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G. Landoni

“Protein C zymogen as adjuvant treatment of severe sepsis in heart surgery patients.” 9° International Winter Meeting on coagulation. Basic, Laboratory and Clinical Aspects of Venous and Arterial Thromboembolic Diseases. Bormio (Sondrio) – Italy April 1-4, 2009. G. Landoni.

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G. Landoni

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  1. “Protein C zymogen as adjuvant treatment of severe sepsis in heart surgery patients.”9° International Winter Meeting on coagulation. Basic, Laboratory and Clinical Aspects of Venous and Arterial Thromboembolic Diseases.Bormio (Sondrio) – Italy April 1-4, 2009 G. Landoni Department of Anesthesia and Intensive Care Istituto Scientifico San Raffaele, Milano, Italia Università Vita-Salute San Raffaele, Milano, Italia

  2. BACKGROUND IN ADULT SEPTIC PATIENTS • XIGRIS (activated C protein) reduces mortality in adult patients with APACHE score >24 or double organ failure.

  3. Contraindications to the use of XIGRIS as per recent international guidelines for the management of severe sepsis and septic shockDellinger et al. Crit Care Med 2008 • Active internal bleeding • Recent (within 3 months) hemorrhagic stroke • Recent (within 2 months) intracranial or intraspinal surgery, or severe head trauma • Trauma with an increased risk of life-threatening bleeding • Presence of an epidural catheter • Intracranial neoplasm or mass lesion or evidence of cerebral herniation • Known hypersensitivity to rhAPC or any component of the product

  4. The committee recommended that platelet count be maintained at > 30.000 during infusion of rhAPC • Furthermore, the same guidelines indicate weak recommendations and low quality of evidence for the use of rhAPC in adult patients within 30 days of surgery

  5. AIM OF THE PRESENTATION CEPROTIN IS NOT ASSOCIATED TO BLEEDING AND COULD BE INDICATED IN ADULT PATIENTS WITH CONTRAINDICATIONS TO XIGRIS: --recent surgery or invasive procedure --at risk for bleeding --bleeding after XIGRIS administration

  6. ADVERSE REACTIONS • 6 modest allergic reactions among 21.988 doses of ceprotin • Bleeding complication: NEVER REPORTED

  7. CEPROTIN (Human) BAXTER PC Zymogen (human) protein C concentrate(s) Protein C zymogen (concentrate) XIGRIS (Recombinant) LILLY APC rhAPC Enzyme Activated protein C Drotrecogin alfa activated NAMES

  8. ADULT PATIENTS AND CEPROTIN CASE SERIES SEPSIS Crivellari M et al. Safe administration of protein C concentrate in patients with sepsis at high risk for bleeding. SMART 2008 submitted Baratto et al. Protein C Concentrate to restore physiological values in adult septic patients. Intensive Care Med. 2008 in press (on pubmed since 7-5-2008) CASE SERIES MENINGITIS • Schellongowski P et al. Treatment of adult patients with sepsis-induced coagulopathy and purpura fulminans using a plasma-derived protein C concentrate (Ceprotin).Vox Sang 2006;90:294-301 • Fourrier F et al. Combined antithrombin and protein C supplementation in meningococcal purpura fulminans: a pharmacokinetic study. Intensive Care Med 2003;29:1081-1087 • Makris PE et al. Treatment of DIC the role of PC. J Thromb Haemost 2003 (Suppl 1):abstract P0600 • Rintala E. et al. Protein C substitution in sepsis-associated purpura fulminans. Critical Care Med 2000;28:2373;2378 CASE REPORTS MENINGITIS • Vaccarella G, Pelella R. Replacement treatment with protein C in an 18-year-old man with meningococcal sepsis and purpura fulminans. Minerva Anestesiol 2003;69:691-3

  9. ADULT PATIENTS AND CEPROTIN CASE SERIES SEPSIS • Landoni G et al. PCc in adul septic patients. A review. Signa Vitae. 2008;3:12-16 • Crivellari M, Marino G, Landoni G et al. Administration of human protein C concentrates in patients with double organ failure and severe sepsis after cardiac surgery. Abstract SIAARTI Congress 2008, Palermo. • Baratto et al. Protein C Concentrate to restore physiological values in adult septic patients. Intensive Care Med. 2008;34:1707-1712 • Tuttolomondo A et al. Plasma derived protein C in severe sepsis: report of two cases. Intern Emerg Med 2008; 3:179-82 CASE SERIES MENINGITIS • Schellongowski P et al. Treatment of adult patients with sepsis-induced coagulopathy and purpura fulminans using a plasma-derived protein C concentrate (Ceprotin).Vox Sang 2006;90:294-301 • Fourrier F et al. Combined antithrombin and protein C supplementation in meningococcal purpura fulminans: a pharmacokinetic study. Intensive Care Med 2003;29:1081-1087 • Makris PE et al. Treatment of DIC the role of PC. J Thromb Haemost 2003 (Suppl 1):abstract P0600 • Rintala E. et al. Protein C substitution in sepsis-associated purpura fulminans. Critical Care Med 2000;28:2373;2378 CASE REPORTS MENINGITIS • Vaccarella G, Pelella R. Replacement treatment with protein C in an 18-year-old man with meningococcal sepsis and purpura fulminans. Minerva Anestesiol 2003;69:691-3

  10. Summary of all published papers reporting on adult patients receiving protein C concentrates

  11. Summary of all published papers reporting on adult patients receiving protein C concentrates

  12. Summary of all published papers reporting on adult patients receiving protein C concentrates

  13. ONGOING STUDIESADULT PATIENTS AND CEPROTIN WWW.CLINICALTRIALS.GOV

  14. CEPROTIN IN CHILDREN

  15. ONGOING STUDIESPAEDIATRIC PATIENTS AND CEPROTIN WWW.CLINICALTRIALS.GOV

  16. CARDIAC SURGERY

  17. CARDIAC OUTPUT AFTER CARDIAC SURGERY

  18. Objective: To describe a case series of nine consecutive adult septic patients at high risk for bleeding who received protein C concentrate after cardiac surgery. • Design: Observational study. • Setting: A 14-bed Cardiothoracic and Vascular intensive care unit • Patients: Nine consecutive critically ill adult patients with severe sepsis or septic shock and two organ failure after cardiac surgery in the period January 2007 to January 2008

  19. 9 PATIENTS Baseline characteristics included • Age 65+8 (2 Females) • respiratory failure (8/9 patients) • acute renal failure requiring renal replacement therapy (7/9 patients). • All patients had severe sepsis with 6 patients experiencing septic shock.

  20. INTERVENTIONS Nine consecutive patients with severe sepsis or septic shock were treated with protein C (Ceprotin – Baxter) with a 50 UI/Kg bolus followed by a 3 UI/Kg/h continuous infusion for 72 hours.

  21. PC activity raised from 41+24 before bolus to 74+14 (p=0.02) and continued to increase thereafter.

  22. PT values reduced significantly (p=0.02) from 1.47+0.29 to 1.19+0,10 during PC administration • AT III values increased significantly (p=0.02) from 51+12 to 81+17% during PC administration • aPTT, XDP, FG, activated PC, platelets, e-selectin didn’t show any modification.

  23. Are you still with me? All of you?

  24. RESULTS Predicted mortality of 68%. • APACHE II (24+3) • SAPS II (60+5) In our case series mortality at 30 days was 1/9 (11%)

  25. All patients had an improvement of the general conditions in the hours following the bolus administration of the study drug with reduction of cathecolamines, that were interrupted in all patients within 4 days

  26. Mechanical ventilation: 6 days before and 6 days after PCc • ICU stay: 6 days before and 9 days after PCc • Postoperative hospital stay 27 (21-40 days) • Renal function recovered in all patients

  27. ADVERSE EVENTS • One patient had haemorragic cystitis 3 days after completing treatment. • One patient experienced Heparin Induced Trombocytopenia (HIT) without thrombosis one week after the administration of the study drug. • One further patient had bilateral jugular vein thrombosis after treatment completion 12 days after PC treatment.

  28. PCc DOSES IN ADULTS

  29. 15.650 IU (3700 IU) Baseline values 41+24% 24 h after bolus 94+18% End of treatment 90+26% 19.065 IU (bolus 4.500 IU) Baseline values 34+9% 24 h after bolus 75+26% End of treatment 98+15% PCc DOSES IN ADULTSThe possibility exists to reduce the costs of this expensive treatment when compared to other studies performed in adult septic patientsCRIVELLARI ET AL. BARATTO ET AL

  30. CONCLUSIONS • PCc was administered in ICU septic patients (6+3 days after cardiac surgery) • PCc administration was safe and no adverse reactions or complications were seen during administration

  31. CONCLUSION • Expected mortality at 30 days was 68% compared to the observed mortality of 11% observed in our case series. • PCc seems to be a useful alternative to the activated form especially in post-operative cardiac surgery patients because there is no risk of bleeding.

  32. TAKE HOME MESSAGE • CEPROTIN (Protein C Zymogen) is currently used in --paediatric septic patients --paediatric and adult septic meningitis patients • CEPROTIN has no bleeding complications and could be used in adult septic patients with contraindications to XIGRIS --recent surgery or invasive procedure --at risk for bleeding --bleeding after XIGRIS administration

  33. TAKE HOME MESSAGECARDIAC SURGERY IS AN INTERESTING SUB-SETTING • 9 out of 1400 = 0.6% • 257 patients in Italy among the 40.000 udergoing cardiac surgery • 6.000/1.000.000 heart surgery operations worldwide.

  34. VOLATILE ANESTHETICS FENOLDOPAM DESMOPRESSIN ESMOLOL LEVOSIMENDAN VALVOLE PERCUTANEE landoni.giovanni@hsr.it www.itacta.org 4 200 AIFA 2006 34 1.000 MINISTRY 2008 3 200 3 200 10 1.000 3 150 ITACTA ONGOING RCTsTOPICS HOSPITALS PATIENTS GRANTS

  35. For these and further slides on these topics please feel free to visit the metcardio.org website:http://www.metcardio.org/slides.html

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