15th Annual Congress of the European Society of Intensive Care Medicine, 29 September-2 October 2002, Barcelona, Spain: clinical research to improve outcome.
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Acute Kidney Injury↗
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Levosimendan may improve survival in patients requiring mechanical assist devices for post-cardiotomy heart failure.
INTRODUCTION: Most case series suggest that less than half of the patients receiving a mechanical cardiac assist device as a bridge to recovery due to severe post-cardiotomy heart failure survive to hospital discharge. Levosimendan is the only inotropic substance known to improve medium term survival in patients suffering from severe heart failure. METHODS: This retrospective analysis covers our single centre experience. Between July 2000 and December 2004, 41 consecutive patients were treated for this complication. Of these, 38 patients are included in this retrospective analysis as 3 patients died in the operating room. Levosimendan was added to the treatment protocol for the last nine patients. RESULTS: Of 29 patients treated without levosimendan, 20 could be weaned off the device, 9 survived to intensive care unit discharge, 7 left hospital alive and 3 survived 180 days. All 9 patients treated with levosimendan could be weaned, 8 were discharged alive from ICU and hospital, and 7 lived 180 days after surgery (p < 0.002 for 180 day survival). Plasma lactate after explantation of the device was significantly lower (p = 0.002), as were epinephrine doses. Time spent on renal replacement therapy was significantly shorter (p = 0.023). CONCLUSION: Levosimendan seems to improve medium term survival in patients failing to wean off cardiopulmonary bypass and requiring cardiac assist devices as a bridge to recovery. This retrospective analysis justifies prospective randomised investigations of levosimendan in this group of patients.
Aged↗
Comparison of the vasorelaxing effect of cromakalim and the new inodilator, levosimendan, in human isolated portal vein.
In the present study the vasorelaxing capacity of cromakalim, an ATP-sensitive potassium-channel (KATP channel) activator, and that of levosimendan, a new positive inotropic and vasodilating drug with calcium sensitizing and potassium-channel-activating properties, were compared in human isolated portal vein. Based on the 50% effective concentrations (EC50), levosimendan was found to be about 16-fold more potent (EC50 = 0.281+/-0.03 microM) as a relaxing agent than cromakalim (EC50 = 4.53+/-0.12 microM) in noradrenaline-precontracted portal venous preparations. Glibenclamide, the known inhibitor of KATP channels, was able to prevent the cromakalim-induced venodilation completely. Glibenclamide (15 microM) decreased the quasi-maximal effect of levosimendan (at 1.27 microm by about 60%) and also the effects of those submicromolar concentrations of the inodilator (at 0.1 microM by 23%, at 0.3 microM by 27% and at 0.7 microM by 19%, on average) which were therapeutically effective in preliminary human studies. These findings indicate that, in the human portal vein, both cromakalim and levosimendan are powerful vasorelaxants and that a considerable part of the relaxing effect induced by levosimendan is of cromakalim type.
Adolescent↗
Vasorelaxing effect of levosimendan against 5-hydroxytryptamine-induced contractions in isolated human conduit bypass grafts.
Levosimendan is a novel inodilator drug developed for the treatment of heart failure. The possible vasodilating property of the drug in human coronary artery bypass grafts was investigated. Isometric tensions of the left internal thoracic artery (LITA, n = 8) as well as the proximal and distal segments of the radial artery (RA, n = 8 and 8) were measured in isolated organ baths. Concentration-relaxation curves for levosimendan (0.009-1.14 micromol L(-1)) were obtained against 5-hydroxytryptamine (5-HT; serotonin, 0.002-9.3 micromol L(-1))-induced contractions. 5-HT-induced contraction of LITA was considerably smaller than that of the proximal and distal RAs. Levosimendan relaxed the grafts in the following order of calculated maximum efficacies (E(max)): LITA > proximal RA > distal RA (LITA 100.3+/-16.2% of 5-HT-induced maximum tension, proximal RA 86.9+/-8.6%, distal RA 59.4+/-17.5%, P < 0.05 LITA vs distal RA). The potency values of levosimendan, expressed as the negative logarithm of 50% effective concentrations (pD(2)), were comparable in the three bypass grafts (LITA -6.52+/-0.44 log mol L(-1), proximal RA -6.60+/-0.49 log mol L(-1), distal RA -6.85+/-0.45 log mol L(-1)). The results suggest that levosimendan is an effective vasorelaxant of conduit bypass grafts and may serve as a new therapeutic tool, especially in the case of LITA and proximal RA grafts, for relieving perioperative spasm and subsequent graft failure.
Aged↗
Successful use of levosimendan in a patient with peripartum cardiomyopathy.
UNLABELLED: This case represents the first reported use of levosimendan, a calcium-sensitizing drug with additional vasodilation properties, for treatment of a woman with peripartum cardiomyopathy. Levosimendan induced a steady decline of increased pulmonary capillary wedge pressure, followed by a definitive increase in cardiac stroke volume. The patient recovered from this serious episode of heart failure, and she ultimately regained left ventricular function. IMPLICATIONS: Acute heart failure is a life-threatening event that only rarely occurs during childbirth. We report a case of a woman who experienced cardiovascular collapse during vaginal delivery. We determined that she met current diagnostic criteria for peripartum cardiomyopathy, and we successfully treated her with levosimendan, a calcium-sensitizing drug with additional vasodilation properties.
Adult↗
The vasodilatory effects of levosimendan on the human internal mammary artery.
BACKGROUND: Levosimendan, an inotropic drug that enhances myocardial contractility through myofilment calcium sensitazion, induces peripheral vasodilation via opening ATP-dependent K(+) channels. It is unknown whether this drug can be used for the treatment of perioperative vasospasm of arterial conduits used for coronary artery bypass grafting. METHODS: We investigated the effects of levosimendan on human internal mammary artery (IMA) specimens taken from patients undergoing coronary artery bypass surgery. The rings were carefully prepared and placed between two wire hooks in organ bath chambers and then constricted submaximally with norepinephrine and thromboxane A(2) analog (U46619). Nitroglycerin, milrinone, and levosimendan were separately added in a cumulative fashion and concentration response curves for relaxation were constructed. In parallel experiments, the response to levosimendan was evaluated on rings with and without functional endothelium. Levosimendan prevention of norepinephrine-induced contraction was also estimated. RESULTS: Nitroglycerin, milrinone, and levosimendan completely reversed the contraction of the IMA segments induced by U46619 and norepinephrine. Levosimendan produced a potent, concentration-dependent preventive effect on the norepinephrine-induced contraction of IMA. The responses to levosimendan were similar in preparations with or without endothelium.
Dose-Response Relationship, Drug↗
On the mechanism of levosimendan-induced dopamine release in the striatum of freely moving rats.
The Ca(2+) sensitizer levosimendan (LEV) improves myocardial contractility by enhancing the sensitivity of the contractile apparatus to Ca(2+). In addition, LEV promotes Ca(2+) entry through L-type channels in human cardiac myocytes. In this study, which was performed using microdialysis, infusion of LEV at 0.25 microM for 160 min increased dopamine (DA) concentrations (up to fivefold baseline) in dialysates from the striatum of freely moving rats. Ca(2+) omission from the perfusion fluid abolished baseline DA release and greatly decreased LEV-induced DA release. Reintroduction of Ca(2+) in the perfusion fluid restored LEV-induced DA release. Chelation of intracellular Ca(2+) by co-infusing 1,2-bis (o-amino-phenoxy)ethane-N,N,N',N'-tetraacetic acid tetra (acetoxymethyl) ester (BAPTA-AM, 0.2 mM) did not affect basal DA release and scarcely affected LEV-induced increases in dialysate DA. In addition, co-infusion of the L-type (Ca(v) 1.1-1.3) voltage-sensitive Ca(2+)-channel inhibitor nifedipine failed to inhibit LEV-induced increases in dialysate DA, which, in contrast, was inhibited by co-infusion of the N-type (Ca(v) 2.2) voltage-sensitive Ca(2+)-channel inhibitor omega-conotoxin GVIA. We conclude that LEV promotes striatal extracellular Ca(2+) entry through N-type Ca(2+) channels with a consequent increase in DA release.
Animals↗
Effects of levosimendan on restrictive left ventricular filling in severe heart failure: a combined hemodynamic and Doppler echocardiographic study.
BACKGROUND: A restrictive pattern of left ventricular filling is often present in patients with severe heart failure. Although the hemodynamic effects of levosimendan have been studied, the effects of levosimendan on LV filling pattern have not been investigated. METHODS: Pulsed-wave Doppler mitral (transthoracic) and pulmonary venous flow (transesophageal) velocity curves were recorded in 30 patients with a restrictive pattern of left ventricular filling with New York Heart Association class III or IV heart failure who had a documented left ventricular ejection fraction < 30% by echocardiography and received a 0.1 microg/kg/min infusion of levosimendan for 24 h. RESULTS: Levosimendan caused significant (p < 0.001) increases in stroke volume (from 46 +/- 4 to 57 +/- 4 mL) and decreases in pulmonary capillary wedge pressure (from 21 +/- 1 to 15 +/- 1 mm Hg). The E wave decreased (from 96 +/- 7 to 71 +/- 5 cm/s), and the A wave increased (from 40 +/- 4 to 46 +/- 4 cm/s). Moreover, deceleration time was increased (from 112 +/- 7 to 189 +/- 14 ms). The S wave of pulmonary venous flow was increased (from 38 +/- 3 to 60 +/- 3 cm/s), and atrial reversal was decreased (from 36 +/- 2 to 29 +/- 2 cm/s). All changes were significant (p < 0.001). Using stepwise linear regression analysis, we found that the percentage changes of the early/late transmitral diastolic peak flow velocity (E/A) ratio and the percentage changes of the isovolumetric relaxation time were independent predictors of the increase in cardiac output. Furthermore, the percentage changes of the systolic/diastolic ratio and the percentage changes of the E/A ratio were independent predictors of the decrease in pulmonary capillary wedge pressure. CONCLUSIONS: Treatment with levosimendan improved measures of left ventricular diastolic function. Consequently, left ventricular stroke volume was increased.
Anti-Arrhythmia Agents↗
Levosimendan: a parenteral calcium-sensitising drug with additional vasodilatory properties.
Levosimendan (Simdax) is a new inodilator developed specifically for the treatment of decompensated heart failure. Its inotropic mechanism is based on calcium sensitisation of myofilaments and its vasodilator actions are related to the opening of ATP-dependent K-channels in the vasculature. Since the inotropic action of levosimendan does not require an increase in cytosolic free calcium, it is less arrhythmogenic than the conventional parenteral beta-agonist inotropes or PDE III inhibiting drugs. Due to the calcium-dependent binding of the drug to troponin C, levosimendan, unlike some other calcium-sensitising drugs, does not prolong diastolic relaxation of the myocytes but acts in synergy with the intramyocellular calcium levels. Furthermore, due to the anti-ischaemic effects of the K-channel opening in myocytes, levosimendan can be used during myocardial ischaemia. In clinical trials, levosimendan has dose-dependently increased cardiac output and decreased pulmonary capillary wedge pressure in patients with heart failure. On the other hand, it also increases heart rate and decreases blood pressure in these patients. In major clinical trials, where patients with decompensated heart failure have been treated with levosimendan, a reduction of overall mortality in comparison to placebo or dobutamine has been seen. This interesting finding should be verified in prospective outcome trials. In any case, the safety of levosimendan during myocardial ischaemia makes this drug valuable in the short-term treatment of decompensated heart failure.
Calcium↗
An emerging role for calcium sensitisation in the treatment of heart failure.
Heart failure occurs in 2 - 3% of the adult population in the developed world. With decompensation of cardiac function, haemodynamic stability can be achieved by using intravenous vasodilators, diuretics and inotropes. Unlike traditional inotropes, Ca2+ sensitisers enhance cardiac function without significantly increasing cardiac oxygen consumption, promoting arrhythmia or impairing lusitropy. The most promising drug in this new class is levosimendan, which has a unique dual mechanism; it enhances cardiac output through a Ca(2+)-dependent stabilisation of cardiac myofilaments and exhibits vasodilatory effects by opening ATP-dependent K(+) channels. Clinical trials have demonstrated the beneficial haemodynamic effects of levosimendan, and prospective trials are currently underway to confirm its potential benefits on long-term prognosis. Updated guidelines from the European Society of Cardiology advise on how to incorporate levosimendan into care for patients who have acute heart failure.
Animals↗
Levosimendan for the treatment of acute heart failure syndromes.
Levosimendan is a novel calcium-sensitising agent that has been shown to have beneficial inotropic, metabolic and vasodilatory effects in the treatment of acute and advanced chronic heart failure. Levosimendan binds to troponin-C in cardiomyocytes and, thereby, improves cardiac contractility without disturbing the metabolic status of the heart and increasing myocardial oxygen demand or provoking fatal cardiac arrhythmias. Levosimendan also opens ATP-sensitive potassium channels, causing peripheral arterial and venous dilatation, and increasing coronary flow reserve. When it is given as a short-term therapy, levosimendan enhances cardiac output, reduces systemic vascular resistance and lowers pulmonary capillary wedge pressure. Clinical outcomes were significantly reduced in decompensated or postmyocardial infarction heart failure patients who received levosimendan, compared with those on dobutamine or placebo. Recent investigations focusing on the anti-inflammatory and antiapoptotic actions of levosimendan in the failing heart indicate that improvement of cardiac contractile performance is closely related with the drug-induced reduction of circulating pro-inflammatory cytokines and apoptosis inducers. The most common adverse effects of levosimendan treatment are hypotension and headache. Overall, levosimendan represents an effective and safe option for the treatment of decompensated heart failure patients.
Acute Disease↗
Levosimendan: first in a new class of inodilator for acute and chronic severe heart failure.
Heart failure is the most common malignant disease in the developed world. Levosimendan (Simdax) is a novel intravenous agent that exerts inotropic effects through sensitization of myofilaments to calcium and vasodilator effects by opening ATP-dependent potassium channels on vascular smooth muscle. Infusion of levosimendan increases cardiac output due to an increase in stroke volume and heart rate, with a fall in pulmonary capillary wedge pressure. It has an active metabolite with a half-life of about 80 h, therefore infusions of 6 to 24 h result in hemodynamic effects that persist for 7 to 10 days. Preliminary observations suggest that a single infusion of levosimendan lasting 6 to 24 h in patients with severe heart failure due to left ventricular systolic dysfunction results in hemodynamic changes, symptomatic benefit and a reduction in morbidity and mortality over the following 2 to 4 weeks compared with placebo in one study and with dobutamine in another. Long-term follow-up suggests no loss of this early benefit over 6 months. Levosimendan is licensed for the treatment of decompensated heart failure in many countries but not in North America. Further large trials are being conducted comparing levosimendan with placebo and with dobutamine in patients with severe heart failure and left ventricular systolic dysfunction. If these studies confirm the benefits of levosimendan, then it may become routine therapy for the management of severe heart failure.
Cardiotonic Agents↗
[Cost analysis of the treatment of acute decompensated heart failure. Levosimendan versus dobutamine].
OBJECTIVE: To assess whether the treatment with levosimendan is more expensive than the usual one with dobutamine, since price of medications does not usually represent the greatest expense in the treatment of cardiac decompensation. METHODS: The cost of treatment of 18 inpatients with cardiac decompensation, 9 of which treated with dobutamine (dobuta group) and 9 with levosimendan (levo group), was compared. Groups were similar concerning age, sex, functional class and cardiac function. RESULTS: Treatment costs were similar for both groups. In the levo group, the costs with the drug were higher than in the dobuta group, but those related to the length of stay in intensive care unit and to the material used during admission were lower. Levo-drug: R$ 5,414.00; material: R$ 399.90; hospital daily rates: R$ 5,061.20; professional honorarium: R$ 3,241.80; total costs: R$ 14,117.00. Dobuta-drug: R$ 2,320.10; materials: R$ 1,665.70; hospital daily rates: R$ 6,261.90; professional honorarium: R$ 3,894.30; total costs: R$ 14,142.00. CONCLUSION: Despite the higher price of levosimendan, the global cost of the treatment was similar for patients who were treated either with dobutamine or levosimendan. Patients who were treated with levosimendan had a shorter length of stay in intensive care unit.
Acute Disease↗
Levosimendan, a new calcium-sensitizing inotrope for heart failure.
Calcium sensitizers are a new class of inotropes that share the in vitro properties of calcium sensitization and phosphodiesterase inhibition. Levosimendan is a distinct calcium sensitizer, as it stabilizes the interaction between calcium and troponin C by binding to troponin C in a calcium-dependent manner, improving inotropy without adversely affecting lusitropy. It does not exhibit clinically relevant phosphodiesterase inhibition at therapeutic concentrations. It also exerts vasodilatory effects, possibly through activation of several potassium channels and other less well characterized mechanisms. The pharmacokinetics of levosimendan are similar in healthy subjects and patients with heart failure and remain relatively unaltered by age, sex, and organ dysfunction. In preclinical and clinical studies, levosimendan exerted potent dose-dependent positive inotropic and vasodilatory activity. Unlike conventional inotropes, levosimendan is not associated with significant increases in myocardial oxygen consumption, proarrhythmia, or neurohormonal activation. The most common adverse effects are attributable to the vasodilation. Two large, double-blind, randomized trials demonstrated favorable hemodynamic effects, improved tolerability, and a possible mortality benefit over dobutamine and placebo in patients who had acute symptoms of failure and required inotropic therapy. The long-term effect on patient outcomes is being confirmed in ongoing placebo- and inotrope-controlled trials. Levosimendan appears to be an effective inodilator devoid of the detrimental effects of conventional inotropes. In the future, levosimendan may provide a promising alternative to conventional inotropes for patients with acutely decompensated heart failure.
Animals↗
Management of acute decompensated heart failure: treatment, controversy, and future directions.
Acute decompensated heart failure is a growing public health care problem worldwide. The goals of treatment are immediate hemodynamic and symptomatic improvement followed by persistent follow-up with adherence to chronic heart failure guidelines. Controversies have centered around the best treatment options and avoidance of serious adverse events. This article highlights our current understanding of acute decompensated heart failure, discusses the controversy surrounding currently available new vasoactive treatments, and details future potential therapies.
Acute Disease↗
Calcium sensitising agents in heart failure.
Congestive heart failure (CHF) is a common cardiovascular disorder that is characterised, in part, by a decreased cardiac output reserve. Accordingly, there is ongoing interest in the role of positive inotropic agents (e.g. adrenergic agonists and phosphodiesterase type III inhibitors, which mediate their cardiovascular effects via a cyclic adenosine monophosphate-dependent mechanism) in the treatment of CHF. However, enthusiasm for positive inotropic therapy in CHF has been dampened by the results of clinical trials, which have shown that these drugs are associated with an increased risk of mortality. Calcium sensitising agents are a heterogeneous group of positive inotropic agents that mediate their cardiovascular actions (at least in part) by increasing the sensitivity of the contractile elements to calcium. Increased sensitivity to calcium may be related to changes in calcium binding to troponin C, or to direct effects on the actin-myosin complex. In addition, the inhibition of phosphodiesterase type III may contribute to the positive inotropic action of calcium sensitising agents. Five agents with calcium sensitising properties (pimobendan, levosimendan, MCI-154, EMD-53998 and CGP-48506) have been studied as possible therapies for CHF. All of these agents have demonstrated a positive inotropic action in isolated cardiac tissue and in animal models of CHF. In clinical trials, pimobendan, the most extensively studied of these drugs, was well tolerated and was associated with improved exercise tolerance during the first 6 months of therapy; however, it was also associated with a nonsignificant trend towards increased mortality. Because many of the calcium sensitising agents also inhibit phosphodiesterase type III activity, the long term safety of these agents is uncertain. Large-scale survival trials are required to determine the long term safety and efficacy of these agents before their role in the treatment of CHF can be defined.
Aged↗
Levosimendan.
Levosimendan, a pyridazinone-dinitrile derivative, is a calcium sensitiser with additional action on adenosine triphosphate (ATP)-sensitive potassium channels. It is used intravenously (IV) for the treatment of decompensated cardiac failure. At therapeutic doses, levosimendan exhibits enhanced contractility with no increase in oxygen demands. It also produces antistunning effects without increasing myocardial intracellular calcium concentrations or prolonging myocardial relaxation. Levosimendan also causes coronary and systemic vasodilation. In patients with decompensated congestive heart failure (CHF), IV levosimendan significantly reduced the incidence of worsening CHF or death. IV levosimendan significantly increased cardiac output or cardiac index and decreased filling pressure in the acute treatment of stable or decompensated CHF in large, double-blind, randomised trials and after cardiac surgery in smaller trials. Levosimendan is well tolerated, with the most common adverse events (headache, hypotension, nausea) being secondary to vasodilation. It has not been shown to be arrhythmogenic. Levosimendan has shown no clinically important pharmacokinetic interactions with captopril, felodipine, beta-blockers, digoxin, warfarin, isosorbide-5-mononitrate, carvedilol, alcohol (ethanol) or itraconazole.
Biological Availability↗
Levosimendan: a review of its use in the management of acute decompensated heart failure.
UNLABELLED: Levosimendan (Simdax) is a calcium-sensitising drug that stabilises the troponin molecule in cardiac muscle, thus prolonging its effects on contractile proteins, with concomitant vasodilating properties. Intravenous levosimendan (12-24 microg/kg loading dose followed by 0.1-0.2 microg/kg/min for 24 hours, adjusted for response and tolerability) is approved for the short-term treatment of acute severe decompensated heart failure. Cardiac output increased by about 30% and pulmonary capillary wedge pressure and systemic vascular resistance decreased by about 17-29% in patients with decompensated heart failure receiving intravenous levosimendan. In large, well controlled trials in patients with decompensated heart failure, intravenous levosimendan was significantly more effective than placebo or dobutamine for overall haemodynamic response rate (primary endpoint). Significant benefits were also seen for mortality (versus placebo or dobutamine) and for the combined risk of worsening heart failure or death (versus dobutamine). Improvements in key symptoms (dyspnoea and fatigue) have not been consistently demonstrated. Hospitalisation costs were similar for levosimendan and dobutamine; the total incremental (hospitalisation plus drug) cost per life-year saved (extrapolated to 3 years) for levosimendan relative to dobutamine was estimated at Euro 3205 (year of costing 2000). Levosimendan is generally well tolerated, with an adverse event profile at recommended dosages similar to that in patients receiving placebo. Cardiac rate/rhythm disorders and headache were the most common events. At higher dosages, patients receiving levosimendan had higher rates of sinus tachycardia than those in placebo recipients. More patients receiving dobutamine than those receiving levosimendan experienced angina pectoris/chest pain/myocardial ischaemia or rate/rhythm disorders. CONCLUSION: Intravenous levosimendan is an effective calcium-sensitising drug with vasodilatory and inotropic effects, and superior efficacy/tolerability to those of intravenous dobutamine in patients with acute decompensated heart failure. It may be associated with reduced mortality compared with both placebo and dobutamine. Levosimendan is generally well tolerated and may have less potential for cardiac rate/rhythm disorders than dobutamine. While evidence from well designed trials confirming the improved mortality over dobutamine and investigating haemodynamic efficacy and mortality versus other positive inotropes is required, intravenous levosimendan appears to be a useful addition to the treatment options for acute decompensated heart failure in patients with low cardiac output.
Acute Disease↗