Enoximone Infusion Research Articles

Double-Blind Placebo-Controlled Comparison of Enoximone and Dobutamine Infusions in Patients With Moderate to Severe Chronic Heart Failure

Few data exist on the safety of transferring patients to standard oral therapy for chronic heart failure (CHF) after acute management with inotropic agents. This study compares hemodynamic responses and cardiac dysrhythmic effects of continuous infusion of enoximone, dobutamine, or placebo in patients with moderate to severe CHF. The authors enrolled 136 patients who were randomly assigned to either open-label dobutamine or double-blind enoximone vs placebo. After 24 hours of treatment, the study was unblinded. Patients receiving placebo completed the study. Patients receiving enoximone or dobutamine received the infusion for an additional 24 hours and were then switched to standard oral therapy for 72 hours. Compared with placebo, both enoximone and dobutamine increased cardiac index and decreased pulmonary capillary wedge pressure (PCWP). Compared with dobutamine, enoximone significantly increased cardiac index after the first 24 hours of infusion and significantly decreased PCWP throughout the infusion period. There was no difference in the incidence of arrhythmias between enoximone and dobutamine. More patients (65%) tolerated the switch to oral therapy in the enoximone group compared with dobutamine (49%; P =.12). Enoximone is effective in improving the hemodynamics in patients with moderate to severe CHF and is tolerated at least as well as dobutamine.

Perioperative Enoximone Infusion Improves Cardiac Enzyme Release After CABG

Perioperative Enoximone Infusion Improves Cardiac Enzyme Release After CABG

Determinants and Prognosis of Myocardial Damage After Coronary Artery Bypass Grafting

Myocardial infarction remains a devastating complication after coronary revascularization. Although electrocardiography (ECG) and echocardiography suggest transmural infarction, myocardial damage and the quality of myocardial protection are not recognized unless troponin I (TnI) is assessed. Determinants and prognosis of TnI elevation after coronary artery bypass grafting (CABG) were evaluated. Data of 776 consecutive patients undergoing CABG between January 2002 and January 2004 were prospectively exposed to univariate and multivariate analysis. We evaluated the prognosis of patients with all the ECG, echocardiographic, and biochemical criteria for acute myocardial infarction and that of patients with only TnI elevation. Twelve-month follow-up survival and freedom from cardiac events (FCE) were accomplished. Troponin I greater than 3.1 mug/L at 12 hours was detected in 6.9% of the population, and correlated with lower in-hospital (p < 0.001) and follow-up survival (p = 0.00001), and lower FCE (p = 0.0009). Twenty-one (38.8%) of these fulfilled ECG-echocardiographic criteria (p = 0.05), demonstrating higher TnI values at 12 (p = 0.001), 24 (p = 0.01), 48 (p = 0.01), and 72 (p = 0.04) hours, prolonged ventilation time (p = 0.001), higher in hospital mortality (p = 0.003), lower follow-up survival (p = 0.023), and lower FCE (p = 0.0084). A EuroSCORE greater than 6, ongoing unstable angina, aortic cross-clamp time greater than 90 minutes, cardiopulmonary bypass time greater than 180 minutes, incomplete revascularization, and intraoperative intraaortic balloon pump were independent predictors of myocardial damage (MD) at multivariate analysis. Combined antegrade and retrograde cardioplegia and postoperative enoximone infusion were associated with a lower TnI elevation. Troponin I greater than 3.1 mug/L at 12 hours defines perioperative MD. Associated ECG-echocardiographic criteria indicate acute myocardial infarction and anticipate a worse outcome. Identification of predictors for MD is important to develop preventative strategies, as antegrade plus retrograde cardioplegia and enoximone infusion.

Perioperative enoximone infusion improves cardiac enzyme release after CABG

Objective: To assess whether routine postoperative enoximone infusion compared with dobutamine improved clinical and biochemical results after coronary artery bypass grafting with cardiopulmonary bypass. Design: Prospective nonrandomized study. Data collection was blinded to the choice of inotrope. Setting: Double-institutional clinical investigation. Participants: Two hundred sixteen consecutive patients undergoing myocardial revascularization between May 2000 and December 2002. Interventions: Seventy-two patients underwent myocardial revascularization and were treated with enoximone, 5 μg/kg/min (group A). They were compared in a ratio of 1:2 to 144 patients treated with dobutamine at the same dose (group B) after aortic cross-clamp removal. The groups proved to be homogenous in preoperative and intraoperative characteristics. Measurements and Main Results: Hospital outcome, electrocardiogram, echocardiography, further inotropic support, and biochemical markers of ischemia were compared. Subsets of patients with comorbidities and total arterial revascularization were analyzed. Perioperative myocardial infarction, postoperative low-output syndrome, intra-aortic balloon pump, atrial fibrillation, ST-segment changes, postoperative echocardiographic findings, and intensive care and hospital durations were similar between groups. In the postoperative course, more patients belonging to group A maintained low-dose inotropic support, whereas more patients belonging to group B required higher doses. Troponin I and creatine kinase—MB values were higher in patients of group B, especially when subgroups with diabetes, left ventricular hypertrophy, or total arterial revascularization were included. Conclusion: Postoperative enoximone reduced troponin I release and need for inotropic support in patients undergoing on-pump myocardial revascularization. Subgroup data were confirmed in diabetes, left ventricular hypertrophy, and total arterial revascularization.

Enoximone coupled to very low dose dobutamine echocardiography detects myocardial viability in akinetic and dyskinetic post-myocardial infarcted areas

Dobutamine and enoximone stimulate independently inotropic reserve by increasing intracellular cyclic adenosine monophosphate. The potential of enoximone (0.75 mg/kg body weight over 10 minutes) followed by very low dose (2.5 μg/kg/min) dobutamine echocardiography to predict recovery of ventricular function in akinetic and dyskinetic postinfarcted areas was studied. We enrolled 22 patients with previous Q-wave myocardial infarction and regional wall motion abnormalities related to left anterior descending arterial disease, left ventricular ejection fraction <40%, and all scheduled for myocardial revascularization. A 10 μg/kg/min dobutamine test was performed 48 hours before the study protocol. Test images obtained at peak of pharmacodynamic effects were compared with those obtained at 4 months after myocardial revascularization. We used a 16-segment ventricular model and a 5-grade scoring system. Resting regional myocardial dysfunction graded ≥2 was present in 267 of 352 segments evaluated. Contractile reserve (decrease in resting wall motion score ≥2 grades) at peak effect of enoximone infusion was present in 34 of 112 severely hypokinetic, 42 of 117 akinetic, and 14 of 38 dyskinetic segments. The inotropic reserve evaluated after very low dose dobutamine was observed in 34 of 112 severely hypokinetic, 49 of 117 akinetic, and 20 of 38 dyskinetic segments. After revascularization, recovery of function was observed in 31 of 112 severely hypokinetic, 49 of 117 akinetic, and 21 of 38 dyskinetic segments. Overall, there was a significant correlation between absolute score changes of segments which were abnormal at baseline (n = 267) to enoximone peak effects (r = 0.49, p <0.001) to predict absolute changes after revascularization; after dobutamine there was progress toward identity (r = 0.62, p <0.001) and the difference was significant among correlation slopes of dobutamine alone, enoximone alone, and enoximone plus very low dose dobutamine echocardiograophy (0.45 ± 0.04, 0.51 ± 0.04, and 0.63 ± 0.04, respectively, F = 5.25, p = 0.005). Therefore, enoximone followed by very low dose dobutamine may assess myocardial viability of postinfarcted akinetic and dyskinetic areas. This test may be useful when evaluating patients with more severe cardiac failure and/or life-threatening arrhythmias.

High-dose enoximone to evaluate reversibility of pulmonary hypertension: Is there a diagnostic value of neurohormonal measurements?

Background Heart transplantation is associated with a reduction of the neurohumoral activation seen in patients with severe congestive heart failure. In this study, we investigated whether pharmacologically induced complex hemodynamic improvement during assessment of reversibility of pulmonary hypertension with a phosphodiesterase inhibitor is able to induce neurohormonal changes of diagnostic importance. Methods and Results Twenty-one patients with New York Heart Association class III-IV heart failure underwent infusion of 3 mg/kg enoximone over a period of 30 minutes. Before and after drug infusion, we determined the plasma concentrations of atrial natriuretic peptide, endothelin-I, angiotensin-II, aldosterone, norepinephrine, epinephrine, and angiotensin-converting enzyme activity sampled from a peripheral vein and the pulmonary artery. In addition to the expected significant reduction of pulmonary hypertension and enhancement of cardiac output, increased levels of the vasoconstrictors endothelin-I, angiotensin-II, and norepinephrine were observed. Aldosterone fell after enoximone infusion; a higher baseline aldosterone level correlated to the degree of reduction of the pulmonary arteriolar resistance by enoximone. Baseline atrial natriuretic peptide levels correlated with parameters, indicating the severity of heart failure. However, the plasma concentration of this peptide did not change significantly after enoximone infusion. Conclusions Acute hemodynamic improvement after enoximone bolus in candidates for heart transplantation is not accompanied by a reduction of the enhanced neurohumoral activity in these patients. The reaction of the investigated hormones cannot predict the individual degree of reversibility of pulmonary hypertension. (Am Heart J 1999;137:887-94.)

Effect of Low-Dose Positive Inotropic Drugs on Human Internal Mammary Artery Flow

Background. Dobutamine (a β-receptor agonist), enoximone (a type III selective phosphodiesterase inhibitor), and epinephrine (an α- and β-mimetic) frequently are used in the perioperative management of patients undergoing coronary artery bypass grafting. Methods. We performed a double-blind clinical study to compare the effects on internal mammary artery free flow of low doses of these three positive inotropic drugs. Thirty patients in whom the left internal mammary artery was used for coronary artery bypass grafting were randomized into three groups. Internal mammary artery free flow and hemodynamic measurements were evaluated before and 10 minutes after the intravenous infusion of dobutamine (3 μg · kg −1 · min −1), enoximone (200 μg/kg), or epinephrine (0.05 μg · kg −1 · min −1). Results. A significant increase in free flow occurred only in the dobutamine group (33 ± 7.5 and 42.2 ± 7.9 mL/min before and after drug infusion, respectively; p = 0.013). Comparison of the increase in flow between the groups, however, showed no difference. These drugs, at doses designed to produce a positive inotropic effect, caused little increase in the free flow of the internal mammary artery. Conclusions. The use of dobutamine, enoximone, and epinephrine as low-dose positive inotropic treatments in the perioperative and postoperative periods of coronary artery bypass grafting should depend on their positive inotropic effects rather than their vasodilative effects on the arterial grafts.

Cardiopulmonary effects of enoximone or dobutamine and nitroglycerin on mitral valve regurgitation and pulmonary venous hypertension

Objective: To compare the cardiovascular and pulmonary effects of the phosphodiesterase III inhibitor enoximone (EN) or a combination of dobutamine (DOB) and nitroglycerin (NTG) before and after mitral valve repair or replacement. Design: Prospective, randomized, controlled clinical study. Setting: University hospital. Participants: Twenty patients with mitral regurgitation and pulmonary venous hypertension scheduled for elective mitral valve surgery. Interventions: Patients fulfilling the inclusion criteria of the study were randomly allocated into a group treated with EN (group 1, n = 10) or DOB and NTG (group 2, n = 10). A cardiopulmonary status was obtained after induction of anesthesia and mechanical ventilation during stable hemodynamic conditions (control). Then the patients received either EN (bolus dose 1.0 mg/kg followed by a continuous infusion of 10 μg/kg/min) or DOB (8.0 μg/kg/min) and NTG (1.0 pg/kg/min) according to the randomization. After a period of 20 minutes, all parameters were measured again. The study drugs were stopped, and cardiac surgery was performed. Infusions of EN (without additional loading dose) or DOB and NTG were started again in the above-described doses 10 minutes before separation from cardiopulmonary bypass (CPB). Respiratory and hemodynamic measurements were made 20 minutes after weaning from CPB and 60 minutes after admission of the patient to the intensive care unit. Measurements and Main Results: Both groups were comparable regarding preoperative and control data. Before mitral valve surgery, cardiac output (CO) and heart rate (HR) increased by 46% ( p < 0.05) and 31% ( p < 0.01) during infusion of EN with minor changes of mean systemic arterial pressure (PSA) and gas exchange. Mean pulmonary arterial pressure (P PA) decreased from 32 ± 11 mmHg to 23 ± 11 mmHg ( p < 0.05). Similar alterations were observed in group 2 (ΔCO + 26%, p < 0.05, ΔHR + 39%, p < 0.01); however, P PA and calculated pulmonary vascular resistance remained unchanged. After separation from CPB, EN and DOB-NTG achieved comparable effects on CO, HR, and P SA, but P PA as significantly lower in group 1. In addition, venous admixture and alveolo-arterial oxygen tension gradient were lower in EN-treated patients. Conclusion: Enoximone or DOB and NTG have comparable effects on CO, P SA, and HR in mitral regurgitation and pulmonary hypertension, but EN is more effective in reducing P PAwithout deterioration of gas exchange.

Effects of selective phosphodiesterase 3 inhibition in the perfused liver of the rat after endotoxin treatment.

1. This study was designed to investigate the role of rat phosphodiesterase 3 (RPDE3) in regulation of liver metabolism in sepsis. We studied the effects of the phosphodiesterase 3 inhibitor (PDI), enoximone, alone and in combination with regulating factors of hepatic carbohydrate metabolism and bile secretion in the perfused liver of rats treated 4 h earlier with endotoxin. In addition, cyclic AMP and cyclic GMP levels were determined in the effluate and bile by radio immunoassay methods. 2. After endotoxin treatment, infusion of enoximone at three concentrations (1 microM, 10 microM) resulted in an increased glucose output from -1.4 +/- 0.9 to 7.8 +/- 2.5 mumol l-1 20 min-1. Bile acid-independent bile flow increased also, in a dose-dependent manner. 3. In untreated livers, cyclic AMP release increased in the effluate from 1000 +/- 73 fmol g-1 min-1 to 1710 +/- 143 fmol g-1 min-1 when enoximone (10 microM) was administered. In bile from untreated livers, the level of cyclic AMP was also significantly increased by enoximone. After endotoxin treatment, the enoximone (10 microM) effect on cyclic AMP levels in effluate and bile was greatly reduced. Levels of cyclic GMP in the effluate and bile appeared unchanged in the presence of enoximone. 4. During co-infusion of glucagon (1 nM) and enoximone (10 microM), cyclic nucleotide levels in the effluate and bile of livers after endotoxin treatment were determined. In the effluate, cyclic AMP release increased from 827 +/- 144 fmol g-1 min-1 to 17802 +/- 2821 fmol g-1 min-1 when glucagon was administered. The presence of enoximone enhanced cyclic AMP further to 41696 +/- 920 fmol g-1 min-1. The same changes in cyclic AMP release were found in bile. Levels of cyclic GMP in the effluate and bile were not significantly affected by the administration of glucagon and the PDI. 5. Glucose release was determined during glucagon, sympathetic nerves stimulation and phenylephrine administration in the presence and absence of enoximone. The addition of enoximone to glucagon increased glucose release by 8.2 +/- 2.8 mumol g-1 20 min-1, without alteration of lactate balance. The PDI enhanced the glycogenolytic effects of nerve stimulation and of phenylephrine, accompanied by a reduction in lactate production. 6. Enoximone significantly enhanced the bile acid independent bile flow after glucagon, nerves stimulation and after administration of phenylephrine. Bile acid secretion was unaffected by the PDI. The vasoconstrictor effect of nerve stimulation was reduced by the PDI. 7. We conclude that endotoxin treatment reduces the ability of the PDI, enoximone, to increase cyclic AMP release in the perfused liver. The significant increase in cyclic AMP release after stimulation with glucagon and enoximone favours the view that RPDE3 is involved in the degradation of cyclic AMP in the liver after exposure to endotoxin. Additionally, the inhibition of the RPDE3 results in glucose release, vasodilatation and choleresis in endotoxin pretreated livers.

Acute enoximone effect on systemic and renal hemodynamics in patients with heart failure.

Patients with heart failure generally show improvement in their clinical condition after enoximone infusion over the period of treatment; this effect cannot be ascribed only to the known hemodynamic action of this drug. Thirty-six patients (age range 44-82 years) with heart failure (NYHA class II-IV) underwent 48-hour enoximone infusion to study whether this prolonged improvement might depend on changes in systemic or renal hemodynamics or in neurohormonal balance. All patients underwent Swan-Ganz hemodynamic monitoring; renal plasma flow, glomerular filtration rate, plasma atrial natriuretic factor (ANF), and plasma renin activity (PRA) were all measured at baseline, at the peak of the enoximone action, and 48 hours after drug discontinuation. The main hemodynamic parameters were significantly improved during enoximone infusion and after drug discontinuation. The cardiac index basal value of 2.2 +/- 0.1 l/min/m2 increased to 3.1 +/- 0.1 l/min/m2 after 24-hour therapy (p < 0.01); similarly, pulmonary wedge pressure, mean pulmonary arterial pressure, and right atrial pressure decreased markedly (p < 0.01). Beneficial effects were also observed in renal hemodynamics; indeed, renal plasma flow (basal value 485 +/- 39 ml/min) increased significantly after 24-hour enoximone infusion (575 +/- 35 ml/min; p < 0.01), and this tendency was also observed 48 hours after drug discontinuation. No significant modifications were observed in plasma hormone data; however, the PRA plasma level had a tendency to decrease. We conclude that in patients with heart failure, enoximone infusion has a less marked effect on renal hemodynamics, but this is more lasting than systemic hemodynamic effects. The tendency of PRA to decrease (although not statistically significant), still detectable 2 days after treatment in the presence of steady high plasma ANF concentrations, may also contribute to the paradoxical longlasting benefit despite the short-lived improvement in systemic hemodynamics after brief cycles of enoximone infusion.

Pharmacokinetics of Enoximone After Various Intravenous Administrations to Healthy Volunteers

The pharmacokinetics of enoximone and its sulfoxide metabolite were investigated in healthy male volunteers after various intravenous adminstrations: a bolus single dose, a continuous infusion, and bolus multiple doses of enoximone. The overall pharmacokinetic profiles of enoximone and sulfoxide metabolite indicated linearity over the range of 0.25–2.0 mg/kg after single doses of enoximone. The hypothetical plasma concentration just after bolus injection of enoximone, the maximum concentration of sulfoxide, and the area under the concentration–time curves of both compounds increased proportionally with dose. The terminal half‐lives of both compounds indicated similar values (2.0–2.7 h) and were not dose related. After four consecutive doses given at 3‐h intervals, no accumulation was observed for either compound, and the pharmacokinetic parameters were not altered. After a 4‐h infusion of enoximone, the areas under the plasma concentration–time curves of both compounds were 30% lower than the estimated values from the single dose study. Also, some pharmacokinetic parameters were changed as compared to those from the single dose study. The pharmacokinetic parameters obtained in Japanese healthy volunteers showed no marked differences from those obtained in Caucasians; thus, no racial difference was suggested in the pharmacokinetic properties of enoximone.

Enoximone and acute left ventricular failure during weaning from mechanical ventilation after cardiac surgery

To evaluate enoximone, a phosphodiesterase III inhibitor, in the treatment of left ventricular failure during the weaning of patients from mechanical ventilation after heart surgery. Open label, prospective, weaning trial. Cardiothoracic surgical intensive care unit (ICU) in a university hospital. Nine patients were studied after one or more unsuccessful attempts at weaning from mechanical ventilation due to left ventricular dysfunction. For each patient, two respiratory weaning attempts were studied: the first one as a control and the second one with enoximone infused at a rate of 30 micrograms/kg/min for 30 mins, then at a rate of 10 micrograms/kg/min. Hemodynamic measurements were performed at the following interval times: baseline during mechanical ventilation; during spontaneous ventilation with a T-piece for a minimum of 10 mins; during mechanical ventilation after the enoximone infusion for 30 mins; during spontaneous ventilation for a minimum of 10 mins with an enoximone infusion running. During spontaneous ventilation, enoximone increased cardiac index by 34% but mean artery, right atrial, and pulmonary artery occlusion pressures did not change. Despite an increase in venous admixture due to augmented cardiac index and inhibition of hypoxic vasoconstriction, no oxygen debt occurred because oxygen delivery increased. Seven of nine patients were weaned successfully from mechanical ventilation. Because of its positive inotropic and vasodilatory properties, enoximone is helpful for respiratory weaning of patients with left ventricular failure after cardiac surgery.

Hemodynamic effects of prolonged enoximone infusion (7 days) in patients with severe chronic heart failure

This study investigated the hemodynamic effects and tolerance of infusion of 10 micrograms/kg/min enoximone over 7 days in 12 patients (mean age 64.3 years) with severe chronic heart failure (10 NYHA Class III and 2 Class IV) with idiopathic dilated cardiomyopathy. Hemodynamic parameters were measured 10 minutes, 3 hours, 6 hours, 18 hours, 24 hours, and 7 days after the start of infusion. Catecholamines were assayed before the start of the infusion and on day 7. The heart rate increased on an average from 90.8 +/- 13.7 before infusion to 108.5 +/- 8.2 beats/min (p < 0.05) on day 7 (+20%). The mean arterial pressure decreased by approximately 10% (p < 0.05) between the start and end of the infusion. The pulmonary artery diastolic pressure dropped by a maximum of 30% at the 24th hour (23.1 +/- 5.1 to 16 +/- 5.4 mm Hg; p < 0.01). This decrease remained significant on day 7; the index cardiac was increased a maximum of 40% between the 18th and the 24th hour; p < 0.01). This increase was still significant on day 7 (2.35 +/- 0.44; p < 0.05; +22%). Finally, the decrease in systemic arterial resistance, which reached a maximum of 30% of the 24th hour, persisted on day 7 (-22%); 2076 +/- 451 to 1612 +/- 283 dynes/sec/cm5; p < 0.05). The norepinephrine level did not change significantly (4.5 +/- 1.2 nmol/l before infusion vs. 4.2 +/- 1.1 nmol/l on day 7). Infusion had to be stopped in one patient after 30 minutes because of prolonged severe hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)

Enoximone therapy as pharmacological bridging to cardiac transplantation.

Keeping pre-transplant patients alive while waiting for a suitable donor is still a major challenge. New pharmacological agents which can provide improved hemodynamics are urgently needed in patients with severe heart failure who are on the waiting list for cardiac transplantation. Intravenous enoximone therapy (an initial 0.5 mg/kg bolus, then 1.25-5.0 mcg/kg/min infusion) was administered to 35 transplant candidates with progressive heart failure despite optimal drug regimen including digoxin, diuretics, and ACE-inhibitors. In 18 out of 35 patients complete hemodynamic, echocardiographic, neurohumoral, and Holter-ECG studies were performed before and 24 hours after intravenous enoximone infusion. Patients were then continued on chronic oral therapy of 100 mg twice a day. Enoximone infusion increased the cardiac index (CI) (1.78 +/- 0.45 l/min/m2 vs 3.04 +/- 0.83 l/min/m2; p < 0.001) and stroke volume index (SVI)(22.33 +/- 9.45 ml/m2 vs 32.28 +/- 7.29 ml/m2; p < 0.05) and decreased wedge pressure (PCP)(24.1 +/- 11.98 mmHg vs 17.78 +/- 8.76 mmHg; p < 0.05) while mean arterial pressure (MAP) was unchanged. Left ventricular ejection time (LVET)(225.1 +/- 26.9 ms vs 242.2 +/- 25.8 ms; p < 0.05) was increased whereas other echocardiographic parameters were unchanged (Left ventricular end-diastolic dimension LVEDD, left ventricular end-systolic dimension LVESD, fractional shortening FS, early diastolic relaxation parameter Te). Plasma neurohumoral parameters did not change (Aldosterone, epinephrine, renin, atrial natriuretic factor) except for a significant drop in norepinephrine (936.7 +/- 443.2 pg/ml vs 522.4 +/- 287.6 pg/ml; p < 0.05). Holter-ECG parameters (ventricular premature beats VPB, couplets, ventricular tachycardia VT) were not influenced by enoximone infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Cardiovascular Drugs on Oxygen Consumption/Oxygen Delivery Relationship in Patients with Congestive Heart Failure

The oxygen consumption (VO2)/oxygen delivery (DO2) relationship was analyzed in ten patients with severe congestive heart failure (CHF) and normal blood lactate levels. First dobutamine and then enoximone, after a washout period, were administered to each patient to increase cardiac output by at least 15 percent. Similar increases in DO2 were obtained with both drugs: from 285 +/- 46 to 393 +/- 87 ml/min/m2 for dobutamine, and from 285 +/- 54 to 392 +/- 99 ml/min/m2 for enoximone. However, while VO2 did not change (132 +/- 24 vs 132 +/- 21 ml/min/m2) (VO2/DO2 independency) with a dobutamine infusion (mean dose of 10 +/- 2 micrograms/kg/min), a significant increase in VO2 from 134 +/- 22 to 157 +/- 21 ml/min/m2 was observed with a bolus infusion of enoximone (mean dose of 1.7 +/- 0.5 mg/kg). These results, observed in patients with CHF without patent oxygen debt, suggest that an artefactual VO2/DO2 dependency might be induced by the cardiovascular drug used to elevate DO2, probably because of a drug-induced oxygen demand increase.

Influence of ischaemic cardioplegic arrest on the haemodynamic efficacy of the PDE-III inhibitor, enoximone

The haemodynamic support from an enoximone infusion (2 x bolus 0.5 mg.kg-1, infusion 0.5 micrograms.kg-1min-1) in the early postischaemic phase is modified by a transient diminution of the drug's positive inotropic and vasodilatory effect (1 to 4 h). Forty-five min after weaning off cardiopulmonary bypass (CPB) the initial increase in cardiac index (CI) induced by enoximone (+26 +/- 8%) faded and was no longer discernible in the control group. A significant increase in CI was observed again 4-6 h after cardioplegic arrest (ultimate steady state values greater than 10 h; CI +0.71.min-1 x m-2; +21%). This pharmacodynamic fading occurred in the presence of constant plasma concentrations of enoximone (442 +/- 31 ng.ml-1) and elevated high plasma norepinephrine (926 +/- 70 pg.ml-1). Two independent processes might be responsible for the ischaemia-induced complex time dependency of the pharmacodynamic effect: (1) sensitization of the adrenergic receptor pathway and/or activation of sarcolemmal Ca-influx, rapidly reversed during reperfusion, and (2) impaired sarcoplasmic reticulum responses, which are slowly repaired after weaning off CPB.

Clinical pharmacology of intravenous enoximone: Pharmacodynamics and pharmacokinetics in patients with heart failure

Twenty-one patients with heart failure (New York Heart Association [NYHA] class II to IV) received a 24-hour infusion of enoximone followed by a 12-hour washout period. Patients were randomly assigned to one of four treatment groups. Groups I to III received an 0.5 mg/kg bolus, followed by a maintenance infusion of 2.5, 5.0, or 10.0 μg/kg/min. Group IV patients received a maintenance infusion of 5.0 μg/kg/min without a loading dose. Serial assessment of hemodynamics, plasma levels of enoximone and enoximone sulfoxide, and ventricular ectopy were performed. Enoximone produced a clinically significant increase in cardiac index, and a decrease in mean pulmonary artery wedge pressure and systemic vascular resistance in all groups. Enoximone mildly increased heart rate, and had a minimal effect on mean arterial pressure. There was no statistically significant change in ventricular ectopy during the infusion. Significant hemodynamic improvement was noted at even the lowest infusion rate, and did not increase in linear fashion at higher infusion rates. In patients who did not receive an initial loading bolus of 0.5 mg/kg, the increase in cardiac index was delayed by approximately 1 hour. Plasma concentrations of both enoximone and its major metabolite continued to rise throughout the 24-hour infusion in group III (10.0 μg/kg/min), rather than reaching steady state as predicted by the terminal exponential half-lives of these compounds. This is suggestive of nonlinear pharmacokinetics and indicates a potential for excessive accumulation of enoximone and its metabolite during prolonged infusion. These findings may have important implications in gulding the intravenous administration of enoximone. Intravenous doses of enoximone above 5.0 μg/kg/min may not provide very much additional hemodynamic benefit compared with lower doses and yet may result in significant accumulation of enoximone and its metabolites, leading to an increased potential for toxicity. An initial intravenous bolus of enoximone should be administered prior to continous infusion of enoximone in cases where immediate hemodynamic benefit is desirable.

Relation between Mixed Venous Oxygen Saturation and Cardiac Index: Nonlinearity and Normalization for Oxygen Uptake and Hemoglobin

The ability of mixed venous oxygen saturation (SvO₂) monitoring to reflect changes in cardiac index (CI) with therapy in critically ill patients is unclear. To this end, SvO₂and CI were measured before and during an infusion of enoximone and/or dobutamine in 30 patients with advanced heart failure. A nonlinear relationship was observed between SvO₂ and CI with the nonlinear correlation coefficient being 0.52. On normalizing for individual differences in hemoglobin and oxygen consumption, this correlation coefficient became 0.90. Further analysis of individual data was performed using linear regression, and the slopes and correlation coefficients were found to span a wide range (slope: −10.0 to 30.9 min-mVL, r: −0.27 to 0.99). However, the mean slope and correlation coefficient for patients with baseline CI and SvO₂ <21/min/m* and <55 percent were 18.3 min-m²/L and 0.87, respectively, while those for the remainder of patients were only 3.1 min-m²/L and 0.42, respectively. Thus, the nonlinear correlation coefficient of the SvO₂-CI relationship in a group of patients is dependent on the homogeneity of their oxygen consumption and hemoglobin concentration. Furthermore, the ability of SvO₂to serve as a therapeutic indicator in any given patient is dependent on baseline SvO₂ and CI.

Hyperosmolality related to propylene glycol in an infant treated with enoximone infusion.

Hyperosmolality related to propylene glycol in an infant treated with enoximone infusion.

Pharmacodynamics of enoximone during intravenous infusion

Twenty-one patients with heart failure (NYHA class II-IV) received a 24-hour infusion of enoximone, followed by a 12-hour washout period. Patients were randomly assigned to one of four treatment groups. Groups I–III received a 0.5 mg/kg bolus, followed by a maintenance infusion of 2.5, 5.0 or 10.0 μg/kg/minute. Group IV patients received a maintenance infusion of 5.0 μg/kg/minute without the bolus. Serial assessments of haemodynamics, plasma levels of enoximone and enoximone sulphoxide, and ventricular ectopy were performed. Enoximone produced a significant increase in cardiac index (28.1–46.7%) and a decrease in mean pulmonary artery wedge pressure (6.4–35.7%) and systemic vascular resistance (34.7–78.9%). Enoximone had minimal effect on heart rate and blood pressure. In patients who did not receive an initial bolus of 0.5 mg/kg, haemodynamic changes were delayed by approximately 1 hour. Significant haemodynamic improvement was noted at even the lowest infusion rate and did not increase in linear fashion at higher infusion rates. During infusion of enoximone at 10.0 μg/kg/minute, both enoximone and its sulphoxide accumulated non-linearly and did not achieve a steady state. No significant adverse effects were noted in these patients. Enoximone infusion at rates greater than 5.0 μg/kg/minute may confer minimal additional haemodynamic benefit, while resulting in significant accumulation of enoximone and enoximone sulphoxide. Ventricular ectopy did not increase significantly in most patients.