Intensive Care Medicine

, Volume 42, Issue 11, pp 1706–1714 | Cite as

Protein C zymogen in severe sepsis: a double-blinded, placebo-controlled, randomized study

  • Federico Pappalardo
  • Martina Crivellari
  • Ambra L. Di Prima
  • Nataliya Agracheva
  • Malgorzata Celinska-Spodar
  • Rosalba Lembo
  • Daiana Taddeo
  • Giovanni Landoni
  • Alberto Zangrillo
Original

Abstract

Purpose

To determine whether protein C zymogen (protein C concentrates or human protein C) improves clinically relevant outcomes in adult patients with severe sepsis and septic shock.

Methods

This is a randomized, double-blind, placebo-controlled, parallel-group trial that from September 2012 to June 2014 enrolled adult patients with severe sepsis or septic shock and high risk of death and of bleeding (e.g., APACHE II greater than 25, extracorporeal membrane oxygenation or disseminated intravascular coagulopathy). All patients completed their follow-up 90 days after randomization and data were analyzed according to the intention-to-treat principle. Follow-up was performed at 30 and 90 days after randomization. The primary endpoint was a composite outcome of prolonged intensive care unit (ICU) stay and/or 30-day mortality. Secondary endpoints included mortality.

Results

The study was stopped early in a situation of futility for the composite outcome of prolonged ICU stay and/or 30-day mortality that was 79 % (15 patients) in the protein C zymogen group and 67 % (12 patients) in the placebo group (p = 0.40) and for a concomitant safety issue: ICU mortality was 79 % (15 patients) in the protein C zymogen group vs 39 % (7 patients) in the placebo group (p = 0.020), and 30-day mortality was 68 vs 39 % (p = 0.072).

Conclusion

Protein C zymogen did not improve clinically relevant outcomes in severe sepsis and septic shock adult patients. Given its high cost and the potential increase in mortality, the use of this drug in adult patients should be discouraged.

Keywords

Sepsis Critical care Protein C Septic shock Intensive care Mortality 

Supplementary material

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References

  1. 1.
    Zhao H, Heard SO, Mullen MT et al (2012) An evaluation of the diagnostic accuracy of the 1991 American College of Chest Physicians/Society of Critical Care Medicine and the 2001 Society of Critical Care Medicine/European Society of Intensive Care Medicine/American College of Chest Physicians/American Thoracic Society/Surgical Infection Society sepsis definition. Crit Care Med 40:1700–1706. doi:10.1097/CCM.0b013e318246b83a CrossRefPubMedGoogle Scholar
  2. 2.
    Gaieski DF, Edwards JM, Kallan MJ, Carr BG (2013) Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med 41:1167–1174. doi:10.1097/CCM.0b013e31827c09f8 CrossRefPubMedGoogle Scholar
  3. 3.
    Brun-Buisson C, Meshaka P, Pinton P, Vallet B (2004) EPISEPSIS Study Group: EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med 30:580–588. doi:10.1007/s00134-003-2121-4 CrossRefPubMedGoogle Scholar
  4. 4.
    Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348:138–150. doi:10.1056/NEJMra021333 CrossRefPubMedGoogle Scholar
  5. 5.
    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 344:699–709. doi:10.1056/NEJM200103083441001 CrossRefPubMedGoogle Scholar
  6. 6.
    Vincent JL, Bernard GR, Beale R et al (2005) Drotecogin alfa (activated) treatment in severe sepsis from the global-label trial ENHANCE: further evidence for survival and safety and implications for early treatment. Crit Care Med 33:2266–2277. doi:10.1097/01.CCM.0000181729.46010.83 CrossRefPubMedGoogle Scholar
  7. 7.
    Dellinger RP, Levy MM, Carlet JM et al (2008) Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med 34:17–60. doi:10.1007/s00134-007-0934-2 CrossRefPubMedGoogle Scholar
  8. 8.
    Ranieri VM, Thompson BT, Barie PS et al (2012) Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 366:2055–2064. doi:10.1056/NEJMoa1202290 CrossRefPubMedGoogle Scholar
  9. 9.
    Vincent JL (2012) The rise and fall of drotrecogin alfa (activated). Lancet Infect Dis 12:649–651. doi:10.1016/S1473-3099(12)70175-5 CrossRefPubMedGoogle Scholar
  10. 10.
    Greco M, Landoni G, Nobile L et al (2014) Decreasing mortality with drotrecogin alfa in high risk septic patients A meta-analysis of randomized trials in adult patients with multiple organ failure and mortality >40 %. Signa Vitae 9:16–21Google Scholar
  11. 11.
    Bruley DF, Jagannath SB, Streiff MB (2011) Zymogen Protein C to prevent clotting without bleeding during invasive medical procedures. Adv Exp Med Biol 701:91–97. doi:10.1007/978-1-4419-7756-4_13 CrossRefPubMedGoogle Scholar
  12. 12.
    Baratto F, Michielan F, Meroni M, Dal Palù A, Boscolo A, Ori C (2008) Protein C concentrate to restore physiological values in adult septic patients. Intensive Care Med 34:1707–1712. doi:10.1007/s00134-008-1140-6 CrossRefPubMedGoogle Scholar
  13. 13.
    Landoni G, Monti G, Facchini A et al (2010) Human protein C concentrate in pediatric septic patients. Signa Vitae 5:13–19Google Scholar
  14. 14.
    Crivellari M, Della Valle P, Landoni G et al (2009) Human protein C zymogen concentrate in patients with severe sepsis and multiple organ failure after adult cardiac surgery. Intensive Care Med 35:1959–1963. doi:10.1007/s00134-009-1584-3 CrossRefPubMedGoogle Scholar
  15. 15.
    Fourrier F, Leclerc F, Aidan K et al (2003) Combined antithrombin and protein C supplementation in meningococcal purpura fulminans: a pharmacokinetic study. Intensive Care Med 29:1081–1087. doi:10.1007/s00134-003-1784-1 CrossRefPubMedGoogle Scholar
  16. 16.
    Silvetti S, Crivellari M, Mucchetti M et al (2013) Administration of protein C concentrates in patients without congenital deficit: a systematic review of the literature. Signa Vitae 8:15–19Google Scholar
  17. 17.
    Esmon CT (2005) The interactions between inflammation and coagulation. Br J Haematol 131:417–430. doi:10.1111/j.1365-2141.2005.05753.x CrossRefPubMedGoogle Scholar
  18. 18.
    Fisher CJ Jr, Yan SB (2000) Protein C levels as a prognostic indicator of outcome in sepsis and related diseases. Crit Care Med 28:S49–S56CrossRefPubMedGoogle Scholar
  19. 19.
    Carobbio A, Finazzi G, Thiele J et al (2012) Blood tests may predict early primary myelofibrosis in patients presenting with essential thrombocythemia. Am J Hematol 87:203–204. doi:10.1002/ajh.22241 CrossRefPubMedGoogle Scholar
  20. 20.
    Piccin A, O’ Marcaigh A, Mc Mahon C et al (2014) Non-activated plasma-derived PC improves amputation rate of children undergoing sepsis. Thromb Res 134:63–67. doi:10.1016/j.thromres.2014.04.019 CrossRefPubMedGoogle Scholar
  21. 21.
    Salvo I, Landoni G, Mucchetti M, Cabrini L, Pani L (2014) Use and reimbursement of off-label drugs in pediatric anesthesia: the Italian experience. Pediatr Anaesth 24:625–631. doi:10.1111/pan.12403 CrossRefGoogle Scholar
  22. 22.
    (2001) ICH harmonised tripartite guideline: guideline for good clinical practice. 8. Essential documents for the conduct of a clinical trial. J Postgrad Med 47: 264–67Google Scholar
  23. 23.
    Schellongowski P, Bauer E, Holzinger U et al (2006) Treatment of adult patients with sepsis-induced coagulopathy and purpura fulminans using a plasma-derived protein C concentrate (Ceprotin). Vox Sang 90:294–301. doi:10.1111/j.1423-0410.2006.00760.x CrossRefPubMedGoogle Scholar
  24. 24.
    Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M, Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH) (2001) Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 86:1327–1330PubMedGoogle Scholar
  25. 25.
    Dellinger RP, Levy MM, Rhodes A et al (2013) Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 39:165–228. doi:10.1007/s00134-012-2769-8 CrossRefPubMedGoogle Scholar
  26. 26.
    Guidet B, Beale R (2015) Should cost considerations be included in medical decisions? Yes. Intensive Care Med 41:1838–1840. doi:10.1007/s00134-015-3988-6 CrossRefPubMedGoogle Scholar
  27. 27.
    De Kleijn ED, de Groot R, Hack CE et al (2003) Activation of protein C following infusion of protein C concentrate in children with severe meningococcal sepsis and purpura fulminans: a randomized, double-blinded, placebo-controlled, dose-finding study. Crit Care Med 31:1839–1847. doi:10.1097/01.CCM.0000072121.61120.D8 CrossRefPubMedGoogle Scholar
  28. 28.
    De Leonardis F, Koronica R, Bruno SD, Santoro N (2014) Non-activated protein C rescue treatment in Wilms tumour associated hepatic sinusoidal obstructive syndrome. Pediatr Blood Cancer 61:940–941. doi:10.1002/pbc.24859 CrossRefPubMedGoogle Scholar
  29. 29.
    Decembrino L, D’Angelo A, Manzato F et al (2010) Protein C concentrate as adjuvant treatment in neonates with sepsis-induced coagulopathy: a pilot study. Shock 34:341–345. doi:10.1097/SHK.0b013e3181e7623e CrossRefPubMedGoogle Scholar
  30. 30.
    Yeo HJ, Kim do H, Jeon D, Kim YS, Cho WH (2015) Low-dose heparin during extracorporeal membrane oxygenation treatment in adults. Intensive Care Med 41:2020–2021. doi:10.1007/s00134-015-4015-7 CrossRefPubMedGoogle Scholar
  31. 31.
    Hernu R, Cour M, de la Salle S, Robert D, Argaud L (2015) Cost awareness of physicians in intensive care units: a multicentric national study. Intensive Care Med 41:1402–1410. doi:10.1007/s00134-015-3859-1 CrossRefPubMedGoogle Scholar
  32. 32.
    Gerson WT, Dickerman JD, Bovill EG, Golden E (1993) Severe acquired protein C deficiency in purpura fulminans associated with disseminated intravascular coagulation: treatment with protein C concentrate. Pediatrics 91:418–422PubMedGoogle Scholar
  33. 33.
    Rintala E, Kauppila M, Seppälä OP et al (2000) Protein C substitution in sepsis-associated purpura fulminans. Crit Care Med 28:2372–2378Google Scholar
  34. 34.
    Crivellari M, Silvetti S, Gerli C et al (2014) Protein C zymogen in adults with severe sepsis or septic shock. Med Intensiva 38:278–282. doi:10.1016/j.medin.2013.04.005 CrossRefPubMedGoogle Scholar
  35. 35.
    Gattinoni L, Giomarelli P (2015) Acquiring knowledge in intensive care: merits and pitfalls of randomized controlled trials. Intensive Care Med 41:1460–1464. doi:10.1007/s00134-015-3837-7 CrossRefPubMedGoogle Scholar
  36. 36.
    Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R (2014) Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000–2012. JAMA 311:1308–1316. doi:10.1001/jama.2014.2637 CrossRefPubMedGoogle Scholar
  37. 37.
    Landoni G, Pasin L, Monti G, Cabrini L, Beretta L, Zangrillo A (2013) Towards zero perioperative mortality. Heart Lung Vessel 5:133–136PubMedPubMedCentralGoogle Scholar
  38. 38.
    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: a randomized clinical trial. JAMA 310:1683–1691. doi:10.1001/jama.2013.278477 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2016

Authors and Affiliations

  • Federico Pappalardo
    • 1
  • Martina Crivellari
    • 1
  • Ambra L. Di Prima
    • 1
  • Nataliya Agracheva
    • 1
    • 2
  • Malgorzata Celinska-Spodar
    • 1
    • 3
  • Rosalba Lembo
    • 1
  • Daiana Taddeo
    • 1
    • 4
  • Giovanni Landoni
    • 1
    • 5
  • Alberto Zangrillo
    • 1
    • 5
  1. 1.IRCCS San Raffaele Scientific InstituteMilanItaly
  2. 2.Städtiches Klinikum BraunschweighBraunschweigGermany
  3. 3.Institute of CardiologyWarsawPoland
  4. 4.Ospedale di RoccadaspideSalernoItaly
  5. 5.Vita-Salute San Raffaele UniversityMilanItaly

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