nach oben

Erschienen in:

19.08.2019 | Original

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

verfasst von: 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. Gordon

Erschienen in: Intensive Care Medicine | Ausgabe 10/2019

Einloggen, um Zugang zu erhalten

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.

Nur mit Berechtigung zugänglich

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRef

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

14.

Groesdonk H, Sander M, Heringlake M (2017) Levosimendan in sepsis. N Engl J Med 376:798–800. https://doi.org/10.1056/nejmc1616632 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRef

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

21.

Ferreira FL, Bota DP, Bross A et al (2001) Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA 286:1754–1758CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRef

26.

R Core Team (2015) R: a language and environment for statistical computing. R Foundation for Statistical Computing

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 CrossRef

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 CrossRefPubMed

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 CrossRefPubMed

Titel: Levosimendan in septic shock in patients with biochemical evidence of cardiac dysfunction: a subgroup analysis of the LeoPARDS randomised trial
verfasst von: 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. Gordon
Publikationsdatum: 19.08.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Intensive Care Medicine / Ausgabe 10/2019
Print ISSN: 0342-4642
Elektronische ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-019-05731-w

Update AINS

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

hier abonnieren

Springer Medizin

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