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Critical Care
Published in: Critical Care 1/2017

Open Access 01-12-2017 | Research

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

Authors: Filippo Sanfilippo, Joshua B. Knight, Sabino Scolletta, Cristina Santonocito, Federico Pastore, Ferdinando L. Lorini, Luigi Tritapepe, Andrea Morelli, Antonio Arcadipane

Published in: Critical Care | Issue 1/2017

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Abstract

Background

Previous studies have shown beneficial effects of levosimendan in high-risk patients undergoing cardiac surgery. Two large randomized controlled trials (RCTs), however, showed no advantages of levosimendan.

Methods

We performed a systematic review and meta-analysis (MEDLINE and Embase from inception until March 30, 2017), investigating whether levosimendan offers advantages compared with placebo in high-risk cardiac surgery patients, as defined by preoperative left ventricular ejection fraction (LVEF) ≤ 35% and/or low cardiac output syndrome (LCOS). The primary outcomes were mortality at longest follow-up and need for postoperative renal replacement therapy (RRT). Secondary postoperative outcomes investigated included myocardial injury, supraventricular arrhythmias, development of LCOS, acute kidney injury (AKI), duration of mechanical ventilation, intensive care unit and hospital lengths of stay, and incidence of hypotension during drug infusion.

Results

Six RCTs were included in the meta-analysis, five of which investigated only patients with LVEF ≤ 35% and one of which included predominantly patients with LCOS. Mortality was similar overall (OR 0.64 [0.37, 1.11], p = 0.11) but lower in the subgroup with LVEF < 35% (OR 0.51 [0.32, 0.82], p = 0.005). Need for RRT was reduced by levosimendan both overall (OR 0.63 [0.42, 0.94], p = 0.02) and in patients with LVEF < 35% (OR 0.55 [0.31, 0.97], p = 0.04). Among secondary outcomes, we found lower postoperative LCOS in patients with LVEF < 35% receiving levosimendan (OR 0.49 [0.27, 0.89], p = 0.02), lower overall AKI (OR 0.62 [0.42, 0.92], p = 0.02), and a trend toward lower mechanical support, both overall (p = 0.07) and in patients with LVEF < 35% (p = 0.05).

Conclusions

Levosimendan reduces mortality in patients with preoperative severely reduced LVEF but does not affect overall mortality. Levosimendan reduces the need for RRT after high-risk cardiac surgery.
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Literature
1.
Hammon JW. Risk factors for cardiac surgery: the high-risk patient. Semin Cardiothorac Vasc Anesth. 2004;8(1):15–7.CrossRefPubMed
2.
Granton J, Cheng D. Risk stratification models for cardiac surgery. Semin Cardiothorac Vasc Anesth. 2008;12(3):167–74.CrossRefPubMed
3.
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP, Fullerton HJ, et al. Executive summary: heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation. 2016;133(4):447–54.CrossRefPubMed
4.
Bridgewater B, Grayson AD, Brooks N, Grotte G, Fabri BM, Au J, Hooper T, Jones M, Keogh B. Has the publication of cardiac surgery outcome data been associated with changes in practice in northwest England: an analysis of 25,730 patients undergoing CABG surgery under 30 surgeons over eight years. Heart. 2007;93(6):744–8.CrossRefPubMedPubMedCentral
5.
Manji RA, Arora RC, Singal RK, Hiebert BM, Menkis AH. Early rehospitalization after prolonged intensive care unit stay post cardiac surgery: outcomes and modifiable risk factors. J Am Heart Assoc. 2017;6(2):e004072.CrossRefPubMedPubMedCentral
6.
Algarni KD, Maganti M, Yau TM. Predictors of low cardiac output syndrome after isolated coronary artery bypass surgery: trends over 20 years. Ann Thorac Surg. 2011;92(5):1678–84.CrossRefPubMed
7.
Kamiya H, Schilling M, Akhyari P, Ruhparwar A, Kallenbach K, Karck M, Lichtenberg A. Outcome analysis for prediction of early and long-term survival in patients receiving intra-aortic balloon pumping after cardiac surgery. Gen Thorac Cardiovasc Surg. 2016;64(10):584–91.CrossRefPubMedPubMedCentral
8.
Toller W, Algotsson L, Guarracino F, Hormann C, Knotzer J, Lehmann A, Rajek A, Salmenpera M, Schirmer U, Tritapepe L, et al. Perioperative use of levosimendan: best practice in operative settings. J Cardiothorac Vasc Anesth. 2013;27(2):361–6.CrossRefPubMed
9.
Toller W, Heringlake M, Guarracino F, Algotsson L, Alvarez J, Argyriadou H, Ben-Gal T, Cerny V, Cholley B, Eremenko A, et al. Preoperative and perioperative use of levosimendan in cardiac surgery: European expert opinion. Int J Cardiol. 2015;184:323–36.CrossRefPubMed
10.
Tritapepe L, De Santis V, Vitale D, Guarracino F, Pellegrini F, Pietropaoli P, Singer M. Levosimendan pre-treatment improves outcomes in patients undergoing coronary artery bypass graft surgery. Br J Anaesth. 2009;102(2):198–204.CrossRefPubMed
11.
Greco T, Calabro MG, Covello RD, Greco M, Pasin L, Morelli A, Landoni G, Zangrillo A. A Bayesian network meta-analysis on the effect of inodilatory agents on mortality. Br J Anaesth. 2015;114(5):746–56.CrossRefPubMed
12.
Harrison RW, Hasselblad V, Mehta RH, Levin R, Harrington RA, Alexander JH. Effect of levosimendan on survival and adverse events after cardiac surgery: a meta-analysis. J Cardiothorac Vasc Anesth. 2013;27(6):1224–32.CrossRefPubMed
13.
Mehta RH, Leimberger JD, van Diepen S, Meza J, Wang A, Jankowich R, Harrison RW, Hay D, Fremes S, Duncan A, et al. Levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery. N Engl J Med. 2017;376(21):2032–42.CrossRefPubMed
14.
Landoni G, Lomivorotov VV, Alvaro G, Lobreglio R, Pisano A, Guarracino F, Calabrò MG, Grigoryev EV, Likhvantsev VV, Salgado-Filho MF, et al. Levosimendan for hemodynamic support after cardiac surgery. N Engl J Med. 2017;376(21):2021–31.CrossRefPubMed
15.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700.CrossRefPubMedPubMedCentral
16.
Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.CrossRefPubMedPubMedCentral
17.
Lomivorotov VV, Boboshko VA, Efremov SM, Kornilov IA, Chernyavskiy AM, Lomivorotov VN, Knazkova LG, Karaskov AM. Levosimendan versus an intra-aortic balloon pump in high-risk cardiac patients. J Cardiothorac Vasc Anesth. 2012;26(4):596–603.CrossRefPubMed
18.
19.
Erb J, Beutlhauser T, Feldheiser A, Schuster B, Treskatsch S, Grubitzsch H, Spies C. Influence of levosimendan on organ dysfunction in patients with severely reduced left ventricular function undergoing cardiac surgery. J Int Med Res. 2014;42(3):750–64.CrossRefPubMed
20.
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.PubMedPubMedCentral
21.
Shah B, Sharma P, Brahmbhatt A, Shah R, Rathod B, Shastri N, Patel J, Malhotra A. 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.CrossRef
22.
Sharma P, Malhotra A, Gandhi S, Garg P, Bishnoi A, Gandhi H. Preoperative levosimendan in ischemic mitral valve repair. Asian Cardiovasc Thorac Ann. 2014;22(5):539–45.CrossRefPubMed
23.
24.
Scolletta S, Biagioli B. Energetic myocardial metabolism and oxidative stress: let’s make them our friends in the fight against heart failure. Biomed Pharmacother. 2010;64(3):203–7.CrossRefPubMed
25.
Gross GJ, Peart JN. KATP channels and myocardial preconditioning: an update. Am J Physiol Heart Circ Physiol. 2003;285(3):H921–30.CrossRefPubMed
26.
Morelli A, Ertmer C, Pietropaoli P, Westphal M. Reducing the risk of major elective non-cardiac surgery: is there a role for levosimendan in the preoperative optimization of cardiac function? Curr Drug Targets. 2009;10(9):863–71.CrossRefPubMed
27.
Garcia-Gonzalez MJ, Jorge-Perez P, Jimenez-Sosa A, Acea AB, Lacalzada Almeida JB, Ferrer Hita JJ. Levosimendan improves hemodynamic status in critically ill patients with severe aortic stenosis and left ventricular dysfunction: an interventional study. Cardiovasc Ther. 2015;33(4):193–9.CrossRefPubMed
28.
Yilmaz MB, Grossini E, Silva Cardoso JC, Edes I, Fedele F, Pollesello P, Kivikko M, Harjola VP, Hasslacher J, Mebazaa A, et al. Renal effects of levosimendan: a consensus report. Cardiovasc Drugs Ther. 2013;27(6):581–90.CrossRefPubMedPubMedCentral
29.
Tritapepe L, De Santis V, Vitale D, Santulli M, Morelli A, Nofroni I, Puddu PE, Singer M, Pietropaoli P. Preconditioning effects of levosimendan in coronary artery bypass grafting—a pilot study. Br J Anaesth. 2006;96(6):694–700.CrossRefPubMed
30.
Tarvasmaki T, Lassus J, Varpula M, Sionis A, Sund R, Kober L, Spinar J, Parissis J, Banaszewski M, Silva Cardoso J, et al. Current real-life use of vasopressors and inotropes in cardiogenic shock - adrenaline use is associated with excess organ injury and mortality. Crit Care. 2016;20(1):208.CrossRefPubMedPubMedCentral
31.
Fellahi JL, Parienti JJ, Hanouz JL, Plaud B, Riou B, Ouattara A. Perioperative use of dobutamine in cardiac surgery and adverse cardiac outcome: propensity-adjusted analyses. Anesthesiology. 2008;108(6):979–87.CrossRefPubMed
32.
Shahin J, DeVarennes B, Tse CW, Amarica DA, Dial S. The relationship between inotrope exposure, six-hour postoperative physiological variables, hospital mortality and renal dysfunction in patients undergoing cardiac surgery. Crit Care. 2011;15(4):R162.CrossRefPubMedPubMedCentral
33.
Pichette M, Liszkowski M, Ducharme A. Preoperative optimization of the heart failure patient undergoing cardiac surgery. Can J Cardiol. 2017;33(1):72–9.CrossRefPubMed
34.
Lahtinen P, Pitkanen O, Polonen P, Turpeinen A, Kiviniemi V, Uusaro A. Levosimendan reduces heart failure after cardiac surgery: a prospective, randomized, placebo-controlled trial. Crit Care Med. 2011;39(10):2263–70.CrossRefPubMed
35.
Malik V, Subramanian A, Hote M, Kiran U. Effect of levosimendan on diastolic function in patients undergoing coronary artery bypass grafting: a comparative study. J Cardiovasc Pharmacol. 2015;66(2):141–7.CrossRefPubMed
36.
Axelsson B, Haggmark S, Svenmarker S, Johansson G, Gupta A, Tyden H, Wouters P, Haney M. Effects of combined milrinone and levosimendan treatment on systolic and diastolic function during postischemic myocardial dysfunction in a porcine model. J Cardiovasc Pharmacol Ther. 2016;21(5):495–503.CrossRefPubMed
37.
Couture P, Denault AY, Pellerin M, Tardif JC. Milrinone enhances systolic, but not diastolic function during coronary artery bypass grafting surgery. Can J Anaesth. 2007;54(7):509–22.CrossRefPubMed
38.
Song JW, Jo YY, Jun NH, Kim HK, Kwak YL. The effect of milrinone on the intraoperative hemodynamics during off-pump coronary bypass surgery in patients with an elevated echocardiographic index of the ventricular filling pressure. Korean J Anesthesiol. 2011;60(3):185–91.CrossRefPubMedPubMedCentral
39.
Lunghetti S, Palmerini E, Urselli R, Maffei S, Guarino E, Focardi M, Mondillo S, Favilli R. Effects of levosimendan without loading dose on systolic and diastolic function in patients with end-stage heart failure. Cardiol J. 2011;18(5):532–7.CrossRefPubMed
40.
Bergh CH, Andersson B, Dahlström U, Forfang K, Kivikko M, Sarapohja T, Ullman B, Wikström G. Intravenous levosimendan vs. dobutamine in acute decompensated heart failure patients on beta-blockers. Eur J Heart Fail. 2010;12(4):404–10.CrossRefPubMedPubMedCentral
41.
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891–975.CrossRefPubMed
42.
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey Jr DE, Colvin MM, Drazner MH, Filippatos G, Fonarow GC, Givertz MM, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2016;68(13):1476–88.CrossRefPubMed
43.
Guerrero Orriach JL, Galan Ortega M, Ramirez Fernandez A, Ariza Villanueva D, Florez Vela A, Moreno Cortes I, Rubio Navarro M, Cruz MJ. Assessing the effect of preoperative levosimendan on renal function in patients with right ventricular dysfunction. J Clin Monit Comput. 2017;31(1):227–30.CrossRefPubMed
44.
Guerrero-Orriach JL, Ariza-Villanueva D, Florez-Vela A, Garrido-Sanchez L, Moreno-Cortes MI, Galan-Ortega M, Ramirez-Fernandez A, Alcaide Torres J, Fernandez CS, Navarro Arce I, et al. Cardiac, renal, and neurological benefits of preoperative levosimendan administration in patients with right ventricular dysfunction and pulmonary hypertension undergoing cardiac surgery: evaluation with two biomarkers neutrophil gelatinase-associated lipocalin and neuronal enolase. Ther Clin Risk Manag. 2016;12:623–30.CrossRefPubMedPubMedCentral
45.
Mansiroglu AK, Oner E, Erturk M, Karakurt H, Somuncu MU, Birant A, Kalkan AK, Ozturk D, Eksik A. Assessment of sustained effects of levosimendan on right ventricular systolic functions in patients with advanced heart failure. Acta Cardiol. 2016;71(4):411–5.CrossRefPubMed
Metadata
Title
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
Authors
Filippo Sanfilippo
Joshua B. Knight
Sabino Scolletta
Cristina Santonocito
Federico Pastore
Ferdinando L. Lorini
Luigi Tritapepe
Andrea Morelli
Antonio Arcadipane
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2017
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-017-1849-0

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