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One of the strategies used in themanagement of congestive heart failure(CHF) is to increase myocardialcontractility without increasing the

afterload. “Inodilators”, as their name suggest, are agroup of drugs that achieve this dual goal byincreasing the contractility and causing vasodi-latation(1). This group includes dobutamine (β-adrenergic agent) and milrinone (phosphodiesteraseIII inhibitor). These agents achieve these effects byincreasing intracellular concentrations of freecalcium. However, this action markedly increasesmyocardial energy consumption, which maycontribute to the risk of arrhythmias. Levosimendanis one of a new class of inodilators, the calciumsensitizers. The present review highlights the clinicalpharmacology, indications and therapeutic efficacyof this drug in clinical practice.

MECHANISM OF ACTION

Levosimendan is a pyridazone-dinitrile derivative. Ithas two important actions. Its primary action is toenhance cardiac contractility. This is achieved by apharmamcological mechanism known as calciumsensitization. It does not increase intracellularconcentrations of free calcium. It binds to cardiactroponin C in a calcium-dependent manner andstabilises troponin C. This causes actin-myosincross-bridges, without increasing myocardialconsumption of adenosine triphosphate (ATP). Thecardiac performance and contractility aresignificantly inproved with no increase in the totalmyocardial energy demand and oxygen con-sumption. The potential for arrhythmia is alsoreduced as total intracellular calcium levels are notraised. An additional benefit is that the stabilization

effect is calcium dependant and levosimendan exertsit effects during systole; it does not effect theduration of diastole and so ventricular relaxation isnot impaired. Consequently adequate ventricularfilling and optimal coronary perfusion still occurs.

Levosimendan also causes venous, arterial andcoronary vasodilation, probably by opening ATP-sensitive potassium channels in smooth muscle.Dose-dependant hypotension may occur. Levo-simendan is also of benefit in the setting ofpulmonary vasoconstriction and right ventriculardysfunction and reduces pulmonary vascularresistance.

Levosimendan is 98% bound to plasma proteinsand completely metabolized prior to excretion.Approxi-mately 5% of a dose is converted in theintestines, and then to a highly-active metabolitewith an elimination half-life of 75–80 h (compared to1 hour elimination half-life for levosimendan itself).This metabolite reaches a peak plasma concentrationabout 2 days after the termination of the infusion andexhibits haemodynamic effects similar to those oflevosimendan. Because of the long half-life of theactive metabolite, these effects last for up to 7 to 9days after discontinuation of a 24-hour infusion oflevosimendan.

Through its non-β-adrenergic actions, it allowsfor interruption of catecholamine infusions, whichmay mitigate the tolerance or tachyphylaxisassociated with these drugs, an approach that hasbeen reported in adult patients. Finally, its inotropicproperties may be particularly desirable in childrenwho are receiving α-blockers, for whomcatecholamines may provide only limited benefit.

LevosimendanSHRISHU R KAMATH, INDIRA JAYKUMAR AND SUNIT MATHA

From Department of Pediatric Intensive Care Unit, Mehta Children’s Hospital, Chennai; and Apollo Hospitals, Chennai, India.Correspondence to: Dr Shrishu R Kamath, 34, 5th Floor, Waterford Apartments, East Coast Road, Thiruvanmaiyur, Chennai,Tamil Nadu 600 041, India. shrishu@yahoo.com.

D R U G R E V I E W

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DOSE

The usual dosage of intravenous levosimendan usedin clinical trials of patients with heart failure is 6 to12 µg/kg loading dose over 10 minutes followed by0.05 to 0.2 µg/kg/min as a continuous infusion.Hemodynamic response is generally observedwithin 5 minutes of commencement of infusion ofthe loading dose. Peak effects are observed within 10to 30 minutes of infusion; duration of action oflevosimendan is about 75-78 hours to 1 week due toactive metabolites. No dosage adjustments arerequired in patients with mild to moderate renalfailure and hepatic impair-ment. Efficacy with oncea week administration makes it a promising drug.The published trials so far have utilized intravenouslevosimendan. However, the agent is also wellabsorbed orally and oral preparation is nowavailable. Comparison of levosimendan withdobutamine and milrinone is given below inTable I.

Levosimendan is currently licensed in 10European countries (Simdax, Abbot Pharma-ceuticals) for the treatment of acute heart failure. Thedrug is not licensed to be marketed in India. It needsto be procured by obtaining a special license.Levosimendan is available in the strength of 2.5 mgper 5 mL per ampoule and 10mL per ampoule. Thecost of each vial accounts to approximately 75,000 to1,00,000 INR depending upon the country it isimported.

SIDE EFFECTS

Levosimendan is well tolerated, with most adverseevents (e.g., headache, hypotension) being dose-related and arising from the vasodilatory actions ofthe drug. In order to avoid undue hypotension it maybe prudent to temporarily stop milrinone and othervasodilators when administering this drug(2,3). Theother side effects that are forthcoming from trialsinclude prolongation of corrected QT interval andrarely, ventricular tachycardia. Nevertheless, itshould be avoided in patients with Torsades or anyother abnormal rhythm.

EVIDENCE SUPPORTING USE OF LEVOSIMENDAN

A study in a pediatric cohort of children with severeheart failure who were inotrope dependentdemonstrated that levosimendan can be safelyadministered to infants and children with severeheart failure(4). In this study, amongst children withacute onset cardiac failure, levosimendan allowedfor substantial reduction in catecholamine infusionsand produced an objective improvement in myocar-dial performance. The effects of levosimendan wasless favaourable in patients with end stage chronicheart failure. In another study from Australia, whenlevosimendan was administered during cardio-pulmonary bypass in children with anticipated lowcardiac output, it demonstrated low arterial lactatelevels, trends toward improved hemodynamics, heartrate reduction, an increase in mean blood pressure,and reduced conventional inotrope use(5).

TABLE I COMPARISON BETWEEN LEVOSIMENDAN, MILRINONE AND DOBUTAMINE

Feature Levosimendan Milrinone Dobutamine

Class Calcium channel sensitizer Phosphodiesterase-III Catecholamineinhibitor (β-adrenergic agent)

Increases intracellular No Yes Yescalcium concentrationsVasodilator Coronary and systemic Peripheral Mild peripheralIncrease myocardial No No Yesoxygen demandArrhythmogenic potential Rare and may be due to Ventricular and supraventricular Ventricular ectopic activity;

QTc prolongation arrhythmias less arrhythmogenic thanmilrinone

Adverse events Headache, hypotension Ventricular irregularities, Tachycardia and increased SBPhypotension, headache on overdosage

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A similar pharmokinetic profile of Levo-simendan was demonstrated in children withcongenital heart disease, comparable to adults(6).Case reports of Levosimendan in myocardial stun-ning have been documented(7). Levosimendanseems to improve medium term survival in patientsfailing to wean off cardiopulmonary bypass andrequiring cardiac assist devices as a bridge torecovery(8). Two large prospective trials- REVIVE II(randomized multicenter evaluation of intravenouslevosimendan efficacy-II) and SURVIVE (survivalof patients with acute heart failure in need ofintravenous inotropic support) evaluated the efficacyof levosimendan in patients hospitalized for acutedecompensated heart failure (ADHF) haveconcluded that this novel inotropic agent does conferearly additional benefit in addition to standardtherapy(9,10). In the LIDO(Levosimendan versusDobutamine) study, Levosimendan improvedhemodynamic performance and survival, comparedwith dobutamine, in adults with severe heartfailure(11). In the Randomized Study on Safety andEffectiveness of Levosimendan in Patients with LeftVentricular Failure after an Acute Myocardial Infarct(RUSSLAN), the drug showed outcome benefits incomparison with dobutamine and placebo,respectively(12). A comparative study, CalciumSensitizer or Inotrope or None in Low-Output HeartFailure (CASINO), suggested mortality benefits withlevosimendan over placebo and dobutamine(13). Aprospective randomized pilot study demonstratedimproved right ventricular performance in patientswith acute respiratory distress syndrome(ARDS) andseptic shock(14). The role of levosimendan in septicmyocardial dysfunction has been studied and foundto be beneficial(15). Levosimendan also finds a placein the management of septic shock in the latestpediatric septic shock guidelines(16). It has beenrecommended by the guidelines to use levosimendan

in refractory cold septic shock.

It has been also been reported that orallevosimendan has favorable cardiac and hemo-dynamic effects in patients with severe congestiveheart failure; these effects are similar to those seenafter intravenous dosing with levosimendan(17).The 4-8 mg daily doses of oral levosimendan showedmoderate inotropic effects(18). Both 6-h infusionand a 2-mg single dose of levosimendan showed thatif has moderate inotropic and vasodilatory effects inpatient with severe congestive heart failure(19).Thus, oral levosimendan may be used as substitutefor intravenous inotropic support in end-stage heartfailure, as pilot results on the use of orallevosimendan are encouraging.

CONCLUSION

Levosimendan has been found to be a safe and usefuldrug when given to the sickest children with acuteheart failure refractory to standard anti-failuremedications. The pharmacokinetics of levo-simendan underpins the prolonged beneficialhemodynamic effects that result from single doseinfusion regime. It is an appealing and promisingalternative or an intermittent adjunct to currenttherapies for heart failure, as well as in refractoryseptic shock in children.

Contributors: SRK, IJ conceived the review. SRK and SMcollected literature. SRK, IJ and SM edited and drafted thepaper.Funding: None.Competing interests: None stated.

REFERENCES

1. Marino P, Sutin KM. Acute heart failuresyndromes. Chapter 14. The ICU Book. 3rd

Edition. Philadelphia. Lippincott Williams andWilkins Publications; 2006. p. 265.

KEY MESSAGES

• Levosimendan, a new inodilator, may be useful in refractory cardiac failure, refractory pulmonary hypertensionand dilated cardiomyopathy.

• Levosimendan may help in decreasing the need for long term inotropic support and may thus act as a bridgeto heart transport.

• Levosimendan with its long half-life appears to be a promising “once a week” inotrope.

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2. Figgitt DP, Gillies PS, Goa KL. Levosimendan.Drugs 2001; 61: 613-627.

3. Remme WJ, Swedberg K and the Task Force for theDiagnosis and Treatment of Chronic Heart failure,European Society of Cardiology. Guidelines for thediagnosis and treatment of chronic heart failure. EurHeart J 2001; 22: 1527-1560.

4. Namachivayam P, Crossland DS, Butt WW,Shekerdemian LS. Early experience withLevosimendan in children with ventriculardysfunction. Pediatr Crit Care Med 2006; 7: 445-448.

5. Egan JR, Clarke AJ, Williams S, Cole AD, Ayer J,Jacobe S, et al. Levosimendan for low cardiacoutput: A Pediatric experience. J Intensive CareMed 2006; 21:.183-187.

6. Turanlahti M, Boldt T, Palkama T, Antila S,Lehtonen L, Pesonen E. Pharmacokinetics oflevosimendan in pediatric patients evaluated forcardiac surgery. Pediatr Crit Care Med 2004; 5:457-462.

7. Lechner E, Moosbauer W, Pinter M, Mair R, TulzerG. Use of levosimendan, a new inodilator, forpostoperative myocardial stunning in a prematureneonate. Pediatr Crit Care Med. 2007; 8: 61-63.

8. Braun JP, Jasulaitis D, Moshirzadeh M, DoepfmerUR, Kastrup M, von Heymann C, et al.Levosimendan may improve survival in patientsrequiring mechanical assist devices for post-cardiotomy heart failure. Crit Care 2006;10: R17.

9. Garratt C, Packer M, Colucci W, Fisher L, MassieB, Teerlink J, et al. Development of acomprehensive new endpoint for the evaluation ofnew treatments for acute decompensated heartfailure: results with levosimendan in the REVIVE Istudy. Crit Care 2004; 8: P89.

10. Mebazaa A, Nieminen M, Packer M, Cohen-SalalA, Kleber F, Pocock S, et al. SURVIVEInvestigators. Levosimendan vs dobutamine forpatients with acute decompensated heart failure: theSURVIVE randomized trial. JAMA 2007; 297:1883–1891.

11. Follath F, Cleland JG, Just H, Papp JG, Schoolz H,Peuhkurinen K, et al.; Steering Committee andInvestigators of the Levosimendan Infusion versusDobutamine (LIDO) Study. Efficacy and safety ofintravenous levosimendan compared withdobutamine in severe low-output heart failure (theLIDO study): a randomised double-blind trial.Lancet 2002; 360: 196-202.

12. Moiseyev VS, Poder P, Andrejevs N, Ruda MY,Golikov AP, Lazebriket LB, et al; RUSSLANStudy Investigators. Safety and efficacy of a novelcalcium sensitizer, levosimendan, in patients withleft ventricular failure due to an acute myocardialinfarction. A randomized, placebo-controlled,double-blind study (RUSSLAN). Eur Heart J 2002;23: 1422- 1432.

13. Zairis MN, Apostolatos C, Anastasiadis P, MytasD, Katsaris C, Kouris N, et al. The effect of acalcium sensitizer or an inotrope or none in chroniclow output decompensated heart failure: resultsdrom the calcium sensitizer or inotrope or none inlow output heart failure study (CASINO). Programand abstracts from the American College ofCardiology Annual Scientific Sessions 2004;March 7-10, 2004; New Orleans, Louisiana.Abstract 835-6.

14. Andrea M, Jean-Louis T, Maurizio S, Baron VA,Rocco H, Conti G, et al. Effects of Leosimendan onright ventricular afterload in patients with acuterespiratory distress syndrome: a pilot study. CritCare Med 2006; 34: 2287-2293.

15. Noto A, Giacomini M, Palandi A, Stabile L, Reali-Forster C, Iapichano G, et al. Levosimendan inseptic cardiac failure. Intensive Care Med 2005;31: 164-165.

16. Brierley J, Choong K, Cornell T, DeCaen A,Deymann A, Doctor A, et al. 2007 AmericanCollege of Critical Care Medicine clinical practiceparameters for hemodynamic support of pediatricand neonatal septic shock. Crit Care Med 2009; 37:1-23.

17. Harjola V-P, Peuhkurinen K, Nieminen MS,Niemala M, Sunderberg G. Oral levosimendanimproves cardiac function and hemodynamicsinpatients with severe congestive heart failure. Am JCardiol 1999; 83: 4I–8I.

18. Poder P, Eha J, Sundberg S, Antila S, Heinpalu M,Loogna I, et al. Pharmacodynamics andpharmacokinetics of oral levosimendan and itsmetabolites in patients with severe congestive heartfailure: a dosing interval study. J Clin Pharmacol2004; 44: 1143–1150.

19. Poder P, Eha J, Sundberg S, Antila S, Heinpalu M,Loogna I, et al. Pharmacokinetic-pharmaco-dynamic interrelationships of intravenous and orallevosimendan in patients with severe congestiveheart failure. Int J Clin Pharmacol Ther 2003; 41:365-373.