Calcium antagonist overdose can cause severe deterioration of hemodynamics unresponsible to treatment with beta adrenergic inotropes. The aim of the study was to evaluate in an experimental model the effects of levosimendan during severe calcium antagonist intoxication.
Twelve landrace-pigs were intoxicated with intravenous verapamil at escalating infusion rates. The infusion containing 2.5 mg/ml verapamil was used aiming to a reduction of cardiac output by 40% from the baseline value. Intoxicated pigs were randomized into two groups: control (saline) and levosimendan (intravenous bolus). Inotropic effect was measured as a change in a maximum of the positive slope of the left ventricular pressure (LV dP/dt). The survival and hemodynamics of the animals were followed for 120 min after the targeted reduction of cardiac output.
In the control group, five out of six pigs died during the experiment. In the levosimendan group, one pig died before completion of the experiment (p = 0.04). In the levosimendan group a change in LV dP/dt was positive in four out of six pigs compared to one out of six pigs in the control group (p = ns).
In this experimental model, the use of levosimendan was associated with improved survival.
OBJECTIVE—To determine whether levosimendan, a calcium sensitiser that facilitates the activation of the contractile apparatus by calcium, improves myocardial contractile function during severe ischaemia and reperfusion without exacerbating the incidence of arrhythmias.
DESIGN—Pigs were pretreated orally twice daily for 10 days with 0.08 mg/kg levosimendan or placebo. On day 11 the left main coronary artery was ligated for 30 minutes, followed by 30 minutes of reperfusion. A bolus dose of levosimendan, 11.2 µg/kg intravenously, or placebo was given 30 minutes before coronary ligation, followed by a continuous infusion of 0.2 µg/kg/min levosimendan or placebo for the remainder of the experiment.
RESULTS—During the ischaemic period, cardiac output was higher in the levosimendan group than in the placebo group (mean (SD): 2.6 (0.5) v 2.0 (0.2) l/min, p < 0.05) and systemic vascular resistance was lower (2024 (188) v 2669 (424) dyne.s−1.cm−5, p < 0.005). During reperfusion, cardiac output and contractility (LVmaxdP/dt (pos), 956 (118) v 784 (130) mm Hg/s, p < 0.05) were increased by levosimendan. The incidence of ischaemic ventricular fibrillation and tachycardia was similar in the two groups but there were more arrhythmic events (ventricular tachycardia and ventricular fibrillation) in the levosimendan treated group (8/12 levosimendan v 1/9 control p = 0.05).
CONCLUSIONS—Levosimendan improved cardiac output and myocardial contractility during coronary artery ligation and reperfusion. However, it increased the number of arrhythmic events during ischaemia in this model of in vivo regional ischaemia.
Keywords: calcium sensitisers; myocardial ischaemia; arrhythmias
Levosimendan improves myocardial contractility, and increases systemic, pulmonary and coronary vasodilation. The present study investigates the perioperative hemodynamic effects of a prophylactic infusion of levosimendan in high-risk cardiac surgery patients with severe left ventricle dysfunction, and compares short-term clinical outcomes with a historical control group in which dobutamine and milrinone were used.
PATIENTS AND METHODS:
A retrospective, observational study was performed in 10 adult patients with EuroSCOREs greater than six and severe left ventricle dysfunction. In the study group, prophylactic levosimendan infusion was started after the induction of general anesthesia (bolus 24 μg/kg over 10 min; continuous infusion 0.1 μg/kg/min over the next 24 h). The historical control group (12 patients) was treated with dobutamine and milrinone. The hemodynamic measurements were performed at eight predetermined time points. Short-term clinical outcomes recorded in both groups were the length of intensive care unit stay, the need for dialysis, the length of hospital stay, predicted mortality (logistic EuroSCORE) and 30-day mortality.
Hemodynamic measurements performed in the study group revealed an increase in cardiac index 30 min after levosimendan infusion was started. Cardiac performance was sufficient throughout the entire perioperative period. The length of intensive care unit stay was not different between the groups, but the length of hospital stay (10.4±5.0 versus 26.6±17.6 days; P=0.01) and 30-day mortality (0% versus 41.7%; P=0.04) were significantly lower in levosimendan-treated patients.
Levosimendan seemed to be an effective choice for preventing left ventricle failure in high-risk cardiac surgical patients with severe left ventricle dysfunction compared with patients receiving dobutamine and milrinone.
EuroSCORE; High-risk cardiac surgery; Inotropic drugs; Left ventricle dysfunction; Levosimendan
The authors examined whether milrinone and levosimendan could exert cardiac postconditioning effects in rats under normoglycemia and hyperglycemia, and whether the effects could be mediated by mitochondrial permeability transition pore (mPTP).
Wistar rats underwent 30-min coronary artery occlusion followed by 2-h reperfusion. The rats received milrinone or levosimendan just before reperfusion under normoglycemic or hyperglycemic conditions with or without atractyloside, an mPTP opener.
Under normoglycemia, both 30 μg/kg milrinone (29 ± 12%) and 10 μg/kg levosimendan (33 ± 13%) reduced infarct size compared with that in the control (58 ± 7%). Under hyperglycemia, milrinone (34 ± 13%) reduced infarct size at the same dose as under normoglycemia. In contrast, neither 10 nor 30 μg/kg levosimendan protected hyperglycemic hearts, and only 100 μg/kg levosimendan (32 ± 9%) reduced infarct size compared with that in the hyperglycemic control (58 ± 13%). All of these cardioprotective effects under normoglycemia and hyperglycemia are abolished by atractyloside.
Milrinone and levosimendan exert postconditioning effects via inhibition of mPTP opening. Hyperglycemia raises the threshold of levosimendan-induced postconditioning, while milrinone-induced postconditioning is not influenced by hyperglycemia.
Hyperglycemia; Postconditioning; Myocardial Infarction; Milrinone; Levosimendan; Mitochondrial permeability transition pore
We investigated the neuroprotective properties of levosimendan, a novel inodilator, in an in vitro model of traumatic brain injury.
Organotypic hippocampal brain slices from mouse pups were subjected to a focal mechanical trauma. Slices were treated after the injury with three different concentrations of levosimendan (0.001, 0.01 and 0.1 μM) and compared to vehicle-treated slices. After 72 hrs, the trauma was quantified using propidium iodide to mark the injured cells.
A significant dose-dependent reduction of both total and secondary tissue injury was observed in cells treated with either 0.01 or 0.1 μM levosimendan compared to vehicle-treated slices.
Levosimendan represents a promising new pharmacological tool for neuroprotection after brain injury and warrants further investigation in an in vivo model.
Background: Levosimendan is a calcium sensitizer that has been shown to prevent myocardial contractile depression in patients post cardiac surgery. This drug exhibits an anti-apoptotic property; however, the underlying mechanism remains elusive. In this report, we characterized the myocardial protective of levosimendan in preventing cardiomyocyte apoptosis and post-operative stunning in an experimental ischemia–reperfusion model. Methods: Three groups of pigs (n = 8 per group) were subjected to 40 min of global, cardioplegic ischemia followed by 240 min of reperfusion. Levosimendan (65 μg/kg body weight) was given to pigs by intravenous infusion (L-IV) before ischemia or intracoronary administration during ischemia (L-IC). The Control group did not receive any levosimendan. Echocardiography was used to monitor cardiac function in all groups. Apoptosis levels were assessed from the left ventricle using the terminal transferase mediated dUTP nick end labeling (TUNEL) assay and immunocytochemical detection of Caspase-3. Results: Pigs after ischemia–reperfusion had a much higher TUNEL%, suggesting that our treatment protocol was effective. Levels of apoptosis were significantly increased in Control pigs that did not receive any levosimendan (0.062 ± 0.044%) relative to those received levosimendan either before (0.02 ± 0.017%, p = 0.03) or during (0.02 ± 0.017%, p = 0.03) the ischemia phase. Longitudinal left ventricular contraction in pigs that received levosimendan before ischemia (0.75 ± 0.12 mm) was significantly higher than those received levosimendan during ischemia (0.53 ± 0.11 mm, p = 0.003) or Control pigs (0.54 ± 0.11 mm, p = 0.01). Conclusion: Our results suggested that pigs received levosimendan displayed a markedly improved cell survival post I–R. The effect on cardiac contractility was only significant in our perfusion heart model when levosimendan was delivered intravenously before ischemia.
myocardial protection; apoptosis; ischemia/reperfusion injury; animal model
Levosimendan is an extensively investigated inodilator showing also cardioprotective and antiinflammatory effects. The aim of our study was to explore the influence of levosimendan on polymorphonuclear leucocytes (PMN), a main source of reactive oxygen species, in vitro and in patients with acute heart failure or septic myocardial depression.
PMN isolated from healthy volunteers were incubated with levosimendan in vitro. After stimulation with N-formyl-Met-Leu-Phe (fMLP) or phorbol 12-myristate 13-acetate (PMA) respiratory burst was quantified using a fluorescent dye. Apoptosis and expression of cell adhesion molecules of PMN were measured by flow cytometry. For determination of in vivo effects patients with acute heart failure (n = 16) or septic cardiac failure (n = 9) receiving levosimendan treatment were enrolled consecutively. PMN were isolated to measure respiratory burst activity before treatment as well as one and two hours after initiation of levosimendan administration. Furthermore inflammatory, hemodynamic and renal function parameters were obtained.
In vitro, levosimendan suppressed respiratory burst activity in fMLP or PMA stimulated PMN in a dose dependent manner by 30 ± 11% (P < 0.001) at 100 ng/mL and by 27 ± 17% (P < 0.001) at 1000 ng/mL respectively. Markers of apoptosis and PMN cell adhesion molecule expression remained unaffected by levosimendan treatment.
In vivo, levosimendan treatment for two hours resulted in a significant reduction of PMA stimulated oxidative burst by 45% (P < 0.01) and fMLP stimulated oxidative burst by 49% (P < 0.05) in patients with acute heart failure. In patients suffering from septic shock levosimendan treatment decreased oxidative burst activity in unstimulated, fMLP and PMA stimulated PMN by 48% (P < 0.05), 46% (P < 0.01) and 43% (P < 0.01) respectively.
Levosimendan appears to exert distinct immunomodulatory effects by decreasing oxidative burst activity of PMN. This property might contribute to the previously described cardioprotective effects of the drug.
Levosimendan is a novel inodilator that improves central haemodynamics and symptoms of patients with decompensated chronic heart failure. The role, however, of repeated levosimendan infusions in the management of these patients has not yet been properly assessed.
This randomised placebo‐controlled trial investigated the effects of serial levosimendan infusions on cardiac geometry and function, and on biomarkers of myocardial injury and neurohormonal and immune activation (troponin T, N‐terminal B‐type natriuretic pro‐peptide (NT‐proBNP), C reactive protein (CRP) and interleukin (IL) 6) in patients with advanced heart failure.
25 patients with decompensated chronic heart failure were randomised (2:1) to receive five serial 24‐h infusions (every 3 weeks) of either levosimendan (n = 17) or placebo (n = 8), and were evaluated echocardiographically and biochemically before and after each drug infusion and 30 days after the final infusion.
Following treatment, cardiac end‐systolic and end‐diastolic dimension and volume indices were significantly reduced only in the levosimendan‐treated patients (p<0.01). A significant decrease in NT‐proBNP (p<0.01), high‐sensitivity CRP (p<0.01) and plasma IL6 (p = 0.05) was also observed in the levosimendan group, whereas these markers remained unchanged in the placebo group; similar changes were observed after each drug infusion. Although the number of patients with a positive troponin T (⩾0.01 ng/ml) was not different between the two groups at baseline, it was significantly higher in the placebo‐treated group during the final evaluation (p<0.05).
Serial levosimendan treatments improved left ventricular performance and modulated neurohormonal and immune activation beneficially in patients with advanced heart failure, without increasing myocardial injury.
Background. Levosimendan is an inotropic drug with unique pharmacological advantages in patients with acute heart failure. Scope of this study is to determine whether longer infusion patterns without the hypotension-inducing loading dose could justify an effective and safe alternative approach. Methods. 70 patients admitted to the emergencies with decompensated chronic heart failure received intravenously levosimendan without a loading dose up to 72 hours. Clinical parameters, BNP (Brain Natriuretic Peptide) and signal-averaged-ECG data (SAECG) were recorded up to 72 hours. Results. The 48-hour group demonstrated a statistically significant BNP decrease (P < .001) after 48 hours, which also maintained after 72 hours. The 72-hour group demonstrated a bordeline decrease of BNP after 48 hours (P = .039), necessitating an additional 24-hour infusion to achieve significant reduction after 72 hours (P < .004). SAECG data demonstrated a statistically significant decrease after 72 hours (P < .04). Apart from two deaths due to advanced heart failure, no major complications were observed. Conclusion. Prolonged infusion of levosimendan without a loading dose is associated with an acceptable clinical and neurohumoral response.
To study the effects of pretreatment with levosimendan (LEVO, a Ca2+-sensitizer and KATP+ channel opener) and/or the KATP+ channel antagonist glibenclamide (GLIB) on systemic hemodynamics, metabolism, and regional gastromucosal oxygenation during hypoxic hypoxemia.
Chronically instrumented, healthy dogs (24–32 kg, n = 6 per group, randomized cross-over design) were repeatedly sedated, mechanically ventilated (FiO2 ~0.3) and subjected to the following interventions: no pretreatment, LEVO pretreatment, GLIB pretreatment, or combined LEVO + GLIB pretreatment, each followed by hypoxic hypoxemia (FiO2 ~0.1). We measured cardiac output (CO, ultrasonic flow probes), oxygen consumption (VO2, indirect calorimetry), and gastromucosal microvascular hemoglobin oxygenation (μHbO2, spectrophotometry). Statistics: data are presented as mean ± SEM and compared by one-way ANOVA (direct drug effects within group) and two-way ANOVA (between all hypoxic conditions) both with Bonferroni corrections; p < 0.05.
In LEVO-pretreated hypoxemia, CO was significantly higher compared to unpretreated hypoxemia. The increased CO was neither associated with an increased VO2 nor with markers of aggravated anaerobiosis (pH, BE, lactate). In addition, LEVO pretreatment did not further compromise gastromucosal μHbO2 in hypoxemia. After combined LEVO + GLIB pretreatment, systemic effects of GLIB were apparent, however, CO was significantly higher than during unpretreated and GLIB-pretreated hypoxemia, but equal to LEVO-pretreated hypoxemia, indicating that GLIB did not prevent the increased CO in LEVO-pretreated hypoxia.
LEVO pretreatment resulted in improved systemic circulation (CO) during hypoxemia without fueling systemic VO2, without aggravating systemic anaerobiosis markers, and without further compromising microvascular gastromucosal oxygenation. Thus, LEVO pretreatment may be an option to support the systemic circulation during hypoxia.
Levosimendan; Hypoxia; Glibenclamide; Microcirculation; Oxygen; Metabolism
This the case of a 63 year-old man with end-stage renal disease (on chronic hemodialysis), unstable angina and significantly impaired myocardial contractility with low left ventricular ejection fraction, who underwent off-pump one vessel coronary bypass surgery. Combined continuous levosimendan and norepinephrine infusion (at 0.07 μg/kg/min and 0.05 μg/kg/min respectively) started immediately after anesthesia induction and continued for 24 hours. The levosimendan/norepinephrine combination helped maintain an appropriate hemodynamic profile, thereby contributing to uneventful completion of surgery and postoperative hemodynamic stability. Although levosimendan is considered contraindicated in ESRD patients, this case report suggests that combined perioperative levosimendan/norepinephrine administration can be useful in carefully selected hemodialysis patients with impaired myocardial contractility and ongoing myocardial ischemia, who undergo off-pump myocardial revascularization surgery.
The purpose of the present study was to investigate microcirculatory blood flow in patients with septic shock treated with levosimendan as compared to an active comparator drug (i.e. dobutamine). The primary end point was a difference of ≥ 20% in the microvascular flow index of small vessels (MFIs) among groups.
The study was designed as a prospective, randomized, double-blind clinical trial and performed in a multidisciplinary intensive care unit. After achieving normovolemia and a mean arterial pressure of at least 65 mmHg, 40 septic shock patients were randomized to receive either levosimendan 0.2 μg·kg-1·min-1 (n = 20) or an active comparator (dobutamine 5 μg·kg-1·min-1; control; n = 20) for 24 hours. Sublingual microcirculatory blood flow of small and medium vessels was assessed by sidestream dark-field imaging. Microcirculatory variables and data from right heart catheterization were obtained at baseline and 24 hours after randomization. Baseline and demographic data were compared by means of Mann-Whitney rank sum test or chi-square test, as appropriate. Microvascular and hemodynamic variables were analyzed using the Mann-Whitney rank sum test.
Microcirculatory flow indices of small and medium vessels increased over time and were significantly higher in the levosimendan group as compared to the control group (24 hrs: MFIm 3.0 (3.0; 3.0) vs. 2.9 (2.8; 3.0); P = .02; MFIs 2.9 (2.9; 3.0) vs. 2.7 (2.3; 2.8); P < .001). The relative increase of perfused vessel density vs. baseline was significantly higher in the levosimendan group than in the control group (dMFIm 10 (3; 23)% vs. 0 (-1; 9)%; P = .007; dMFIs 47 (26; 83)% vs. 10 (-3; 27); P < .001). In addition, the heterogeneity index decreased only in the levosimendan group (dHI -93 (-100; -84)% vs. 0 (-78; 57)%; P < .001). There was no statistically significant correlation between systemic and microcirculatory flow variables within each group (each P > .05).
Compared to a standard dose of 5 μg·kg-1·min-1 of dobutamine, levosimendan at 0.2 μg·kg-1·min-1 improved sublingual microcirculatory blood flow in patients with septic shock, as reflected by changes in microcirculatory flow indices of small and medium vessels.
The aim of this study is to compare the effects of a 24 h intravenous infusion of levosimendan and a 48 h infusion of dobutamine on invasive haemodynamics in patients with acutely decompensated chronic NYHA class III–IV heart failure. All patients were receiving optimal oral therapy including a β-blocker.
Methods and results
This was a multinational, randomized, double-blind, phase IV study in 60 patients; follow-up was 1 month. There was a significant increase in cardiac index and a significant decrease in pulmonary capillary wedge pressure (PCWP) at 24 and 48 h for both dobutamine and levosimendan. The improvement in cardiac index with levosimendan was not significantly different from dobutamine at 24 h (P = 0.07), but became significant at 48 h (0.44 ± 0.56 vs. 0.66 ± 0.63 L/min/m2; P = 0.04). At 24 h, the reduction in the mean change in PCWP from baseline was similar for levosimendan and dobutamine, however, at 48 h the difference was more marked for levosimendan (−3.6 ± 7.6 vs. −8.3 ± 6.7 mmHg; P = 0.02). No difference was observed between the groups for change in NYHA class, β-blocker use, hospitalizations, treatment discontinuations or rescue medication use. Reduction in B-type natriuretic peptide (BNP) was significantly greater with levosimendan at 48 h (P = 0.03). According to physician's assessment, the improvement in fatigue (P = 0.01) and dyspnoea (P = 0.04) was in favour of dobutamine treatment, and hypotension was significantly more frequent with levosimendan (P = 0.007). No increase in atrial fibrillation or ventricular tachycardia was seen in either group.
A 24 h levosimendan infusion achieved haemodynamic and neurohormonal improvement that was at least comparable at 24 h and superior at 48 h to a 48 h dobutamine infusion.
Levosimendan; Dobutamine; Decompensated heart failure; Invasive monitoring
The aim of this study was to evaluate the effect of levosimendan on mortality in cardiogenic shock (CS) after ST elevation myocardial infarction (STEMI).
Methods and results:
Data were obtained prospectively from the SCAAR (Swedish Coronary Angiography and Angioplasty Register) and the RIKS-HIA (Register of Information and Knowledge about Swedish Heart Intensive Care Admissions) about 94 consecutive patients with CS due to STEMI. Patients were classified into levosimendan-mandatory and levosimendan-contraindicated cohorts. Inotropic support with levosimendan was mandatory in all patients between January 2004 and December 2005 (n = 46). After the SURVIVE and REVIVE II studies were presented, levosimendan was considered contraindicated and was not used in consecutive patients between December 2005 and December 2006 (n = 48). The cohorts were similar with respect to pre-treatment characteristics and concomitant medications. There was no difference in the incidence of new-onset atrial fibrillation, in-hospital cardiac arrest and length of stay at the coronary care unit. There was no difference in adjusted mortality at 30 days and at one year.
The use of levosimendan neither improves nor worsens mortality in patients with CS due to STEMI. Well-designed randomized clinical trials are needed to define the role of inotropic therapy in the treatment of CS.
shock; myocardial infarction; inotropic agents; heart failure; pharmacology
Patients undergoing coronary revascularization often require inotropic support that has been associated with an increased risk for death and morbidity. The purpose of this study was to evaluate the effect of levosimendan versus control on survival after coronary revascularization.
A systemic review and meta-analysis of the literature was carried out on published randomized controlled clinical trials that investigated the efficacy of levosimendan compared to other therapy in patients having coronary revascularisaion. The databases searched were Pubmed, EMBASE, the Cochrane Registry of Clinical Trials and the metaRegister of Controlled Trials. Studies that compared levosimendan to any other therapy for coronary revascularisation in adult humans and reported at least one outcome of interest were considered for inclusion. Both percutaneous coronary intervention and cardiac surgery were included. Data extraction was performed independently by two reviewers using predefined criteria. Relevant outcomes included mortality, cardiac index, cardiac enzymes, length of stay and post-procedural atrial fibrillation.
The meta-analysis included 729 patients from 17 studies. Levosimendan was associated with a mortality reduction after coronary revascularization, (19/386 in the levosimendan group vs 39/343 in the control arm) odds ratio (OR) 0.40 (95% confidence interval (CI) 0.21 to 0.76, P for overall effect 0.005, P for heterogeneity = 0.33, I2 = 12% with a total of 729 patients. Levosimendan also had a favourable effect on cardiac index (standardised mean difference 1.63, 95% CI 1.43 to 1.83, P for overall effect < 0.00001), length of intensive care stay (random effects model, mean difference - 26.18 hours 95% CI 46.20 to 6.16, P for heterogeneity < 0.00001, I2 = 95%, P for overall effect P = 0.01), reductions in the rate of atrial fibrillation (OR 0.54, 95% CI 0.36 to 0.82, P for effect = 0.004, P for heterogeneity 0.84, I2 = 0% for 465 patients) and troponin I levels group (mean difference -1.59, 95% CI 1.78 to 1.40, P for overall effect < 0.00001, P for heterogeneity < 0.00001, I2 = 95%). Limitations of this analysis are discussed.
Levosimendan is associated with a significant improvement in mortality after coronary revascularization. There are also improvements in several secondary endpoints. A suitably powered randomised controlled trial is required to confirm these findings and to address the unresolved questions about the timing and dosing of levosimendan.
Cardiovascular shock due to verapamil intoxication is often refractory to standard resuscitation methods. Recommended therapy includes prevention of further absorption of the drug, inotropic therapy, calcium gluconate, and hyperinsulinemia/euglycemia therapy. Often further measures are needed such as ventricular pacing or mechanical circulatory support. Still, mortality remains high.
Levosimendan, an inotropic agent, that enhances myofilament response to calcium, increases myocardial contraction and could therefore be beneficial in verapamil intoxication. Here, we report the case of a 60-year-old patient with clinically severe verapamil poisoning who presented with shock, bradycardia, and sopor. Standard therapy including high-dose inotropes failed to ameliorate the signs of intoxication. But additional therapy with levosimendan led to rapid improvement. Based on this observation, the literature is reviewed focusing on utilization of levosimendan in the treatment of calcium channel blocker overdose. We suggest to consider levosimendan as additional treatment option in patients with cardiovascular shock due to verapamil intoxication that are refractory to standard management.
Heart failure is a relatively important public health problem due to its increasing incidence, poor prognosis, and frequent need of re-hospitalization. Intravenous positive inotropic agents play an important role in treating acute decompensation of patients with heart failure due to left ventricular systolic dysfunction. Although frequently used, the inotropic agents β-adrenergic agonists and phosphodiesterase inhibitors seem effective for improving symptoms in the short term; it has been shown that they increase morbidity and mortality by elevating intracellular cyclic adenosine monophosphate (cAMP) and calcium levels. Levosimendan is a new positive inotropic agent having ATP-dependent potassium-channel-opening and calcium-sensitizing effects. In studies on its effects without increasing intracellular calcium concentrations and on its effects that depend on available intracellular calcium levels, it has been shown to have favorable characteristics different from those of current inotropic agents, which exert their effects by increasing calcium concentrations. This study aims to review other important studies about levosimendan by revealing the underlying mechanisms of its activity, efficiency, and safety.
heart failure; positive inotropic therapy; levosimendan
Although the effects of levosimendan on the left ventricle (LV) have been studied, its effect on left atrial (LA) function is poorly understood, despite its key role in optimizing LV function.
To compare the effects of levosimendan and dobutamine on LA and LV function in patients with decompensated heart failure (DHF).
Seventy-four patients (mean [± SD] age 64±10 years) with DHF and an LV ejection fraction of 35% or lower were randomly assigned to receive levosimendan (n=37) or dobutamine (n=37). LA active emptying fraction, LA passive emptying fraction (PEF) and the ratio of mitral inflow early diastolic velocity to annulus velocity (E/e) were evaluated with pulsed wave and tissue Doppler imaging along with plasma B-type natriuretic peptide (BNP) level measurements before and after drug infusion.
The ejection fraction was significantly increased in both groups. The levosimendan group had a greater decrease in BNP and a greater increase in active emptying fraction at 24 h compared with the dobutamine group. The PEF, E/e and deceleration time of the E wave were significantly improved in the levosimendan group, but not in the dobutamine group. Levosimendan-induced percentage change of BNP was significantly correlated with the percentage change of E/e and PEF (r=0.48 [P<0.005] and r=−0.38 [P<0.05], respectively).
In patients with DHF, levosimendan and dobutamine both improve LV systolic function. However, levosimendan also improves LV diastolic function and LA performance in parallel with a greater improvement in neurohormonal activation compared with dobutamine.
Decompensated heart failure; Dobutamine; Left atrial function; Levosimendan
Levosimendan has pharmacologic and hemodynamic advantages over conventional intravenous inotropic agents. It has been used mainly as a rescue drug in the pediatric intensive care unit or in the operating room. We present the largest single-center experience of levosimendan in children.
Retrospective analysis of all children who received levosimendan infusions between July 5, 2001 and July 4, 2010 in a pediatric intensive care unit. The results of a questionnaire for physicians (anesthesiologist/intensivists, cardiologists and cardiac surgeons) concerning their clinical perceptions of levosimendan are evaluated
During the study period a total of 484 infusions were delivered to 293 patients 53% of whom were male. The median age of the patients was 0.4 years (4 hours-21.1 years) at the time of levosimendan administration. A majority of levosimendan infusions were administered to children who were undergoing cardiac surgery (72%), 14% to children with cardiomyopathy and 14% to children with cardiac failure. Eighty-nine out of the 293 patients (30.4%) received repeated doses of levosimendan (up to 11 infusions). The most common indication for the use of levosimendan (94%) was when the other inotropic agents were insufficient to maintain stable hemodynamics. Levosimendan was especially used in children with cardiomyopathy (100%) or with low cardiac output syndrome (94%). A majority (89%) of the respondents believed that levosimendan administration postponed the need for mechanical assist devices in some children with cardiomyopathy. Moreover, 44% of respondents thought that the mechanical support was totally avoided in some patients undergoing cardiac surgery after receiving levosimendan.
Levosimendan is widely used in our institution and many physicians believe that its use could decrease the need for mechanical support in children undergoing cardiac surgery or in children with decompensated heart failure. However, there is a lack of good empirical evidence in children to support this perception.
We describe the case of an 83-year-old patient requiring repair of a large symptomatic abdominal aortic aneurysm (AAA). The patient was known to have coronary artery disease (CAD) with symptoms and signs of significant myocardial dysfunction, left-heart failure, and severe aortic insufficiency. The procedure was performed with the help of both mechanical and pharmacological circulatory support. Distal perfusion was provided by an axillofemoral bypass with a centrifugal pump, with dobutamine and levosimendan administered as pharmacological inotropic support. The patient's hemodynamic status was monitored with continuous cardiac output monitoring and transesophageal echocardiography. No serious circulatory complications were recorded during the perioperative and postoperative periods. This paper suggests a potential novel approach to combined circulatory support in patients with heart failure, scheduled for open abdominal aortic aneurysm repair.
The interaction of Cardiac Troponin C (cTnC) and Cardiac Troponin I (cTnI) plays a critical role in transmitting the Ca2+ signal to the other myofilament proteins in the activation of cardiac muscle contraction. As such, the cTnC−cTnI interface is a logical target for cardiotonic agents such as levosimendan that can modulate the Ca2+ sensitivity of the myofilaments. Evidence indicates that drug candidates may exert their effects by targeting a site formed by binding of the switch region of cTnI to the regulatory N domain of cTnC (cNTnC). In this study, we utilized two-dimensional 1H−15N HSQC NMR spectroscopy to monitor the binding of levosimendan and its analogues, CMDP, AMDP, CI-930, imazodan, and MPDP, to cNTnC·Ca2+ in complex with two versions of the switch region of cTnI (cTnI147−163 and cTnI144−163). Levosimendan, CMDP, AMDP, and CI-930 were found to bind to both cNTnC·Ca2+·cTnI147−163 and cNTnC·Ca2+·cTnI144−163 complexes. These compounds contain a methyl group that is absent in MPDP or imazodan. Thus, the methyl group is one of the pharmacophores responsible for the action of these pyridazinone drugs on cTnC. Furthermore, the results showed that the cNTnC·Ca2+·cTnI144−163 complex presents a higher-affinity binding site for these compounds than the cNTnC·Ca2+·cTnI147−163 complex. This is consistent with our observation that the affinity of cTnI144−163 for cNTnC·Ca2+ is ∼10-fold stronger than that of cTnI147−163, likely a result of electrostatic forces between the N-terminal RRV extension in cTnI144−163 and the acidic residues in the C and D helices of cNTnC. These results will help in the delineation of the mode of action of levosimendan on the important functional unit of cardiac troponin that constitutes the regulatory domain of cTnC and the switch region of cTnI.
Levosimendan, in addition to its inotropic properties, could have anti-inflammatory and anti-oxidative properties, and can potentially decrease the deleterious effects of reactive oxygen species on the tissues. In their study, Hasslacher and colleagues provided not only in vitro but also in vivo evidence that levosimendan could preserve organ function in acute heart failure and septic-shock-induced myocardial depression via cooling down the oxidative burst of circulating cells.
Myocardial ischaemia–reperfusion injury can be significantly reduced by an episode(s) of ischaemia–reperfusion applied prior to or during myocardial ischaemia (MI) to peripheral tissue located at a distance from the heart; this phenomenon is called remote ischaemic conditioning (RIc). Here, we compared the efficacy of RIc in protecting the heart when the RIc stimulus is applied prior to, during and at different time points after MI. A rat model of myocardial ischaemia–reperfusion injury involved 30 min of left coronary artery occlusion followed by 120 min of reperfusion. Remote ischaemic conditioning was induced by 15 min occlusion of femoral arteries and conferred a similar degree of cardioprotection when applied 25 min prior to MI, 10 or 25 min after the onset of MI, or starting 10 min after the onset of reperfusion. These RIc stimuli reduced infarct size by 54, 56, 56 and 48% (all P < 0.001), respectively. Remote ischaemic conditioning applied 30 min into the reperfusion period was ineffective. Activation of sensory nerves by application of capsaicin was effective in establishing cardioprotection only when elicited prior to MI. Vagotomy or denervation of the peripheral ischaemic tissue both completely abolished cardioprotection induced by RIc applied prior to MI. Cardioprotection conferred by delayed remote postconditioning was not affected by either vagotomy or peripheral denervation. These results indicate that RIc confers potent cardioprotection even if applied with a significant delay after the onset of myocardial reperfusion. Cardioprotection by remote preconditioning is critically dependent on afferent innervation of the remote organ and intact parasympathetic activity, while delayed remote postconditioning appears to rely on a different signalling pathway(s).
In the rat brain, heat‐stroke‐induced damage to cerebral neurons is attenuated through heat‐shock‐induced overexpression of heat‐shock protein 72 (HSP72).
To ascertain whether progressive exercise preconditioning induces HSP72 expression in the rat brain and prevents heat‐stroke‐induced cerebral ischaemia and injury.
Male Wistar rats were randomly assigned to either a sedentary group or an exercise group. Those in the exercise group progressively ran on a treadmill 5 days/week, for 30–60 min/day at an intensity of 20–30 m/min for 3 weeks. The effects of heat stroke on mean arterial pressure, cerebral blood flow, brain ischaemia markers (glutamate, lactate/pyruvate ratio and nitric oxide), a cerebral injury marker (glycerol) and brain neuronal damage score in the preconditioned animals were compared with effects in unexercised controls. Heat stroke was induced by exposing urethane‐anaesthetised animals to a temperature of 43°C for 55 min, which caused the body temperature to reach 42°C.
Three weeks of progressive exercise pretreatment induced HSP72 preconditioning in the brain and conferred significant protection against heat‐stroke‐induced hyperthermia, arterial hypotension, cerebral ischaemia and neuronal damage; it also prolonged survival.
Exercise for 3 weeks can improve heat tolerance as well as attenuate heat‐stroke‐induced cerebral ischaemia in rats. The maintenance of mean arterial pressure and cerebral blood flow at appropriate levels in the rat brain may be related to overexpression of HSP72.
hyperthermia; heat stress; brain damage; exercise training; heat shock protein 72
There is considerable experimental evidence that hypothermia is neuroprotective
and can reduce the severity of brain damage after global or focal cerebral
ischaemia. However, despite successful clinical trials for cardiac arrest and
perinatal hypoxia-ischaemia and a number of trials demonstrating the safety of
moderate and mild hypothermia in stroke, there are still no established
guidelines for its use clinically. Based upon a review of the experimental
studies we discuss the clinical implications for the use of hypothermia as an
adjunctive therapy in global cerebral ischaemia and stroke and make some
suggestions for its use in these situations.
hypothermia; stroke; cardiac arrest; focal cerebral ischaemia; global cerebral ischaemia