Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure

Nieminen, Markku S.; Akkila, Juha; Hasenfuß, Gerd; Kleber, Franz X.; Lehtonen, Lasse; Mitrović, Veselin; Nyquist, O.; Remme, Willem J.

doi:10.1016/s0735-1097(00)00961-x

Cited by 318 publications

(268 citation statements)

References 23 publications

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“…[5][6][7][8] Although Levo has an elimination half-life of Ϸ1 hour, its active metabolite, OR-1896, has a much longer elimination half-life of Ϸ70 to 80 hours. 9 We previously found that the intravenous administration of Levo for 6 hours increased stroke volume and decreased systemic vascular resistance (SVR) and pulmonary artery wedge pressure (PAWP) in a dose-dependent manner in patients with decompensated heart failure.…”

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confidence: 99%

Sustained Hemodynamic Effects of Intravenous Levosimendan

2003

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Background-The short-term infusion of levosimendan (Levo) improves hemodynamic function in patients with decompensated heart failure. The metabolites of Levo have a prolonged half-life, and one is hemodynamically active. The goal of this study was to determine whether the hemodynamic effects of Levo are sustained during a long-term infusion and beyond the discontinuation of drug infusion. Methods and Results-Patients with decompensated heart failure received escalating infusion rates of intravenous Levo (nϭ98) or placebo (nϭ48) for 6 hours. At the end of 6 hours, 85 of the Levo-treated patients were continued on open-label drug for a total of 24 hours, at which time they were randomized 1:1 to an additional 24 hours of Levo (nϭ43) or placebo (nϭ42).The hemodynamic effects observed at 24 hours were maintained at 48 hours in both the continuation and withdrawal groups and did not differ between groups. Although the plasma concentration of Levo decreased rapidly in the withdrawal group, concentrations of the active metabolite OR-1896 were similar in the continuation and withdrawal groups at 24 hours and increased further (3.5-fold to 4-fold) and to a similar extent in both groups at 48 hours. Conclusions-The hemodynamic effects of Levo were maintained during a 48-hour continuous infusion and for at least 24 hours after discontinuation of a 24-hour infusion. The active metabolite OR-1896 increased for at least 24 hours after cessation of drug infusion and may account for the prolonged hemodynamic effects of Levo.

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Sustained Hemodynamic Effects of Intravenous Levosimendan

2003

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“…[1][2][3] This pharmacologic profile of levosimendan offers new therapeutic possibilities in patients with AHFS. In initial dose-finding 4,5 and therapeutic trials, 6 a rapid and prolonged hemodynamic improvement with an increase in cardiac index, reduction of pulmonary capillary wedge pressure (PCWP), and reduction of peripheral vascular resistance without proarrhythmic effects were documented. Furthermore, positive effects on long-term survival up to 6 months were observed.…”

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European Experience on the Practical Use of Levosimendan in Patients with Acute Heart Failure Syndromes

Folláth

Franco

Silva-Cardoso

2005

The American Journal of Cardiology

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The novel calcium sensitizer and ATP-dependent potassium channel opener levosimendan has been introduced for routine use in several European countries. Recent reports on clinical experience confirm the positive hemodynamic results and beneficial clinical effects described in the initial dose-finding and randomized comparative therapeutic trials in patients with severe low-output heart failure. In addition, studies in small series of patients with cardiogenic shock after myocardial infarction and/or surgical interventions and postinterventional myocardial dysfunction ( Levosimendan is a new calcium-sensitizing drug that opens adenosine triphosphate-dependent potassium (K ATP ) channels with effects that increase myocardial contraction and cause vasodilation. Compared with other agents for acute heart failure syndromes (AHFS), its main potential advantages are the improvement of myocardial contractility without increasing oxygen requirements, reduction of ventricular preload, and an antistunning, anti-ischemic effect by opening K ATP channels. [1][2][3] This pharmacologic profile of levosimendan offers new therapeutic possibilities in patients with AHFS. In initial dose-finding 4,5 and therapeutic trials, 6 a rapid and prolonged hemodynamic improvement with an increase in cardiac index, reduction of pulmonary capillary wedge pressure (PCWP), and reduction of peripheral vascular resistance without proarrhythmic effects were documented. Furthermore, positive effects on long-term survival up to 6 months were observed. 6,7 Levosimendan is registered for clinical use in several countries in Europe, South America, and Asia. There are an increasing number of reports on practical experiences and therapeutic successes in different clinical situations. In this article, we summarize recent publications on therapeutic indications, dose schedules, outcomes, and tolerance. MethodsClinical reports on levosimendan therapy in patients with severe decompensated acute or chronic heart failure (HF), cardiogenic shock after myocardial infarction (MI), or cardiac interventions and perioperative administration are reviewed. These publications were mostly smaller randomized or observational trials, with good descriptions of patient inclusion criteria, levosimendan administration, and methods of clinical and/or hemodynamic evaluation. Therapeutic Efficacy of Levosimendan in Acute Heart Failure SyndromesDecompensated low-output heart failure: Decompensated low-output HF is the best documented therapeutic indication for levosimendan administered as a single intravenous infusion lasting 6 to 24 hours. Patients included in the dose-finding and comparative clinical trials 4 -6 were characterized by dyspnea (New York Heart Association [NYHA] functional class III to IV) and signs of venous and pulmonary congestion accompanied by peripheral vasoconstriction. Hemodynamic inclusion criteria were reduced cardiac index (Ͻ2.5 L/min per m 2 ) and increased PCWP (Ͼ16 mm Hg). Patients with systolic blood pressure Ͻ90 mm Hg were excluded in these initial ...

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“…After application of the inclusion criteria, 14 studies [25][26][27][28][29][30][31][32][33][34][35][36][37][38] including a total of 673 participants were included in the systematic review, and 13 [25,[27][28][29][30][31][32][33][34][35][36][37][38] studies reported mortality data and were included in the meta-analysis. One study reported a change in symptoms and was included in the qualitative synthesis only [26].…”

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confidence: 99%

“…General health questionnaire; 43% reduction (control) vs. 40% reduction (dobutamine) Oliva [36] 5 (control) vs. 7 (dobutamine) required hospitalisation for heart failure 1 (dobutamine) showed increased rate of nonsustained VT on Holter Median NYHA class at 6 months; 3 (control) and 2.5 (dobutamine) Wimmer [38] NR 2 (dobutamine) complained of repeated palpitations Nieminen [35] NR 20% (placebo) vs. 35% (dobutamine) reported adverse events including hypertension, tachycardia and arrhythmias 1 (control) vs. 5 (dobutamine) experienced tachycardia Nanas [34] Mean NYHA at 6 months fell from 4 to 2. Given the strengths and limitations of this study, what are the implications for clinicians?…”

Section: Nrmentioning

confidence: 99%

Dobutamine for patients with severe heart failure: a systematic review and meta-analysis of randomised controlled trials

2011

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Purpose: Dobutamine is recommended for patients with severe heart failure; however uncertainty exists as to its effect on mortality. This study aims to critically review the literature to evaluate whether dobutamine, compared with placebo or standard care, is associated with lower mortality and a range of secondary outcomes, in patients with severe heart failure. Methods: A systematic review and meta-analysis of randomised controlled trials was performed. PubMed, EMBASE, the Cochrane Central Trials Registry, the metaRegister of Controlled Trials and bibliographies of retrieved articles were searched. Randomised trials comparing dobutamine with placebo or standard care, in human, adult patients with severe heart failure, were included if they reported at least one outcome of interest. Data regarding trial validity, methodological processes and clinical outcomes were extracted, and a meta-analysis was performed. Results: Fourteen studies, with 673 participants, met the inclusion criteria and were included; 13 studies reported mortality. There was minimal heterogeneity (I 2 = 4.5%). The estimate of the odds ratio for mortality for patients with severe heart failure treated with dobutamine compared with standard care or placebo was 1.47 (95% confidence interval 0.98-2.21, p = 0.06).Conclusions: This meta-analysis showed that dobutamine is not associated with improved mortality in patients with heart failure, and there is a suggestion of increased mortality associated with its use, although this did not reach the conventional level of statistical significance. Further research to define the role of dobutamine in treatment of severe heart failure should be a priority.

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Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure

Abstract: Dosing of levosimendan with a 10-min bolus of 6 to 24 microg/kg followed by an infusion of 0.05 to 0.2 microg/kg/min is well tolerated and leads to favorable hemodynamic effects.

Cited by 318 publications

References 23 publications

Sustained Hemodynamic Effects of Intravenous Levosimendan

Sustained Hemodynamic Effects of Intravenous Levosimendan

European Experience on the Practical Use of Levosimendan in Patients with Acute Heart Failure Syndromes

Dobutamine for patients with severe heart failure: a systematic review and meta-analysis of randomised controlled trials

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