[Effects of amrinone on the Ca(2+)-related functions of skinned skeletal muscle fibers of guinea pigs].

In malignant hyperthermia (MH) patients, the rate of Ca(2+)-induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR) has been reported to be enhanced. The effects of amrinone on the Ca(2+)-related functions (CICR, Ca2+ uptake by the SR and Ca2+ sensitivity of the contractile system) of the skeletal muscle were examined using the chemically skinned fiber technique in the extensor digitorum longus of guinea pigs. Amrinone enhanced the CICR rate in a dose-dependent manner, but not around its clinical concentrations. Ca2+ uptake, initial rate of Ca2+ uptake by the SR and Ca2+ sensitivity of the contractile system were not affected at 1 mM of amrinone. These results suggest that amrinone may be clinically safe to use in MH susceptible patients.

Comparative effects of dobutamine and amrinone on coronary blood flow in patients with idiopathic dilated cardiomyopathy.

Although amrinone has favorable hemodynamic effects in patients with congestive heart failure, little is known about its effects on coronary blood flow (CBF). We compared the effects of intravenous low-dose dobutamine and amrinone on CBF in 10 patients with dilated cardiomyopathy using a Doppler guidewire. We infused dobutamine at a dose of 5 and 10 microg/kg/min for 5 min. After the end of each stage, coronary flow velocity (CFV) and coronary arterial diameter (CAD) in the proximal left anterior descending coronary artery, and hemodynamic variables were obtained. After the CFV and hemodynamics returned to baseline, we infused 1 mg/kg of amrinone over 5 min, and obtained these variables at 5 and 10 min after the cessation of the infusion. CAD did not increase with dobutamine, but significantly increased after amrinone (% increase: 10 +/- 7%; P < 0.001 vs. baseline). CFV progressively increased with dobutamine (5 microg/kg/min: 21 +/- 26%; P < 0.05 vs. baseline; 10 microg/kg/min: 53 +/- 42%; P < 0.005 vs. baseline and 5 microg/kg/min), but slightly decreased after amrinone (-4 +/- 17%; P = not significant vs. baseline). CBF increased during dobutamine (5 microg/kg/min: 25 +/- 29%; P < 0.05; 10 microg/kg/min: 66 +/- 55%; P < 0.005) and after amrinone (19 +/- 22%; P < 0.05) compared to that at baseline. Although there was a significant correlation between the percent increase in CFV and that in dP/dt during dobutamine infusion (r = 0.82, P < 0.001), this correlation was not observed after amrinone (r = 0.23). In conclusion, although both agents significantly increased CBF in patients with dilated cardiomyopathy, they do so by different mechanisms. Amrinone mainly increases CBF by causing dilatation of epicardial coronary arteries. These results suggest that amrinone has beneficial effects on coronary flow dynamics in dilated cardiomyopathy.

Anterior ischemic optic neuropathy after open heart operations.

BACKGROUND: The overall incidence of anterior ischemic optic neuropathy after open heart operations at the Lahey Clinic is less than 0.5%. However, during the 2-year period, March 1, 1990, to March 1, 1992, an increased incidence (8 of 602 patients or 1.3%) of this complication was observed. METHODS: A rigorous analysis was conducted of all 602 patients who underwent operation during this period. RESULTS: No preoperative risk factors were identified. The development of anterior ischemic optic neuropathy was associated with prolonged cardiopulmonary bypass time, low hematocrit levels, excessive perioperative body weight gain, and the use of epinephrine and amrinone. Other hypothetical risk factors include systemic hypothermia, anemia, increased intraocular pressure, and microembolization. Treatment options include the use of corticosteroid medications, reduction of intraocular pressure, and optic nerve fenestration, although recent evidence and our experience indicate that the fenestration procedure is of no benefit. CONCLUSIONS: Because all methods of treatment have had limited success, efforts to prevent this complication are of paramount importance.

Electrophysiologic and proarrhythmic effects of intravenous inotropic agents.

Intravenous inotropic agents promote increased myocardial contractility via elevation of myocyte calcium concentrations, a mechanism that is also known to promote the development of cardiac arrhythmias. The purpose of this article is to review the electrophysiologic effects and relative potential for proarrhythmia associated with dobutamine, dopamine, and the phosphodiesterase inhibitors amrinone and milrinone. Dobutamine increases sinoatrial node automaticity and decreases atrial and atrioventricular (AV) node refractoriness and AV nodal conduction time. The drug also decreases ventricular refractoriness in both healthy and ischemic myocardium. Dobutamine has been shown to increase heart rate in a dose-related fashion in animals and in humans. In humans, dobutamine has been reported to induce ventricular ectopic activity (VEA) in 3% to 15% of patients, although VEAs are often asymptomatic, requiring no intervention. Ventricular tachycardia (VT) associated with dobutamine appears to occur rarely. Patients with underlying arrhythmias or heart failure or those receiving excessive doses of dobutamine are at greatest risk for proarrhythmia. Dopamine increases automaticity in Purkinje fibers and has a biphasic effect on action potential duration. Dopamine has been reported to induce atrial or ventricular arrhythmias in animals. In humans, dopamine may be associated with dose-related sinus tachycardia but has also been reported to cause VEA, which is usually asymptomatic. Dopamine-associated VT appears to occur rarely. Dopamine produces greater elevations in heart rate or frequency of ventricular premature beats at a given value of cardiac index than does dobutamine. The phosphodiesterase inhibitors amrinone and milrinone increase conduction through the AV node and decrease atrial refractoriness. Intravenous administration of these drugs may result in sinus tachycardia in some patients and has been reported to cause VEA, which is often asymptomatic, in up to 17% of patients. VT has also been reported in association with short-term use of intravenous phosphodiesterase inhibitors. In summary, intravenous inotropic agents may be associated with proarrhythmic effects in some patients. The primary arrhythmias reported are sinus tachycardia and VEA, although other supraventricular or ventricular arrhythmias have been reported less commonly. However, clinically significant proarrhythmic effects associated with these agents appear to occur rarely, and, at conventional doses, intravenous inotropic agents are relatively safe with respect to proarrhythmic effects.

[Concept for therapy of heart failure in heart surgery]. / Konzept zur Therapie der Herzinsuffizienz in der Herzchirurgie.

Perioperative deterioration of the circulatory performance of patients undergoing heart surgery ranges from transitory impairment in cardiac output by deterioration of the compensation range of the oxygen transport system to manifest circulatory failure without previous myocardial damage and the acute decompensation of pre-existing chronic heart failure. On the basis of the current state of knowledge in this field, a concept for rational staged treatment should be based on the different myocardial beta-adrenoceptor conditions related to the type and stage of the individual underlying heart disease and on adrenoceptor subtype specific properties of positive inotropic drugs. 1. The therapy of perioperative "circulatory" insufficiency after extra-corporal circulation consists of the use of drugs to adapt the performance of the oxygen transport system to increased overall oxygen demand. Simultaneous volume loading (by CVP) and positive inotropic support with dobutamine are the best means of treating this (normally transitory) dysregulation. 2. In the case of manifest severe circulatory insufficiency (low cardiac output syndrome), sepsis or acute heart failure (e.g., following acute myocardial infarction), the use of a pulmonary artery catheter for determining perioperative cardiac output and resistance is essential. In such cases, positive inotropic therapy is based on catecholamines of medium (dobutamine) to high (adrenaline) efficacy, because it can be assumed that the beta-adrenoceptor pattern will remain normal with regular functioning and regulation of the (remaining) myocardium up to the onset of acute heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of amrinone and colloid administration in children following cardiac surgery.

Amrinone was used as the sole vasoactive medication in 9 of 14 children (aged 5 months to 8.25 years) given the drug following open repair of congenital cardiac lesions. Four children received a concomitant dopamine infusion and one infant had the infusion stopped after 5 hours for low mean arterial pressure (49 mmHg). In the 10 children receiving only amrinone, cardiac index increased 21% (range, 0 to 94%) after a total loading dose of 4.5 mg/kg given over 1 hour. Four of 14 patients (29%) required dopamine infusions to maintain mean arterial pressure over 55 mmHg and in these children cardiac index increased from baseline and was maintained during the amrinone infusion. Preload was held constant by administration of whole blood or plasmanate during amrinone loading; a decrease in systemic vascular resistance index was seen resulting in a stable arterial blood pressure. Minimal chronotropic effect was seen and no arrhythmias occurred. The sole child with postoperative pulmonary hypertension had a beneficial decrease in pulmonary artery pressure, increase in cardiac index, and stable systemic blood pressure during amrinone use. Cardiac index changes during amrinone loading in these children were variable and less clearly related to serum levels than reported in adults. Pharmacokinetic analysis in 12 children showed a clearance of 3.4 mL/min/kg, a volume of distribution of 1.65 L/kg, and an elimination half-life of 5.75 hours. Decreases in platelet counts were seen in 6 children and platelet transfusion was needed in 1; thus, serial platelet counts should be monitored.(ABSTRACT TRUNCATED AT 250 WORDS)

Amrinone-associated thrombocytopenia: pharmacokinetic analysis.

Amrinone-associated thrombocytopenia is thought to result from nonimmune-mediated peripheral platelet destruction. Platelet destruction may be a concentration-dependent toxic effect of amrinone or its principal metabolite N-acetylamrinone. Eighteen children receiving amrinone after heart surgery were prospectively evaluated to correlate the pharmacokinetics of amrinone and N-acetylamrinone with thrombocytopenia. Amrinone and N-acetylamrinone plasma concentrations were determined by HPLC during loading, infusion, and terminal elimination, with concurrent monitoring of platelet counts. Thrombocytopenia developed in eight patients (platelet count, 66 +/- 17 x 10(9) platelets/L [mean +/- SD]). Peak and steady-state amrinone plasma concentration, amrinone total dose, duration of amrinone exposure, and amrinone area under curve (AUC) were similar between patients with and without thrombocytopenia. N-Acetylamrinone peak concentration, steady-state concentration, N-acetylamrinone AUC, and ratio of N-acetylamrinone to amrinone were greater in patients with thrombocytopenia. This association suggests that N-acetylamrinone, and not amrinone, may be the mediator of thrombocytopenia in children receiving amrinone.

Intermittent intravenous amrinone infusion: a potentially cost effective mode of treatment of patients with refractory heart failure.

OBJECTIVE: To describe the experience of 41 New York Heart Association (NYHA) class III and IV heart failure patients treated with intermittent intravenous amrinone infusions in addition to conventional therapy. BACKGROUND: Congestive heart failure is a condition often requiring repeated admission to hospital. Accordingly, a treatment modality which can reduce the number of admissions is desirable and potentially cost-effective. DESIGN: Retrospective analysis of data from hospital and office charts. SETTING: Community hospital with 640 active beds. INTERVENTION: The initial amrinone infusion was administered in the hospital under electrocardiographic monitoring; subsequent infusions were given in an out-patient unit. A bolus injection of 0.75 mg/kg followed by an infusion of 5 to 10 micrograms/kg/min for 8 to 12 h was administered every two to six weeks as clinically indicated. RESULTS: Results are reported for the first 51 months. Sixty-six per cent of the patients improved their NYHA class, 34% remained unchanged or deteriorated. Survival paralleled that of other studies involving similar patients not receiving nonglycoside positive inotropes. The number of days spent in the hospital in the six months after starting on amrinone compared with the six months before treatment was reduced to 50% (P < 0.05), and the number of hospital admissions in the six months after starting amrinone compared with the six months before decreased to 56% (P < 0.05). CONCLUSIONS: Intermittent intravenous amrinone infusions can be given in an out-patient setting in patients with NYHA class III to IV heart failure. This program is cost-effective, reducing hospital admissions and in-patient hospital days.

Perioperative experience with amrinone.

Amrinone is the only phosphodiesterase fraction III inhibitor currently available in the USA for the treatment of perioperative biventricular failure. Patients with chronic congestive heart failure (CHF) show down-regulation of the beta 1-adrenergic receptor with a decrease in receptor density and altered responses to catecholamines. Intravenous administration of amrinone can transiently restore beta 1-adrenergic responses in patients who have CHF. Amrinone's mechanism of vasodilatation, independent of the beta 1-adrenergic receptor, nitrates, and calcium entry blockers, proves an important therapeutic option for pulmonary hypertension. The elimination half-life of amrinone in volunteers is 2.6-4.1 h, and 3.5 h when administered into the cardiopulmonary bypass (CPB) circuit. Different loading and infusion doses have been reported for amrinone. Investigators have demonstrated that increases in cardiac output following amrinone administration are directly related to plasma concentration. In cardiac surgical patients, following a dose of 0.75 mg kg-1 administered into the CPB circuit, plasma concentrations are subtherapeutic after 10 min. We believe that, when using amrinone to facilitate separation from CPB, a bolus dose of 1.5 mg kg-1 or more should be administered. If therapeutic levels need to be maintained in patients with biventricular failure, an infusion should also be administered after the bolus dose. Additive effects have been demonstrated when catecholamines are administered concomitantly with amrinone and other PDE III inhibitors to increase cyclic AMP in cardiac muscle and improve contractility. The use of amrinone with catecholamines is also important clinically, because together they attenuate the vasoconstrictive effects of catecholamines alone, while the catecholamines support perfusion pressure. Amrinone represents a novel drug for managing biventricular dysfunction in cardiac surgical patients.

Use of intravenous amrinone in the short-term management of refractory heart failure in pregnancy.

The use of amrinone, a cardiac inotropic agent with vasodilatory properties, has not been described in human pregnancy. We report the use of amrinone in a woman at 18 weeks' gestation who had congestive heart failure secondary to bacterial endocarditis. Although her cardiac output and congestive heart failure improved, she developed hypoxemia, metabolic acidosis, and premature ventricular contractions. These effects resolved when the amrinone treatment was stopped.

Inotropic agents. Catecholamines, digoxin, amrinone.

Three broad categories of pharmacologic support that enhance myocardial contractility and modify organ blood flow are reviewed. Appropriate selection among these compounds will minimize the occurrence of adverse effects. The catecholamines increase cardiac work and myocardial oxygen demand. In the setting of a failing ventricle, the increase in oxygen requirement may be balanced by improved coronary blood flow. Problems associated with catecholamines include tachycardia, induction of dysrhythmias, and unsuitable vasoconstriction. Epinephrine and isoproterenol are most likely to increase heart rate excessively. Norepinephrine is most likely to be associated with poor tissue perfusion. Amrinone, a bipyridine, has a favorable effect on oxygen balance in the failing ventricle and is unlikely to produce tachycardia or dysrhythmias. Principal concerns are the potential for accumulation in the patient with multiple organ system failure and the lack of pharmacokinetic information in critically ill patients, including children. Thrombocytopenia may be a problem as well. Digitalis glycosides are venerable drugs. Acute and chronic toxicity are problems that the intensivist is called on to treat frequently. Therapy with digitalis Fab fragments is now routine for severe intoxications and should improve outcome.

Acute positive inotropic intervention: the phosphodiesterase inhibitors.

Phosphodiesterase inhibitors that are selective for cAMP-specific cardiac and vascular PDE III comprise a new group of agents for the treatment of heart failure, which at present are limited to clinical shortterm intravenous use and research uses only. Although both intravenous amrinone and milrinone are FDA approved, only amrinone is available for general clinical use. Selective phosphodiesterase inhibition produces beneficial actions of positive inotropy and peripheral vasodilation that result from increased cardiac and vascular muscle concentrations of intracellular cAMP and ionic calcium. In addition, a positive lusitropic action (enhancement of cardiac relaxation) has been observed. Neither beta-adrenergic agonist activity nor inhibition of the sodium-potassium ATPase is produced by these agents. The magnitude of hemodynamic improvement generally exceeds that of the cardiac glycosides and is comparable with that of intravenous catecholamines such as dobutamine. The different pharmacodynamic profile of the PDE inhibitors is additive to the effects of cardiac glycosides, complementary and synergistic to the actions of catecholamines, and has been shown to have favorable effects on coronary hemodynamics. As a result there is continued enthusiasm for the short-term intravenous use of amrinone and potentially milrinone in the setting of acute heart failure resulting from systolic dysfunction (after myocardial infarction, open heart surgery, or infectious or toxic myocarditis), heart failure resulting from right ventricular systolic dysfunction, and when patients with severe heart failure await cardiac transplantation. Initiation of treatment with an intravenous bolus followed by a maintenance infusion provides prompt increases in stroke volume and cardiac output and simultaneous reductions in right and left ventricular filling pressures and systemic vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

[Hemodynamic and clinical effects and treatment tolerance with low-dose iv amrinone in patients with refractory heart failure: a multicenter study. The Group for Research on Amrinone in the Treatment of Refractory Heart Failure]. / Effetti emodinamici, clinici e tollerabilità del trattamento con amrinone ev a basso dosaggio, in pazienti con insufficienza cardiaca refrattaria: studio policentrico. Gruppo di Ricerca su l'Amrinone nel Trattamento dello Scompenso Cardiaco Refrattario.

We report the results of a multicenter study performed on 70 patients with severe congestive heart failure of different etiology (ischemic, idiopathic, alcoholic, valvular and secondary to antiblastic drugs) to evaluate the clinical and hemodynamic effects and tolerability of low dose amrinone iv (0.75 mg bolus followed by a continuous 48-hour infusion at the dose of 5-10 mcg/kg/min). Forty-one patients underwent invasive hemodynamic monitoring with right heart Swan-Ganz catheterization. Heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP), mean arterial pressure (MAP), cardiac index (CI), stroke volume index (SVI), stroke work index (SWI), right atrial pressure (RAP), pulmonary wedge pressure (PWP), mean arterial pulmonary pressure (PAP), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR) and total pulmonary resistance (TPR) were evaluated before and after 1, 4, 6, 24 and 48 hours of amrinone infusion and 2 and 4 hours after amrinone withdrawal. Clinical parameters (dyspnea, orthopnea, pulmonary congestion) were quantitated using a score; diuresis was assessed hourly; hematochemical parameters were evaluated before and 48 hours after amrinone infusion. HR and MAP were not significantly changed; CI, SVI and SWI presented, respectively, a significant 31.6, 55.1 and 72% increment, which peaked 48 hours after amrinone infusion. Concomitantly RAP, PAP, PWP, SVR, PVR and TPR were significantly reduced to 36.6, 22, 23.6, 9.4, 39.2 and 37.7% of the basal values, respectively. Two and 4 hours after amrinone withdrawal, hemodynamic changes similar to those observed acutely, were still present. Diuresis increased from 58.25 ml/hr to 113.18 ml/hr after 24 hours (+95%) and to 88.9 ml/hr (+53%) after 48 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Pancytopenia secondary to short-term, high-dose intravenous infusion of amrinone.

The incidence of amrinone-induced thrombocytopenia has been reported to be 2.4 percent in patients receiving intravenous therapy. To date there have been no reports of bleeding in these patients nor have there been reports of other hematologic abnormalities secondary to amrinone administration. This case report describes a patient whose hematologic values began to decrease after two days of amrinone therapy, reaching a nadir at day 8. Values returned to baseline eight days after treatment was discontinued. This report provides the first evidence that amrinone may induce pancytopenia in patients who receive short courses of high-dose, continuous-infusion amrinone.

Comparison of intravenous amrinone and dobutamine in congestive heart failure due to idiopathic dilated cardiomyopathy.

A prospective randomized study was performed in 46 consecutive patients with refractory congestive heart failure (CHF) due to idiopathic dilated cardiomyopathy to compare the hemodynamic responses to 48-hour infusions of amrinone and dobutamine. Both drugs substantially reduced pulmonary arterial wedge pressure, right atrial pressure and systemic vascular resistance and increased cardiac index. Amrinone caused a greater decrease in right atrial pressure than dobutamine (p less than 0.02) and had a positive chronotropic effect not observed with dobutamine (p less than 0.01). The increase in heart rate produced by amrinone correlated inversely with the changes in right atrial and pulmonary arterial wedge pressures, suggesting a baroreceptor response to reduced preload. Dobutamine produced a larger increase in stroke volume index than amrinone (p less than 0.01). Ninety-one percent of patients receiving amrinone and only 65% receiving dobutamine had reduction of greater than or equal to 30% in pulmonary arterial wedge pressure (p less than 0.05). Cardiac index increased greater than or equal to 30% in similar numbers of patients given amrinone (74%) and dobutamine (65%). Negative fluid balance was recorded in all patients receiving amrinone and in 78% of patients receiving dobutamine (p less than 0.05). Target hemodynamic criteria were achieved in 83% of patients receiving 10 micrograms/kg/min of amrinone. The effective maintenance dose of dobutamine was extremely variable. No clinically important adverse effects were observed with either drug regimen. Both amrinone and dobutamine are effective and safe agents for short-term parenteral therapy of patients with dilated cardiomyopathy in severe CHF that is unresponsive to oral medication.(ABSTRACT TRUNCATED AT 250 WORDS)