Intensive Care Medicine

, Volume 41, Issue 2, pp 203–221 | Cite as

Effects of levosimendan for low cardiac output syndrome in critically ill patients: systematic review with meta-analysis and trial sequential analysis

  • Geert KosterEmail author
  • Jørn Wetterslev
  • Christian Gluud
  • Jan G. Zijlstra
  • Thomas W. L. Scheeren
  • Iwan C. C. van der Horst
  • Frederik Keus
Systematic Review



To assess the benefits and harms of levosimendan for low cardiac output syndrome in critically ill patients.


We conducted a systematic review with meta-analyses and trial sequential analyses (TSA) of randomised clinical trials comparing levosimendan with any type of control. Two reviewers independently assessed studies for inclusion. The Cochrane Collaboration methodology was used. Random-effects risk ratios (RR) and 95 % confidence intervals (CI) were derived for the principal primary outcome mortality at maximal follow-up.


A total of 88 trials were included in the systematic review and 49 trials (6,688 patients) in the meta-analysis. One trial had low risk of bias and nine trials (2,490 patients) were considered lower risk of bias. Trials compared levosimendan with placebo, control interventions, and other inotropes. Pooling all trials including heterogenous populations was considered inappropriate. Pooled analysis of 30 trials including critically ill patients not having cardiac surgery showed an association between levosimendan and mortality (RR 0.83, TSA-adjusted 95 % CI 0.59–0.97), while trials with lower risk of bias showed no significant difference (RR 0.83, TSA-adjusted 95 % CI 0.48–1.55). Conventional meta-analysis of all 14 trials including cardiac surgery patients showed an association, while lower risk of bias trials showed no association between levosimendan and mortality (RR 0.52, 95 % CI 0.37–0.73 versus RR 1.02, 95 % CI 0.48–2.16).


The available evidence is inconclusive whether or not levosimendan may have a beneficial effect on mortality due to risks of systematic errors and random errors. Further well-designed randomised trials are needed.


Heart failure Mortality Cardiac surgery Cardiotonic agents Levosimendan Meta-analysis Trial sequential analysis 



Diversity adjusted required information size


Grading of Recommendations Assessment, Development and Evaluation


Intensive care unit


Left ventricular ejection fraction


Myocardial infarction


Serious adverse events


Supraventricular tachyarrhythmia


Ventricular tachyarrhythmia


Trial sequential analysis



We thank Sarah Louise Klingenberg, trials search coordinator at the Copenhagen Trial Unit for her assistance with the search strategy.

Conflicts of interest

The authors declare that they have no conflict of interest.

Supplementary material

134_2014_3604_MOESM1_ESM.doc (1.8 mb)
Supplementary material 1 (DOC 1847 kb)


  1. 1.
    Lilleberg J, Sundberg S, Nieminen MS (1995) Dose-range study of a new calcium sensitizer, levosimendan, in patients with left ventricular dysfunction. J Cardiovasc Pharmacol 26(Suppl 1):S63–S69PubMedCrossRefGoogle Scholar
  2. 2.
    Moiseyev VS, Poder P, Andrejevs N et al (2002) 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 23:1422–1432PubMedCrossRefGoogle Scholar
  3. 3.
    Zairis M, Apostolatos C, Anastasiadis P et al (2004) The effect of a calcium sensitizer or an inotrope or none in chronic low output decompensated heart failure: results from the calcium sensitizer or inotrope or none in low output heart failure study (CASINO). J Am Coll Cardiol 43:206A–207A. doi: 10.1016/S0735-1097(04)90879-0 CrossRefGoogle Scholar
  4. 4.
    Levin R, Degrange M, Porcile R et al (2008) Preoperative use of calcium sensitizer levosimendan reduces mortality and low cardiac output syndrome in patients with aortic stenosis and left ventricular dysfunction. Circulation 118:E217Google Scholar
  5. 5.
    Levin R, Porcile R, Salvagio F et al (2009) Levosimendan reduces mortality in postoperative low cardiac output syndrome after coronary surgery. Circulation 120:S987–S988CrossRefGoogle Scholar
  6. 6.
    Mebazaa A, Nieminen MS, Filippatos GS et al (2009) Levosimendan vs. dobutamine: outcomes for acute heart failure patients on beta-blockers in SURVIVE. Eur J Heart Fail 11:304–311. doi: 10.1093/eurjhf/hfn045 PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Packer M, Colucci W, Fisher L et al (2013) Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JACC Heart Fail 1:103–111PubMedCrossRefGoogle Scholar
  8. 8.
    Delaney A, Bradford C, McCaffrey J, Bagshaw SM, Lee R (2010) Levosimendan for the treatment of acute severe heart failure: a meta-analysis of randomised controlled trials. Int J Cardiol 138:281–289. doi: 10.1016/j.ijcard.2008.08.020 PubMedCrossRefGoogle Scholar
  9. 9.
    Landoni G, Biondi-Zoccai G, Greco M et al (2012) Effects of levosimendan on mortality and hospitalization. A meta-analysis of randomized controlled studies. Crit Care Med 40:634–646PubMedCrossRefGoogle Scholar
  10. 10.
    Huang X, Lei S, Zhu MF, Jiang RL, Huang LQ, Xia GL, Zhi YH (2013) Levosimendan versus dobutamine in critically ill patients: a meta-analysis of randomized controlled trials. J Zhejiang Univ Sci B 14:400–415. doi: 10.1631/jzus.B1200290 PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Harrison RW, Hasselblad V, Mehta RH, Levin R, Harrington RA, Alexander JH (2013) Effect of levosimendan on survival and adverse events after cardiac surgery: a meta-analysis. J Cardiothorac Vasc Anesth 27:1224–1232. doi: 10.1053/j.jvca.2013.03.027 PubMedCrossRefGoogle Scholar
  12. 12.
    Keus F, Wetterslev J, Gluud C, van Laarhoven CJ (2010) Evidence at a glance: error matrix approach for overviewing available evidence. BMC Med Res Methodol 10:90. doi: 10.1186/1471-2288-10-90 PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Higgins JPT, Green S (editors) (2011) Cochrane handbook for systematic reviews of interventions version 5.1.0 (updated March 2011). The Cochrane CollaborationGoogle Scholar
  14. 14.
    Brok J, Thorlund K, Wetterslev J, Gluud C (2009) Apparently conclusive meta-analyses may be inconclusive—trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses. Int J Epidemiol 38:287–298. doi: 10.1093/ije/dyn188 PubMedCrossRefGoogle Scholar
  15. 15.
    Thorlund K, Devereaux PJ, Wetterslev J et al (2009) Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses? Int J Epidemiol 38:276–286. doi: 10.1093/ije/dyn179 PubMedCrossRefGoogle Scholar
  16. 16.
    Pogue JM,Yusuf S (1997) Cumulating evidence from randomized trials: utilizing sequential monitoring boundaries for cumulative meta-analysis. Control Clin Trials 18:580–593; discussion 661–6Google Scholar
  17. 17.
    Pogue J, Yusuf S (1998) Overcoming the limitations of current meta-analysis of randomised controlled trials. Lancet 351:47–52. doi: 10.1016/S0140-6736(97)08461-4 PubMedCrossRefGoogle Scholar
  18. 18.
    Thorlund K, Imberger G, Walsh M et al (2011) The number of patients and events required to limit the risk of overestimation of intervention effects in meta-analysis–a simulation study. PLoS ONE 6:e25491. doi: 10.1371/journal.pone.0025491 PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schunemann HJ, GRADE Working Group (2008) What is “quality of evidence” and why is it important to clinicians? BMJ 336:995–998. doi: 10.1136/bmj.39490.551019.BE PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Keus F, Koster G, van der Horst ICC, Zijlstra JG, Wetterslev J, Gluud C (2013) Levosimendan for low cardiac output syndromes: a systematic review with meta-analysis and trial sequential analysis.
  21. 21.
    Rao V, Ivanov J, Weisel RD, Ikonomidis JS, Christakis GT, David TE (1996) Predictors of low cardiac output syndrome after coronary artery bypass. J Thorac Cardiovasc Surg 112:38–51. doi: 10.1016/S0022-5223(96)70176-9 PubMedCrossRefGoogle Scholar
  22. 22.
    International Conference on Harmonisation Expert Working Group. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use, ed. ICH harmonised tripartite guideline; guideline for good clinical practice.
  23. 23.
    Review Manager (RevMan) [Computer Program] Version 5.2 Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012Google Scholar
  24. 24.
    Copenhagen Trial Unit (2011) TSA—trial sequential analysis. Accessed 4 September 2012
  25. 25.
    Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G, Gluud C (2011) User manual for trial sequential analysis (TSA). Accessed 12 May 2014
  26. 26.
    Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558. doi: 10.1002/sim.1186 PubMedCrossRefGoogle Scholar
  27. 27.
    Wetterslev J, Thorlund K, Brok J, Gluud C (2008) Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol 61:64–75. doi: 10.1016/j.jclinepi.2007.03.013 PubMedCrossRefGoogle Scholar
  28. 28.
    Wetterslev J, Engstrøm J, Gluud C, Thorlund K (2012) Trial sequential analysis: methods and software for cumulative meta-analyses. Cochrane Methods Cochrane Database Syst Rev Suppl 1:29–31Google Scholar
  29. 29.
    Wetterslev J, Thorlund K, Brok J, Gluud C (2009) Estimating required information size by quantifying diversity in random-effects model meta-analyses. BMC Med Res Methodol 9:86. doi: 10.1186/1471-2288-9-86 PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Adamopoulos S, Parissis JT, Iliodromitis EK et al (2006) Effects of levosimendan versus dobutamine on inflammatory and apoptotic pathways in acutely decompensated chronic heart failure. Am J Cardiol 98:102–106. doi: 10.1016/j.amjcard.2006.01.068 PubMedCrossRefGoogle Scholar
  31. 31.
    Asaad OM, Hanafy MS (2011) Levosimendan’s effect on coronary artery grafts blood flow in patients with left ventricular dysfunction, assessment by transit time flow meter. Egypt J Anaesth 27:45–53CrossRefGoogle Scholar
  32. 32.
    Dogan OF (2013) Levosimendan use decreases atrial fibrillation in patients after coronary artery bypass grafting: a pilot study. Heart Surg Forum 16:E287–E294. doi: 10.1532/HSF98.2013190 PubMedCrossRefGoogle Scholar
  33. 33.
    Eriksson HI, Jalonen JR, Heikkinen LO et al (2009) Levosimendan facilitates weaning from cardiopulmonary bypass in patients undergoing coronary artery bypass grafting with impaired left ventricular function. Ann Thorac Surg 87:448–454. doi: 10.1016/j.athoracsur.2008.10.029 PubMedCrossRefGoogle Scholar
  34. 34.
    Flevari P, Parissis JT, Leftheriotis D, Panou F, Kourea K, Kremastinos DT (2006) Effect of levosimendan on ventricular arrhythmias and prognostic autonomic indexes in patients with decompensated advanced heart failure secondary to ischemic or dilated cardiomyopathy. Am J Cardiol 98:1641–1645. doi: 10.1016/j.amjcard.2006.07.043 PubMedCrossRefGoogle Scholar
  35. 35.
    Husebye T, Eritsland J, Muller C et al (2013) Levosimendan in acute heart failure following primary percutaneous coronary intervention-treated acute ST-elevation myocardial infarction. Results from the LEAF trial: a randomized, placebo-controlled study. Eur J Heart Fail 15:565–572. doi: 10.1093/eurjhf/hfs215 PubMedCrossRefGoogle Scholar
  36. 36.
    Iliuta L (2009) The Cost-Benefit Report associated with routinely using levosimendan in patients with systolic dysfunction undergoing coronary artery bypass grafting. Eur J Heart Fail 8(Suppl S2):ii392. doi: 10.1093/eurjhf/hfp082 Google Scholar
  37. 37.
    Kleber FX, Bollmann T, Borst MM et al (2009) Repetitive dosing of intravenous levosimendan improves pulmonary hemodynamics in patients with pulmonary hypertension: results of a pilot study. J Clin Pharmacol 49:109–115. doi: 10.1177/0091270008325150 PubMedCrossRefGoogle Scholar
  38. 38.
    Lahtinen P, Pitkänen O, Pölönen P, Turpeinen A, Kiviniemi V, Uusaro A (2011) Levosimendan reduces heart failure after cardiac surgery: a prospective, randomized, placebo-controlled trial. Crit Care Med 39:2263–2270PubMedCrossRefGoogle Scholar
  39. 39.
    Levin R, Porcile R, Tanus E, Degrange M (2009) The intermittent infusion of levosimendan reduces mortality and re-admisions in patients with advanced heart failure. Circulation 120:S865–S865CrossRefGoogle Scholar
  40. 40.
    Lilleberg J, Laine A, Palkama T, Kivikko A, Pohjanjousi P, Kupari M (2007) Duration of the haemodynamic action of a 24-h infusion of levosimendan in patients with congestive heart failure. Eur J Heart Fail 9:75–82. doi: 10.1016/j.ejheart.2006.04.012 PubMedCrossRefGoogle Scholar
  41. 41.
    Llorens P, Miro O, Roman F, Zapater P, Carbajosa-Dalmau J, Llanos L (2012) Efficacy of early administration of levosimendan in emergency department in patients with acute heart failure: a randomized pilot clinical trial. Emergencias 24:268–276Google Scholar
  42. 42.
    Nieminen MS, Akkila J, Hasenfuss G et al (2000) Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. J Am Coll Cardiol 36:1903–1912PubMedCrossRefGoogle Scholar
  43. 43.
    Slawsky MT, Colucci WS, Gottlieb SS et al (2000) Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Circulation 102:2222–2227PubMedCrossRefGoogle Scholar
  44. 44.
    Tritapepe L, De Santis V, Vitale D, Guarracino F, Pellegrini F, Pietropaoli P, Singer M (2009) Levosimendan pre-treatment improves outcomes in patients undergoing coronary artery bypass graft surgery. Br J Anaesth 102:198–204PubMedCrossRefGoogle Scholar
  45. 45.
    Berger R, Moertl D, Huelsmann M, Bojic A, Ahmadi R, Heissenberger I, Pacher R (2007) Levosimendan and prostaglandin E1 for uptitration of beta-blockade in patients with refractory, advanced chronic heart failure. Eur J Heart Fail 9:202–208. doi: 10.1016/j.ejheart.2006.06.001 PubMedCrossRefGoogle Scholar
  46. 46.
    Biteker M, Duran NE, Kaya H et al (2011) Effect of levosimendan and predictors of recovery in patients with peripartum cardiomyopathy, a randomized clinical trial. Clin Res Cardiol 100:571–577. doi: 10.1007/s00392-010-0279-7 PubMedCrossRefGoogle Scholar
  47. 47.
    Kurt IH, Yavuzer K, Batur MK (2010) Short-term effect of levosimendan on free light chain kappa and lambda levels in patients with decompensated chronic heart failure. Heart Vessels 25:392–399. doi: 10.1007/s00380-009-1216-4 PubMedCrossRefGoogle Scholar
  48. 48.
    Lomivorotov VV, Boboshko VA, Efremov SM et al (2012) Levosimendan versus an intra-aortic balloon pump in high-risk cardiac patients. J Cardiothorac Vasc Anesth 26:596–603. doi: 10.1053/j.jvca.2011.09.006 PubMedCrossRefGoogle Scholar
  49. 49.
    Malfatto G, Della Rosa F, Villani A, Rella V, Branzi G, Facchini M, Parati G (2012) Intermittent levosimendan infusions in advanced heart failure: favourable effects on left ventricular function, neurohormonal balance, and one-year survival. J Cardiovasc Pharmacol 60:450–455PubMedCrossRefGoogle Scholar
  50. 50.
    Mavrogeni S, Giamouzis G, Papadopoulou E et al (2007) A 6-month follow-up of intermittent levosimendan administration effect on systolic function, specific activity questionnaire, and arrhythmia in advanced heart failure. J Card Fail 13:556–559PubMedCrossRefGoogle Scholar
  51. 51.
    Zemljic G, Bunc M, Yazdanbakhsh AP, Vrtovec B (2007) Levosimendan improves renal function in patients with advanced chronic heart failure awaiting cardiac transplantation. J Card Fail 13:417–421. doi: 10.1016/j.cardfail.2007.03.005 PubMedCrossRefGoogle Scholar
  52. 52.
    Alhashemi JA, Alotaibi Q (2009) Levosimendan versus dobutamine in septic shock. Crit Care 13(Suppl 1): Abstract no: p171. doi: 10.1186/cc7335
  53. 53.
    Al-Shawaf E, Ayed A, Vislocky I, Radomir B, Dehrab N, Tarazi R (2006) Levosimendan or milrinone in the type 2 diabetic patient with low ejection fraction undergoing elective coronary artery surgery. J Cardiothorac Vasc Anesth 20:353–357. doi: 10.1053/j.jvca.2006.02.012 PubMedCrossRefGoogle Scholar
  54. 54.
    Alvarez J, Bouzada M, Fernandez A et al (2006) Hemodynamic effects of levosimendan compared with dobutamine in patients with low cardiac output after cardiac surgery. Rev Esp Cardiol 59:338–345. doi: 10.1157/13087055 PubMedCrossRefGoogle Scholar
  55. 55.
    Baysal A, Yanartas M, Dogukan M, Gundogus N, Kocak T, Koksal C (2014) Levosimendan improves renal outcome in cardiac surgery: a randomized trial. J Cardiothorac Vasc Anesth 28:586–594PubMedCrossRefGoogle Scholar
  56. 56.
    Bergh CH, Andersson B, Dahlstrom U et al (2010) Intravenous levosimendan vs. dobutamine in acute decompensated heart failure patients on beta-blockers. Eur J Heart Fail 12:404–410. doi: 10.1093/eurjhf/hfq032 PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Bonios MJ, Terrovitis JV, Drakos SG et al (2012) Comparison of three different regimens of intermittent inotrope infusions for end stage heart failure. Int J Cardiol 159:225–229. doi: 10.1016/j.ijcard.2011.03.013 PubMedCrossRefGoogle Scholar
  58. 58.
    De Hert SG, Lorsomradee S, Cromheecke S, Van DL (2007) The effects of levosimendan in cardiac surgery patients with poor left ventricular function. Anesth Analg 104:766–773PubMedCrossRefGoogle Scholar
  59. 59.
    Duygu H, Ozerkan F, Nalbantgil S et al (2008) Effect of levosimendan on E/E’ ratio in patients with ischemic heart failure. Int J Cardiol 123:201–203PubMedCrossRefGoogle Scholar
  60. 60.
    Duygu H, Turk U, Ozdogan O et al (2008) Levosimendan versus dobutamine in heart failure patients treated chronically with carvedilol. Cardiovasc Ther 26:182–188. doi: 10.1111/j.1755-5922.2008.00050.x PubMedCrossRefGoogle Scholar
  61. 61.
    Follath F, Cleland JG, Just H et al (2002) Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet 360:196–202PubMedCrossRefGoogle Scholar
  62. 62.
    Fuhrmann JT, Schmeisser A, Schulze MR et al (2008) Levosimendan is superior to enoximone in refractory cardiogenic shock complicating acute myocardial infarction [corrected] [published erratum appears in Crit Care Med 2008 Oct; 36(10):2966]. Crit Care Med 36:2257–2266PubMedCrossRefGoogle Scholar
  63. 63.
    Garcia-Gonzalez M, Dominguez-Rodriguez A, Ferrer-Hita J, Abreu-Gonzalez P, Munoz MB (2006) Cardiogenic shock after primary percutaneous coronary intervention: effects of levosimendan compared with dobutamine on haemodynamics. Eur J Heart Fail 8:723–728PubMedCrossRefGoogle Scholar
  64. 64.
    Iyisoy A, Celik T, Celik M, Bugan B, Yaman H (2010) Comparative effects of levosimendan and dobutamine infusion on p wave dispersion in patients with acute decompensated heart failure. Turk J Med Sci 40:761–770Google Scholar
  65. 65.
    Levin RL, Degrange MA, Porcile R et al (2008) The calcium sensitizer levosimendan gives superior results to dobutamine in postoperative low cardiac output syndrome. Rev Esp Cardiol 61:471–479PubMedCrossRefGoogle Scholar
  66. 66.
    Levin R, Degrange M, Del Mazo C et al (2008) Superiority of Levosimendan over Dobutamine in low cardiac output syndrome after aortic valve replacement. Circulation 118:E231Google Scholar
  67. 67.
    Mebazaa A, Nieminen MS, Packer M et al (2007) Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE randomized trial. JAMA 297:1883–1891PubMedCrossRefGoogle Scholar
  68. 68.
    Memis D, Inal MT, Sut N (2012) The effects of levosimendan vs dobutamine added to dopamine on liver functions assessed with noninvasive liver function monitoring in patients with septic shock. J Crit Care 27:318.e1–318.e6. doi: 10.1016/j.jcrc.2011.06.008 CrossRefGoogle Scholar
  69. 69.
    Morelli A, Castro S, Teboul JL et al (2005) Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Med 31:638–644. doi: 10.1007/s00134-005-2619-z PubMedCrossRefGoogle Scholar
  70. 70.
    Morelli A, Donati A, Ertmer C et al (2010) Levosimendan for resuscitating the microcirculation in patients with septic shock: a randomized controlled study. Crit Care 14:R232. doi: 10.1186/cc9387 PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Vaitsis J, Michalopoulou H, Thomopoulos C, Massias S, Stamatis P (2009) Use of levosimendan in myocardial dysfunction due to sepsis. Crit Care 13:S67Google Scholar
  72. 72.
    Yilmaz MB, Yontar C, Erdem A et al (2009) Comparative effects of levosimendan and dobutamine on right ventricular function in patients with biventricular heart failure. Heart Vessels 24:16–21. doi: 10.1007/s00380-008-1077-2 PubMedCrossRefGoogle Scholar
  73. 73.
    Yontar OC, Yilmaz MB, Yalta K, Erdem A, Tandogan I (2010) Acute effects of levosimendan and dobutamine on QRS duration in patients with heart failure. Arq Bras Cardiol 95:738–742PubMedCrossRefGoogle Scholar
  74. 74.
    Savovic J, Jones HE, Altman DG et al (2012) Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Ann Intern Med 157:429–438. doi: 10.7326/0003-4819-157-6-201209180-00537 PubMedCrossRefGoogle Scholar
  75. 75.
    Wood L, Egger M, Gluud LL et al (2008) Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ 336:601–605. doi: 10.1136/bmj.39465.451748.AD PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Kjaergard LL, Villumsen J, Gluud C (2001) Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med 135:982–989PubMedCrossRefGoogle Scholar
  77. 77.
    Schulz KF, Chalmers I, Hayes RJ, Altman DG (1995) Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 273:408–412PubMedCrossRefGoogle Scholar
  78. 78.
    Chan A, Tetzlaff JM, Altman DG et al (2013) SPIRIT 2013 Statement: defining Standard Protocol Items for Clinical Trials. Ann Intern Med 158:200–207. doi: 10.7326/0003-4819-158-3-201302050-00583 PubMedCrossRefGoogle Scholar
  79. 79.
    Schulz KF, Altman DG, Moher D, for the CONSORT Group (2010) CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ 340:c332. doi: 10.1136/bmj.c332 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2014

Authors and Affiliations

  • Geert Koster
    • 1
    Email author
  • Jørn Wetterslev
    • 2
  • Christian Gluud
    • 2
  • Jan G. Zijlstra
    • 1
  • Thomas W. L. Scheeren
    • 3
  • Iwan C. C. van der Horst
    • 1
  • Frederik Keus
    • 1
  1. 1.Department of Critical CareUniversity of Groningen, University Medical Centre GroningenGroningenThe Netherlands
  2. 2.The Copenhagen Trial Unit (CTU), Centre for Clinical Intervention Research, Department 7812, RigshospitaletCopenhagen University HospitalCopenhagenDenmark
  3. 3.Department of AnaesthesiologyUniversity of Groningen, University Medical Centre GroningenGroningenThe Netherlands

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