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.

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.

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.

[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.

[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 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.

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.

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.

[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.

[Neurohumoral and hemodynamic effects in combination therapy of enoximone and dopamine]. / Neurohumorale und hämodynamische Effekte in der Kombinationstherapie von Enoximon und Dopamin.

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)

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)

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

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

[Enoximone in the postoperative phase of heart surgery]. / Enoximon in der postoperativen Phase der Herzchirurgie.

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)

[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.

[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)

[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.

[Treatment of low cardiac output syndrome in newborn infants and children]. / Behandlung des Low-cardiac-output-Syndromes bei Neugeborenen und Kindern.

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)