Advertisement

Levosimendan: What Have We Learned So Far?

  • Giulia Villa
  • Guido Tavazzi
  • Fabio Guarracino
  • Fabio SangalliEmail author
Cardiovascular Anesthesia (J Fassl, Section Editor)
Part of the following topical collections:
  1. Cardiovascular Anesthesia

Abstract

Purpose of Review

Vasoactive therapy represents a pivotal yet debated topic in critically ill patients and in those with chronic heart failure. Levosimendan, a calcium sensitizer agent with inodilating properties, has been in the market for 27 years and new indications came out over time. The aim of the present review is to highlight what is actually proven and what is debated on the use of levosimendan in light of its pharmacologic features and the pathophysiological evidence.

Recent Findings

Levosimendan was firstly seen as an inodilator acting through calcium sensitization in myocytes both in the myocardium and in vascular smooth muscle. Over the years, its anti-inflammatory properties became clearer and a role in preconditioning and weaning from mechanical circulatory support was postulated. More recently, a possible action on other muscular fibers, namely, diaphragmatic myocytes, was observed, leading to a possible application in mechanical ventilation-related diaphragmatic dysfunction.

Summary

Preliminary data showed promising effects of levosimendan in patients with sepsis-related and stress-related (Takotsubo) myocardial dysfunction, in those difficult-to-wean from mechanical circulatory support and in ventilator-associated diaphragmatic dysfunction. Moreover, its vasodilating, anti-oxidant, and neuroendocrine properties pave the way to a number of additional possible applications. Larger studies yielding to more conclusive results on these indications are under way or need to be planned in the future.

Keywords

Levosimendan Vasoactive therapy Shock Weaning Inotrope 

Notes

Compliance with Ethical Standards

Conflict of Interest

Giulia Villa, Guido Tavazzi, Fabio Guarracino, and Fabio Sangalli declare they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Raasmaja ATA, Haikala H, Nissinen E, Lindén IB, Pohto P. Biochemical properties of OR-1259--a positive inotropic and vasodilatory compound with an antiarrhythmic effect. Adv Exp Med Biol. 1992;1(311):423.Google Scholar
  2. 2.
    Hasenfuss GPB, Kretschmann B, Holubarsch C, Alpert NR, Just H. Effects of calcium sensitizers on intracellular calcium handling and myocardial energetics. J Cardiovasc Pharmacol. 1995;26:s45–51.Google Scholar
  3. 3.
    Ukkonen HSM, Akkila J, et al. Myocardial efficiency during calcium sensitization with levosimendan: a noninvasive study with positron emission tomography and echocardiography in healthy volunteers. Clin Pharmacol Ther. 1997;61:596–607.Google Scholar
  4. 4.
    Hasenfuss GPB, Castell M, Kretschmann B, Maier LS, Just H. Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium. Circulation. 1998;20:2141–7.Google Scholar
  5. 5.
    Sundberg SAS, Scheinin H, et al. Integrated pharmacokinetics and pharmacodynamics of the novel calcium sensitizer levosimendan as assessed by systolic time intervals. Int J Clin Pharmacol Ther. 1998;36:629–35.Google Scholar
  6. 6.
    Sundberg SLL. Haemodynamic interactions between the novel calcium sensitiser levosimendan and isosorbide-5- mononitrate in healthy subjects. Eur J Clin Pharmacol. 2000;55:793–9.Google Scholar
  7. 7.
    Brixius KRS, Schwinger RH. Beneficial effects of the Ca2+ sensitizer levosimendan in human myocardium. Am J Physiol Heart Circ Physiol. 2002;282:H131–7.Google Scholar
  8. 8.
    Nieminen MSAJ, Hasenfuss G, et al. Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. J Am Coll Cardiol. 2000;36:1903–12.Google Scholar
  9. 9.
    Slawsky MTCW, Gottlieb SS, et al. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Circulation. 2000;102:2222–7.Google Scholar
  10. 10.
    Follath F, Cleland JG, Just H, Papp JG, Scholz H, Peuhkurinen K, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet. 2002;360(9328):196–202.Google Scholar
  11. 11.
    Moiseyev VS, Poder P, Andrejevs N, Ruda MY, Golikov AP, Lazebnik LB, et al. Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. A randomized, placebo-controlled, double-blind study (RUSSLAN). Eur Heart J. 2002;23(18):1422–32.Google Scholar
  12. 12.
    Coletta AP, Cleland JG, Freemantle N, Clark AL. Clinical trials update from the European Society of Cardiology Heart Failure meeting: SHAPE, BRING-UP 2 VAS, COLA II, FOSIDIAL, BETACAR, CASINO and meta-analysis of cardiac resynchronisation therapy. Eur J Heart Fail. 2004;6(5):673–6.Google Scholar
  13. 13.
    Sonntag S, Sundberg S, Lehtonen LA, Kleber FX. The calcium sensitizer levosimendan improves the function of stunned myocardium after percutaneous transluminal coronary angioplasty in acute myocardial ischemia. J Am Coll Cardiol. 2004;43(12):2177–82.Google Scholar
  14. 14.
    Mebazaa A, Nieminen MS, Packer M, Cohen-Solal A, Kleber FX, Pocock SJ, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE randomized trial. JAMA. 2007;297(17):1883–91.Google Scholar
  15. 15.
    Cleland JG, Freemantle N, Coletta AP, Clark AL. Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE. Eur J Heart Fail. 2006;8(1):105–10.Google Scholar
  16. 16.
    Papp Z, Edes I, Fruhwald S, De Hert SG, Salmenpera M, Leppikangas H, et al. Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol. 2012;159(2):82–7.Google Scholar
  17. 17.
    Gong BLZ, Yat Wong PC. Levosimendan treatment for heart failure: a systematic review and meta-analysis. J Cardiothorac Vasc Anesth. 2015;6:1415–25.Google Scholar
  18. 18.
    Fuhrmann JTSA, Schulze MR, Wunderlich C, Schoen SP, Rauwolf T, Weinbrenner C, et al. Levosimendan is superior to enoximone in refractory cardiogenic shock complicating acute myocardial infarction. Crit Care Med. 2008;26:2257–66.Google Scholar
  19. 19.
    Christoph A, Prondzinsky R, Russ M, Janusch M, Schlitt A, Lemm H, et al. Early and sustained haemodynamic improvement with levosimendan compared to intraaortic balloon counterpulsation (IABP) in cardiogenic shock complicating acute myocardial infarction. Acute Card Care. 2008;10(1):49–57.Google Scholar
  20. 20.
    Garcia-Gonzalez MJ, de Mora-Martin M, Lopez-Fernandez S, Lopez-Diaz J, Martinez-Selles M, Romero-Garcia J, et al. Rationale and design of a randomized, double-blind, placebo controlled multicenter trial to study efficacy, security, and long term effects of intermittent repeated levosimendan administration in patients with advanced heart failure: LAICA study. Cardiovasc Drugs Ther. 2013;27(6):573–9.Google Scholar
  21. 21.
    Altenberger J, Parissis JT, Costard-Jaeckle A, Winter A, Ebner C, Karavidas A, et al. Efficacy and safety of the pulsed infusions of levosimendan in outpatients with advanced heart failure (LevoRep) study: a multicentre randomized trial. Eur J Heart Fail. 2014;16(8):898–906.Google Scholar
  22. 22.
    • Comin-Colet J, Manito N, Segovia-Cubero J, Delgado J, Garcia Pinilla JM, Almenar L, et al. Efficacy and safety of intermittent intravenous outpatient administration of levosimendan in patients with advanced heart failure: the LION-HEART multicentre randomised trial. Eur J Heart Fail. 2018;20(7):1128–36 Levosimendan improved the quality of life and reduced hospitalizations in ambulatory patients with advanced systolic heart function. Google Scholar
  23. 23.
    Oliva F, Comin-Colet J, Fedele F, Fruhwald F, Gustafsson F, Kivikko M, et al. Repetitive levosimendan treatment in the management of advanced heart failure. Eur Heart J Suppl. 2018;20(Suppl I):I11–20.Google Scholar
  24. 24.
    Mehta RH, Bruckman D, Das S, Tsai T, Russman P, Karavite D, et al. Implications of increased left ventricular mass index on in-hospital outcomes in patients undergoing aortic valve surgery. J Thorac Cardiovasc Surg. 2001;122(5):919–28.Google Scholar
  25. 25.
    Polonen P, Ruokonen E, Hippelainen M, Poyhonen M, Takala J. A prospective, randomized study of goal-oriented hemodynamic therapy in cardiac surgical patients. Anesth Analg. 2000;90(5):1052–9.Google Scholar
  26. 26.
    Leppikangas HJK, Sisto T, Maaranen P, Virtanen M, Lehto P, Karlsson S, et al. Preoperative levosimendan infusion in combined aortic valve and coronary bypass surgery. Br J Anaesth. 2011;106:298–304.Google Scholar
  27. 27.
    Greco T, Calabro MG, Covello RD, Greco M, Pasin L, Morelli A, et al. A Bayesian network meta-analysis on the effect of inodilatory agents on mortality. Br J Anaesth. 2015;114(5):746–56.Google Scholar
  28. 28.
    • Landoni G, Lomivorotov VV, Alvaro G, Lobreglio R, Pisano A, Guarracino F, et al. Levosimendan for hemodynamic support after cardiac surgery. N Engl J Med. 2017;376(21):2021–31 In a mixed population of cardiac surgical patients requiring vasoactive support, the addition of low-dose levosimendan did not reduce 30-day mortality when compared with placebo. Google Scholar
  29. 29.
    • Mehta RH, Leimberger JD, van Diepen S, Meza J, Wang A, Jankowich R, et al. Levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery. N Engl J Med. 2017;376(21):2032–42 In patients with low preoperative ejection fraction undergoing cardiac surgery with cardiopulmonary by-pass, the prophylactic administration of levosimendan did not result in an improvement in a composite outcome of death, renal-replacement therapy, perioperative myocardial infarction, or use of mechanical circulatory support. A reduction was observed in the incidence of low-cardiac output syndrome or the use of inotropes at or beyond 24 h. Google Scholar
  30. 30.
    •• Sanfilippo F, Knight JB, Scolletta S, Santonocito C, Pastore F, Lorini FL. Levosimendan for patients with severely reduced left ventricular systolic function and/or low cardiac output syndrome undergoing cardiac surgery: a systematic review and meta-analysis. Crit Care. et al, 2017;21(1):252 In this systematic review and meta-analysis, the use of levosimendan appears to reduce mortality in patients with preoperative severely reduced ejection fraction while not affecting overall mortality. It also reduces the need for renal replacement therapy after high-risk cardiac surgery. Google Scholar
  31. 31.
    Levin R, Degrange M, Del Mazo C, Tanus E, Porcile R. Preoperative levosimendan decreases mortality and the development of low cardiac output in high-risk patients with severe left ventricular dysfunction undergoing coronary artery bypass grafting with cardiopulmonary bypass. Exp Clin Cardiol. 2012;17(3):125–30.Google Scholar
  32. 32.
    Shah B, Sharma P, Brahmbhatt A, Shah R, Rathod B, Shastri N, et al. Study of levosimendan during off-pump coronary artery bypass grafting in patients with LV dysfunction: a double-blind randomized study. Indian J Pharm. 2014;46(1):29–34.Google Scholar
  33. 33.
    Tritapepe L, De Santis V, Vitale D, Guarracino F, Pellegrini F, Pietropaoli P, et al. Levosimendan pre-treatment improves outcomes in patients undergoing coronary artery bypass graft surgery. Br J Anaesth. 2009;102(2):198–204.Google Scholar
  34. 34.
    Zangrillo A, Biondi-Zoccai G, Mizzi A, Bruno G, Bignami E, Gerli C, et al. Levosimendan reduces cardiac troponin release after cardiac surgery: a meta-analysis of randomized controlled studies. J Cardiothorac Vasc Anesth. 2009;23(4):474–8.Google Scholar
  35. 35.
    Chen QH, Zheng RQ, Lin H, Shao J, Yu JQ, Wang HL. Effect of levosimendan on prognosis in adult patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials. Crit Care. 2017;21(1):253.Google Scholar
  36. 36.
    Mehta RH, Van Diepen S, Meza J, Bokesch P, Leimberger JD, Tourt-Uhlig S, et al. Levosimendan in patients with left ventricular systolic dysfunction undergoing cardiac surgery on cardiopulmonary bypass: rationale and study design of the levosimendan in patients with left ventricular systolic dysfunction undergoing cardiac surgery requiring cardiopulmonary bypass (LEVO-CTS) trial. Am Heart J. 2016;182:62–71.Google Scholar
  37. 37.
    Zangrillo A, Alvaro G, Pisano A, Guarracino F, Lobreglio R, Bradic N, et al. A randomized controlled trial of levosimendan to reduce mortality in high-risk cardiac surgery patients (CHEETAH): rationale and design. Am Heart J. 2016;177:66–73.Google Scholar
  38. 38.
    •• Guarracino FHM, Cholley B, Bettex D, Bouchez S, Lomivorotov VV, Rajek A, et al. Use of levosimendan in cardiac surgery: an update after the LEVO-CTS, CHEETAH, and LICORN trials in the light of clinical practice. J Cardiovasc Pharmacol. 2018;71:1–9 In this expert opinion, the use of levosimendan in cardiac surgery is reviewed in light of recent RCTs. The authors conclude for the pathophysiological plausibility of the benefit of levosimendan despite neutral results from recent randomized trials. Google Scholar
  39. 39.
    •• Landoni G, Lomivorotov V, Silvetti S, Nigro Neto C, Pisano A, Alvaro G, et al. Nonsurgical strategies to reduce mortality in patients undergoing cardiac surgery: an updated consensus process. J Cardiothorac Vasc Anesth. 2018;32(1):225–35 Levosimendan was recognized as one of the ten interventions that significantly reduce mortality in cardiac surgery. Google Scholar
  40. 40.
    De Witt BJ, Ibrahim IN, Bayer E, Fields AM, Richards TA, Banister RE, et al. An analysis of responses to levosimendan in the pulmonary vascular bed of the cat. Anesth Analg. 2002;94(6):1427–33 table of contents.Google Scholar
  41. 41.
    Kerbaul F, Rondelet B, Demester JP, Fesler P, Huez S, Naeije R, et al. Effects of levosimendan versus dobutamine on pressure load-induced right ventricular failure. Crit Care Med. 2006;34(11):2814–9.Google Scholar
  42. 42.
    Missant CRS, Segers P, Wouters PF. Levosimendan improves right ventriculovascular coupling in a porcine model of right ventricular dysfunction. Crit Care Med. 2007;35:707–15.Google Scholar
  43. 43.
    Schwarte LASI, Thomas K, Schober P, Picker O. The effects of levosimendan and glibenclamide on circulatory and metabolic variables in a canine model of acute hypoxia. Intensive Care Med. 2011;37:701–10.Google Scholar
  44. 44.
    Cavusoglu Y, Beyaztas A, Birdane A, Ata N. Levosimendan is not effective in reducing pulmonary pressures in patients with idiopathic pulmonary arterial hypertension: report of two cases. J Cardiovasc Med (Hagerstown). 2009;10(6):503–7.Google Scholar
  45. 45.
    Kleber FX, Bollmann T, Borst MM, Costard-Jackle A, Ewert R, Kivikko M, et al. Repetitive dosing of intravenous levosimendan improves pulmonary hemodynamics in patients with pulmonary hypertension: results of a pilot study. J Clin Pharmacol. 2009;49(1):109–15.Google Scholar
  46. 46.
    Martyniuk TVAO, Kobal’ EA, Danilov NM, Chazova IE. Possibilities of using levosimendan in patients with idiopathic pulmonary hypertension. Ter Arkh. 2012;84:83–8.Google Scholar
  47. 47.
    Rosenkranz S, Gibbs JS, Wachter R, De Marco T, Vonk-Noordegraaf A, Vachiery JL. Left ventricular heart failure and pulmonary hypertension. Eur Heart J. 2016;37(12):942–54.Google Scholar
  48. 48.
    • Jiang RZQ, Wu WH, Zhang R, Yuan P, Gong SG, He J, et al. Efficacy and safety of a calcium sensitizer, levosimendan, in patients with right heart failure due to pulmonary hypertension. Clin Respir J. 2018;12:1518–25 In patients with pulmonary hypertension, levosimendan significantly improved right heart failure. Google Scholar
  49. 49.
    Slawsky MT, Colucci WS, Gottlieb SS, Greenberg BH, Haeusslein E, Hare J, et al. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Study Investigators. Circulation. 2000;102(18):2222–7.Google Scholar
  50. 50.
    Parissis JT, Paraskevaidis I, Bistola V, Farmakis D, Panou F, Kourea K, et al. Effects of levosimendan on right ventricular function in patients with advanced heart failure. Am J Cardiol. 2006;98(11):1489–92.Google Scholar
  51. 51.
    Russ MA, Prondzinsky R, Carter JM, Schlitt A, Ebelt H, Schmidt H, et al. Right ventricular function in myocardial infarction complicated by cardiogenic shock: improvement with levosimendan. Crit Care Med. 2009;37(12):3017–23.Google Scholar
  52. 52.
    Alibaz-Oner FGO, Oner E, Yurdakul S, Erguney M. Impact of levosimendan on right ventricular functions by using novel tissue Doppler derived indices in patients with ischaemic left ventricular failure. Kardiol Pol. 2013;71:1036–41.Google Scholar
  53. 53.
    Morelli A, Teboul JL, Maggiore SM, Vieillard-Baron A, Rocco M, Conti G, et al. Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: a pilot study. Crit Care Med. 2006;34(9):2287–93.Google Scholar
  54. 54.
    Powell BP, Simes D. Levosimendan in acute pulmonary embolism. Anaesth Intensive Care. 2007;35(5):771–2.Google Scholar
  55. 55.
    Pitsiou GPA, Bagalas V, Boutou AK, Stanopoulos I. Inhaled iloprost plus levosimendan to decompensate right heart failure due to chronic thromboembolic pulmonary hypertension. Anaesth Intensive Care. 2013;41:554–6.Google Scholar
  56. 56.
    Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801–10.Google Scholar
  57. 57.
    Vieillard-Baron A. Septic cardiomyopathy. Ann Intensive Care. 2011;1(1):6.  https://doi.org/10.1186/2110-5820-1-6.Google Scholar
  58. 58.
    Beesley SJ, Weber G, Sarge T, Nikravan S, Grissom CK, Lanspa MJ, et al. Septic cardiomyopathy. Crit Care Med. 2018;46(4):625–34.Google Scholar
  59. 59.
    Morelli A, Donati A, Ertmer C, Rehberg S, Lange M, Orecchioni A, et al. Levosimendan for resuscitating the microcirculation in patients with septic shock: a randomized controlled study. Crit Care. 2010;14(6):R232.Google Scholar
  60. 60.
    • Hajjej Z, Meddeb B, Sellami W, Labbene I, Morelli A, Ferjani M. Effects of levosimendan on cellular metabolic alterations in patients with septic shock: a randomized controlled pilot study. Shock. 2017;48(3):307–12 In this pilot study, levosimendan seems to improve cellular metabolic alterations in patients with septic shock. Google Scholar
  61. 61.
    Lannemyr L, Ricksten SE, Rundqvist B, Andersson B, Bartfay SE, Ljungman C, et al. Differential Effects of Levosimendan and Dobutamine on Glomerular Filtration Rate in Patients With Heart Failure and Renal Impairment:A Randomized Double-Blind Controlled Trial. J Am Heart Assoc. 2018 Aug;7(16):e008455.  https://doi.org/10.1161/JAHA.117.008455.
  62. 62.
    Zangrillo A, Putzu A, Monaco F, Oriani A, Frau G, De Luca M, et al. Levosimendan reduces mortality in patients with severe sepsis and septic shock: a meta-analysis of randomized trials. J Crit Care. 2015;30(5):908–13.Google Scholar
  63. 63.
    Orme RM, Perkins GD, McAuley DF, Liu KD, Mason AJ, Morelli A, et al. An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS): protocol for a randomized controlled trial. Trials. 2014;15:199.Google Scholar
  64. 64.
    •• Herpain ABS, Girardis M, Guarracino F, Knotzer J, Levy B, Liebregts T, et al. Use of levosimendan in intensive care unit settings: an opinion paper. J Cardiovasc Pharmacol. 2019;73:3–14 This opinion paper reviews the current uses of levosimendan and its novel applications. Google Scholar
  65. 65.
    Van Hees HW, Dekhuijzen PN, Heunks LM. Levosimendan enhances force generation of diaphragm muscle from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;179(1):41–7.Google Scholar
  66. 66.
    Van Hees HW, Andrade Acuna G, Linkels M, Dekhuijzen PN, Heunks LM. Levosimendan improves calcium sensitivity of diaphragm muscle fibres from a rat model of heart failure. Br J Pharmacol. 2011;162(3):566–73.Google Scholar
  67. 67.
    Doorduin J, Sinderby CA, Beck J, Stegeman DF, van Hees HW, van der Hoeven JG, et al. The calcium sensitizer levosimendan improves human diaphragm function. Am J Respir Crit Care Med. 2012;185(1):90–5.Google Scholar
  68. 68.
    Ouanes-Besbes L, Ouanes I, Dachraoui F, Dimassi S, Mebazaa A, Abroug F. Weaning difficult-to-wean chronic obstructive pulmonary disease patients: a pilot study comparing initial hemodynamic effects of levosimendan and dobutamine. J Crit Care. 2011;26(1):15–21.Google Scholar
  69. 69.
    Affronti A dBI, Carino D, Ragni T. Levosimendan may improve weaning outcomes in venoarterial ECMO patients. ASAIO J. 2013;59:554–7.Google Scholar
  70. 70.
    • Distelmaier K, Roth C, Schrutka L, Binder C, Steinlechner B, Heinz G, et al. Beneficial effects of levosimendan on survival in patients undergoing extracorporeal membrane oxygenation after cardiovascular surgery. Br J Anaesth. 2016;117(1):52–8 Levosimendan seems to improve weaning and survival in venoarterial ECMO patients after cardiac surgery. Google Scholar
  71. 71.
    • Sangalli F, Avalli L, Laratta M, Formica F, Maggioni E, Caruso R, et al. Effects of levosimendan on endothelial function and hemodynamics during weaning from Veno-arterial extracorporeal life support. J Cardiothorac Vasc Anesth. 2016;30(6):1449–53 Levosimendan infusion before a weaning trial from venoarterial ECMO improved hemodynamics and endothelial function. Google Scholar
  72. 72.
    Konczalla J, Wanderer S, Mrosek J, Gueresir E, Schuss P, Platz J, et al. Levosimendan, a new therapeutic approach to prevent delayed cerebral vasospasm after subarachnoid hemorrhage? Acta Neurochir. 2016;158(11):2075–83.Google Scholar
  73. 73.
    Osthaus WA, Boethig D, Winterhalter M, Huber D, Goerler H, Sasse M, et al. First experiences with intraoperative Levosimendan in pediatric cardiac surgery. Eur J Pediatr. 2009;168(6):735–40.Google Scholar
  74. 74.
    Momeni M, Rubay J, Matta A, Rennotte MT, Veyckemans F, Poncelet AJ, et al. Levosimendan in congenital cardiac surgery: a randomized, double-blind clinical trial. J Cardiothorac Vasc Anesth. 2011;25(3):419–24.Google Scholar
  75. 75.
    ìRyerson LM, Alexander PM, Butt WW, Shann FA, Penny DJ, Shekerdemian LS. Rotating inotrope therapy in a pediatric population with decompensated heart failure. Pediatr Crit Care Med. 2011;12(1):57–60.Google Scholar
  76. 76.
    Suominen PK. Single-center experience with levosimendan in children undergoing cardiac surgery and in children with decompensated heart failure. BMC Anesthesiol. 2011;11:18.Google Scholar
  77. 77.
    Lechner E, Hofer A, Leitner-Peneder G, Freynschlag R, Mair R, Weinzettel R, et al. Levosimendan versus milrinone in neonates and infants after corrective open-heart surgery: a pilot study. Pediatr Crit Care Med. 2012;13(5):542–8.Google Scholar
  78. 78.
    Papoff P, Caresta E, Versacci P, Pinto R, Moretti C, Midulla F. Beneficial effects of levosimendan in infants with sepsis-associated cardiac dysfunction: report of 2 cases. Pediatr Emerg Care. 2012;28(10):1062–5.Google Scholar
  79. 79.
    Ricci Z, Garisto C, Favia I, Vitale V, Di Chiara L, Cogo PE. Levosimendan infusion in newborns after corrective surgery for congenital heart disease: randomized controlled trial. Intensive Care Med. 2012;38(7):1198–204.Google Scholar
  80. 80.
    Ebade AAKM, Mohamed AK. Levosimendan is superior to dobutamine as an inodilator in the treatment of pulmonary hypertension for children undergoing cardiac surgery. J Anesth. 2013;27:334–9.Google Scholar
  81. 81.
    DA Tosoni A, Mohseni-Bod H. The use of levosimendan in children with cancer with severe acute cardiac dysfunction: case series and a review of the literature. Cardiol Young. 2014;24:524–7.Google Scholar
  82. 82.
    Silvetti S, Silvani P, Azzolini ML, Dossi R, Landoni G, Zangrillo A. A systematic review on levosimendan in paediatric patients. Curr Vasc Pharmacol. 2015;13(1):128–33.Google Scholar
  83. 83.
    Pelliccia F, Kaski JC, Crea F, Camici PG. Pathophysiology of Takotsubo syndrome. Circulation. 2017 Jun 13;135(24):2426–41.  https://doi.org/10.1161/CIRCULATIONAHA.116.027121.Google Scholar
  84. 84.
    • Distelmaier K, Roth C, Schrutka L, Binder C, Steinlechner B, Heinz G, et al. Beneficial effects of levosimendan on survival in patients undergoing extracorporeal membrane oxygenation after cardiovascular surgery. Br J Anaesth. 2016;117(1):52–8 Levosimendan seems to improve weaning and survival in venoarterial ECMO patients after cardiac surgery. Google Scholar
  85. 85.
    Templin C, Ghadri JR, Diekmann J, Napp LC, Bataiosu DR, Jaguszewski M, et al. Clinical features and outcomes of Takotsubo (stress) cardiomyopathy. N Engl J Med. 2015 Sep 3;373(10):929–38.  https://doi.org/10.1056/NEJMoa1406761.Google Scholar
  86. 86.
    •• Jelena-Rima G, et al. International expert consensus document on Takotsubo syndrome (part ii): diagnostic workup, outcome, and management. Eur Heart J. 2018;39(22):2047–62.  https://doi.org/10.1093/eurheartj/ehy077 This international expert consensus reviews pathophysiology, diagnosis, and management of the Takotsubo syndrome. Levosimendan is recommended for Takotsubo-related pump failure. Google Scholar
  87. 87.
    Santoro F, Ieva R, Ferraretti A, Ienco V, Carpagnano G, Lodispoto M, et al. Safety and feasibility of levosimendan administration in takotsubo cardiomyopathy: a case series. Cardiovasc Ther. 2013 Dec;31(6):e133–7.  https://doi.org/10.1111/1755-5922.12047.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Giulia Villa
    • 1
  • Guido Tavazzi
    • 2
  • Fabio Guarracino
    • 3
  • Fabio Sangalli
    • 1
    Email author
  1. 1.Department of Anesthesia and Intensive Care MedicineASST Monza, Ospedale San Gerardo - University of Milano-BicoccaMonzaItaly
  2. 2.Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, Unit of Anaesthesia and Intensive CareUniversity of PaviaPaviaItaly
  3. 3.Cardiothoracic and Vascular Anaesthesia and Intensive Care, Department of Anaesthesia and Critical Care MedicineAzienda Ospedaliero Universitaria PisanaPisaItaly

Personalised recommendations