Skip to main content
SpringerLink
Log in

Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression

  • Original
  • Published:
Intensive Care Medicine Aims and scope Submit manuscript

Abstract

Objective

Calcium desensitization plays an important part in the pathophysiology of septic myocardial depression. We postulated that levosimendan, a new calcium sensitizer, would be beneficial in sepsis-induced cardiac dysfunction.

Design and setting

Prospective, randomized, controlled study in two university hospital intensive care units

Patients and participants

Twenty-eight patients with persisting left ventricular dysfunction related to septic shock after 48 h of conventional treatment including dobutamine (5 µg/kg per minute).

Interventions

After 48 h of conventional treatment patients were randomized to receive a 24-h infusion of either levosimendan (0.2 µg/kg per minute, n=15) or dobutamine (5 µg/kg per minute, n=13).

Measurements and results

Data from right heart catheterization, echocardiography, gastric tonometry, laser-Doppler flowmetry, and lactate concentrations and creatinine clearance were obtained before and after the 24-h drug infusion. Dobutamine did not change systemic or regional hemodynamic variables. By contrast, at the same mean arterial pressure levosimendan decreased pulmonary artery occlusion pressure and increased cardiac index. Levosimendan decreased left ventricular end-diastolic volume and increased left ventricular ejection fraction. Levosimendan increased gastric mucosal flow, creatinine clearance, and urinary output while it decreased lactate concentrations.

Conclusions

These findings show that levosimendan improves systemic hemodynamics and regional perfusion in patients with septic cardiac dysfunction under conditions where administration of 5 µg/kg dobutamine per minute is no longer efficacious. Accordingly, our results suggest that levosimendan can be an alternative to the strategy of increasing the dose of dobutamine under such conditions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Parker MM, Shetlander J, Bacharach SL, Green MV, Natanson C, Frederick TM, Damske BA, Parrillo JE (1984) Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 100:483–490

    CAS  PubMed  Google Scholar 

  2. Parker MM, McCarthy KE, Ognibene FP, Parrillo JE (1990) Right ventricular dysfunction and dilatation, similar to left ventricular changes, characterize the cardiac depression of septic shock in humans. Chest 97:126–131

    CAS  PubMed  Google Scholar 

  3. Parillo JE (1993) Pathogenetic mechanisms of septic shock. N Engl J Med 328:1471–1477

    Article  CAS  PubMed  Google Scholar 

  4. Silverman HJ, Peneranda R, Orens JB, Lee NH (1993) Impaired beta-adrenergic receptor stimulation of cyclic adenosine monophosphate in human septic shock: Association with myocardial hyporesponsiveness to catecholamines. Crit Care Med 21:31–39

    Google Scholar 

  5. Kumar A, Thota V, Dee L, Olson J, Uretz E, Parrillo JE (1996) Tumor necrosis factor-alpha and interleukin 1-beta are responsible for depression of in vitro myocardial cell contractility induced by serum from humans with septic shock. J Exp Med 183:949–958

    Google Scholar 

  6. Yokoyama T, Vaca L, Rossen RD, Durante W, Hazarika P, Mann DL (1993) Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in adult mammalian heart. J Clin Invest 92:2303–2312

    Google Scholar 

  7. Goldhaber JI, Kim KH, Natterson PD, Lawrence T, Yang P, Weiss JN (1996) Effects of TNF-alpha on [Ca2+] and contractility in isolated adult rabbit ventricular myocytes. Am J Physiol 271 [Suppl 4]: H 1499–1505 g

  8. Tavernier B, Mebazaa A, Mateo P, Sys S, Ventura-Clapier R, Veksler V (2001) Phosphorilation-dependent alteration in myofilament Ca2+ sensitivity but normal mitochondrial function in septic heart. Am J Respir Crit Care Med 163:362–367

    Google Scholar 

  9. Shah AM, Spurgeon HA, Sollott S, Talo A, Lakatta EG (1994) 8Bromo-cGMP reduces the myofilament response to Ca2+ in intact cardiac myocytes. Circ Res 74:970–978

    Google Scholar 

  10. Zhong J, Hwang T, Adams H, Rubin L (1997) Reduced L-type calcium current in ventricular myocites from endotoxemic guinea pigs. Am J Physiol 273:H2312–H2324

    Google Scholar 

  11. Hollenberg SM, Ahrens TS, Annane D, Astiz ME, Chalfin DB, Dasta JF, Heard SO, Martin C, Napolitano LM, Susla GM, Totaro R, Vincent JL, Zanotti-Cavazzoni S (2004) Practice parameters for hemodynamic support of sepsis in adult patient: 2004 update. Crit Care Med 32:1928–1948

    Google Scholar 

  12. Ming MJ, Hu DY, Chen HS, Liu LM, Nan X, Lu RO (2000) Effects of MCI-154, a calcium sensitizer on cardiac dysfunction in endotoxic shock in rabbits. Shock 13:459–463

    Google Scholar 

  13. Usta C, Puddu PE, Papalia U, De Santis V, Vitale D, Tritapepe L, Mazzesi G, Mirali F, Ozdem SS (2004) Comparison of the inotropic effects of levosimendan, rolipram and dobutamine on human atrial trabeculae. J Cardiovasc Pharmacol 44:622–625

    Google Scholar 

  14. Follath F, Cleland JG, Just H, Papp JG, Scholz H, Peuhkurinen K, Harjola VP, Mitrovic V, Abdalla M, Sandell EP, Lehtonen L; Steering Committee and Investigators of the Levosimendan Infusion versus Dobutamine (LIDO) Study (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 360:196–202

    Google Scholar 

  15. Duranteau J, Sitbon P, Teboul JL, Vicaut E, Anguel N, Richard C, Samii K (1999) Effects of epinephrine, norepinephrine or combination of norepinephrine and dobutamine on gastric mucosa in septic shock. Crit Care Med 27:893–900

    Google Scholar 

  16. Poelaert J, Declerck C, Vogelaers D, Colardyn F, Visser CA (1997) Left ventricular systolic and diastolic function in septic shock. Intensive Care Med 23:553–560

    Google Scholar 

  17. Yasuda S, Lew WYW (1997) Lipopolysaccharide depresses cardiac contractility and β-adrenergic contractile response by decreasing myofilament response to Ca2+ in cardiac myocytes. Circulation Res 81:1011–1020

    Google Scholar 

  18. Bernardin G, Kisoka RL, Delporte C, Robberecht P, Vincent JL (2003) Impairment of beta-adrenergic signaling in healthy peripheral blood mononuclear cells exposed to serum from patients with septic shock: involvement of the inhibitory pathway of adenylyl cyclase stimulation. Shock 19:108–112

    Google Scholar 

  19. Matsuda N, Hattori Y, Akaishi Y, Suzuki Y, Kemmotsu O, Gando S (2000) Impairment of cardiac beta-adrenoceptor cellular signaling by decreased expression of G (s alpha) in septic rabbits. Anesthesiology 93:1465–1473

    Google Scholar 

  20. Levy B, Nace L, Bollaert PE, Dousset B, Mallie JP, Larcan A (1999) Comparison of systemic and regional effects of dobutamine and dopexamine in norepinephrine-treated septic shock. Intensive Care Med 25:942–948

    Google Scholar 

  21. Creteur J, De Backer D, Vincent JL (1999) A dobutamine test can disclose hepatosplanchnic hypoperfusion in septic patients. Am J Respir Crit Care Med 160:839–845

    CAS  PubMed  Google Scholar 

  22. Teboul JL, Mercat A, Lenique F, Berton C, Richard C (1998) Value of the venous-arterial PCO2 gradient to reflect the oxygen supply to demands in humans: effects of dobutamine. Crit Care Med 26:1007–1010

    Google Scholar 

  23. Hung J, Lew WY (1993) Cellular mechanisms of endotoxin-induced myocardial depression in rabbits. Circ Res 73:125–134

    Google Scholar 

  24. Hasenfuss G, Pieske B, Castell M, Kretschmann B, Maier LS, Just H (1998) Influence of the novel inotropic agents levosimendan on isometric tension and calcium cycling in failing human myocardium. Circulation 98:2141–2147

    Google Scholar 

  25. Oldner A, Konrad D, Weitzberg E, Rudehill A, Rossi P, Wanacek M (2001) Effect of levosimendan a novel inotropic calcium-sensitizing drug, in experimental septic shock. Crit Care Med 29:2185–2193

    Article  CAS  PubMed  Google Scholar 

  26. Nieminen MS, Akkila J, Hasenfuss G, Kleber FX, Lehtonen LA, Mitrovic V, Nyquist O, Remme WJ (2000) Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. J Am Coll Cardiol 36:1903–1912

    Google Scholar 

  27. Slawsky MT, Colucci WS, Gottlieb SS, Greenberg BH, Haeusslein E, Hare J, Hutchins S, Leier CV, LeJemtel TH, Loh E, Nicklas J, Ogilby D, Singh BN, Smith W (2000) Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Circulation 102:2222–2227

    Google Scholar 

  28. Ukkonen H, Saraste M, Akkila J, Knuuti J, Karanko M, Iida H, Lehikonen P, Nagren K, Lehtonen L, Voipio-Pulkki LM (2000) Myocardial efficiency during levosimendan infusion in congestive heart failure. Clin Pharmacol Ther 68:522–531

    Google Scholar 

  29. Kaheinen P, Pollesello P, Levijoki J, Haikala H (2001) Levosimendan increases diastolic coronary flow in isolated guinea-pig heart by opening ATP-sensitive potassium channels. J Cardiovasc Pharmacol 37:367–374

    Google Scholar 

  30. Sibbald WJ, Paterson NA, Holliday RL, Anderson RA, Lobb TR, Duff JH (1978) Pulmonary hypertension in sepsis: measurement by the pulmonary artery diastolic-pulmonary wedge pressure gradient and the influence of passive and active factors. Chest 73:583–591

    Google Scholar 

  31. Kimchi A, Ellrodt GA, Berman DS, Riedinger MS, Swan HJ, Murata GH (1984) Right ventricular performance in septic shock: a combined radionuclide and hemodynamic study. J Am Coll Cardiol 4:945–951

    Google Scholar 

  32. Fiddian-Green RG (1993) Associations between intramucosal acidosis in the gut and organ failure. Crit Care Med 21 [Suppl]:S103–S107

    Google Scholar 

  33. Shepherd AP, Riedel GL, Maxwell LC, Kiel JW (1984) Selective vasodilators redistribute intestinal blood flow and depress oxygen uptake. Am J Physiol 247:G377–G384

    Google Scholar 

  34. Maynard ND, Bihari DJ, Dalton RN, Smithies MN, Mason RC (1995) Increasing splanchnic blood flow in the critically ill. Chest 108:1648–1654

    Google Scholar 

  35. Lebuffe G, Levy B, Nevière R, Chagnon JL, Perrigault PF, Duranteau J, Edouard A, Teboul JL, Vallet B (2002) Dobutamine and gastric-to-arterial carbon dioxide gap in severe sepsis without shock. Intensive Care Med 28:265–271

    Google Scholar 

  36. Pagel PS, Hettrick DA, Warltier DC (1996) Influence of levosimendan, pimobendan, and milrinone on the regional distribution of cardiac output in anesthetized dogs. Br J Pharmacol 119:609–615

    Google Scholar 

  37. Scarpace PJ, Abrass IB (1982) Desensitization of adenylate cyclase and down regulation of beta adrenergic receptors after in vivo administration of beta agonist. J Pharmacol Exp Ther 223:327–331

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anesthesiology and Intensive Care, University of Rome La Sapienza, Rome, Italy

    Andrea Morelli, Monica Rocco, Alessandra Orecchioni & Paolo Pietropaoli

  2. Department of Cardiovascular and Respiratory Sciences, University of Rome La Sapienza, Rome, Italy

    Stefano De Castro & Leonardo De Luca

  3. Service de Reanimation Medicale, Hôpital de Bicêtre, University of Paris XI, Le Kremlin-Bicêtre, France

    Jean-Louis Teboul

  4. Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK

    Mervyn Singer

  5. Department of Anesthesiology and Intensive Care, Catholic University of Rome, Rome, Italy

    Giorgio Conti

  6. Department of Internal Medicine, University of Rome La Sapienza, Rome, Italy

    Emanuele Di Angelantonio

  7. New England Medical Center, Tufts University, Boston, Mass., USA

    Natesa G. Pandian

Authors
  1. Andrea Morelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stefano De Castro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jean-Louis Teboul
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mervyn Singer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Monica Rocco
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giorgio Conti
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Leonardo De Luca
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Emanuele Di Angelantonio
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Alessandra Orecchioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Natesa G. Pandian
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Paolo Pietropaoli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrea Morelli.

Additional information

This study was funded by an independent research grant from the Department of Anesthesiology and Intensive Care of the University of Rome La Sapienza

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morelli, A., De Castro, S., Teboul, JL. et al. Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Med 31, 638–644 (2005). https://doi.org/10.1007/s00134-005-2619-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00134-005-2619-z

Keywords

Search

Navigation