Advertisement

Intensive Care Medicine

, Volume 45, Issue 10, pp 1392–1400 | Cite as

Levosimendan in septic shock in patients with biochemical evidence of cardiac dysfunction: a subgroup analysis of the LeoPARDS randomised trial

  • David B. Antcliffe
  • Shalini Santhakumaran
  • Robert M. L. Orme
  • Josie K. Ward
  • Farah Al-Beidh
  • Kieran O’Dea
  • Gavin D. Perkins
  • Mervyn Singer
  • Daniel F. McAuley
  • Alexina J. Mason
  • Mary Cross
  • Deborah Ashby
  • Anthony C. GordonEmail author
Original

Abstract

Purpose

Myocardial dysfunction is common in sepsis but optimal treatment strategies are unclear. The inodilator, levosimendan was suggested as a possible therapy; however, the levosimendan to prevent acute organ dysfunction in Sepsis (LeoPARDS) trial found it to have no benefit in reducing organ dysfunction in septic shock. In this study we evaluated the effects of levosimendan in patients with and without biochemical cardiac dysfunction and examined its non-inotropic effects.

Methods

Two cardiac biomarkers, troponin I (cTnI) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and five inflammatory mediators were measured in plasma from patients recruited to the LeoPARDS trial at baseline and over the first 6 days. Mean total Sequential Organ Failure Assessment (SOFA) score and 28-day mortality were compared between patients with normal and raised cTnI and NT-proBNP values, and between patients above and below median values.

Results

Levosimendan produced no benefit in SOFA score or 28-day mortality in patients with cardiac dysfunction. There was a statistically significant treatment by subgroup interaction (p = 0.04) in patients with NT-proBNP above or below the median value. Those with NT-proBNP values above the median receiving levosimendan had higher SOFA scores than those receiving placebo (mean daily total SOFA score 7.64 (4.41) vs 6.09 (3.88), mean difference 1.55, 95% CI 0.43–2.68). Levosimendan had no effect on the rate of decline of inflammatory biomarkers.

Conclusion

Adding levosimendan to standard care in septic shock was not associated with less severe organ dysfunction nor lower mortality in patients with biochemical evidence of cardiac dysfunction.

Keywords

Septic shock Levosimendan Troponin cTnI N-terminal prohormone of brain natriuretic peptide Inflammation 

Notes

Funding

The trial was funded by the Efficacy and Mechanism Evaluation Programme (11-14-08), a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. Orion Pharma provided levosimendan and placebo free of charge. Tenax Therapeutics provided additional grant support. The NIHR Comprehensive Biomedical Research Centre (based at Imperial College Healthcare NHS Trust and Imperial College London) and the U.K. Intensive Care Foundation provided general research support. ACG is funded by an NIHR Research Professorship award (RP-2015-06-018). The funders, the sponsor (Imperial College London), Orion Pharma and Tenax Therapeutics had no role in designing the trial, gathering or analysing the data, writing the manuscript, nor making the decision to submit the manuscript for publication.

Compliance with ethical standards

Conflicts of interest

The views expressed in this article are those of the authors and not necessarily those of the MRC, the National Health Service (NHS), the NIHR, or the Department of Health. ACG reports receiving speaker fees from Amomed Pharma, consulting fees from Ferring Pharmaceuticals, Baxter Healthcare, Bristol-Myers Squibb and GlaxoSmithKline and grant support from HCA International, all paid to his institution; GDP receives fees for serving on an advisory board for GlaxoSmithKline; DFM receives consulting fees from Peptinnovate, Sobi, Bayer, Boehringer Ingelheim, and GlaxoSmithKline and fees to his institution from GlaxoSmithKline for participating in a clinical trial, and being named on a patent related to a new treatment for the acute respiratory distress syndrome (Canada, US, Australia, and European Union patent no., WO 2011073685, issued to Queen’s University Belfast). MS receives consulting fees and grant support from Apollo Therapeutics, Baxter, Deltex Medical, Defence Science and Technology Laboratory, GE Healthcare, Medical Technology Associates II and New Beta Innovation all paid to his institution, and heads a Data Safety Monitoring Board on behalf of Shionogi. No other potential conflict of interest relevant to this article was reported.

Supplementary material

134_2019_5731_MOESM1_ESM.pdf (193 kb)
Supplementary material 1 (PDF 192 kb)
134_2019_5731_MOESM2_ESM.docx (717 kb)
Supplementary material 2 (DOCX 717 kb)

References

  1. 1.
    Rhodes A, Evans LE, Alhazzani W et al (2017) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 43:304–377.  https://doi.org/10.1007/s00134-017-4683-6 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Vieillard-Baron A, Caille V, Charron C et al (2008) Actual incidence of global left ventricular hypokinesia in adult septic shock. Crit Care Med 36:1701–1706.  https://doi.org/10.1097/CCM.0b013e318174db05 CrossRefPubMedGoogle Scholar
  3. 3.
    Jardin F, Fourme T, Page B et al (1999) Persistent preload defect in severe sepsis despite fluid loading. Chest 116:1354–1359.  https://doi.org/10.1378/chest.116.5.1354 CrossRefPubMedGoogle Scholar
  4. 4.
    Frencken JF, Donker DW, Spitoni C et al (2018) Myocardial injury in patients with sepsis and its association with long-term outcome. Circ Cardiovasc Qual Outcomes 11:1–9.  https://doi.org/10.1161/CIRCOUTCOMES.117.004040 CrossRefGoogle Scholar
  5. 5.
    Aneman A, Vieillard-Baron A (2016) Cardiac dysfunction in sepsis. Intensive Care Med 42:2073–2076.  https://doi.org/10.1007/s00134-016-4503-4 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Schmittinger CA, Torgersen C, Luckner G et al (2012) Adverse cardiac events during catecholamine vasopressor therapy: a prospective observational study. Intensive Care Med 38:950–958.  https://doi.org/10.1007/s00134-012-2531-2 CrossRefPubMedGoogle Scholar
  7. 7.
    Dünser MW, Ruokonen E, Pettilä V et al (2009) Association of arterial blood pressure and vasopressor load with septic shock mortality: a post hoc analysis of a multicenter trial. Crit Care 13:R181.  https://doi.org/10.1186/cc8167 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Andreis DT, Singer M (2016) Catecholamines for inflammatory shock: a Jekyll-and-Hyde conundrum. Intensive Care Med 42:1387–1397.  https://doi.org/10.1007/s00134-016-4249-z CrossRefPubMedGoogle Scholar
  9. 9.
    Gordon AC, Perkins GD, Singer M et al (2016) Levosimendan for the prevention of acute organ dysfunction in sepsis. N Engl J Med 375:1638–1648.  https://doi.org/10.1056/NEJMoa1609409 CrossRefGoogle Scholar
  10. 10.
    Ukkonen H, Saraste M, Akkila J et al (1997) Myocardial efficiency during calcium sensitization with levosimendan: a noninvasive study with positron emission tomography and echocardiography in healthy volunteers. Clin Pharmacol Ther 61:596–607.  https://doi.org/10.1016/S0009-9236(97)90139-9 CrossRefPubMedGoogle Scholar
  11. 11.
    Wang Q, Yokoo H, Takashina M et al (2015) Anti-inflammatory profile of levosimendan in cecal ligation-induced septic mice and in lipopolysaccharide-stimulated macrophages. Crit Care Med 43:e508–e520.  https://doi.org/10.1097/CCM.0000000000001269 CrossRefPubMedGoogle Scholar
  12. 12.
    Hasslacher J, Bijuklic K, Bertocchi C et al (2011) Levosimendan inhibits release of reactive oxygen species in polymorphonuclear leukocytes in vitro and in patients with acute heart failure and septic shock: a prospective observational study. Crit Care 15:R166.  https://doi.org/10.1186/cc10307 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Parissis JT, Adamopoulos S, Antoniades C et al (2004) Effects of levosimendan on circulating pro-inflammatory cytokines and soluble apoptosis mediators in patients with decompensated advanced heart failure. Am J Cardiol 93:1309–1312.  https://doi.org/10.1016/j.amjcard.2004.01.073 CrossRefPubMedGoogle Scholar
  14. 14.
    Groesdonk H, Sander M, Heringlake M (2017) Levosimendan in sepsis. N Engl J Med 376:798–800.  https://doi.org/10.1056/nejmc1616632 CrossRefPubMedGoogle Scholar
  15. 15.
    Orme RML, Perkins GD, McAuley DF et al (2014) 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 15:199.  https://doi.org/10.1186/1745-6215-15-199 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Gordon AC, Santhakumaran S, Al-Beidh F et al (2018) Levosimendan to prevent acute organ dysfunction in sepsis: the LeoPARDS RCT. Eff Mech Eval 5:1–94.  https://doi.org/10.3310/eme05060 CrossRefGoogle Scholar
  17. 17.
    Landesberg G, Jaffe AS, Gilon D et al (2014) Troponin elevation in severe sepsis and septic shock: the role of left ventricular diastolic dysfunction and right ventricular dilatation. Crit Care Med 42:790–800.  https://doi.org/10.1097/CCM.0000000000000107 CrossRefPubMedGoogle Scholar
  18. 18.
    Charpentier J, Luyt C-E, Fulla Y et al (2004) Brain natriuretic peptide: a marker of myocardial dysfunction and prognosis during severe sepsis. Crit Care Med 32:660–665.  https://doi.org/10.1097/01.ccm.0000114827.93410.d8 CrossRefPubMedGoogle Scholar
  19. 19.
    Post F, Weilemann LS, Messow C-M et al (2008) B-type natriuretic peptide as a marker for sepsis-induced myocardial depression in intensive care patients. Crit Care Med 36:3030–3037.  https://doi.org/10.1097/CCM.0b013e31818b9153 CrossRefPubMedGoogle Scholar
  20. 20.
    Famous KR, Delucchi K, Ware LB et al (2017) Acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy. Am J Respir Crit Care Med 195:331–338.  https://doi.org/10.1164/rccm.201603-0645OC CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Ferreira FL, Bota DP, Bross A et al (2001) Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA 286:1754–1758CrossRefGoogle Scholar
  22. 22.
    Gordon AC, Mason AJ, Perkins GD et al (2014) The interaction of vasopressin and corticosteroids in septic shock: a pilot randomized controlled trial. Crit Care Med 42:1325–1333.  https://doi.org/10.1097/CCM.0000000000000212 CrossRefPubMedGoogle Scholar
  23. 23.
    Gordon AC, Mason AJ, Thirunavukkarasu N et al (2016) Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial. JAMA 316:509–518.  https://doi.org/10.1001/jama.2016.10485 CrossRefPubMedGoogle Scholar
  24. 24.
    Al-Mohammad A, Mant J, Laramee P et al (2010) Diagnosis and management of adults with chronic heart failure: summary of updated NICE guidance. BMJ 341:c4130.  https://doi.org/10.1136/bmj.c4130 CrossRefPubMedGoogle Scholar
  25. 25.
    Anderson MJ, Ter Braak CJF (2003) Permutation tests for multi-factorial analysis of variance. J Stat Comput Simul 73:85–113.  https://doi.org/10.1080/00949650215733 CrossRefGoogle Scholar
  26. 26.
    R Core Team (2015) R: a language and environment for statistical computing. R Foundation for Statistical ComputingGoogle Scholar
  27. 27.
    Lunn DJ, Thomas A, Best N, Spiegelhalter D (2000) WinBUGS - A Bayesian modelling framework: concepts, structure, and extensibility. Stat Comput 10:325–337.  https://doi.org/10.1023/A:1008929526011 CrossRefGoogle Scholar
  28. 28.
    Boldt J, Menges T, Kuhn D et al (1995) Alterations in circulating vasoactive substances in the critically ill—a comparison between survivors and non-survivors. Intensive Care Med 21:218–225.  https://doi.org/10.1007/BF01701475 CrossRefPubMedGoogle Scholar
  29. 29.
    Morelli A, Ertmer C, Westphal M et al (2013) Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock. JAMA 310:1683–1691.  https://doi.org/10.1001/jama.2013.278477 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • David B. Antcliffe
    • 1
  • Shalini Santhakumaran
    • 2
  • Robert M. L. Orme
    • 3
  • Josie K. Ward
    • 1
  • Farah Al-Beidh
    • 1
  • Kieran O’Dea
    • 1
  • Gavin D. Perkins
    • 4
    • 10
  • Mervyn Singer
    • 5
  • Daniel F. McAuley
    • 6
    • 7
  • Alexina J. Mason
    • 8
  • Mary Cross
    • 2
  • Deborah Ashby
    • 2
  • Anthony C. Gordon
    • 1
    • 9
    Email author
  1. 1.Section of Anaesthetics, Pain Medicine and Intensive Care Medicine, Department of Surgery and CancerImperial College London and Imperial College Healthcare NHS TrustLondonUK
  2. 2.Imperial Clinical Trials UnitImperial College LondonLondonUK
  3. 3.Department of Critical CareCheltenham General HospitalCheltenhamUK
  4. 4.Warwick Clinical Trials Unit, Warwick Medical SchoolUniversity of WarwickWarwickUK
  5. 5.Bloomsbury Institute of Intensive Care MedicineUniversity College LondonLondonUK
  6. 6.Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical SciencesQueen’s University BelfastBelfastUK
  7. 7.Regional Intensive Care UnitRoyal Victoria HospitalBelfastUK
  8. 8.Department of Health Services Research and PolicyLondon School of Hygiene and Tropical MedicineLondonUK
  9. 9.Intensive Care UnitImperial College/St Mary’s HospitalLondonUK
  10. 10.University Hospitals BirminghamBirminghamUK

Personalised recommendations