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At least 199 records · Page 11Linked to original sources
PubMed2005

Comparison between dobutamine and levosimendan for management of postresuscitation myocardial dysfunction.

OBJECTIVE: To investigate the effects of levosimendan, a nonadrenergic inotropic calcium sensitizer, in comparison with adrenergic dobutamine for the management of postresuscitation myocardial dysfunction following resuscitation from prolonged cardiac arrest. DESIGN: Randomized prospective animal study. SETTING: Animal research laboratory. SUBJECTS: Male Yorkshire-cross domestic pigs INTERVENTIONS: Ventricular fibrillation was induced in male domestic pigs weighing between 35 and 40 kg. Cardiopulmonary resuscitation, including precordial compression and mechanical ventilation, was started after 7 mins of untreated cardiac arrest. Electrical defibrillation was attempted after 5 mins of cardiopulmonary resuscitation. Each animal was successfully resuscitated without pharmacologic intervention. Resuscitated animals were randomized to treatment with levosimendan, dobutamine, or saline placebo. The inotropic agents or an equivalent volume of placebo diluents was administered 10 mins after restoration of spontaneous circulation. Levosimendan was administered in a loading dose of 20 microg.kg over 10 mins followed by a 220-min infusion of 0.4 microg.kg.min. Dobutamine was infused into the right atrium in an amount of 5 microg.kg.min. Treatment was continued for a total of 230 mins. MEASUREMENTS AND MAIN RESULTS: Levosimendan and dobutamine produced comparable increases in cardiac output. However, levosimendan produced significantly greater left ventricular ejection fraction and fractional area changes compared with dobutamine and saline placebo. CONCLUSIONS: Levosimendan has the potential of improving postresuscitation myocardial function. It is likely to serve as an alternative to dobutamine as an inotropic agent for management of postresuscitation myocardial dysfunction.

Analysis of Variance↗
PubMed2006

Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: a pilot study.

OBJECTIVE: Acute respiratory distress syndrome (ARDS) is frequently associated with increased pulmonary vascular resistance and thus with systolic load of the right ventricle. We hypothesized that levosimendan, a new calcium sensitizer with potential pulmonary vasodilator properties, improves hemodynamics by unloading the right ventricle in patients with ARDS. DESIGN: Prospective, randomized, placebo-controlled, pilot study. SETTING: Twenty-two-bed multidisciplinary intensive care unit of a university hospital. PATIENTS: Thirty-five patients with ARDS in association with septic shock. INTERVENTIONS: Patients were randomly allocated to receive a 24-hr infusion of either levosimendan 0.2 microg/kg/min (n = 18) or placebo (n = 17). Data from right heart catheterization, cardiac magnetic resonance, arterial and mixed venous oxygen tensions and saturations, and carbon dioxide tensions were obtained before and 24 hrs after drug infusion. MEASUREMENTS AND MAIN RESULTS: At a mean arterial pressure between 70 and 80 mm Hg (sustained with norepinephrine infusion), levosimendan increased cardiac index (from 3.8 +/- 1.1 to 4.2 +/- 1.0 L/min/m) and decreased mean pulmonary artery pressure (from 29 +/- 3 to 25 +/- 3 mm Hg) and pulmonary vascular resistance index (from 290 +/- 77 to 213 +/- 50 dynes/s/cm(5)/m(2); each p < .05). Levosimendan also decreased right ventricular end-systolic volume and increased right ventricular ejection fraction (p < .05). In addition, levosimendan increased mixed venous oxygen saturation (from 63 +/- 8 to 70 +/- 8%; p < .01). CONCLUSIONS: This study provides evidence that levosimendan improves right ventricular performance through pulmonary vasodilator effects in septic patients with ARDS. A large multiple-center trial is needed to investigate whether levosimendan is able to improve the overall prognosis of patients with sepsis and ARDS.

Aged↗
PubMed2006

Effects of levosimendan versus dobutamine on pressure load-induced right ventricular failure.

OBJECTIVE: A transient increase in pulmonary arterial (PA) pressure can persistently depress right ventricular (RV) contractility. We investigated the effects of dobutamine and levosimendan on RV-PA coupling in this model of RV failure. DESIGN: Prospective, controlled, randomized animal study. SETTING: University research laboratory. SUBJECTS: Fifteen anesthetized dogs. INTERVENTIONS: Transient (90-min) PA constriction to induce persistent RV failure. Random assignment to dobutamine 5 and 10 microg/kg/min or levosimendan 12 microg/kg for 10 mins followed by 0.1 and 0.2 microg/kg/min. MEASUREMENTS AND MAIN RESULTS: We measured PA distal resistance and proximal elastance by pressure-flow relationships and vascular impedance. We measured RV contractility by the end-systolic pressure-volume relationship (Ees), PA effective elastance by the end-diastolic to end-systolic relationship (Ea), and RV-PA coupling efficiency by the Ees/Ea ratio. PA constriction persistently increased PA resistance and elastance, increased Ea from 0.95 +/- 0.07 to 3.01 +/- 0.28 mm Hg/mL, decreased Ees from 1.17 +/- 0.09 to 0.58 +/- 0.07 mm Hg/mL, and decreased Ees/Ea from 1.26 +/- 0.09 to 0.22 +/- 0.03 (p < .05). Dobutamine did not affect pulmonary hemodynamics, markedly increased RV contractility, and improved RV-PA coupling. Levosimendan decreased PA resistance and elastance, increased RV contractility, and restored RV-PA coupling. Compared with dobutamine, levosimendan decreased RV afterload and therefore better restored RV-PA coupling at similar inotropic state. CONCLUSIONS: A transient increase in PA pressure persistently worsens PA hemodynamics, RV contractility, RV-PA coupling, and cardiac output. Levosimendan restores RV-PA coupling better than dobutamine because of similar inotropic effects and additional pulmonary vasodilatory effects.

Animals↗
PubMed2007

Mechanisms of a reduced cardiac output and the effects of milrinone and levosimendan in a model of infant cardiopulmonary bypass.

OBJECTIVES: A low cardiac output state is an important cause of morbidity after pediatric cardiopulmonary bypass. The objectives of our study were to define the early precipitants of the reduced cardiac output and to investigate the effects on these of milrinone and levosimendan in a model of pediatric cardiopulmonary bypass. DESIGN: Experimental study. SETTING: : Research laboratory at a university-affiliated, tertiary pediatric center. SUBJECTS: Eighteen piglets. INTERVENTIONS: Piglets, instrumented with systemic, pulmonary arterial, and coronary sinus catheters, pulmonary and circumflex arterial flow probes, and a left ventricular conductance-micromanometer-tipped catheter, underwent cardiopulmonary bypass with aortic cross-clamp and cardioplegic arrest. At 120 mins, they were assigned to control, milrinone, or levosimendan groups and studied for a further 120 mins. MEASUREMENTS AND MAIN RESULTS: In controls, between 120 and 240 mins, cardiac output decreased by 15%. Systemic vascular resistance was unchanged, but pulmonary vascular resistance increased by 19%. Systemic arterial elastance increased by 17%, indicating increased afterload. End-systolic elastance was unchanged, and coronary sinus oxygen tension decreased by 4.0 +/- 1.7 mm Hg. In animals receiving milrinone cardiac output was preserved, and in animals receiving levosimendan cardiac output increased by 14%. Both drugs prevented an increase in arterial elastance and pulmonary vascular resistance after cardiopulmonary bypass. Systemic vascular resistance decreased by 31% after levosimendan, and end-systolic elastance increased by 48%, indicating improved contractility. Both agents prevented a decrease in coronary sinus oxygen tension. CONCLUSIONS: Increased afterload, which is not matched by an equivalent elevation in contractility, contributes to the reduced cardiac output early after pediatric cardiopulmonary bypass in this model. This increase is prevented by milrinone and levosimendan. Both agents exert additional beneficial effects on pulmonary vascular resistance and myocardial oxygen balance, although levosimendan has greater inotropic properties.

Age Factors↗
PubMed2007

Severe stunned myocardium after lightning strike.

OBJECTIVE: To report the development of myocardial stunning and severe heart failure after lightning strike with total recovery of function. DESIGN: Case report. SETTING: Coronary care unit at Medica Sur Clinic, Mexico. PATIENT: A 42-yr-old woman who was hit by lightning developed rapid and progressive hemodynamic deterioration manifested by cardiogenic shock that required invasive monitoring. Twenty-four hours after the strike, intravenous levosimendan and intra-aortic balloon pump were initiated because the patient demonstrated no significant response to management with conventional inotropic agents. Two days later, echocardiographic signs of systolic and diastolic dysfunction improved markedly. Dual-isotope-imaging myocardial perfusion testing with technetium-99m-sestamibi and thallium-201, performed 9 days after admission, showed normal perfusion and normal left ventricular systolic function. The patient exhibited complete recovery of function. The exact mechanism of abnormal contractility in the absence of direct electrofulguration is unknown but may be explained by release of oxygen free radicals, proteolysis of the contractile apparatus, and cytosolic overload of intracellular calcium, followed by reduced myofilament sensitivity to calcium. These abnormalities are consistent with stunned myocardium. CONCLUSIONS: Lightning strike may cause serious contractile dysfunction in the absence of irreversible myocardial injury, but the exact mechanism of this phenomenon remains unknown. We propose that lighting strike can cause myocardial stunning resulting in severe but reversible left ventricular dysfunction. The patient's recovery was facilitated by support treatment including administration of levosimendan, which increases the intracellular sensitivity to calcium, a mechanism disturbed in patients with myocardial stunning.

Adult↗
PubMed2004

Effect of levosimendan on balance between ATP production and consumption in isolated perfused guinea-pig heart before ischemia or after reperfusion.

Levosimendan is a novel drug developed for treatment of decompensated heart failure. Levosimendan is a calcium sensitizer that increases contractile force of the myocardium by enhancing the sensitivity of myofilaments to calcium without increasing intracellular calcium concentration. The present study was carried out to investigate whether levosimendan induces any changes in the phosphorylation potential (ie, the balance between ATP production and consumption) in the normal heart and in the post-ischemic heart while exerting its positive inotropic effect. We show that 0.1 microM levosimendan increased the left ventricle developed pressure in the pre-ischemic and in the post ischemic hearts by 16 and 18% respectively, and the +dP/dt by 16 and 19%, respectively. At that concentration levosimendan did not cause any effect on the phosphorylation potential (1 x 10(5) M(-1) and 0.2 x 10(5) M(-1) in the pre-ischemic and post-ischemic heart, respectively) as assessed by P-NMR, although an increased beating rate (13%) and oxygen consumption (10%) was observed when adding the drug post-ischemically. Our findings are consistent with the results of a recent clinical trial (RUSSLAN), which showed that levosimendan does not induce ischemia and reduces the risk of worsening heart failure and death, in patients with left ventricular failure complicating acute myocardial infarction.

Adenosine Diphosphate↗
PubMed2005

Hemodynamic effect of intracoronary administration of levosimendan in the anesthetized pig.

In this study the hemodynamic effects of intracoronary injection of levosimendan in anesthetized pigs and the mechanisms involved were examined. In 12 anesthetized pigs instrumented for measurement of heart rate (HR), aortic blood pressure (ABP), central venous pressure (CVP), left ventricular end-diastolic blood pressure, left ventricular contractility and relaxation, and mean coronary blood flow (CBF), levosimendan has been injected into the left anterior descending coronary artery at doses corresponding to the ones commonly used in clinics as bolus administration but adapted to the measured CBF. In a further 9 pigs levosimendan has been administered after the blockade of alpha and beta adrenoceptors, muscarinic receptors, and coronary nitric oxide synthase (NOS) to investigate the action mechanism of the drug. The intracoronary bolus administration of doses of levosimendan corresponding to 12 and 24 microg/kg in 10 minutes exerted, respectively, CBF increases of 26.3% and 41.3% of the control values in the absence of changes in the other hemodynamic variables. The blockade of the autonomic nervous system did not prevent the coronary vasodilation, which was, however, abolished by the NOS inhibition. The intracoronary administration of levosimendan exerts positive effects on myocardial blood supply without changes in ABP, HR, CVP, or in myocardial kinetics. The coronary effects of levosimendan are related to NO production.

Anesthesia↗
PubMed2005

Two inotropes with different mechanisms of action: contractile, PDE-inhibitory and direct myofibrillar effects of levosimendan and enoximone.

We characterized the Ca2+-sensitizing and phosphodiesterase (PDE)-inhibitory potentials of levosimendan and enoximone to assess their contributions to the positive inotropic effects of these drugs. In guinea pig hearts perfused in the working-heart mode, the maximal increase in cardiac output (55%, P<0.05) was attained at 50 nM levosimendan. The corresponding value for enoximone (36%) was significantly smaller (P<0.05) and was observed at a higher concentration (500 nM). In permeabilized myocyte-sized preparations levosimendan evoked a maximal increase of 55.8+/-8% (mean+/-SEM) in isometric force production via Ca2+ sensitization (pCa 6.2, EC50 8.4 nM). Enoximone up to a concentration of 10 microM failed to influence the isometric force. The PDE-inhibitory effects were probed on the PDE III and PDE IV isoforms. Levosimendan proved to be a 1300-fold more potent and a 90-fold more selective PDE III inhibitor (IC50 for PDE III 1.4 nM, and IC50 for PDE IV 11 microM, selectivity factor approximately 8000) than enoximone (IC50 for PDE III 1.8 microM, and IC50 for PDE IV 160 microM, selectivity factor approximately 90). Hence, our data support the hypothesis that levosimendan exerts positive inotropy via a Ca2+-sensitizing mechanism, whereas enoximone does so via PDE inhibition with a limited PDE III versus PDE IV selectivity.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

Duration of the beneficial effects of levosimendan in decompensated heart failure as measured by echocardiographic indices and B-type natriuretic peptide.

Levosimendan is effective in the treatment of decompensated heart failure. The beneficial effects of a single dose of levosimendan last much longer than those of other inotropes. However, the exact duration of the beneficial effects is unknown. We prospectively determined the duration of the cardiac effects, as measured by echocardiography, of levosimendan (LS) following a 24-hour infusion regimen in patients with decompensated heart failure (DHF). The effects of LS on plasma B-type natriuretic peptide (BNP) were also examined. Twenty patients with DHF displaying (1) deteriorating symptoms despite optimal oral therapy, (2) left ventricular ejection fractions (LVEF) < 35%, and (3) cardiac indices of < 2.5 L/m/min received 24 hours of LS infusion. Echocardiography and BNP measurements were performed pre- and postinfusion and were reassessed on days 7, 30, and 90. Left ventricular systolic function indices (cardiac output and LVEF), LV filling pressure indices, and right ventricular systolic function indices all improved following LS treatment. Most of these improvements were sustained for at least 7 days (P < 0.05) and returned to baseline by day 30 postinfusion and remained so on day 90. Plasma BNP also displayed the same pattern of transient improvements. In conclusion, LS transiently improved the cardiac function, and the effects lasted for at least 7 days after discontinuation of infusion. Most effects, except LVEF, were not significantly different from baseline on day 30.

Adult↗
PubMed2006

Preconditioning effects of levosimendan in a rabbit cardiac ischemia-reperfusion model.

The preconditioning effects of levosimendan were investigated on ischemia-reperfusion induced morphological and functional cardiac damage. Langendorff-perfused rabbit hearts were reserved as controls or subjected either to global myocardial ischemic preconditioning or to perfusion with levosimendan (0.1 micromol/l) for two 5-minute cycles. After a washout period, all hearts were then subjected to 30 minutes of global ischemia and 120 minutes of drug-free reperfusion. Intraventricular pressure and coronary flow were measured, and infarct size determined after nitroblue-tetrazolium staining on completion of the experiments. Levosimendan pretreatment resulted in a significantly smaller elevation from the preischemic level in left ventricular end-diastolic pressure during reperfusion (37 +/- 17 mm Hg) compared with controls (56 +/- 14 mm Hg) and ischemia-preconditioned hearts (53 +/- 34 mm Hg). The left ventricular developed pressure-representing the functional recovery of the heart after ischemia-that was significantly improved by levosimendan pretreatment (38 +/- 6% vs 16 +/- 5% in controls, P < 0.05). In addition, contractility and relaxability parameters (+dP/dt and -dP/dt, respectively) were better preserved in the levosimendan hearts. The volume of infarcted myocardium after global ischemia-reperfusion was significantly (P < 0.05) decreased by both ischemic preconditioning (38 +/- 2%) or levosimendan pretreatment (45 +/- 2%) versus controls (52 +/- 2%). The results of this study suggest that levosimendan pretreatment is capable of decreasing infarct size in an ischemia-reperfusion model and improving recovery of cardiac function following ex vivo global ischemia.

Animals↗
PubMed2004

Pharmacokinetics of levosimendan in pediatric patients evaluated for cardiac surgery.

OBJECTIVE: The objective of the study was to evaluate the pharmacokinetics, hemodynamic effects, and safety of levosimendan in children with congenital heart disease. DESIGN: Open, one group, single-dose study. SETTING: Cardiac catheter laboratory in a pediatric cardiology department of a university hospital. PATIENTS AND TREATMENTS: Thirteen children between the ages of 3 months and 7 yrs coming for preoperative cardiac catheterization were enrolled into this study. All children received 12 microg/kg levosimendan as an intravenous infusion given over 10 mins during the catheterization. MEASUREMENTS: Concentrations of levosimendan and its metabolites were determined at specified time points before and after infusion (0-4 hrs). Invasive hemodynamics was evaluated up to 25 mins after the start of the infusion and echocardiography up to 2 hrs after the start of the infusion. MAIN RESULTS: The mean maximum concentration of levosimendan was 59 +/- 23 ng/mL in children older than 6 months of age. Levosimendan was rapidly distributed, with a mean half-life of 0.24 +/- 0.07 hrs. Mean terminal elimination half-life was 1.6 +/- 0.80 hrs. Total plasma clearance for the 10-min infusion was 3.6 +/- 1.3 mL/min/kg. Terminal elimination half-life in children aged 3-6 months was slower than in older children, i.e., 2.3 hrs vs. 1.6 hrs. Values of other pharmacokinetic variables were on the same level between the two age groups. The changes in hemodynamic variables were not statistically significant. There were no serious adverse events or unexpected adverse drug reactions during the study. CONCLUSIONS: The pharmacokinetic profile of levosimendan in children with congenital heart disease is similar to that in adult patients with congestive heart failure. The minimal hemodynamic efficacy after the 12 microg/kg levosimendan bolus was probably due to a small dose relative to body surface area.

Biological Availability↗
PubMed2006

Early experience with Levosimendan in children with ventricular dysfunction.

OBJECTIVE: To describe our preliminary experience with Levosimendan, a new calcium-sensitizing agent in critically unwell infants and children with severe heart failure. DESIGN: Retrospective cohort analysis. SETTING: Pediatric intensive care unit. PATIENTS: Fifteen children aged 7 days to 18 yrs (median age 38 months) with severe myocardial dysfunction secondary to end-stage heart failure, or acute heart failure, who were inotrope-dependent (requiring at least one catecholamine). INTERVENTIONS: A single dose (bolus and intravenous infusion over 24-48 hrs) of Levosimendan was given under continuous hemodynamic monitoring in our intensive care unit. Eleven children received a single dose, three children received two doses, and one child received four doses. Echocardiographic assessments of ventricular function were made before and 3-5 days after Levosimendan infusion. MEASUREMENTS AND MAIN RESULTS: Heart rate, systolic pressure, diastolic pressure, mean blood pressure, and central venous pressure were unchanged during and after Levosimendan. Levosimendan allowed for discontinuation of catecholamines in ten patients and a dose reduction in three. The dose of dobutamine was reduced from 6.4 microg/kg/min pre-Levosimendan to 1.8 microg/kg/min on day 5 (p < .01). Ejection fraction for the group as a whole improved from 29.8% to 40.5% (p = .015); this did not increase significantly in patients with end-stage heart failure but increased by 63% in the children with acute heart failure. CONCLUSIONS: Levosimendan can be safely administered to infants and children with severe heart failure. Levosimendan allowed for substantial reduction in catecholamine infusions in children with end-stage or acute heart failure and also produced an objective improvement in myocardial performance in children with acute heart failure.

Adolescent↗
PubMed2007

Use of levosimendan, a new inodilator, for postoperative myocardial stunning in a premature neonate.

OBJECTIVE: To first report the successful use of the new inodilator levosimendan in a premature infant with congestive heart failure (CHF) following cardiac surgery. Although the calcium sensitizer levosimendan improves hemodynamics in adults with CHF, no data are available on the use of levosimendan in premature infants with CHF. DESIGN: Single case report. SETTING: Twenty-bed postoperative adult and pediatric cardiac intensive care unit. PATIENT: A 32 wks gestational age, 1525-g premature male twin with transposition of the great arteries. INTERVENTIONS: The patient underwent arterial switch operation. MEASUREMENTS AND MAIN RESULTS: Immediately after operation, the patient developed signs of low cardiac output syndrome. Mixed venous saturation was 56%, serum lactate increased to 14.8 mmol/L, systolic arterial pressure was 40 mm Hg, left atrial pressure was 24 mm Hg, and echocardiography showed reduced left ventricular function with a fractional shortening of 10%. There were no signs of reduced coronary perfusion. Milrinone, dobutamine, and epinephrine did not improve hemodynamics. Levosimendan was initiated at a dose of 0.05 mug.kg.min, increased to 0.1 mug.kg.min, and continuously infused for 24 hrs. Within 6 hrs after starting the levosimendan infusion, left atrial pressure decreased to 7 mm Hg and systolic arterial pressure increased to 60 mm Hg; within 24 hrs after initiation serum lactate level normalized to 1.7 mmol/L and mixed venous saturation increased to 81%. Echocardiography revealed improvement of left ventricular function with a fractional shortening of 25%. No side effects were recognized during administration of levosimendan. CONCLUSIONS: In this premature neonate with postoperative low cardiac output syndrome due to failing myocardial function, levosimendan was a potent inotropic agent.

Cardiac Output, Low↗
PubMed2006

Levosimendan treatment after primary organ failure in heart transplantation: a direct way to recovery?

Heart transplantation is considered nowadays the gold standard in the therapy of chronic and terminal heart insufficiency. Primary organ failure after heart transplantation is a severe complication generally related to prolonged ischemia time, poor quality of the organ, or acute rejection. All these factors can potentially lead to multiorgan failure. Pharmacological and mechanical support for these patients is limited and often related to side effects. Ca sensitizers have been proposed to increase cardiac contractility without altering intracellular Ca levels, thus avoiding the side effects of Ca overload. We report two cases of heart transplanted patients suffering from acute graft failure in the early postoperative period who recovered after intravenous administration of levosimendan, a Ca sensitizer.

Adolescent↗
PubMed2006

Levosimendan: a promising treatment for myocardial stunning?

We report a case of a 55-year-old male undergoing major orofacial cancer surgery. A stent to the left anterior descending artery had been implanted for ischaemic heart disease 3 years previously. Twenty-four hours after uneventful anaesthesia and surgery, the patient developed myocardial infarction and cardiogenic shock. Immediate percutaneous transluminal coronary angioplasty, intra aortic balloon counterpulsation, and catecholamine therapy failed to stabilise haemodynamics. In light of successful reperfusion therapy and an only moderate elevation of troponin I, myocardial stunning rather than myonecrosis was considered to be the major contributor to life-threatening left ventricular failure. Therefore, the calcium-sensitising drug levosimendan, which exerts positive inotropic activity without increasing myocardial oxygen demand, was administered as a rescue medication. Within 24 h, levosimendan resulted in decreased filling pressures, reduced left ventricular end-diastolic volume, and augmented systemic pressures. Seven days following surgery, the patient was discharged from the intensive care unit in good clinical condition.

Cardiotonic Agents↗