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

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

4 Contraindications to the use of XIGRIS as per recent international guidelines for the management of severe sepsis and septic shock Dellinger 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

5 The committee recommended that platelet count be maintained at > 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

6 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

7 ADVERSE REACTIONS 6 modest allergic reactions among doses of ceprotin Bleeding complication: NEVER REPORTED

8 NAMES CEPROTIN (Human) BAXTER PC Zymogen (human) protein C concentrate(s) Protein C zymogen (concentrate) XIGRIS (Recombinant) LILLY APCrhAPC Enzyme Activated protein C Drotrecogin alfa activated

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10 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 in press (on pubmed since ) 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: Fourrier F et al. Combined antithrombin and protein C supplementation in meningococcal purpura fulminans: a pharmacokinetic study. Intensive Care Med 2003;29: 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

11 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: Tuttolomondo A et al. Plasma derived protein C in severe sepsis: report of two cases. Intern Emerg Med 2008; 3: 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: Fourrier F et al. Combined antithrombin and protein C supplementation in meningococcal purpura fulminans: a pharmacokinetic study. Intensive Care Med 2003;29: 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

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13 AuthorYearJournalN Landoni G2009Signa Vitae2 Crivellari M2008Siaarti congr Baratto F2008; 2004Intensive Care Med20 Tuttolomondo A2008Intern Emerg Med2 Schellongowski P2006Vox Sang<8 Fourrier F2003Intensive Care Med<5<5 Makris PE2003J Thromb Haemost7 Vaccarella G2003Minerva Anestesiol1 Rintala E2000; 1998Critical Care Med12 TOTAL<66 Summary of all published papers reporting on adult patients receiving protein C concentrates

14 AuthorSettingSurvival Landoni GSepsis100% Crivellari M (18) Sepsis after cardiac surgery89% Baratto F (19) Sepsis (10 surgical and 10 medical patients) 65% Tuttolomondo A (20) Meningitis100% Schellongowski P (21) Purpura fulminans75% Fourrier F (22) Purpura fulminans40% Makris PE (23) DIC71% Vaccarella G (24) Purpura fulminans100% Rintala E (25, 26) Purpura fulminans58% TOTAL46/66=70% Summary of all published papers reporting on adult patients receiving protein C concentrates

15 AuthorBolus doseFollowing doses Landoni G50 IU /kg3 IU/kg/h Crivellari M50 IU /kg3 IU/kg/h Baratto F(100 – PC plasma level) x body weight (Kg) According to plasma levels Tuttolomondo AVarious Schellongowski PVarious Fourrier F100 IU/Kg100 IU/Kg/day Makris PEVarious Vaccarella G80 IU/kg2000 IU every 4h * 4days Rintala E100 IU/Kg100 IU/Kg every 6 hours TOTAL Summary of all published papers reporting on adult patients receiving protein C concentrates

16 ONGOING STUDIES ADULT PATIENTS AND CEPROTIN

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18 AuthorPATIENTSdose Clarke1 100 IU/kg x 3/day De Carolis1 unknown dosage, for 96 hours De Kleijn20 50, 100, 150 IU/kg 6-12 h Ettingshausen8 Fourrier 100 IU/kg bolus x4/die Leclerc2 100 IU/kg day Pettenazzo8 100 IU/kg bolus, IU/kg every 6-12 h upon plasma dosing PC Rintala3 100 UI/kg x4/die Rivard4 100 UI/kg x4/die Silvani11 mean 324 UI/kg/day (66-400) Smith IU/kg bolus, IU/kg/h continuously White IU/kg as loading dose and continous infusion 10 IU/kg/h. After 24h titrated to a plasma PC level IU/ml TOTAL 124 CEPROTIN IN CHILDREN

19 ONGOING STUDIES PAEDIATRIC PATIENTS AND CEPROTIN

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21 CARDIAC SURGERY

22 CARDIAC OUTPUT AFTER CARDIAC SURGERY

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27 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

28 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.

29 PathogensSite of infection negative blood culture ? Enterobacter Cloacae PNEUMONIA Acinetobacter Baumanii, Klebsiella Pneumofila PNEUMONIA Acinetobacter Baumanii, Citrobacter Braakii PNEUMONIA negative blood culture ? MRSA Staph. epidermidis sepsis BLOOD MSSA Staph. Aureus sepsis in bronchial sample, E.Coli in urine sample BLOOD+PNEUMONIA+URINE Pseudomonas Aeruginosa, Serratia Marcescens PNEUMONIA negative blood culture ?

30 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.

31 PC activity raised from before bolus to (p=0.02) and continued to increase thereafter.

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

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34 Are you still with me? All of you?

35 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%)

36 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

37 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

38 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.

39 PCc DOSES IN ADULTS Crivellari M (18) 50 IU /kg3 IU/kg/h Baratto F (19) (100 – PC plasma level) x body weight (Kg) 3 IU/kg/h + adjusting according to plasma levels

40 PCc DOSES IN ADULTS The possibility exists to reduce the costs of this expensive treatment when compared to other studies performed in adult septic patients CRIVELLARI ET AL.BARATTO ET AL IU (3700 IU) Baseline values 41+24% 24 h after bolus 94+18% End of treatment90+26% IU (bolus IU) Baseline values 34+9% 24 h after bolus 75+26% End of treatment98+15%

41 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

42 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.

43 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

44 TAKE HOME MESSAGE CARDIAC SURGERY IS AN INTERESTING SUB-SETTING 9 out of 1400 = 0.6% 257 patients in Italy among the udergoing cardiac surgery 6.000/ heart surgery operations worldwide.

45 ITACTA ONGOING RCTs TOPICSHOSPITALSPATIENTS GRANTS VOLATILE ANESTHETICS FENOLDOPAM DESMOPRESSIN ESMOLOL LEVOSIMENDAN VALVOLE PERCUTANEE AIFA MINISTRY

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