Improvement in Hemodynamics by Activated Protein C in Septic Shock

  • X. Monnet
  • H. Ksouri
  • J. -L. Teboul
Conference paper


Recombinant human activated protein C (rhAPC) has been approved by the US Food and Drug Administration (FDA) for treating patients with sepsis or septic shock with an APACHE II score of more than 25 and by the European Agency for the Evaluation of Medicinal Products for multiple organ failure (MOF) related to sepsis. Furthermore, guidelines of the Surviving Sepsis Campaign recommend rhAPC as a standard-of-care for patients with severe sepsis and septic shock [1]. These approvals and recommendations were mainly supported by the results of the worldwide Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study [2], in which rhAPC was demonstrated to increase the survival rate of patients with the most severe forms of septic shock. This seminal study was focused on the overall mortality as the main criterion of judgement. Nevertheless in the following years, experimental and clinical studies suggested that rhAPC induces a specific improvement in the cardiovascular failure during septic shock. In this chapter, we will review these studies and the underlying mechanisms that are supposed to explain the effects of APC.


Septic Shock Severe Sepsis Mean Arterial Pressure Septic Shock Patient Survive Sepsis Campaign 
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  1. 1.
    Dellinger RP, Carlet JM, Masur H, et al (2004) Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Intensive Care Med 30: 536–555PubMedCrossRefGoogle Scholar
  2. 2.
    Bernard GR, Vincent JL, Laterre PF, et al (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344: 699–709PubMedCrossRefGoogle Scholar
  3. 3.
    Kalil AC, Coyle SM, Urn JY, et al (2004) Effects of drotrecogin alfa (activated) in human endotoxemia. Shock 21: 222–229PubMedCrossRefGoogle Scholar
  4. 4.
    Derhaschnig U, Reiter R, Knobl P, Baumgartner M, Keen P, Jilma B (2003) Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) has minimal effect on markers of coagulation, fibrinolysis, and inflammation in acute human endotoxemia. Blood 102: 2093–2098PubMedCrossRefGoogle Scholar
  5. 5.
    Vincent JL, Angus DC, Artigas A, et al (2003) Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial. Crit Care Med 31: 834–840PubMedCrossRefGoogle Scholar
  6. 6.
    Dhainaut JF, Laterre PF, Janes JM, et al (2003) Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple-organ dysfunction: data from the PROWESS trial. Intensive Care Med 29: 894–903PubMedGoogle Scholar
  7. 7.
    Monnet X, Lamia B, Anguel N, Richard C, Bonmarchand G, Teboul JL (2005) Rapid and beneficial hemodynamic effects of activated protein C in septic shock patients. Intensive Care Med 31: 1573–1576PubMedCrossRefGoogle Scholar
  8. 8.
    Ksouri H, Cour M, Monnet X, Richard C, Teboul JL (2007) An observational study of the use of activated protein C in septic shock patients with emphasis on hemodynamic effects. Intensive Care Med 33(suppl 2): S166 (Abst)Google Scholar
  9. 9.
    De Backer D, Verdant C, Chierego M, Koch M, Gullo A, Vincent JL (2006) Effects of drotrecogin alfa activated on microcirculatory alterations in patients with severe sepsis. Crit Care Med 34: 1918–1924PubMedCrossRefGoogle Scholar
  10. 10.
    Taylor FB Jr, Chang A, Esmon CT, D’Angelo A, Vigano-D’Angelo S, Blick KE (1987) Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 79: 918–925PubMedCrossRefGoogle Scholar
  11. 11.
    Isobe H, Okajima K, Uchiba M, et al (2001) Activated protein C prevents endotoxin-induced hypotension in rats by inhibiting excessive production of nitric oxide. Circulation 104: 1171–1175PubMedCrossRefGoogle Scholar
  12. 12.
    White B, Schmidt M, Murphy C, et al (2000) Activated protein C inhibits lipopolysaccharideinduced nuclear translocation of nuclear factor kappaB (NF-kappaB) and tumour necrosis factor alpha (TNF-alpha) production in the THP-1 monocytic cell line. Br J Haematol 110: 130–134PubMedCrossRefGoogle Scholar
  13. 13.
    Favory R, Lancel S, Marechal X, Tissier S, Neviere R (2006) Cardiovascular protective role for activated protein C during endotoxemia in rats. Intensive Care Med 32: 899–905PubMedCrossRefGoogle Scholar
  14. 14.
    Wang Z, Su F, Rogiers P, Vincent JL (2007) Beneficial effects of recombinant human activated protein C in a ewe model of septic shock. Crit Care Med 35: 2594–2600PubMedCrossRefGoogle Scholar
  15. 15.
    Hoffmann JN, Vollmar B, Laschke MW, et al (2004) Microhemodynamic and cellular mechanisms of activated protein C action during endotoxemia. Crit Care Med 32: 1011–1017PubMedCrossRefGoogle Scholar
  16. 16.
    Iba T, Kidokoro A, Fukunaga M, Nagakari K, Shirahama A, Ida Y (2005) Activated protein C improves the visceral microcirculation by attenuating the leukocyte-endothelial interaction in a rat lipopolysaccharide model. Crit Care Med 33: 368–372PubMedCrossRefGoogle Scholar
  17. 17.
    Young JD (2004) The heart and circulation in severe sepsis. Br J Anaesth 93: 114–120PubMedCrossRefGoogle Scholar
  18. 18.
    Annane D, Bellissant E, Cavaillon JM (2005) Septic shock. Lancet 365: 63–78PubMedCrossRefGoogle Scholar
  19. 19.
    Drapier JC, Wietzerbin J, Hibbs JB Jr (1988) Interferon-gamma and tumor necrosis factor induce the L-arginine-dependent cytotoxic effector mechanism in murine macrophages. Eur J Immunol 18: 1587–1592PubMedCrossRefGoogle Scholar
  20. 20.
    Nick JA, Coldren CD, Geraci MW, et al (2004) Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis. Blood 104: 3878–3885PubMedCrossRefGoogle Scholar
  21. 21.
    Sennoun N, Desebbe O, Levy B (2007) Hemodynamic effects of activated protein C in septic shock. In: Vincent JL (eds) Yearbook of Intensive Care and Emergency Medicine. Springer, Heidelberg, pp 75–80Google Scholar
  22. 22.
    Wiel E, Costecalde ME, Lebuffe G, et al (2006) Activated protein C increases sensitivity to vasoconstriction in rabbit Escherichia coli endotoxin-induced shock. Crit Care 10: R47PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media Inc. 2008

Authors and Affiliations

  • X. Monnet
    • 1
  • H. Ksouri
    • 1
  • J. -L. Teboul
    • 1
  1. 1.Department of Intensive CareCentre Hospitalier Universitaire de BicetreLe Kremlin-BicetreFrance

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