The Potential Role of Aerosolized Phosphodiesterase 3 Inhibitor Enoximone in the Management of Coronavirus Disease 2019 Hypoxemia: A Case Report.

Despite the various parenchymal presentation of coronavirus disease 2019 (COVID-19) pneumonia, the involvement of the vascular component, the reduction of perfusion in noninjured part of the lung and secondary right to left shunt play an important role in the genesis of the respiratory insufficiency. We present the case of a 72-year-old woman admitted to Livorno Hospital for severe respiratory insufficiency due to SARS-CoV-2 infection unresponsive to noninvasive in whom administration of nebulized phosphodiesterase 3 (PDE3) inhibitor enoximone was able to improve oxygenation avoiding tracheal intubation. Intravenous infusions of phosphodiesterase inhibitors are commonly used as pulmonary vasodilators in the management of pulmonary hypertension. This is the first case showing that inhaled route administration of PDE3 inhibitor enoximone could be important in the management of COVID-19 hypoxemia, to restore perfusion in noninjured part of the lung, improving oxygenation and avoiding risks of systemic infusion.

Conventional hemodynamic resuscitation may fail to optimize tissue perfusion: an observational study on the effects of dobutamine, enoximone, and norepinephrine in patients with acute myocardial infarction complicated by cardiogenic shock.

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.

Emergency treatment of status asthmaticus with enoximone.

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.

Perioperative administration of enoximone and renal function after cardiac surgery: a propensity-matched analysis.

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.

Enoxaparin, effective dosage for intensive care patients: double-blinded, randomised clinical trial.

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.

Effects of low-dose oral enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced heart failure: the randomized, double-blind, placebo-controlled, parallel group ESSENTIAL trials.

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.

Influence of continuous perioperative beta-blockade in combination with phosphodiesterase inhibition on haemodynamics and myocardial ischaemia in high-risk vascular surgery patients.

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.

Influence of calcium chloride on the cardio-respiratory effects of a bolus of enoximone in isoflurane anaesthetized ponies.

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.

Cardiorespiratory effects of enoximone in anaesthetised colic horses.

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.

Effects of enoximone on peripheral and central chemoreflex responses in humans.

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.

Low-dose oral enoximone enhances the ability to wean patients with ultra-advanced heart failure from intravenous inotropic support: results of the oral enoximone in intravenous inotrope-dependent subjects trial.

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.

Cardiovascular effects of enoximone in isoflurane anaesthetized ponies.

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.

Combined use of ultra-short acting beta-blocker esmolol and intravenous phosphodiesterase 3 inhibitor enoximone.

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.

Rationale and design of the enoximone clinical trials program.

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.

Natriuretic peptides and E-selectin as predictors of acute deterioration in patients with inotrope-dependent 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.

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 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.

Comparison of enoximone, amrinone, or levosimendan enriched St. Thomas' hospital cardioplegic solutions used for myocardial preservation in isolated guinea pig hearts.

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.

Low-dose enoximone improves exercise capacity in chronic heart failure. Enoximone Study Group.

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.

Effects of the phosphodiesterase-III inhibitor enoximone on skeletal muscle specimens from malignant hyperthermia susceptible patients.

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.

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.