneficial effects. These effects are achieved through increased cardiac index and exercise tolerance, and reduced ventricular filling pressure and systemic vascular resistance. In a double-blind, multicentre study of 230 patients with moderate to severe failure receiving diuretic therapy, treatment with milrinone or digoxin significantly improved exercise capacity. No additional benefit was obtained using combined treatment with the two drugs. A sub-study of 60 patients showed that milrinone produced a significantly higher peak oxygen consumption during treadmill exercise compared with placebo, and approached a significant improvement over digoxin. Milrinone and digoxin favourably influenced symptoms and quality of life measures, but NYHA class was unaltered. Both treatments were well tolerated, alone or combined. A similar study of 155 patients showed comparable results, with no evidence of tolerance development during chronic (3-month) treatment. Survival during the 3-month studies showed a strong correlation with baseline resting left ventricular ejection fraction and was independent of treatment. Neither treatment adversely affected survival. These studies show that milrinone is a well-tolerated and effective oral agent that provides clinical benefits beyond those obtained with diuretics alone in moderate to severe heart failure.
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PMID:Clinical results with oral milrinone in heart failure. 268 Apr 97


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