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

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.

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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.

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Correspondence to Anthony C. Gordon.

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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.

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Antcliffe, D.B., Santhakumaran, S., Orme, R.M.L. et al. Levosimendan in septic shock in patients with biochemical evidence of cardiac dysfunction: a subgroup analysis of the LeoPARDS randomised trial. Intensive Care Med 45, 1392–1400 (2019). https://doi.org/10.1007/s00134-019-05731-w

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Keywords

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