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.

Pharmacological bridge to cardiac transplantation: current limitations.

Addition of intravenous enoximone to sympathomimetic agents permits a rapid and drastic improvement in the clinical and hemodynamical condition of patients in cardiogenic shock referred for a mechanical bridge to transplantation. The present experience, based on the management of 52 patients, permits us to point out the current limitations of this pharmacological bridge: the rate of sudden death, the incompleteness of the physical rehabilitation of the patients, and the vanishing effect of intravenous enoximone.

Acute left ventricular dysfunction and subarachnoid hemorrhage.

OBJECTIVE: Severe left ventricular (LV) dysfunction associated with acute subarachnoid hemorrhage (SAH) due to cerebral aneurysm rupture. SETTING: An adult 12-bed surgical intensive care unit of a university hospital. PATIENT: A female patient presenting with SAH (Hunt & Hess grade III) and severe left ventricular dysfunction. INTERVENTIONS: Central venous pressure, arterial blood pressure, extravascular lung water catheter, transesophageal echocardiography, blood gas analysis, electrocardiograms, and chest x-ray for clinical management. MEASUREMENTS AND MAIN RESULTS: On admission to the district hospital, an electrocardiogram (ECG) revealed a sinus rhythm with transient ST elevations. A transesophageal echocardiography showed a left ventricular ejection fraction (LV-EF) of approximately 10%. Severe LV dysfunction required inotropic and vasopressor support to maintain mean arterial pressure above 60 mmHg, while the first measurement of an extravascular lung water catheter revealed a cardiac index of 2.0 L/min/m2 and moderate hypovolemia. Despite stepwise volume loading that increased intrathoracic blood volume--an indicator of cardiac preload--from 719 mL/m2 to 927 mL/m2, cardiac index remained poor. Enoximone lead to a marked increase of cardiac index up to 3.9 L/min/m2 and LV-EF to about 30%, but had to be stopped due to thrombopenia. Surgical clipping of an intracranial aneurysm was postponed because of the impaired cardiac function and was performed on day 18 after admission. Interestingly, neurologic outcome was not as poor as might be expected from the literature. CONCLUSION: Severe left ventricular dysfunction may occur in acute SAH and may necessitate delay of aneurysm surgery.

Treatment of severe heart failure: quantity or quality of life? A trial of enoximone. Enoximone Investigators.

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.

Efficacy of enoximone in the management of refractory low-output states following cardiac surgery.

Fifteen consecutive patients with post-cardiac surgery low-output states refractory to catecholamine inotropic support and intra-aortic balloon counter-pulsation (seven patients), were given enoximone (MDL 17,043, a phosphodiesterase inhibitor), 1 to 2 mg/kg, as a slow intravenous bolus injection, followed by a continuous infusion of 3 to 10 microg/kg/min. Enoximone resulted in a marked improvement in clinical and hemodynamic conditions. Despite the severity of their initial status, all the patients survived their acute circulatory failure and all but two were discharged from the hospital. Hemodynamic improvement was observed as early as 15 minutes after the drug administration and reflected the previously reported inotropic and vasodilatory properties of enoximone. No serious adverse effects were observed. Enoximone thus appears safe and effective in the management of post-cardiac surgery low-output states. Its effects are additive to those of high-dose catecholamines.

[Clinico-pharmacologic aspects of therapy with enoximone]. / Klinisch-pharmakologische Aspekte der Therapie mit Enoximon.

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)

[Enoximone--clinical experiences in heart surgery]. / Enoximon--klinische Erfahrungen in der Herzchirurgie.

In 1991 and 1992, we introduced the new phosphodiesterase-III-inhibitor, enoximone, in the treatment of cardiac low-output-syndromes in the early phase after valve replacement or coronary bypass grafting. We introduced enoximone in cases which met the following criteria: cardiac index < or = 2.4 l/min/m2; systolic arterial pressure < or = 90 mmHg; left ventricular filling pressure > or = 20 mmHg despite the use of dopamine (> or = 12 micrograms/kg/ min); epinephrine (> or = 0.12 microgram/kg/min) and glyceroltrinitrate (1 microgram/kg/min). After clarification of preoperative risk factors and postoperative complications, retrospective evaluation of complete haemodynamic monitoring in patients after valve replacement (14 out of 86) and patients after coronary bypass grafting (22 out of 228) led to the following conclusions. Enoximone is of essential importance for the treatment of cardiac low-output at the end of extracorporeal circulation, particularly in cases complicated by preoperative myocardial deterioration. The use of enoximone is especially effective combined with beta-sympathomimetics as a result of elevation of cAMP-levels in two ways: by stimulation of beta-adrenoceptors directly and by inhibition of phosphodiesterase. Cardiac indices early after bypass, compared with measurements taken before bypass, reveal a clear rise indeed caused by increase in heart rate. Only in patients who underwent coronary bypass grafting did we observe a moderate increase in stroke volume indices. The therapeutic principle of using vasodilators--to lower peripheral resistance for improving stroke volume --appears to be effective immediately after extracorporeal circulation only in part. The vasodilating effect of enoximone has to be constantly compensated for by volume supplementation and alpha-mimetic stimulation, especially after valve replacement surgery. In contrast to this, we continued the application of glyceroltrinitrate in about 25% of the cases. Coronary surgery patients tolerated the vasodilating action particularly well; consequently, despite inotropic stimulation to a high degree, these patients showed no additional signs of ischaemia. Based on our therapeutic measures, the therapy led to very good short-term results. However, this therapeutic regime failed in patients suffering from extended myocardial infarction or irreversible pulmonary hypertension.

[Treatment of acute low cardiac output syndrome after surgery of congenital heart defects: value of enoximone]. / Behandlung des akuten Low-cardiac-output-Syndroms nach Operationen angeborener Herzfehler: Stellenwert von Enoximon.

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.

Oral enoximone as a substitute for intravenous catecholamine support in end-stage congestive 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.

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

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

Comparison of the haemodynamic effects of enoximone and piroximone in patients after cardiac surgery.

We have compared the haemodynamic effects of the imidazole derivative phosphodiesterase inhibitors enoximone and piroximone in patients with low cardiac output after cardiac surgery. Ten patients (group E) received enoximone and 10 patients (group P) received piroximone, both at a loading dose of 0.5 mg kg-1 followed by an infusion of 5 micrograms kg-1 min-1. In both groups the main changes with time were increases in cardiac index (maximum 24.5% in group E, 25.8% in group P) and decreases in systemic vascular resistance (maximum 26.8% in group E and 24.8% in group P). There were moderate increases in heart rate (maximum 11.3% in group E and 13% in group P) but a greater percentage decrease in mean arterial pressure in group E (maximum 11.9% vs 7.9%) with time. One patient in group E developed hypertension during the loading dose. Two patients in group E and two in group P developed hypotension during the loading dose. One patient in group E developed ventricular extrasystoles which may have been related to the drug being studied.

Intravenous enoximone or dobutamine for severe heart failure after acute myocardial infarction: a randomized double-blind trial.

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.

Low-dose enoximone therapy in pre-transplant patients: hemodynamic, echocardiographic, and neurohumoral findings.

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)

[New avenues in therapy of postoperative low output syndrome]. / Neue Wege in der Therapie des postoperativen Low-output-Syndroms.

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.

Enoximon-echocardiography. A new diagnostic approach for the detection of viable myocardium comparison to dobutamin-echocardiography.

UNLABELLED: Hypo- or akinetic myocardial regions can be identified as viable myocardium through recruitment of inotropic reserve. Both, dobutamine (D) as well as enoximone (E) mediate their inotropic action via an increase in intracellular c-AMP concentration based on a different action. In 10 patients with documented myocardial infarction either D (5 to 40 micrograms/kg/min, increments of 5 micrograms/kg/min every 3 min) or E (1 to 9 micrograms/kg/min, increments of 1 microgram/kg/min every 2 min) was administered intravenously on two consecutive days. Heart rate (HR), systolic and diastolic blood pressure (BP), as well as a wall motion score in 16 segment (WMS) and ejection fraction (EF) with 2D-echocardiography were determined at rest and during each increment. Viability of myocardial regions was assessed with 201thallium-SPECT (Table 1). RESULTS: *p < 0.05 vs. rest, data: mean +/- SD. While E did not cause any side effects, patients complained about rash (n = 10), headache (n = 8), angina pectoris (n = 5), and anxiety (n = 2) during the administration of D. D and E are both able to recruit a potential inotropic reserve in infarcted myocardium, and thus, identify viable myocardium. In contrast to E, D caused an increase in HR and systolic BP. Enoximone-echocardiography seems to be a new, promising tool for the identification of viable myocardium.

The influence of clinical intervention on pressure-volume relationships--the conductance (volume) technique.

We analysed end-systolic pressure-volume relations (ESPVR), using the conductance technique, to study the potential inotropic effects of (1) PDE inhibitor drugs, (2) class 1 anti-arrhythmic drugs and (3) PTCA-induced myocardial ischaemia (MIS). The question of contractility involvement is of clinical importance, since with inotropy-induced rise in MVO2 there is a risk of MIS, should any of the cardiotonic drugs (amrinone, enoximone, piroximone) be used in patients with CAD. Accordingly, we analysed their haemodynamic effects, identified improved contractility as one factor of these drugs' mode of action and proved their inability to induce MIS. Anti-arrhythmic drugs may cause cardiodepression, a risk theoretically well recognized but clinically poorly defined. We monitored the haemodynamics of six class 1 anti-arrhythmic drugs and found that drug-induced moderate impairments of contractility (at rest and during tachycardia) proved significant, but clinically asymptomatic, and did not differ significantly from drug to drug. PTCA provides routine models of MIS in man. We analysed ESPVR and haemodynamics during MIS with PTCA and coronary angiography (CORO) and the induced diminished LV function during CORO v PTCA appeared quantitatively less. Inotropy impairment was rather modest during ischaemia: dP/dtmax was reduced by 11%, slope k of the ESPVR by 14%, while the EDV was increased by 67%. All changes were reversible about 90 s after PTCA balloon occlusion and 20 s after CORO.

[Acute effects of enoximone after intracoronary administration on hemodynamics, myocardial perfusion and regional wall motion]. / Akutauswirkungen von Enoximon nach intrakoronarer Applikation auf die Hämodynamik, Myokardperfusion und die regionale Wandbewegung.

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.

Identification of viable myocardium early after acute myocardial infarction under beta-blockade by enoximone echocardiography.

The influence of the beta-blocker metoprolol on the capacity either of low-dose dobutamine echocardiography or the recently introduced enoximone echocardiography to detect viable dysfunctioning myocardium after myocardial infarction was investigated. Initial clinical experience would suggest that the phosphodiesterase III inhibitor enoximona could be an alternative pharmacological stimulation, inducing an increase in contractility in the presence or absence of beta-receptor stimulation. Ten patients with a baseline low-dose dobutamine-echocardiographic test (up to 10 micrograms/kg/min) positive for myocardial viability in > or = 1 segment(s), performed 4-5 days after a first acute myocardial infarction treated with rtPA, were randomized after the administration of intravenous metoprolol (15 mg in three 5-mg boluses) either to dobutamine (up to 15 micrograms/kg/min) or to an enoximone intravenous bolus (1 mg/kg over 5 min) under echocardiographic monitoring, in a crossover sequence, with a 24-h interval. The infarct related artery was patent (TIMI grade 2 o 3) in all the patients. Follow-up echocardiograms were performed 5-7 weeks later. Resting asynergy was found in 40 segments; of these, 17 were viable. All the viable segments remained unresponsive during the post-metoprolol dobutamine infusion, while improved their contractility during enoximone echocardiography. Two patients suffering from early post-infarction angina underwent coronary angioplasty successfully. Eight out of ten patients (2 revascularized and 6 not) showed contractile recovery in a total of 14 segments at the follow-up echocardiogram. Sensitivity, specificity and overall accuracy in predicting reversible dysfunction after acute myocardial infarction for enoximone echocardiography were 93, 85, and 88%, respectively. Our results support the value of enoximone echocardiography in the identification of myocardial viability after myocardial infarction, in patients treated with beta-blockers, which interfere heavily with the results of dobutamine echocardiography.

[Use of enoximone in patients with acute and subacute heart failure in the intensive care unit]. / Einsatz von Enoximon bei Patienten mit akuter und subakuter Herzinsuffizienz auf der Intensivstation.

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.

[The anti-ischemic effect of phosphodiesterase III inhibitors]. / Antiischämische Wirkung von PDE-III-Hemmern.

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.