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Ann Thorac Surg 2006;81:1536-1546
© 2006 The Society of Thoracic Surgeons

Review

Levosimendan in Cardiac Surgery: Current Best Available Evidence

Shahzad G. Raja, MRCS a , * , Benson S. Rayen, DCH b

a Department of Cardiac Surgery, Royal Hospital for Sick Children, Glasgow, United Kingdom
b Department of Cardiology, Royal Hospital for Sick Children, Glasgow, United Kingdom

Accepted for publication August 25, 2005.

* Address correspondence to Dr Raja, Department of Cardiac Surgery, Royal Hospital for Sick Children, Yorkhill NHS Trust, Dalnair Street, Glasgow G3 8SJ, United Kingdom (Email: drrajashahzad{at}hotmail.com).


   Abstract
Top
 Abstract
Introduction
 Pharmacodynamics of Levosimendan
 Pharmacokinetics of Levosimendan
 Clinical Efficacy in Heart...
 Levosimendan Usage in Cardiac...
 Search Methodology
 Results
 Comment
 Conclusion
 References
 
Recent upsurge in referral of patients with high perioperative risk or compromised left ventricular function for cardiac surgery has lead to an increasing use of pharmacologic support in the form of vasodilator and inotropic therapy to achieve improvement of tissue perfusion in the perioperative period or to support weaning from cardiopulmonary bypass. Traditionally, perioperatively used inotropic agents, epinephrine, dobutamine, and milrinone, are limited by significant increases in myocardial oxygen consumption, proarrhythmia, or neurohormonal activation. Levosimendan, a new inodilator for the treatment of decompensated heart failure, has also shown promise in elective therapy of cardiac surgical patients with high perioperative risk or compromised left ventricular function, as well as in rescue therapy of patients with difficult weaning from cardiopulmonary bypass. This review article briefly discusses the pharmacology of levosimendan and evaluates current best available evidence to assess the safety and efficacy of levosimendan usage in cardiac surgery.


   Introduction
Top
 Abstract
 Introduction
Pharmacodynamics of Levosimendan
 Pharmacokinetics of Levosimendan
 Clinical Efficacy in Heart...
 Levosimendan Usage in Cardiac...
 Search Methodology
 Results
 Comment
 Conclusion
 References
 
Recent upsurge in referral of patients with high perioperative risk or compromised left ventricular function for cardiac surgery has lead to an increasing use of pharmacologic support in the form of vasodilator and inotropic therapy to achieve improvement of tissue perfusion in the perioperative period or to support weaning from cardiopulmonary bypass (CPB). Traditionally, catecholamines including dopamine, dobutamine, epinephrine, and isoproterenol have been used as inotropic support after cardiac surgery [1, 2]. Dopamine is commonly used to support cardiac output (CO) after CBP. Epinephrine is occasionally useful during the immediate postoperative period when high systemic blood pressures are sought. Isoproterenol is often used during the immediate postoperative period after heart transplantation for its chronotropic and vasodilatory effects. The adverse effects of high-dose catecholamines include an increase in myocardial oxygen consumption, heart rate (HR), systemic afterload, and the risk of arrhythmia [3]. Similarly, phosphodiesterase III (PD III) inhibitors, amrinone, milrinone, and enoximone, have also been used as inotropes after cardiac surgery [4–7]. However, valid concerns persist that PD III inhibitors are responsible for an increase in mortality rate compared with placebo, possibly due to the deleterious effects of raised intracellular calcium as well as neurohormone levels on the failing myocardium, in patients suffering from chronic heart failure [8, 9].

Recently, levosimendan, a pyridazinone-dinitrite and a member of a new class of agents, the calcium sensitizers, that increase myocardial contractility without increasing intracellular calcium, has emerged as an inotropic agent [10–12]. In preclinical and clinical studies, levosimendan has been shown to exert potent dose-dependent positive inotropic and vasodilatory activity and has emerged as a promising alternative to conventional inotropic agents for patients with decompensated heart failure. This review will focus on the pharmacology and clinical data on the safety and efficacy of levosimendan usage in cardiac surgery.


   Pharmacodynamics of Levosimendan
Top
 Abstract
 Introduction
 Pharmacodynamics of Levosimendan
Pharmacokinetics of Levosimendan
 Clinical Efficacy in Heart...
 Levosimendan Usage in Cardiac...
 Search Methodology
 Results
 Comment
 Conclusion
 References
 
Mechanism of Action and Pharmacologic Effects
Agents currently available for the treatment of decompensated heart failure increase myocardial concentrations of cyclic adenosine monophosphate (cAMP), which ultimately causes an inotropic effect by increasing myocardial concentrations of calcium [13]. Catecholamines such as dobutamine stimulate beta-1 adenoceptors on the myocardial cells, causing increases in cAMP, while phosphodiesterase inhibitors such as milrinone prevent the breakdown of cAMP by phosphodiesterase. The increase in cAMP provided by catecholamines and phosphodiesterase inhibitors causes an up-regulation in the activity of protein kinase C, which increases the calcium current into myocytes during systole to cause an increased inotropic effect [13]. In contrast, levosimendan reduces the calcium-binding coefficient of troponin C by stabilizing the conformational shape of the protein in its active form [13]. This enhances myocardial contraction similar to traditional agents but with lower intracellular calcium concentration requirements (Fig 1). Even though levosimendan does not enhance intracellular calcium, there is a concentration-response relationship between intracellular calcium and inotropy [13].


Figure 1
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  		Fig 1. Mechanisms of action of levosimendan and other cardiotonic agents. Mechanisms of action of cardiotonic agents are classified in the upper row in relation to the site of action on cardiac excitation-contraction (EC) coupling in the lower row. Horizontal lines with arrows in the middle of a myocardial cell surrounded by half-tone broad line represent the main stream of cardiac EC coupling. Modulation of Ca2+· troponin (Tn) · tropomyosin complex is reflected either to class I or to class II Ca2+ sensitizing action. Dotted lines indicate the feedback regulation of Ca2+ binding affinity to troponin C induced by tension development (crossbridge cycling). (CICR = Ca2+-induced Ca2+ release; DHPR = dihydropyridine receptor [L-type Ca2+ channel]; NCX = Na+/Ca2+exchanger; SERCA2, SR Ca2+pump ATPase; PLB = phospholamban; RyR = ryanodine receptor [SR Ca2+release channel]; SR = sarcoplasmic reticulum.) (Reproduced with permission from Endoh M. Mechanisms of action of novel cardiotonic agents. J Cardiovasc Pharmacol 2002;40:323-8.)

 
Levosimendan offers the advantage of increasing systolic force without compromising coronary perfusion due in part to a synergistic mechanism of action attributed to opening of the adenosine triphosphate-sensitive potassium channels [11, 12, 14–16]. The opening of adenosine triphosphate-sensitive potassium channels by adenosine triphosphate (ATP) produces peripheral vasodilation, coronary artery dilation, and myocyte mitochondrial activation [13]. All these beneficial effects work synergistically with calcium sensitization to improve myocardial performance.

Unlike classic inotropes, levosimendan does not impair diastolic function or lusitropy. In vitro studies have consistently demonstrated either a neutral or a positive lusitropic effect [13]. It is hypothesized that the neutral effect on diastolic function is secondary to the calcium-dependent binding to troponin C [13]. The mechanism for the positive lusitropic effects can be attributed to PD III inhibition at higher concentrations [12]. Phosphodiesterase inhibition leads to increased cAMP levels, augmented phosphorylation of phospholamban, and thus enhanced removal of cytosolic calcium by the sarcoplasmic-endoplasmic reticulum ATPase pump, resulting in accelerated relaxation of the myofilaments [12].

Although levosimendan is a potent and highly selective inhibitor of PD III, this action, at low doses, does not contribute to its inotropic and vasodilator properties because the extent of this activity does not cause an increase in the intracellular levels of cAMP [10, 17]. Furthermore, in contrast to specific PD III inhibitors such as amrinone and milrinone, the positive inotropic effect of levosimendan in cardiac tissue is not attenuated by disease [10].

At therapeutic doses, levosimendan exhibits enhanced myocardial contractility with no increase in oxygen demands [11, 12]. Intravenous (IV) levosimendan significantly increases cardiac output (CO) or cardiac index and decreases ventricular filing pressures in the acute treatment of stable or decompensated congestive heart failure [18, 19]. It is also of benefit in the setting of pulmonary vasoconstriction and right ventricular dysfunction. The drug has been shown to increase ventricular contractility and hydraulic power without changing pulmonary vascular resistance in experimental setup [20]. In patients with heart failure, the drug has been shown to reduce pulmonary vascular resistance [18, 19].

Elevation of neurohormones (eg, norepinephrine, renin, endothelin-1, and brain natriuretic peptide) in heart failure has been associated with a worsening prognosis [21]. Despite producing a hemodynamic benefit, the clinical utility of currently available inotropic therapy is limited because these agents increase mortality perhaps due to drug-induced increases in neurohormone levels [13]. Levosimendan has been shown to reduce significantly endothelin-1 levels compared with placebo (p < 0.001) [22]. However, compared with dobutamine it has not demonstrated a sustained lowering of atrial natriuretic peptide, norepinephrine, epinephrine or renin [18]. Furthermore, in experimental and clinical studies, levosimendan, in therapeutic doses, has not shown to be arrhythmogenic [11], as it does not increase the intracellular concentrations of cyclic adenosine monophosphate or calcium, a problem with all other positive inotropic agents (Table 1).


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  		Table 1. Comparison of Levosimendan with Milrinone and Dobutamine
 
Adverse Effects
The most common adverse effect seen in healthy volunteers is headache, reported by some 40% of subjects in oral dosing but only 10% in IV dosing. The incidence of headache does not correlate well with the total daily dose of the drug [23]. However, the controlled release formulations tested appear to cause vasodilatory symptoms more frequently than IV or rapid release oral formulations. The other typical vasodilatory adverse effects seen in healthy volunteers are nausea, palpitation, and dizziness [23]. Symptomatic hypotension is rarely encountered. Higher doses of levosimendan reduce arterial pressure, systemic vascular resistance (SVR), and ventricular filling pressures [24] leading to the use of vasoactive drugs to support arterial pressure. This can be of significance in postoperative cardiac surgical patients. It appears that heart failure patients tolerate the vasodilatory actions of the drug better than healthy volunteers [23]. Only individual cases of headache, vertigo, and flushing have been reported, and injection site irritation has been the most commonly reported adverse reaction (with an incidence < 5%) [23]. All patients who have received levosimendan have been monitored with an ambulatory electrocardiogram. Even though some increase in heart rate is seen with high doses of the drug, there are thus far no signs of an increased incidence of ventricular tachyarrhythmias, nor have there been any noteworthy changes in the clinical laboratory safety tests [23].


   Pharmacokinetics of Levosimendan
Top
 Abstract
 Introduction
 Pharmacodynamics of Levosimendan
 Pharmacokinetics of Levosimendan
Clinical Efficacy in Heart...
 Levosimendan Usage in Cardiac...
 Search Methodology
 Results
 Comment
 Conclusion
 References
 
The pharmacokinetic profile of levosimendan is linear, and the plasma concentrations of the drug increase in a dose-proportional manner after a single-dose administration or intravenous infusion [25, 26]. Levosimendan has a half-life of approximately 1 hour [27]. It is rapidly distributed to the tissues and 97% to 98% of the drug is bound to plasma proteins, mainly human plasma albumin [27]. Levosimendan is reduced in the gut to an amine metabolite, OR-1855, which is further acetylated to an active metabolite, OR-1896. The half-life of OR-1896 is longer than that of levosimendan (approximately 80 hours). Because OR-1896 has a similar hemodynamic profile to levosimendan, the longer half-life of OR-1896 compared with levosimendan most likely explains the long-lasting hemodynamic effects after levosimendan infusion [28, 29]. The pharmacokinetics of levosimendan are similar in healthy subjects and patients with heart failure and remain relatively unaltered by age, sex, and organ dysfunction [30]. Clearance of levosimendan is 296–368 mL/minute [30]. Roughly 70% of the unchanged levosimendan and its metabolites are excreted in the urine (30%) and feces (40%) [30]. Whole blood, red blood cell, and saliva concentrations are 60%, 10%, and 20% of plasma concentrations, respectively [30]. Furthermore, levosimendan does not have clinically important pharmacokinetic interactions with captopril, ß-blockers, felodipine, digoxin, warfarin, isosorbide mononitrate, carvedilol, ethanol, or itraconazole [11].


   Clinical Efficacy in Heart Failure
Top
 Abstract
 Introduction
 Pharmacodynamics of Levosimendan
 Pharmacokinetics of Levosimendan
 Clinical Efficacy in Heart...
Levosimendan Usage in Cardiac...
 Search Methodology
 Results
 Comment
 Conclusion
 References
 
Clinical research experience has been accumulating with levosimendan. At present four phase III trials [31–34] evaluating the effect of levosimendan on clinical end points in patients with heart failure have been completed (Table 2). In the multicenter, randomized, double-blind, double-dummy, parallel-group levosimendan infusion versus dobutamine (LIDO) trial, recruiting patients with severe low-output heart failure, intravenous levosimendan improved hemodynamic performance more effectively than dobutamine [31]. This benefit was accompanied by a lower mortality rate in the levosimendan group than in the dobutamine group for up to 180 days. In this trial, patients who received levosimendan had fewer serious side effects than patients treated with dobutamine [31]. In the randomized study on safety and effectiveness of levosimendan in patients with left ventricular failure due to an acute myocardial infarct (RUSSLAN) study, levosimendan also has been shown to be a safe and effective therapy for patients with left ventricular failure complicating acute myocardial infarction [32].


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  		Table 2. Phase III Clinical Trials Demonstrating Efficacy of Levosimendan in Congestive Heart Failure
 
In the calcium sensitizer or inotropic agent or none in low output heart failure (CASINO) study, designed to recruit 600 patients, a clear mortality benefit in favor of levosimendan compared with dobutamine, resulted in the recruitment being stopped at 299 patients [33]. At the same time, the REVIVE I trial has shown that levosimendan administration to patients in acute decompensated heart failure reduces the length of intensive care and hospital stay with significant economic impact [34]. Several other studies have also confirmed the findings of these phase III trials and validated the safety and efficacy of levosimendan as an inotropic agent [24, 35–39].


   Levosimendan Usage in Cardiac Surgery
Top
 Abstract
 Introduction
 Pharmacodynamics of Levosimendan
 Pharmacokinetics of Levosimendan
 Clinical Efficacy in Heart...
 Levosimendan Usage in Cardiac...
Search Methodology
 Results
 Comment
 Conclusion
 References
 
After successful impact of levosimendan as an inotropic agent for patients with acute and chronic heart failure, several promising human studies on levosimendan usage in cardiac surgery have been published recently suggesting levosimendan can be beneficial in low-output states after cardiac surgery. We are currently practicing in an era of evidence-based medicine (EBM) [40]. In this era of EBM any new therapy can only be adopted for universal clinical usage after it has been validated by rigorous scrutiny of current best available scientific evidence. In the hierarchy of clinical evidence, the randomized clinical trial (RCT) is generally considered the best approach to ascertain the value of a particular therapy [40, 41]. However, a logical and comprehensive approach to evaluating clinically relevant research incorporates many different types of evidence including RCTs, nonrandomized clinical trials, and experimental data and analyzes the information's content for its consistency, coherence and clarity [41]. The next section of this review evaluates the current best available evidence to validate the safety and efficacy of the perioperative use of levosimendan in cardiac surgical patients with high perioperative risk, compromised left ventricular function, or with difficulties in weaning from CPB.


   Search Methodology
Top
 Abstract
 Introduction
 Pharmacodynamics of Levosimendan
 Pharmacokinetics of Levosimendan
 Clinical Efficacy in Heart...
 Levosimendan Usage in Cardiac...
 Search Methodology
Results
 Comment
 Conclusion
 References
 
The MEDLINE database was searched from the date of its inception to the end of May 2005 using Medical Subject Headings (MeSH) search terms "levosimendan," "cardiac surgery," and "cardiopulmonary bypass" as well as non-MeSH search terms "calcium sensitizer" and "inotropic agents." The search was done in stages to achieve the search strategy with a high sensitivity (meaning that it has the highest likelihood of retrieving all relevant papers). Similar search terms were combined using the Boolean operator 'OR' to find all abstracts that contained information about a particular search term. These individual terms were then combined using the Boolean operator 'AND' to find papers that contained information on all the search terms. This is a well-recognized method for performing sensitive searches and has been described in detail in the British Medical Journal [42].

The EMBASE, Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Science Citation Index, Current Contents, NHS Economic Evaluation Database, and International Network of Agencies for Health Technology Assessment databases were also searched from the date of their inception to the end of May 2005. In addition, tangential electronic exploration of related articles and hand searches of bibliographies, scientific meeting abstracts, and related journals were performed.

Inclusion Criteria
All English and non-English articles reporting use of levosimendan in cardiac surgery recruiting adult or pediatric patients were included in this review.

Data Extraction and Validation of the Studies
The papers found by the search strategy were then appraised. The appraisal of each paper was performed in a structured format, using critical appraisal checklists. These are widely available in several formats and aid in assessing the paper for methodologic and analytical soundness and help uncover any significant methodologic flaws [43]. The following information was extracted from each study: first author, year of publication, study type, study population characteristics, number of patients, and key outcomes. Finally, a conclusion was formulated based on the validity of the studies identified, taking into consideration the source and the strength of the evidence by using the grading system proposed by the Centre for Evidence Based Medicine (Table 3) [44].


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  		Table 3. Grading of Recommendations and Level of Evidence
 

   Results
Top
 Abstract
 Introduction
 Pharmacodynamics of Levosimendan
 Pharmacokinetics of Levosimendan
 Clinical Efficacy in Heart...
 Levosimendan Usage in Cardiac...
 Search Methodology
 Results
Comment
 Conclusion
 References
 
A total of 14 studies [45–58], including four RCTs [49, 56–58], fulfilling the inclusion criteria were retrieved for evaluation after screening a total of 617 citations. Only two studies reported use of levosimendan in pediatric cardiac surgical patients [47, 48]. Except for the randomized and four-times masked controlled study by Barisin and colleagues [49], reporting levosimendan usage in off-pump coronary artery bypass (OPCAB) surgery, all other studies reported perioperative use of levosimendan after cardiac surgery on CPB (Table 4).


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  		Table 4. Studies Reporting Levosimendan Use in Cardiac Surgery
 
Experience with Levosimendan in Adult Cardiac Surgery Patients With Normal Preoperative Left Ventricular Function
Lilleberg and colleagues [58] performed the first ever randomized, double-blind study to evaluate the effects on systemic and coronary hemodynamics and myocardial substrate utilization of levosimendan after coronary artery bypass grafting (CABG). Twenty-three low-risk patients, with ejection fraction greater than 30% and isolated coronary artery disease, received placebo (n = 8), 8 mcg/kg (n = 8) or 24 mcg/kg (n = 7) of levosimendan after elective CABG. Systemic and coronary sinus hemodynamics with thermodilution and myocardial substrate utilization were measured. The heart rate (HR) increased 11 beats/minute after the higher dose (p < 0.05). Cardiac output increased by 0.7 and 1.61/minute (p < 0.05 for both) after 8 and 24 mcg/kg of levosimendan, respectively. Systemic and pulmonary vascular resistance decreased significantly after both doses. Coronary sinus blood flow increased by 28 and 42 mL/minute (p = 0.054 for the combined effect) after the lower and higher dose, respectively. Despite improved cardiac performance, levosimendan did not increase myocardial oxygen consumption or change myocardial substrate utilization.

Nijhawan and colleagues [57] confirmed and extended the findings of Lilleberg and colleagues [58]. In their randomized, double-blind, placebo-controlled trial, 18 elective patients, with ejection fraction greater than 30%, were randomly assigned to receive levosimendan (18 or 36 mcg/kg loading dose and 0.2 or 0.3 mcg/kg/minute infusion, respectively) or placebo 15 minutes before and continued for 6 hours after CPB. Immediate and sustained increases in CO and reductions in SVR after CPB were obtained with loading doses followed by continuous infusions of levosimendan. According to Nijhawan and colleagues [57] the increases in CO produced by low-dose levosimendan probably resulted from the combined actions of reduced left ventricular afterload and modestly increased stroke volume. In addition to these factors, modest increases in HR may also have contributed to enhanced CO during administration of high-dose levosimendan. Furthermore, in this study levosimendan did not affect arterial oxygenation or cause arrhythmogenic effects and the low dose of levosimendan demonstrated equivalent efficacy with the high dose. These findings were also confirmed by the randomized, double-blind, placebo-controlled trial of Sandell and colleagues [56].

Experience with Levosimendan in Adult Cardiac Surgery Patients With Poor Preoperative Left Ventricular Function
Rajek and colleagues [53] were the first to report the use of levosimendan in patients with congestive heart failure and a preoperative left ventricular ejection fraction of 19 ± 5% undergoing elective cardiac surgery. Eight patients (7 men and 1 woman) undergoing CABG (n=5), mitral valve replacement (n=2), and aortic valve replacement (n = 1) received a loading dose of 0.6 mcg · kg · minute for 10 minutes before sternotomy followed by a reduced dose of 0.2 mcg · kg · minute until the end of the infusion. There was a dramatic increase in CO after 60 minutes of levosimendan infusion and it stayed higher than 5 L/min during the first postoperative day, while pulmonary capillary wedge pressure (PCWP) decreased. Heart rate, mean arterial pressure (MAP), and pulmonary arterial pressure did not change during levosimendan infusion. Furthermore, weaning from CPB was successful in every patient without the need for an intraaortic balloon pump (IABP) and there was a reduction in catecholamine requirements and the duration of critical care. Several other publications [45, 46, 50, 51, 55] have confirmed these findings of Rajek and colleagues [53].

Experience with Levosimendan in Adult Cardiac Surgery Patients With Acute Coronary Syndrome Undergoing Emergent Surgical Revascularization
Levosimendan has also been shown to exert positive inotropic and cardioprotective effects in high-risk patients with acute myocardial ischemia undergoing emergency surgical revascularization [52, 54]. Lehmann and colleagues [52] administered levosimendan (bolus 6 mcg/kg, continuous infusion 0.2 mcg/kg/min) in addition to catecholamines to 10 patients, with acute myocardial ischemia, cardiogenic shock, and/or cardiopulmonary resuscitation, undergoing emergency surgical revascularization. All patients treated with levosimendan and catecholamines were weaned successfully from CPB on the first attempt and only 2 needed an additional IABP. Furthermore, 8 of the 10 patients survived without any multiorgan failure.

Experience With Levosimendan in Off-Pump Coronary Artery Bypass Surgery
Barisin and colleagues [49] in their randomized, placebo-controlled, and four-times masked study, tested the hypothesis that levosimendan produced beneficial hemodynamic effects during and after OPCAB in patients with good preoperative left ventricular function. Thirty-one patients were administered a placebo (n = 10) or levosimendan, at a dose of 12 mcg/kg (n = 11) and 24 mcg/kg (n = 10), 20 minutes before starting of operation over a period of 10 minutes. Significant increases in CO and left ventricular ejection fraction occurred after high-dose (p < 0.001; p = 0.006) and low-dose levosimendan (p = 0.001; p = 0.002). Both doses of levosimendan produced significant increased stroke volume and decreased SVR. The MAP, PCWP, and left ventricular end-systolic volumes were not significantly different among groups. Based on their findings the authors concluded that low-dose levosimendan produced better hemodynamic response than high-dose and may be preferable in patients undergoing OPCAB.

Experience With Levosimendan in Pediatric Cardiac Surgery Patients
As an inotropic agent with potent vasodilating effects on pulmonary vasculature, levosimendan offers the potential as a new pre-, peri-, and postoperative therapy for children with congenital heart diseases and low cardiac output or increased pulmonary artery pressure [47]. Turanlahti and colleagues [47] have shown that the pharmacokinetic profile of levosimendan in children with congenital heart disease is similar to that in adult patients with congestive heart failure. Levosimendan has been shown to be effective in pediatric patients, with combination of reduced myocardial function, pulmonary hypertension, and the prevalence of a septal defect, when epinephrine, enoximone, epoprostenol, and nitroglycerine have proven ineffective [48]. Furthermore, absence of serious adverse events or unexpected adverse drug reactions makes it an attractive inotropic agent for pediatric patients [47].


   Comment
Top
 Abstract
 Introduction
 Pharmacodynamics of Levosimendan
 Pharmacokinetics of Levosimendan
 Clinical Efficacy in Heart...
 Levosimendan Usage in Cardiac...
 Search Methodology
 Results
 Comment
Conclusion
 References
 
Since reperfusion injury is a frequent complication of surgery on CPB, the use of inotropes is frequently employed to reverse myocardial hypokinesis [13]. Unfortunately, the use of currently available inotropic agents such as milrinone and dobutamine can produce an increase in myocardial oxygen consumption and may increase the incidence of arrhythmias. Levosimendan is a novel calcium sensitizer, which has been discovered by using cardiac troponin C as target protein. This drug has been proved a well-tolerated and effective treatment for patients with severe decompensated heart failure. It causes a positive inotropic effect on cardiomyocytes by interacting directly with the contractile apparatus. Its mechanism of action is not accompanied by an increase in intracellular calcium concentration at therapeutic doses, as seen for the classic positive inotropic drugs, and thus does not induce calcium-related deleterious effects such as arrhythmias or apoptosis [59].

Preliminary experience of its use in cardiac surgery for patients requiring inotropic support in the perioperative period appears promising. One of the major theoretic advantages of levosimendan over conventional inotropic agents is its ability to augment systolic function without increasing myocardial oxygen demand. The open-label, nonrandomized study by Ukkonen and colleagues [60], employing positron emission tomography with [11C]acetate to measure myocardial oxygen consumption noninvasively and assess myocardial efficiency in 16 healthy men, clearly showed that myocardial oxygen consumption per heart beat was unchanged with levosimendan, as opposed to being increased with dobutamine. Similar effects on myocardial energetics and oxygen consumption have been shown by the same group [39] in their RCT recruiting patients with congestive heart failure, as well as by Nijhawan and colleagues [57] in their RCT recruiting patients undergoing CABG on CPB. These studies suggest that levosimendan is a distinct inotropic agent that does not appear to augment contractility at the expense of increased myocardial oxygen demand with bolus doses up to 24 mcg/kg and infusions up to 0.3 mcg · kg · minute.

Inotropic agents have been notorious for exerting proarrhythmic effects. Although levosimendan does not increase intracellular calcium concentrations, its ability to alter potassium currents and inhibit the PD III enzyme in vitro, could be proarrhythmic [30]. Levosimendan has been associated with dose-dependent ventricular ectopy. Two important dose-ranging studies [18, 24] have shown that infusion dose of 0.6 mcg · kg · minute and bolus doses of 2–4 mg result in an increase in ventricular extrasystoles compared with placebo. On the other hand, in patients undergoing CABG, lower dosages (< 0.4 mcg/kg/min) have not been associated with an increase in ventricular ectopy compared with placebo [58]. Levosimendan is also associated with prolongation of the QT interval; however, this effect is again dose dependent with a linear dose relationship evident in all studies [18, 61, 62]. Although in a pooled analysis of 10 studies, no increase in the development of ventricular ectopy was detected when levosimendan was used at recommended dosages (0.05–0.2 mcg/kg/min) [63], isolated reports of ventricular ectopy in clinical trials suggest monitoring of the electrocardiograph during levosimendan therapy would be prudent until more clinical experience is gained with this agent [30].

Levosimendan is also emerging as an attractive option for the maintenance of hemodynamic stability in OPCAB. The main cause of hemodynamic instability (decreases of CO and arterial pressure; increases of left and right atrial pressures; and left and right ventricular end-diastolic pressures) is the disturbance of ventricular diastolic filling by direct ventricular compression [64, 65]. In the early days of OPCAB revival, the management of patients undergoing OPCAB was mainly focused on the maintenance of the MAP, HR, and cardiac rhythm between stable limits during coronary anastomosis [65]. Especially, intravenous fluid loading, head down position, were recommended to compensate decreased MAP and CO [66], and the use of inotropic drugs were relatively contraindicated [65]. This was mainly based on the concept that inotropic drugs that act on the ß-adrenergic receptors increased myocardial oxygen consumption and HR resulting in myocardial ischemia and hemodynamic instability [67]. However, with increasing experience it was found that the augmentation of preload with head down position and fluid loading was not enough to compensate the reduced CO during anastomosis and low doses of inotropic agents, or boluses of vasoconstrictors were needed for maintenance of hemodynamic stability [68, 69]. There is, however, no consensus of opinion about ideal vasoactive drug support in OPCAB. Catecholamines are not routinely recommended in this setting because they could cause significant hemodynamic disturbances (primarily tachycardia) and increase in myocardial oxygen consumption. On the other hand, vasoconstrictors are the medications most often used in these situations but they could have an effect on CO and on the patency of arterial grafts due to increasing SVR [49]. Hence, levosimendan owing to its more favorable impact on hemodynamics could be an alternative agent for the maintenance of hemodynamic stability in OPCAB.

Other Potential Indications
Apart from improved hemodynamics and diminished wall stress, levosimendan purports three properties that could be of value in myocardial ischemia: vasodilation of coronary vasculature, calcium sensitization, and adenosine triphosphate-sensitive potassium channel activation [30]. Coronary artery vasodilation could improve cardiac muscle perfusion and alleviate ischemia. The antiischemic effect of levosimendan has been shown in an isolated rabbit heart subjected to circumflex artery ligation [70]. Levosimendan infused continuously 30–120 minutes after ischemia resulted in dose-dependent increases in coronary flow and a reduction in ischemic zone size at 60 and 120 minutes.

Calcium sensitization during ischemia may improve the contractile function of stunned myocardium and oxygen utilization efficiency, thereby reducing oxygen consumption and minimizing ischemic damage. In addition, activation of adenosine triphosphate-sensitive potassium channels may facilitate repolarization, inducing myocytes into a resting state similar to that seen in ischemic preconditioning [30]. This protective effect of levosimendan, coupled with its positive effects on lusitropy and lack of significant neurohormonal activation, may have implications for CPB-induced ischemia-reperfusion injury and requires further investigation.

Owing to its ability to reduce pulmonary vascular resistance, secondary to activation of adenosine triphosphate-sensitive potassium channels [30], it could also be useful in the setting of pulmonary hypertension and right ventricular dysfunction. Finally, levosimendan can be potentially effective in treating as well as preventing perioperative spasm of coronary artery bypass grafts as it has been shown in vitro to produce a concentration-dependent relaxation of the internal mammary artery rings precontracted with norepinephrine [71].

Limitations of Available Evidence
Experience is limited in patients undergoing cardiac surgery. Although hemodynamic efficacy has been established in the perioperative period, levosimendan has been studied only as a short-term therapy, generally infused for 6 to 24 hours. There is nothing in the literature to suggest an optimum duration of therapy. Furthermore, data for determination of an optimum dosage also are limited. Beneficial hemodynamic effects are dose dependent; however, so are most of the adverse effects. Based on available information it can be recommended that lower dosage regimen (bolus < 36 mcg/kg/min and infusion < 0.4 mcg/kg/min) would be safe and effective. Finally, no data are available at present to validate its long-term safety necessitating mandatory electrocardiographic monitoring to detect QT prolongation and ventricular arrhythmias as well as routine monitoring for other vasodilatory effects such as hypotension and headache.


   Conclusion
Top
 Abstract
 Introduction
 Pharmacodynamics of Levosimendan
 Pharmacokinetics of Levosimendan
 Clinical Efficacy in Heart...
 Levosimendan Usage in Cardiac...
 Search Methodology
 Results
 Comment
 Conclusion
References
 
Current best available evidence (grade A/level 1b) suggests that levosimendan enhances cardiac performance and reduces left ventricular afterload after CPB in patients with normal preoperative left ventricular function. Furthermore, in addition to being effective in postoperative rescue therapy for patients with difficult weaning from CPB, elective preoperative initiation of levosimendan in patients with high perioperative risk or compromised left ventricular function appears to reduce catecholamine requirements, the need for mechanical circulatory support, and the duration of critical care. It has a favorable pharmacokinetic profile and is well-tolerated by adult as well as pediatric postoperative cardiac surgical patients. However, these encouraging preliminary results with levosimendan in cardiac surgical patients need to be verified by a larger, multicenter RCT, evaluating the optimum dosage and duration of therapy, its role in specific subgroups of patients (such as by etiology and age), its combination with other vasoactive intravenous therapy, and finally its long-term effects on symptomology, duration of hospitalization, and mortality as well as its cost-effectiveness.


   References
Top
 Abstract
 Introduction
 Pharmacodynamics of Levosimendan
 Pharmacokinetics of Levosimendan
 Clinical Efficacy in Heart...
 Levosimendan Usage in Cardiac...
 Search Methodology
 Results
 Comment
 Conclusion
 References
 

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