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Aim: To investigate the effects of inotropic agents on parameters of tissue perfusion in patients with cardiogenic shock., Methods and Results: Thirty patients with cardiogenic shock were included. Patients received dobutamine, enoximone, or norepinephrine. We performed hemodynamic measurements at baseline and after titration of the inotropic agent until cardiac index (CI) ≥ 2.5 L.min-1.m(-2) or mixed-venous oxygen saturation (SvO2) ≥ 70% (dobutamine or enoximone), and mean arterial pressure (MAP) ≥ 70 mmHg (norepinephrine). As parameters of tissue perfusion, we measured central-peripheral temperature gradient (delta-T) and sublingual perfused capillary density (PCD). All patients reached predefined therapeutic targets. The inotropes did not significantly change delta-T. Dobutamine did not change PCD. Enoximone increased PCD (9.1 [8.9-10.2] vs. 11.4 [8.4-13.9] mm.mm(-2); p<0.05), and norepinephrine tended to decrease PCD (9.8 [8.5-11.9] vs. 8.8 [8.2-9.6] mm.mm-2, p = 0.08). Fifteen patients (50%) died within 30 days after admission. Patients who had low final PCD (≤ 10.3 mm.mm-2; 64%) were more likely to die than patients who had preserved PCD (>10.3 mm.mm(-2); mortality 72% vs. 17%, p = 0.003)., Conclusion: This study demonstrates the effects of commonly used inotropic agents on parameters of tissue perfusion in patients with cardiogenic shock. Despite hemodynamic optimization, tissue perfusion was not sufficiently restored in most patients. In these patients, mortality was high. Interventions directed at improving microcirculation may eventually help bridging the gap between improved hemodynamics and dismal patient outcome in cardiogenic shock.

This report describes the treatment of eight patients with status asthmaticus, six of whom were already maximally treated. They were consequently treated with enoximone, a selective phosphodiesterase III inhibitor, in their refractory phase. Bronchodilatation in these patients was immediate. No side-effects were observed. Enoximone appears to be a valuable addition to the treatment of status asthmaticus. I.V. administration bypasses inhalation incapability in severe asthma. It is likely to reduce or altogether prevent the need for resorting to secondary or tertiary high-tech therapy such as mechanical ventilation or anaesthetics, thus avoiding complications, as well as for transfers to specialized intensive care units. Not only do these aspects enable substantial cost savings, but they also may spare the patient a lot of anguish and a prolonged recovery., (© The Author [2014]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Perioperative administration of enoximone has been shown to improve hemodynamics, organ function, and inflammatory response. Aim of the present study is to evaluate the impact of enoximone on postoperative renal function after on-pump cardiac surgery., Methods: A total of 3727 patients undergoing cardiac surgery at one Institution between May 2004 and November 2010 were reviewed. A propensity score was built and a 1:1 perfect matching was performed, providing two fairly comparable cohorts of 712 patients each, receiving or not enoximone after surgery. Renal function was evaluated by lower glomerular filtration rate (GFR) value reached postoperatively., Results: Overall 30-day mortality rate was 4.3% (62/1424). Cumulative incidence of postoperative renal failure (RF) was 157/1424(11%), of which 99/1424(7%) needed renal replacement therapy. Mean lower postoperative GFR in patients who received or not enoximone was 63 ± 30.1 and 53.5 ± 26.1 ml/min/1.73 m(2) (p<0.0001), respectively. At multivariable analysis age (OR2.75, p=0.0004), diabetes (OR1.82, p=0.006), preoperative GFR (OR3.81, p<0.0001), preoperative cardiogenic shock (OR1.65, p=0.004), previous cardiac surgery (OR2.12, p=0.0002), type of intervention (OR1.96, p=0.005), and enoximone (OR0.38, p=0.001) were found to be independently associated with postoperative RF. Logistic regression analysis showed that the administration of enoximone (OR0.41, p=0.0001), and of no inotropes (OR0.27, p<0.0001) were protective vs. the occurrence of postoperative RF., Conclusion: Patients perioperatively receiving enoximone showed a statistically significant better renal function after cardiac surgery., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Intensive care unit (ICU) patients are predisposed to thromboembolism. Routine prophylactic anticoagulation is widely recommended. Low-molecular-weight heparins, such as enoxaparin, are increasingly used because of predictable pharmacokinetics. This study aims to determine the subcutaneous (SC) dose of enoxaparin that would give the best anti-factor Xa levels in ICU patients., Methods: The 72 patients admitted to a mixed ICU at Odense University Hospital (OUH) in Denmark were randomised into four groups to receive 40, 50, 60, or 70 mg SC enoxaparin for a period of 24 hours. Anti-factor Xa activity (aFXa) was measured before, and at 4, 12, and 24 hours after administration. An AFXa level between 0.1 to 0.3 IU/ml was considered evidence of effective antithrombotic activity., Results: Median peak (4 hours after administration), aFXa levels increased significantly with an increase in enoxaparin dose, from 0.13 IU/ml at 40 mg, to 0.14 IU/ml at 50 mg, 0.27 IU/ml at 60 mg, and 0.29 IU/ml at 70 mg (P = 0.002). At 12 hours after administration, median aFXa levels were still within therapeutic range for those patients who received 60 mg (P = 0.02)., Conclusions: Our study confirmed that a standard dose of 40 mg enoxaparin yielded subtherapeutic levels of aFXa in critically ill patients. Higher doses resulted in better peak aFXa levels, with a ceiling effect observed at 60 mg. The present study seems to suggest inadequate dosage as one of the possible mechanisms for the higher failure rate of enoxaparin in ICU patients., Trial Registration: ISRCTN03037804.

Aims: Use of inotropic agents in patients with heart failure (HF) has been limited by adverse effects on outcomes. However, administration of positive inotropes at lower doses and concomitant treatment with beta-blockers might increase benefit-risk ratio. We investigated the effects of low doses of the positive inotrope enoximone on symptoms, exercise capacity, and major clinical outcomes in patients with advanced HF who were also treated with beta-blockers and other guideline-recommended background therapy., Methods and Results: The Studies of Oral Enoximone Therapy in Advanced HF (ESSENTIAL) programme consisted of two identical, randomized, double-blind, placebo-controlled trials that differed only by geographic location (North and South America: ESSENTIAL-I; Europe: ESSENTIAL-II). Patients with New York Heart Association class III-IV HF symptoms, left ventricular ejection fraction < or = 30%, and one hospitalization or two ambulatory visits for worsening HF in the previous year were eligible for participation in the trials. The trials had three co-primary endpoints: (i) the composite of time to all-cause mortality or cardiovascular hospitalization, analysed in the two ESSENTIAL trials combined; (ii) the 6 month change from baseline in the 6 min walk test distance (6MWTD); and (iii) the Patient Global Assessment (PGA) at 6 months, both analysed in each trial separately. ESSENTIAL-I and -II randomized 1854 subjects at 211 sites in 16 countries. In the combined trials, all-cause mortality and the composite, first co-primary endpoint did not differ between the two treatment groups [hazard ratio (HR) 0.97; 95% confidence interval (CI) 0.80-1.17; and HR 0.98; 95% CI 0.86-1.12, respectively, for enoximone vs. placebo]. The two other co-primary endpoints were analysed separately in the two ESSENTIAL trials, as prospectively designed in the protocol. The 6MWTD increased with enoximone, compared with placebo, in ESSENTIAL-I (P = 0.025, not reaching, however, the pre-specified criterion for statistical significance of P < 0.020), but not in ESSENTIAL-II. No difference in PGA was observed in either trial., Conclusion: Although low-dose enoximone appears to be safe in patients with advanced HF, major clinical outcomes are not improved.

Reasons for Performing Study: No studies have been reported on the effects of enoximone in anaesthetised colic horses., Objective: To examine whether enoximone improves cardiovascular function and reduces dobutamine requirement in anaesthetised colic horses., Methods: Forty-eight mature colic horses were enrolled in this prospective, randomised clinical trial. After sedation (xylazine 0.7 mg/kg bwt) and induction (midazolam 0.06 mg/kg bwt, ketamine 2.2 mg/kg bwt), anaesthesia was maintained with isoflurane in oxygen and a lidocaine constant rate infusion (15 mg/kg bwt, 2 mg/kg/h). Horses were ventilated (PaCO2 < 8.00 kPa). If hypotension occurred, dobutamine and/or colloids were administered. Ten minutes after skin incision, horses randomly received an i.v. bolus of enoximone (0.5 mg/kg bwt) or saline. Monitoring included respiratory and arterial blood gases, heart rate (HR), arterial pressure and cardiac index (CI). Systemic vascular resistance (SVR), stroke index (SI) and oxygen delivery index (DO2I) were calculated. For each variable, changes between baseline and T10 within each treatment group and/or colic type (small intestines, large intestines or mixed) were analysed and compared between treatments in a fixed effects model. Differences between treatments until T30 were investigated using a mixed model (a = 0.05)., Results: Ten minutes after enoximone treatment, CI (P = 0.0010), HR (P = 0.0033) and DO2I (P = 0.0007) were higher and SVR lower (P = 0.0043) than at baseline. The changes in CI, HR and SVR were significantly different from those after saline treatment. During the first 30 min after enoximone treatment, DO2I (P = 0.0224) and HR (P = 0.0003) were higher than after saline administration. Because the difference in HR between treatments was much clearer in large intestine colic cases, an interaction was detected between treatment and colic type in both analyses (P = 0.0076 and 0.0038, respectively)., Conclusions: Enoximone produced significant, but short lasting, cardiovascular effects in colic horses., Potential Relevance: Enoximone's cardiovascular effects in colic horses were of shorter duration than in healthy ponies.

Background: We sought to assess the intra- and postoperative haemodynamic effects of continuous perioperative beta-adrenergic blockade combined with phosphodiesterase (PDE) III inhibition and its potential benefits in limiting perioperative myocardial ischaemia in high-risk vascular surgery patients., Methods: Seventy-five patients were randomly assigned to receive tight heart rate (HR) control by a continuous infusion of: esmolol in combination with the PDE III inhibitor enoximone (esmolol+enoximone group), esmolol infusion alone (esmolol group), or standard therapy (control group) for a period of 48 h. Myocardial ischaemia and dysfunction were detected by serial plasma Troponin T (TnT) and B-type natriuretic peptide (BNP) measurements., Results: Cardiac index (CI) increased significantly only in esmolol+enoximone-treated patients [CI: from 2.4 (0.2) litre min(-1) m(-2) at baseline to 3.2 (0.2) litre min(-1) m(-2) at 24 h after surgery; P=0.001] and was significantly higher than in the esmolol [CI: from 2.5 (0.2) litre min(-1) m(-2) at baseline to 2.6 (0.2) litre min(-1) m(-2) at 24 h; P=0.18] and the control groups [CI: from 2.4 (0.2) litre min(-1) m(-2) at baseline to 2.7 (0.2) litre min(-1) m(-2) at 24 h; P=0.13]. A significant postoperative release of TnT was detected only in control patients. Plasma BNP levels increased towards the end of surgery in all patients. Peak plasma BNP concentrations were significantly higher in control patients [293 (98) pg ml(-1)] than in esmolol [118 (71) pg ml(-1)] and in esmolol+enoximone-treated patients [78 (21) pg ml(-1)]., Conclusions: Inotropic therapy with the PDE III inhibitor enoximone combined with tight HR control by a continuous infusion of esmolol improved cardiac function and reduced myocardial ischaemia in high-risk vascular surgery patients. CLINICAL TRIAL REGISTRATION INFORMATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00348101.

Objective: To investigate the influence of calcium chloride (CaCl(2)) on the cardio-respiratory effects of enoximone in isoflurane anaesthetized ponies., Study Design: Prospective consecutive experimental trial. Animals Six healthy ponies, weighing 287 +/- 55 kg were included in this study., Methods: After sedation (romifidine, 80 microg kg(-1)), anaesthesia was induced with midazolam (0.06 mg kg(-1)) and ketamine (2.2 mg kg(-1)) and maintained with isoflurane in oxygen. The ponies' lungs were ventilated to maintain normocapnia. After 90 minutes, a bolus of enoximone (0.5 mg kg(-1)) was administered, followed by a CaCl(2) infusion (0.5 mg kg(-1) minute(-1) over 10 minutes) (treatment EC). Sodium, potassium, ionized and total calcium concentrations, cardiovascular variables and blood-gases were measured in the 120 minutes after treatment. Using a mixed model anova, the results were compared to those of a previous report [Vet Anaesth Analg, 34 (2007) 416], evaluating the effects of 0.5 mg kg(-1) enoximone in the same ponies and under identical circumstances (treatment E). Both an overall comparison and comparisons at specific time points after treatment were performed (alpha = 0.05)., Results: Although ionized and total calcium concentrations were higher during treatment EC, the cardio-respiratory effects of enoximone were comparable for both treatments. A small but significant difference in packed cell volume was detected., Conclusions and Clinical Relevance: Calcium chloride did not enhance the effects of enoximone in normocalcaemic anaesthetized ponies.

cAMP plays an important role in peripheral chemoreflex function in animals. We tested the hypothesis that the phosphodiesterase inhibitor and inotropic medication enoximone increases peripheral chemoreflex function in humans. In a single-blind, randomized, placebo-controlled crossover study of 15 men, we measured ventilatory, muscle sympathetic nerve activity, and hemodynamic responses to 5 min of isocapnic hypoxia, 5 min of hyperoxic hypercapnia, and 3 min of isometric handgrip exercise, separated by 1 wk, with enoximone and placebo administration. Enoximone increased cardiac output by 120 +/- 3.7% from baseline (P < 0.001); it also increased the ventilatory response to acute hypoxia [13.6 +/- 1 vs. 11.2 +/- 0.7 l/min at 5 min of hypoxia, P = 0.03 vs. placebo (by ANOVA)]. Despite a larger minute ventilation and a smaller decrease in O(2) desaturation (83 +/- 1 vs. 79 +/- 2%, P = 0.003), the muscle sympathetic nerve response to hypoxia was similar between enoximone and placebo (123 +/- 6 and 117 +/- 6%, respectively, P = 0.28). In multivariate regression analyses, enoximone enhanced the ventilatory (P < 0.001) and sympathetic responses to isocapnic hypoxia. Hyperoxic hypercapnia and isometric handgrip responses were not different between enoximone and placebo (P = 0.13). Enoximone increases modestly the chemoreflex responses to isocapnic hypoxia. Moreover, this effect is specific for the peripheral chemoreflex, inasmuch as central chemoreflex and isometric handgrip responses were not altered by enoximone.

Objective: Enoximone is a phosphodiesterase III inhibitor frequently used to improve cardiac output (CO) in man. As the use of enoximone has not been reported in horses, the effects of this inodilator were examined in isoflurane anaesthetized ponies., Study Design: Prospective, randomised, experimental study., Animals: Six healthy ponies, weighing 286 (212-367) +/- 52 kg, aged 5.0 +/- 1.6 years (4-6.5)., Methods: After sedation with romifidine [80 microg kg(-1) intravenously (IV)], general anaesthesia was induced with midazolam (0.06 mg kg(-1) IV) and ketamine (2.2 mg kg(-1) IV) and maintained with isoflurane in oxygen (Et Iso 1.7%). The ponies were ventilated to maintain eucapnia (PaCO(2) 4.66-6.00 kPa). Each pony was anaesthetized twice with an interval of 3 weeks; receiving enoximone 0.5 mg kg(-1) IV (E) or saline (S) 90 minutes post-induction. Heart rate (HR), arterial (AP) and right atrial pressure (RAP) were measured before treatment, every 5 minutes between T0 (treatment) and T30 and then every 10 minutes until T120. Cardiac output measurements (lithium dilution technique) and blood gas analysis (arterial and central venous samples) were performed before T0 and at T5, T10, T20, T40, T60, T80, T100 and T120. Stroke volume (SV), systemic vascular resistance (SVR), venous admixture (Qs/Qt) and oxygen delivery (DO(2)) were calculated., Results: Enoximone induced significant increases in HR, CO, SV, Qs/Qt and DO(2) and a significant decrease in RAP. No significant differences were detected for AP, SVR and blood gases. No cardiac arrhythmias or other side effects were observed., Conclusions and Clinical Relevance: The present results suggest that in isoflurane anaesthetized ponies, enoximone has beneficial effects on CO and SV without producing significant changes in blood pressure. Despite an increase in Qs/Qt, DO(2) to the tissues was improved.

Background: We determined whether low-dose oral enoximone could wean patients with ultra-advanced heart failure (UA-HF) from intravenous (i.v.) inotropic support. Chronic parenteral inotropic therapy in UA-HF is costly and requires an indwelling catheter. An effective and safe oral inotrope would have value., Methods: In this placebo-controlled study, 201 subjects with UA-HF requiring i.v. inotropic therapy were randomized to enoximone or placebo. Subjects receiving intermittent i.v. inotropes were administered study medication of 25 or 50 mg 3 times a day (tid). Subjects receiving continuous i.v. inotropes were administered 50 or 75 mg tid for 1 week, which was reduced to 25 or 50 mg tid. The ability of subjects to remain alive and free of inotropic therapy was assessed for up to 182 days., Results: Thirty days after weaning, 51 (51%) subjects on placebo and 62 (61.4%) subjects in the enoximone group were alive and free of i.v. inotropic therapy (unadjusted primary end point P = 0.14, adjusted for etiology P = .17). At 60 days, the wean rate was 30% in the placebo group and 46.5% in the enoximone group (unadjusted P = .016) Kaplan-Meier curves demonstrated a trend toward a decrease in the time to death or reinitiation of i.v. inotropic therapy over the 182-day study period (hazard ratio 0.76 [95% CI 0.55-1.04]) and a reduction at 60 days (0.62 [95% CI 0.43-0.89], P = .009) and 90 days (0.69 [95% CI 0.49-0.97], P = .031) after weaning in the enoximone group., Conclusions: Although there was no benefit over placebo in weaning patients from i.v. inotropes from 0 to 30 days, the EMOTE data suggest that low-dose oral enoximone can be used to wean a modest percentage of subjects from i.v. inotropic support for up to 90 days after initiation of therapy.

In patients with impaired myocardial contractility associated with downregulation of the beta-receptors, compounds inhibiting phosphodiesterase (PDE) 3 may be useful to increase contractility. The PDE3 inhibitor enoximone has been shown to improve pump-function independent from the beta-receptor pathway. A simultaneous decrease in ventricular preload and afterload by vasodilation has led to the term 'inodilator'. Esmolol is the only available ultra-short acting intravenous beta-blocking agent. Due to its half-life of approximately 9 min, beta-blockade, and thus, heart rate, can easily be titrated. Esmolol appears to be a helpful tool to avoid myocardial ischemia (e.g., in the perioperative setting). As with all other beta-blockers, it has dose-dependent negative inotropic effects, and this limits its use in patients with severe heart failure showing low cardiac output. It seems reasonable that an intravenous combination of both approaches, enoximone-induced positive inotropy and esmolol-associated protection from myocardial ischemia, might offer advantages by producing beneficial hemodynamic effects and by compensating each other's limitations in a complementary way. In spite of some promising results, the place of a combination of enoximone and esmolol in the process of treating patients with (acute) heart failure showing low output is still not entirely clear, and needs further confirmation.

Background: Chronic heart failure is a disease syndrome characterized in its advanced stages by a poor quality of life, frequent hospitalizations, and a high risk of mortality. In advanced and ultra-advanced chronic heart failure, many treatment options, such as cardiac transplantation and mechanical devices, are severely limited by availability and cost. Short-term Phase II clinical trials suggest that low-dose oral inotropic therapy with enoximone may improve hemodynamics and exercise capacity, without adversely affecting mortality, in selected subjects with advanced chronic heart failure. Based on these data, the ability of enoximone to deliver safe and efficacious palliative treatment of advanced/ultra-advanced chronic heart failure is being evaluated in Phase III clinical trials., Methods and Results: The Enoximone Clinical Trials Program is a series of 4 clinical trials designed to evaluate the safety and efficacy of oral enoximone in advanced chronic heart failure. ESSENTIAL I and II (The Studies of Oral Enoximone Therapy in Advanced Heart Failure) will investigate the effects of oral enoximone on all-cause mortality and cardiovascular hospitalization, submaximal exercise capacity, and quality of life in subjects with New York Heart Association Class III/IV chronic heart failure. EMOTE (Oral Enoximone in Intravenous Inotrope-Dependent Subjects) will evaluate the potential of oral enoximone to wean subjects with ultra-advanced chronic heart failure from chronic intravenous inotropic therapy to which they have been shown to be dependent. EMPOWER (Enoximone Plus Extended-Release Metoprolol Succinate in Subjects with Advanced Chronic Heart Failure) will explore the potential of enoximone to increase the tolerability of continuous release metoprolol in subjects shown previously to be hemodynamically intolerant to beta-blocker treatment., Conclusion: These studies are Phase III, multicenter, randomized, double-blinded, placebo-controlled trials designed to test the general hypothesis that chronic oral administration of low doses of enoximone can produce beneficial effects in subjects with advanced or ultra-advanced chronic heart failure.

Objective: In patients with inotrope-dependent end-stage heart failure the timely application of the most suitable treatment, i.e. heart transplantation, implantation of a ventricular assist device or conservative treatment, is a key issue for therapeutic success., Methods: Seventy-six inotrope-dependent patients with end-stage heart failure were enrolled. Measurements of hemodynamics, routine laboratory parameters, and clinical examination were performed daily. Additionally, natriuretic peptides (BNP and NT-proBNP) and E-selectin were measured at the end of the study. The patients were retrospectively divided into groups with regard to the following end-points: Group I-deterioration into cardiogenic shock after an initially stable clinical course (n=26); Group II-stable clinical course without deterioration into cardiogenic (n=41); Group III-weaning from inotropic support (n=9)., Results: One day before cardiogenic shock occurred, BNP, NT-proBNP and E-selectin were significantly elevated in group I compared with group II. A logistic regression model showed that only BNP and E-selectin were independent predictors of clinical deterioration on the following day. The odds ratio (OR) for E-selectin using a cut-off point of 65ng/ml was 8.7 and for BNP using a cut-off of 500pg/ml it was 4.8. In combination, the OR increased to 11.1. Continuous decrease of NT-proBNP predicted patients in whom weaning from inotropes was possible., Conclusions: While routine parameters did not predict the clinical course, elevated BNP and E-selectin independently predicted cardiogenic shock on admission and 1 day before its occurrence. The combination showed increased predictive value.

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 microg/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.

Myocardial contractile function after cardioplegic arrest is often depressed and an ideal cardioplegic solution has not been developed yet. The aim of this study was to assess the efficacy of phosphodiesterase III inhibitors, amrinone and enoximone, and levosimendan, a novel Ca2+ sensitizing agent, on recovery of hearts after normothermic cardioplegic arrest when added to the St. Thomas' hospital cardioplegic solution. In the control group, isolated guinea pig hearts were perfused in Langendorff apparatus and arrested with standard St. Thomas' solution. In other groups, amrinone (10(-5) mol.L-1), levosimendan (10(-5) mol.L-1), or enoximone (10(-4) mol.L-1) were added to the cardioplegic solution. In all hearts, intraventricular pressure, +dp/dtmax, -dp/dtmax, area under pressure-time curve, heart rate, coronary flow, lactate dehydrogenase and creatine kinase enzyme leakage, and oxygen consumption were measured. In the enoximone group, contractility force and +dp/dtmax, were found to be significantly high in the reperfusion and inotropic periods in comparison with other groups (p < 0.05). -dp/dtmax and area under contractility-time curve values were significantly high in inotropic period in enoximone group (p < 0.05). No statistically significant difference was noted in other groups. Cardioplegic solution enrichment with enoximone augmented mechanic functions in reperfusion period. No positive effect of amrinone or levosimendan was observed in this study.

Objectives: This study was designed to evaluate the effects of low-dose enoximone on exercise capacity., Background: At higher doses the phosphodiesterase inhibitor, enoximone, has been shown to increase exercise capacity and decrease symptoms in heart failure patients but also to increase mortality. The effects of lower doses of enoximone on exercise capacity and adverse events have not been evaluated., Methods: This is a prospective, double-blind, placebo-controlled, multicenter trial (nine U.S. centers) conducted in 105 patients with New York Heart Association class II to III, ischemic or nonischemic chronic heart failure (CHF). Patients were randomized to placebo or enoximone at 25 or 50 mg orally three times a day. Treadmill maximal exercise testing was done at baseline and after 4, 8 and 12 weeks of treatment, using a modified Naughton protocol. Patients were also evaluated for changes in quality of life and for increased arrhythmias by Holter monitoring., Results: By the protocol-specified method of statistical analysis (the last observation carried-forward method), enoximone at 50 mg three times a day improved exercise capacity by 117 s at 12 weeks (p = 0.003). Enoximone at 25 mg three times a day also improved exercise capacity at 12 weeks by 115 s (p = 0.013). No increases in ventricular arrhythmias were noted. There were four deaths in the placebo group and 2 and 0 deaths in the enoximone 25 mg three times a day and enoximone 50 mg three times a day groups, respectively. Effects on degree of dyspnea and patient and physician assessments of clinical status favored the enoximone groups., Conclusions: Twelve weeks of treatment with low-dose enoximone improves exercise capacity in patients with CHF, without increasing adverse events.

Study Objectives: To study the in vitro effects of the phosphodiesterase-III inhibitor enoximone on skeletal muscle specimens from malignant hyperthermia susceptible (MHS) and normal (MHN) patients., Design: Prospective study., Setting: Malignant hyperthermia (MH) laboratory at a university hospital., Patients: 47 patients with clinical suspicion for MH undergoing in vitro contracture test (IVCT) for diagnosis of MH susceptibility., Interventions: Biopsies of M. quadriceps femoris were performed in adult patients with a 3-in-1 nerve block and in children with trigger-free general anesthesia., Measurements and Main Result: Patients were first classified as MHS or MHN by the IVCT according to the protocol of the European MH Group (EMHG). Patients with equivocal results (MHE) or with neuromuscular diseases were excluded from the study. Enoximone was added to the organ bath to surplus vital muscle specimens in single bolus concentrations of 0.4, 0.6, 0. 8, or 1.6 mmol/L. The in vitro effects of enoximone on muscle contractures and twitch were measured. Seventeen patients were classified as MHS and 30 as MHN by the EMHG criteria. Enoximone induced contractures in skeletal muscles in a dose-dependent manner. Contractures of MHS compared to MHN muscle specimens were significantly larger at all concentrations used in this study. No overlap in maximum contractures was seen between MHS and MHN muscles at a bath concentration of 0.6 mmol/L enoximone only., Conclusions: Diagnosis of MH by an IVCT test with a single bolus administration of enoximone seems to be possible using a concentration of 0.6 mmol/L. The findings of this study may indicate an involvement of the phosphodiesterase-III and cAMP system in pathogenesis of MH. Further in vivo investigation should determine the trigger potency of enoximone in MH susceptible individuals.

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.

Background: Several reports indicate that aprotinin treatment before and during cardiopulmonary bypass (CPB) might have a protective effect on the myocardium. We evaluated the hemodynamic effects of perioperative aprotinin treatment., Methods: We conducted a randomized, double-blind, placebo-controlled trial in 34 infants (mean age, 2.5 years) who had cardiac operations. Half of the patients received high-dose aprotinin therapy. There were no significant differences between the aprotinin and placebo groups with respect to age, weight, sex, aortic cross-clamp time, and CPB time. The following data were recorded at arrival in the intensive care unit 6, 12, 24, and 48 hours after termination of CPB: heart rate, blood pressure, left atrial pressure, central-peripheral temperature difference, arterial-central venous oxygen saturation difference, urine output, serum creatinine, lactate and neutrophil elastase levels, the Doppler echocardiographic factors shortening fraction and preejection period/left-ventricular ejection time, and cumulative doses of catecholamines (epinephrine), enoximone, and furosemide., Results: No hemodynamic variable showed any significant difference between aprotinin and placebo groups. Urine output, creatinine, lactate, and elastase levels, as well as the cumulative doses of furosemide and epinephrine were not significantly different. Twelve hours after CPB 10 patients in the placebo group and 4 in the aprotinin group had received enoximone (p<0.05). The placebo group had received significantly larger doses of enoximone than the aprotinin group at arrival in the intensive care unit (0.13+/-0.05 versus 0 mg/kg), 12 hours after CPB (0.58+/-0.14 versus 0.18+/-0.09 mg/kg), 24 hours after CPB (1.11+/-0.24 versus 0.42+/-0.16 mg/kg), and 48 hours after CPB (1.61+/-0.40 versus 0.86+/-0.28). At 6 hours the difference did not reach statistical significance., Conclusions: Clinical and hemodynamic status of the aprotinin-treated patients was similar to that of the placebo-treated patients in the first 48 hours after CPB. The placebo group, however, required significantly more inotropic support by enoximone than the aprotinin group to achieve this goal.

In this study we investigated the effects of isoproterenol and enoximone on protamine cardiotoxicity because administration of protamine for heparin reversal during open heart surgery depresses left ventricular function. Eighteen mongrel dogs were entered into this study. After induction of general anesthesia and a stabilization period, a thermodilution catheter was inserted via the jugular vein. Another 2 catheters were inserted into the left ventricle and femoral artery. Heparin and protamine were used in all animals. Heparin dosage was 300 U/kg, and protamine dosage was 4.5 mg/kg. The animals were divided into 3 groups. Six animals received enoximone (5 micrograms/kg per min), 6 animals received isoproterenol (0.05 microgram/kg per min), and 6 animals received no inotropic agent. Measurements were performed before treatment, 5 min after protamine administration, and at 15-min intervals for 1 h. Cardiac output (CO), mean arterial pressure, pulmonary capillary wedge pressure, first derivative of left ventricular pressure (1 +/-) left ventricular systolic pressure, and heart rate were measured. CO was 1582 +/- 34 ml/min in the isoproterenol group (I + P), 1684 +/- 61 ml/min in the enoximone group (E + P), and 1471 +/- 37 ml/min in the protamine group (P) (p < 0.05 E + P vs I + P and P) 60 min after protamine administration. The first derivative of left ventricular pressure (dP/dt) was 1995 +/- 61 mmHg/sec in the I + P group, 2320 +/- 85 mmHg/sec in the E + P group, and 1816 +/- 48 mmHg/sec in the P group (p < 0.05 E + P vs I + P and P). In our experimental study, the isoproterenol and protamine combination did not increase hemodynamic activity. However, isoproterenol alone significantly increased hemodynamic activity as determined by dP/dt values. Protamine administration impairs the effects of beta agonists on the myocardium. In the protamine group, CO and pressure-dependent values were significantly reduced. Isoproterenol administration did not reverse this deterioration because of the loss of the beta-receptor activity. Inotropic agents acting through the beta-adrenergic system have partial effects on myocardium. Enoximone, a phosphodiesterase inhibitor, reverses deterioration of cardiac function after protamine administration because it increases myocardial function via the phosphodiesterase system.

Background: Pulmonary hypertension is responsible for a substantial part of perioperative and postoperative mortality and morbidity after cardiac transplantation. Treatment of right ventricular failure after increased pulmonary vascular resistance is difficult especially in infants and children. Therefore we started a preventive therapy of pulmonary hypertension after cardiac transplantation to avoid right ventricular failure and compared the results with a group of patients with conventional therapy., Methods: Group 1 (n = 13), with transplantation from 1988 to 1991, was treated with vasodilators when symptoms of right ventricular failure developed. Group 2 (n = 19) had preventive treatment with prostaglandin E1 (PGE1), the phosphodiesterase-III inhibitor enoximone, and alkalinazation starting during weaning from cardiopulmonary bypass., Results: Six patients in group 1 died; four of them as the result of right ventricular failure in the immediate postoperative course despite aggressive treatment. In group 2 there were three deaths as the results of rejection (2) and infection (1). None of these patients developed right ventricular failure (p = 0.02). Cold ischemic time, extracorporeal circulation time, and waiting time before transplantation were significantly longer in group 2. Side effects of this preventive therapy were not observed., Conclusions: We conclude that prophylactic therapy of pulmonary hypertension with vasodilators in infants and children after heart transplantation is safe and effective in preventing right ventricular failure in the postoperative course.

Background: Dobutamine (a beta-receptor agonist), enoximone (a type III selective phosphodiesterase inhibitor), and epinephrine (an alpha- and beta-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 microg x kg(-1) x min(-1)), enoximone (200 microg/kg), or epinephrine (0.05 microg x kg(-1) x 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.

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 micrograms/kg/min) or DOB (8.0 micrograms/kg/min) and NTG (1.0 microgram/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 (PPA) decreased from 32 +/- 11 mmHg to 23 +/- 11 mmHg (p < 0.05). Similar alterations were observed in group 2 (delta CO + 26%, p < 0.05, delta HR + 39%, p < 0.01); however, PPA and calculated pulmonary vascular resistance remained unchanged. After separation from CPB, EN and DOB-NTG achieved comparable effects on CO, HR, and PSA, but PPA was 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, PSA, and HR in mitral regurgitation and pulmonary hypertension, but EN is more effective in reducing PPA without deterioration of gas exchange.

Objective: We investigated whether the administration of enoximone during and after cardiopulmonary bypass (CPB) improves splanchnic oxygen utilization and thereby gut mucosal integrity in humans by its vasodilating and inotropic properties., Setting: Surgical intensive care unit (ICU) in a university hospital., Design/patients: 21 patients (ASA III classification) scheduled for elective coronary artery bypass grafting were enrolled in the study. After induction of general anesthesia, patients were randomly assigned to received a bolus of 0.2 mg/kg enoximone, followed by 5 microg/kg per min (enoximone group), or followed by an equal volume of saline (NaCl group) during and 24 h after the surgical procedure. The following parameters were evaluated at different time intervals: systemic and pulmonary hemodynamics, blood gas analysis of arterial, mixed venous, and liver venous blood, venous and liver venous lactate level, venous and liver venous endotoxin level and intramucosal partial pressure of carbon dioxide for calculation of intramucosal pH (pHi)., Results: Enoximone raised cardiac output and oxygen delivery to higher levels than those observed in the NaCl group. In both groups, gastric pHi fell continuously during the study period. The values were significantly decreased 12 h following admission to the ICU. Endotoxin was not detectable at baseline. Both groups showed increased endotoxin levels, with the highest values during the first 6 h postoperatively. The hepatic venous endotoxin level was almost doubled in the NaCl group in comparison to the enoximone group. Endotoxin levels differed in the two groups 6 and 12 h after admission to the ICU., Conclusions: Improvement of oxygen delivery by enoximone did not prevent gastric mucosal acidosis following CPB. However, since the increase in endotoxin levels in liver venous blood was diminished by using enoximone, the drug seems to have a beneficial effect on tissue damage and barrier function of the gut.

The influence of intracoronary enoximone at a dose of 0.075 mg/ kg/10 min on global and regional wall motion and myocardial perfusion (Group I, n = 10) as well as on diastolic LV function (Group II, n = 8) during pacing-induced ischemia was investigated in 18 patients with significant LAD stenoses. The hemodynamic parameters were determined by left heart catheterization, the systolic and diastolic left ventricular function by echocardiography including Doppler technique, and myocardial perfusion analysis was done after intracoronary application of contrast medium. Enoximone did not change either heart rate (79 +/- 9 vs 80 +/- 9 min-1) or blood pressure (LVSP: 159 +/- 7 vs 162 +/- 5 mm Hg) at rest. In the postpacing ischemic period after enoximone, LVEDP fell from a mean of 28.9 to 18.4 mm Hg (p < 0.001), dp/dtmax increased from 1050 to 1369 mm Hg/s (p < 0.001) and regional EF from 47% to 58% (p < 0.01), while global EF remained unchanged (45% vs 47%). ST-segment depression was reduced significantly from 2.3 to 1.5 mm (p < 0.01). Enoximone induced an increase in myocardial perfusion by 129% (p < 0.001) in the stenosis-dependent myocardial areas with shortening of the wash-out half-life time of the echo contrast medium from a mean of 14 s to 5 s (p < 0.001). The isovolumetric relaxation was shortened by 13% (p < 0.05), the E wave by 5%, and dp/dtmin increased by 17% (p < 0.01). In summary, intracoronary application of enoximone led to an improvement in both systolic and diastolic LV function without concomitant peripheral effect due to regression of myocardial ischemia.

The internal mammary artery (IMA) is the preferred conduit for myocardial revascularization, but it changes diameter in response to injury or thromboxane release to decrease myocardial blood supply. Papaverine, a phosphodiesterase (PDE) inhibitor, is injected in the IMA bed during surgery to prevent spasm. We evaluated the ability of papaverine and cyclic adenosine monophosphate PDE Type III (cAMP-PDE) inhibitors (amrinone, enoximone, and milrinone) in vitro to reverse the constriction of human IMA rings, induced by a thromboxane A2 analog, U46619, and evaluated amrinone's ability to modify the constricting effect of norepinephrine (NE). All cAMP-PDE inhibitors produced complete relaxation of U46619-induced contractions. The contractions necessary to produce 50% relaxation (EC50) were within therapeutic ranges. The vasodilatory potency of amrinone was greater after NE than after U46619 (EC50, 1.9 +/- 0.5 vs 4.3 +/- 2.2 x 10(-5)M; mean +/- SD; P < 0.05). Response to constriction after a submaximal dose of NE was attenuated to 38% (P < 0.001) from that observed in the control rings by a pretreatment with amrinone. These results suggest that cAMP-PDE inhibitors have the potential utility to reverse IMA spasm, and represent a potential therapeutic modality for IMA spasm after myocardial revascularization.

We conducted a randomized, double-blind investigation to determine whether enoximone affects the actions of dobutamine in patients taking beta adrenoceptor antagonists. We studied sixteen patients with good ventricular function after coronary artery bypass operations. All patients were taking a beta adrenoceptor antagonist. The patients received a standardized intravenous anaesthetic, which was maintained throughout the investigation. They received a masked infusion, containing either normal saline or enoximone. Haemodynamic data were recorded before, during, and after an infusion of dobutamine, which was given at three different rates. Patients receiving enoximone had a greater cardiac output, a higher heart rate and a lower systemic vascular resistance than patients receiving saline. They also required an average of 1500 ml more intravenous colloid in the immediate postoperative period to achieve haemodynamic stability. Dobutamine produced a consistent, significant peripheral vasoconstriction, but no inotropic or chronotropic effect. There was no significant difference in this effect between the two groups, and it was not influenced by concurrent therapy with enoximone. The alpha adrenergic action of dobutamine prevented us from using high enough rates of infusion to explore any interaction between the inotropic actions of dobutamine and enoximone.

Study Objectives: We measured the individual and combined effects of the beta-agonist dobutamine and the phosphodiesterase inhibitor enoximone both in vitro and in vivo in the failing human heart., Design: This was an unblinded, prospective study., Setting and Patients: The in vitro measurements were performed on 20 hearts obtained from subjects with end-stage biventricular failure and from seven normal hearts. The in vivo measurements were performed in eight subjects with class IV heart failure., Interventions and Measurements: The in vitro measurements of enoximone, dobutamine, and the combination of these agents were phosphodiesterase activity using a sarcoplasmic reticulum-enriched preparation, cyclic adenosine monophosphate (cAMP) accumulation using particulate fractions, and tension response using isolated right ventricular trabeculae. The dose response to dobutamine, the combination of enoximone and dobutamine, and the combination of nitroprusside and dobutamine were measured in vivo using invasive hemodynamic monitoring., Results: In vitro, enoximone exhibited dose-dependent inhibition of phosphodiesterase activity. The addition of enoximone to dobutamine resulted in an upward and leftward shift of the dobutamine dose-response curve for both cAMP production and contractile response. In vivo, enoximone significantly shifted the dobutamine dose-response curves for cardiac index, left ventricular stroke work index, and heart rate upward and to the left; and shifted the dobutamine dose-response curves for right atrial, pulmonary arterial, and pulmonary wedge pressures downward and to the right., Conclusions: Enoximone exerts favorable effects on cardiac performance that are additive to those produced by dobutamine. These effects are mediated by increasing cellular cAMP concentrations through independent, additive mechanisms.

The pharmacokinetics of enoximone and its sulfoxide metabolite were investigated in healthy male volunteers after various intravenous administrations: 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.

Objectives: To determine the effects of enoximone on mortality and quality of life in patients with severe end stage heart failure., Design: A randomised, double blind, placebo controlled trial of the addition of enoximone to conventional treatment. Planned minimum follow up of one year., Setting: District general hospitals and cardiological referral centres in the United Kingdom., Patients: Planned 200 patients with severe, symptomatic heart failure despite treatment with diuretics and where appropriate and tolerated angiotensin converting enzyme inhibitors and digoxin., Results: The study was ended early by the ethics committee after 151 patients had been recruited because of an excess mortality in the enoximone group: 27 deaths compared with 18 in the placebo group (P < 0.05). Quality of life measured with a disease specific questionnaire showed a clinically significant improvement at week 2 with a mean increase score of 0.48 in the enoximone treated patients compared with 0.14 in those receiving placebo (P = 0.0086). With the Nottingham health profile questionnaire the physical mobility score was improved after three months in the enoximone group, median 21.3 compared with 41.8 in the placebo group (P = 0.008)., Conclusions: In patients with severe heart failure who remain incapacitated despite conventional treatment enoximone reduced survival but had a beneficial effect on the quality of life. Drugs that improve symptoms in severe end stage heart failure should not be discarded lightly.

Postoperative spasm of the internal mammary artery graft can cause morbidity and mortality after myocardial revascularization. To our knowledge, the ability of systemic vasodilators to overcome internal mammary artery spasm has not been studied clinically. In 50 patients in whom the left internal mammary artery was used for myocardial revascularization, we have investigated the effect of five agents on internal mammary artery free flow: normal saline, dobutamine, glyceryl trinitrate, sodium nitroprusside, and enoximone, a phosphodiesterase III inhibitor. After the internal mammary artery was harvested, free flow was measured under controlled hemodynamic conditions before any pharmacologic intervention (flow 1) and a mean of 18.5 +/- 3 (standard deviation) minutes after a systemic infusion of one of the five agents was begun (flow 2). The increase in free flow expressed as a percentage of initial flow was greater for enoximone (94% +/- 24%) than for normal saline (18% +/- 11%), dobutamine (40% +/- 27%), and glyceryl trinitrate (52% +/- 36%) (all three p < 0.01). The increase in flow for sodium nitroprusside (78% +/- 37%) was greater than for normal saline and dobutamine (both p < 0.05). We therefore recommend the systemic use of enoximone and sodium nitroprusside, in rank order, to prevent and treat postoperative spasm of the internal mammary artery.

Enoximone, a phosphodiesterase inhibitor (PDEI), has both positive inotropic and vasodilatory properties. We examined the effect of a single oral dose of enoximone as compared with placebo on myocardial ischaemia and global left ventricular (LV) function using both exercise ECG and Doppler measurements of aortic blood flow, respectively. Twenty patients (16 men, 4 women) with a mean age of 59 years and stable angina were studied. Total exercise duration was significantly longer after enoximone as compared with placebo treatment, with a mean difference of 22.8 s (p = 0.003). Times (mean +/- SD) to onset of angina and development of significant ST-segment decrease were similar after placebo (454 +/- 101 and 352 +/- 155 s, respectively) or enoximone (500 +/- 155 and 413 +/- 192 s, respectively), although both showed trends in favour of enoximone. As compared with placebo, significantly higher heart rate (HR) was measured for enoximone both at rest (75 +/- 18 vs. 90 +/- 22 beats/min, p < 0.01) and on recovery from exercise (81 +/- 18 vs. 89 +/- 19 beats/min, p < 0.05). Enoximone had no significant effect on systolic or diastolic blood pressure (SBP, DBP) or rate-pressure product (RPP) generated at rest or during exercise. Changes in both acceleration and velocity of aortic blood flow during exercise were similar after administration of enoximone or placebo. We showed that a single oral dose of enoximone is well tolerated in patients with ischaemic heart disease, improving both exercise capacity and favourably influencing ST-segment changes with no increase in adverse events or significant haemodynamic disturbances.

Objective: To evaluate efficacy and tolerability of enoximone, a phosphodiesterase inhibitor, in the treatment of cardiogenic shock., Design: A prospective non randomized, non comparative study., Setting: A general intensive care unit of a university hospital., Patients: Six patients with cardiogenic shock (cardiac index < 2.5 l/min/m2, PWP > 15 mmHg) unsuccessfully treated with catecholamines., Interventions: Enoximone was administered (0.5-1 mg/kg)by iv bolus according to clinical response (CI > or = 2.5 l/min/m2), then was continued by iv infusion (5-16 micrograms/kg/min). Dopamine infusion at low doses (3 micrograms/kg/min) was maintained during the study. In all patients a pulmonary artery catheter was inserted before the study began., Measurements and Main Results: Direct and measured (using standard formula) haemodynamic parameters were registered. Basal data (before treatment) were compared with values after 30 minutes (bolus) and 8 hours (maintenance). CI (+57%) and O2 delivery (+74.7%) were significantly increased after 30 minutes and 8 hours, O2 extraction ratio normalized whereas heart rate and systemic blood pressure were unchanged., Conclusions: Enoximone proved to be safe and effective in the treatment of cardiogenic shock. Its pharmacological effects combines inotropic and vasodilatant action without any change of heart rate thus avoiding an increase of O2 consumption in the jeopardized myocardium. Further studies will define better its routine use in critically ill patients with acute heart failure.

We performed a double-blind, placebo-controlled study to determine whether oral enoximone would aid weaning dobutamine-dependent patients. Twenty-four patients 64 +/- 10 years, with an echocardiographic ejection fraction of 0.20 +/- 0.06, and receiving maximal therapy were studied. After failure of dobutamine weaning, a dobutamine infusion was set up at 10 micrograms.kg-1.min-1 for 48 h. Oral enoximone (100 mg t.i.d.) or placebo was added from D0 for the next 28 days, while the dobutamine dosage was progressively decreased after D4 and eventually stopped at D7. The patients were then followed-up for 21 days (i.e. until enoximone administration had continued for 28 days). In the placebo group, two patients suffered a relapse of congestive heart failure (CHF) before D4, six patients withdrew during dobutamine tapering (five with a relapse of CHF and one with septic shock) and two during follow-up (one with a relapse of CHF and one with sustained ventricular tachycardia). In the enoximone group, three patients withdrew during dobutamine tapering (two with a relapse of CHF, one with a cutaneous rash). Four patients on placebo and nine receiving enoximone could be weaned from dobutamine, P < 0.05. Echocardiographic LV ejection fraction significantly increased and Doppler-derived indexes of systolic function tended to increase when enoximone but not placebo was associated with dobutamine. Oral enoximone might be helpful in weaning patients with end-stage congestive heart failure from i.v. dobutamine.

Keeping pre-transplant patients alive while waiting for a suitable donor to be found 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 18 transplant candidates with heart failure progression despite optimal drug regimen including digoxin, diuretics, and ACE-inhibitors. Complete hemodynamic, echocardiographic, and neurohumoral studies were performed before and 24 h after intravenous enoximone infusion. Enoximone infusion increased cardiac index (1.78 +/- 0.45 l/min/qm vs. 3.04 +/- 0.83 l/min/qm; p < 0.001) and stroke volume index (22.33 +/- 9.45 ml/qm vs. 32.28 +/- 7.29 ml/qm; p < 0.05) and decreased wedge pressure (24.1 +/- 11.98 mmHg vs. 17.78 +/- 8.76 mmHg; p < 0.05) and systemic vascular resistance (1700.8 +/- 555.8 dyn x s x cm-5 vs. 952.8 +/- 384.0 dyn x s x cm-5; p < 0.001). Heart rate and mean arterial pressure were unchanged. Left ventricular ejection time (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, left ventricular end-systolic dimension, fractional shortening, early diastolic relaxation parameter Te). Plasma neurohumoral parameters did not change (aldosterone, epinephrine, renin, atrial natriuretic factor) except for a significant drop of norepinephrine (936.7 +/- 443.2 pg/ml vs. 522.4 +/- 287.6 pg/ml; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

A refractory low-cardiac-output syndrome is, in pediatric patients, most often due to impaired myocardial function after corrective surgery in congenital heart disease. Therapy has to focus on postoperative adaptation, which usually takes place within a few days. We report on three therapeutic strategies to "bridge" this phase of postoperative adaptation. Improving the contractile state of the myocardium using enoximone was attempted in 16 neonates with low-cardiac-output syndrome refractory to catecholamines (Dosage: loading-dose 1 mg/kg in 10 min intravenously, followed by an infusion of 10 mcg/kg/min). In 12/16 neonates cardiac index increased by more than 20% ("responder"), while in 4/16 neonates cardiac index remained unchanged ("non-responder"). All non-responders succumbed due to refractory low-cardiac-output syndrome, while only one responder died in low-cardiac-output syndrome. Hemodynamically, enoximone resulted in an increase of cardiac index and stroke volume (p < 0.003), a reduced systemic vascular resistance (p < 0.0022), and reduced right and left atrial pressures (p < 0.003). Heart rate and mean arterial pressure remained unchanged. No rhythm disturbances were observed. Another therapeutic approach to postoperative low-cardiac-output syndrome is atrial decompression by creating an atrial septal defect. Due to the possibility of later transcatheter closure of these defects, the acceptance for the intraoperative creation of an atrial communication to decompress the right or left atrium is increased. The defect size is critical and should be below 9 mm, so that the Rashkind-PDA-Occluder can be used for later transcatheter closure. We performed such a "surgical-interventional" decompression in 18 patients (age: 2 weeks to 7 years). In six patients the atrial defect was created because of an underdeveloped left ventricle (body weight 2.9-9.2 kg), in 12 patients for right atrial decompression during a total cavopulmonary shunt (body weight 15.2-54.2 kg). A spontaneous closure of the defect did not occurred in any of the patients, thus, transvenous closure of the defect was performed 2 to 10 weeks postoperatively. In the follow-up period of 4 to 22 months no complications such as thrombus formation, thromboembolic events or infections occurred. In low-cardiac-output syndrome refractory to all therapeutic measures mechanical circulatory support is the final method to keep the patient alive. In 11 children with refractory low-cardiac-output syndrome mechanical circulatory support was performed. In three of these, extracorporal membrane oxygenation (ECMO) was used, in eight children a ventricular assist device (Berlin Heart) was used.(ABSTRACT TRUNCATED AT 400 WORDS)

Twelve patients with severe heart failure (NYHA class III-IV) were investigated by intraindividual comparison for the hemodynamic and neurohumoral effects of dopamine (3 and 6 micrograms/kg/min), enoximone (8 micrograms/kg/min), and the combination of both medications (dopamine 3 micrograms/kg/min+enoximone 8 micrograms/kg/min) using right heart catheterization. The duration of active treatment was 8 h for each substance with a subsequent washout time of 16 h. Dopamine led to a dose-dependent increase in cardiac index of 10-13% and 18-37% under 3 and 6 micrograms/kg/min, respectively (p < 0.001). Enoximone monotherapy produced a comparable increase in cardiac index between 27 and 32% (p < 0.001). Enoximone, but not dopamine, resulted in a significant decrease in mean pulmonary artery pressure (21-26%; p < 0.01), pulmonary capillary wedge pressure (24-30%; p < 0.01), and right atrial mean pressure (26-28%; p < 0.001). The systemic vascular resistance was without significant changes at low-dose dopamine therapy, decreased by 10-19% insignificantly at a dose of 6 micrograms/kg/min, and reached the level of significance with enoximone therapy (-20 to -25%; p < 0.001). There was a highly significant decrease by 49-55% in systemic vascular resistance with enoximone (p < 0.001), in contrast to dopamine. Heart rate and blood pressure remained without significant changes at low-dose dopamine, with the heart rate increasing significantly by 25% at a dose of 6 micrograms/kg/min within the first 2 h (p < 0.01). Enoximone produced a heart rate increase by 8-13% (being significant after 2 h; p < 0.05) with no changes in blood pressure. The combination therapy with dopamine and enoximone led to an additive increase in cardiac index by 35-43% (p < 0.001), a decrease in right atrial mean pressure by 28-36% (p < 0.01), a decrease in systemic vascular resistance by 27-30% (p < 0.01) and in pulmonary vascular resistance by 46-51%. An additive effect on heart rate was not observed. The respective monotherapies with low-dose dopamine and enoximone had no remarkable effect on plasma catecholamines, while dopamine at a dose of 6 micrograms/kg/min and combination therapy led to a significant increase in noradrenaline levels. There was a highly significant decrease in the plasma concentration of the atrial natriuretic factor under enoximone and combination therapy (p < 0.001) as well as a significant decrease in aldosterone (0 < 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

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)

Enoximone is an imidazole derivative which proved to be a selective inhibitor of the isoenzymes III/IV of the cAMP-specific phosphodiesterase. It has been shown in various experimental models that the drug exerts both positive inotropic and vasodilating properties which can be attributed to the proposed mode of action. A marked dose-dependent improvement in left ventricular pump performance was observed, with only minor changes in heart rate or systemic blood pressure, if enoximone was administered as i.v. -bolus to patients with moderate to severe congestive heart failure. These effects coincided with vasodilatory effects as determined by decreases in systemic vascular resistance and pulmonary capillary wedge pressure. Enoximone is eliminated by intensive metabolism, predominantly in the liver, with enoximone sulfoxide being the major metabolite in man. Enoximone exhibits a marked firstpass metabolism following oral administration. There is evidence in the literature that the metabolism can be saturated either during long-term administration or by increasing the dose of enoximone. In experimental settings, the metabolite exerts weak positive inotropic effects, too, and reconversion to the parent compound enoximone has been demonstrated in addition. The half-life of elimination of enoximone seems to be about 1 h in healthy volunteers and approximately 3 to 7 h in patients with congestive heart failure, with marked inter-individual differences. In patients with renal failure mainly enoximone sulfoxide accumulates in plasma depending on the degree of renal impairment. The elimination of enoximone seems to be impaired in these patients, too, which might be caused by enhanced reconversion due to the high plasma concentrations of the metabolite.(ABSTRACT TRUNCATED AT 250 WORDS)

When enoximone is acutely administered to patients with stable angina and angiographically proven relevant coronary stenosis i.v. application of 0.75 mg/kg exhibits pronounced antiischemic effects. This could be observed in patients during exercise and in those in whom the ischemia was provoked by rapid cardiac stimulation. The antiischemic effects were documented by relief of symptoms, reduction of ST-depression, improvement of impaired myocardial wall motion, decrease to normalization of pathologically elevated filling pressure, amelioration of coronary blood flow as evidenced by myocard scintigraphy and washout time of an intracoronarily injected echo-contrast medium. There was also a definite improvement of ischemia-caused mitral regurgitation. Similar observations were found when the drug was injected in the diseased coronary arteries in a small dose (0.075 mg/kg) so that peripheral effects were not present. In comparison to the Ca(++)-blocker Gallopamil the antiischemic effects of Enoximone were more pronounced, a synergistic action was, however, observed. Negative dromotropic effects of Gallopamil could be abolished by Enoximone. With oral administration of the drug over a period of one week antiischemic effects could also be documented with Holter monitoring as well as during exercise. There was a reduction of ST-depression both at spontaneously occurring ischemic episodes and during exercise, in the number and duration of episodes of silent ischemia, particularly, however, a decrease in symptomatic episodes. In none of the patients under study proarrhythmic effects were observed.

Children undergoing cardiac surgery are at additional risk for postoperative low cardiac output syndrome (LCOS). Anticipation of the syndrome from preoperative hemodynamic condition, surgical procedure, and adverse intraoperative events is a key to successful postoperative management. Inotropic support is primarily based on catecholamines. However, uncoupling of human cardiac beta-adrenoceptors during cardiopulmonary bypass with cardioplegic cardiac arrest may be the reason why many patients respond only weakly to beta-adrenoceptor agonists. Phosphodiesterase (PDE) inhibitors act by reducing intracellular breakdown of cAMP, which is elevated independently from beta-receptors. The use of PDE-inhibitors might be advantageous in patients with uncoupled beta-adrenoceptors, as occurs after cardiopulmonary bypass. In addition, PDE-inhibitors can prevent further downregulation of the adrenoceptors due to avoiding prolonged therapy by beta-agonists. In this context, the addition of enoximone, a PDE-inhibitor, to adrenergic agents has been found useful in increasing cardiac output in children with catecholamine-resistant LCO, as well as in children with compensated hemodynamics during catecholamine therapy.

The present definitions of low-output syndrome (LOS) associated with cardiac surgery are based on data obtained via the Swan-Ganz-catheter. However, further important data such as signs of chronic renal insufficiency, arterial vascular disease, and perioperative volume overload have hardly been considered. At the Heart Center NRW, FRG, the Swan-Ganz-Catheter is not used routinely to monitor patients following cardiac surgery. According to our experience, the definition of low-output syndrome includes a wider spectrum of relevant criteria. In addition to the data obtained by means of a central venous catheter the clinical aspect of the patient as well as laboratory analysis should be regarded as well. In 1259 consecutive patients (pts) (914 with coronary surgery and 318 with valve surgery) the incidence and mortality of low-output syndrome were determined. In 49 of the 941 coronary surgery pts (5.2%) a postoperative low-output syndrome occurred. Nine pts (0.95%) died as a result of this complication. According to our therapeutical strategy, the low-output syndrome was treated medically in 28 pts (2.9%); in 14 pts (1.5%) IABP implantation was necessary, and 7 pts needed mechanical circulatory support. Surprisingly, the same incidence of LOS occurred in the valve surgery group of pts as in the coronary group. We saw a low-output syndrome in 17 of the 318 pts (5.3%), with fatal outcome in three pts. In 14 of these pts (4.4%) the LOS was treated medically, while the remaining three pts (0.9%) required diastolic augmentation of the IABP.

The phosphodiesterase inhibitor enoximone has both vasodilating and positive inotropic pharmacological properties. The balance between vasodilation and positive inotropism may be different between the various types of heart failure as well as the various stages of heart failure. Therefore, we investigated the effect of intravenous application of enoximone (1 mg/kg body weight) in a cohort of patients (n = 10) suffering from acute or subacute heart failure mainly due to ischemia or hypoxia. All patients had high left ventricular filling pressure, low cardiac output and were pretreated with intravenous dobutamine. Enoximone increased cardiac output from 3.2 +/- 1.2 to 5.5 +/- 2.2 l/min, increased heart rate from 94 +/- 20 to 100 +/- 18 beats/min, decreased systemic peripheral resistance from 1770 +/- 861 to 931 +/- 340 dyn.sec.cm-5 and decreased pulmonary wedge pressure from 24 +/- 5 to 20 +/- 6 mmHg, significantly. However, systolic aortic pressure, systolic pulmonary pressure and right atrial pressure were not significantly altered. We conclude that in a selected group of patients enoximone-given intravenously and acutely in the intensive care unity-can induce beneficial effects on central hemodynamics without critical falls in perfusion pressure.

Ten patients with low cardiac output syndrome (LCOS, cardiac index [CI] = 1.8 +/- 0.24 L.min-1.m-2, pulmonary artery occlusion pressure [PAOP] = 19 +/- 4 mmHg, systolic arterial pressure [APsys] = 76 +/- 5 mmHg) were treated with catecholamines and nitroglycerin. This therapy achieved stable hemodynamic conditions (CI 2.5 +/- 0.2 L.min-1.m-2, PAOP 14 +/- 5 mmHg, APsys = 110 +/- 17 mmHg). Addition of enoximone (bolus dose 1.0 mg.kg-1 followed by continuous infusion of 7 micrograms.kg-1.min-1) induced an increase of CI to 3.6 +/- 1.3 L.min-1.m-2 (p < 0.05) and of left ventricular stroke work index (LVSWI) from 21.8 +/- 3.6 g.m.m-2 to 29.3 +/- 10.1 g.m.m-2 (p < 0.05). Systemic vascular resistance decreased from 1300 +/- 415 dyn.s.cm-5 to 972 +/- 390 dyn.s.cm-5 (p < 0.01). No alterations of heart rate, mean arterial or pulmonary arterial pressure and PAOP were observed. Likewise, enoximone had no effect on gas exchange. Oxygen consumption index (VO2I) was elevated from 83 +/- 22 mL.min-1.m-2 to 126 +/- 31 mL.min-1.m-2 (p < 0.01) and oxygen delivery index (DO2I) increased from 348 +/- 112 mL.min-1.m-2 to 498 +/- 206 mL.min-1.m-2 (p < 0.05). In contrast, oxygen extraction ration remained unchanged (29 +/- 10% n.s.). Oxygen consumption and delivery were significantly lower during treatment of LCOS with catecholamines and nitroglycerin when compared with a matched group of patients without postoperative cardiac failure.(ABSTRACT TRUNCATED AT 250 WORDS)

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)

Intravenous infusions of enoximone or dobutamine were given, using a double dummy technique, in a randomized, double-blind study, to 18 patients with acute myocardial infarction who had persisting signs of left ventricular failure after treatment with intravenous diuretics. Blood pressure, heart rate and cardiac output, by transcutaneous Doppler aortovelography, were measured and any arrhythmias recorded by Holter monitoring. Eight of the nine enoximone treated patients showed clinical improvement. One patient in the enoximone group failed to respond and subsequently died. Five of the nine dobutamine treated patients showed clinical improvement. The other four patients in the dobutamine group experienced tachyarrhythmias and were withdrawn from the study; one of these patients also deteriorated and died. There were no significant differences in systolic or diastolic blood pressure either within or between the two treatment groups during the study. Enoximone increased cardiac output by 32% (P = 0.003), and dobutamine by 46% (P < 0.001); there was no significant difference between groups. Dobutamine also significantly increased heart rate from a mean of 108 beats.min-1 to 117 beats.min-1 (P < 0.001). There was no difference between the two groups in ventricular ectopic counts, but dobutamine produced significantly more runs of supraventricular and ventricular tachycardia (P = 0.0003). Enoximone was better tolerated with fewer side-effects than dobutamine in doses which produced similar increases in cardiac output. In the setting of an acute myocardial infarction when inotropic therapy is indicated, enoximone is a better choice than dobutamine.

The aim of this study was to evaluate the efficacy and safety of enoximone, an imidazolonic compound inhibiting cardiac phosphodiesterase III, during the postoperative period. The drug was administered prior to the usual stages of weaning the patient off extracorporeal circulation, to a group of 20 subjects who presented an ejection fraction of less than 35% following hemodynamic studies. Patients were randomly subdivided into 4 groups each of which received a different dose of enoximone according to the following protocol: Group A, 1 mg/kg bolus and slow infusion at 10 gamma/kg/min; Group B, 0.5 mg/kg bolus and slow infusion at 15 gamma/kg/min; Group C, 0.5 mg/kg bolus and slow infusion at 10 gamma/kg/min; Group D, slow infusion at 10 gamma/kg/min. The best results in hemodynamic terms and with regard to the positive inotropic and vasodilatory action of the drug in question were obtained in Group C. Increased cardiac output was observed in all patients within 120 minutes of enoximone administration and reduced systemic vascular resistance after approximately 6 hours of infusion. Special attention should be drawn to the use of the drug in patients who do not respond to conventional therapy due to its mechanism of action which is not dependent on beta receptors, thus enabling good results to be achieved even when these are down regulated. Special care must be taken however in administrating enoximone to platelet-deficient patients since the reduction of platelet levels is one of its collateral effect. Other collateral effects observed were: supraventricular arrhythmias and ventricular tachyarrhythmias.