1. C protein concentrates in paediatric septic patients Giacomo Monti, MD University Vita – Salute S. Raffaele Milano Department of Anesthesia and Intensive Care

2. 2 monti.giacomo@hsr.it

3. 3 C- protein concentrate C protein.. Virtually side – effect free drug No bleeding risk Few papers but very often used in clinical practice, expecially in Italy Active in a disease that causes severe mortality and morbidity

4. 4 Protein C 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 4

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6. 6 PC in literature Extensive literature scan by PubMed, Embase, Google Scholar Contact with expert Update to January 2009

7. 7 Sepsis in children: US In the United States, there were 42,000 cases of severe sepsis in children in 1995; in 1997 the total number of cases increased to 47,700 Hospital mortality among U.S. children with severe sepsis was 10.3% 7

8. 8 Sepsis in children: US - 2 Sepsis is the 2 nd cause of death among children, 4 th among infants Children who develop severe sepsis consume substantial healthcare resources, with an average length of stay of 31 days and cost of $40,600 8

9. 9 Sepsis in children: Italy In 2004-2005 lower overall incidence of sepsis, severe sepsis and septic shock (7.9, 1.6 and 2.1% of PICU admission) Severe sepsis and septic shock had a mortality rate of 17.7 and 50.8%, respectively Incidence of and mortality due to sepsis, severe sepsis and septic shock in Italian Pediatric Intensive Care Units: a prospective national survey. Wolfler A et al. Intensive Care Med 2008; 34:1690-7 9

10. 10 “Protein C concentrations in children reach adult values at the age of 3 yrs. This might indicate that the importance of protein C supplementation either as protein C concentrate or as rhAPC is greater in young children than in adults.”

11. 11 The “RESOLVE” study Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Nadel S et al. Lancet 2007; 369: 836–43 Our results showed no significant difference between groups in CTCOFR score (p=0·72) or in 28-day mortality (placebo 17·5%; DrotAA, 17·2%; p=0·93). 11

12. 12 AuthorYearJournalN Gerson1993Pediatrics1 Rivard1995J Pediatr4 Smith1997Lancet12 Rintala1998Crit Care Med3 Ettingshausen1999Semin Thromb Hemost8 Clarke2000Intensive Care Med1 Leclerc2000Crit Care Med2 White2000Blood36 De Kleijn2003Crit Care Med30 Fourrier2003Intensive Care Med15 Pettenazzo2004Minerva Anestesiol8 Silvani2005Minerva Anestesiol11 De Carolis2008Turk J Pediatr1 TOTAL131 Summary of all published papers reporting on children patients receiving protein C concentrates 12

13. 13 AuthorNSettingSurvival Gerson1Meningococcal purpura fulminans1 Rivard4Meningococcal septic shock4 Smith12Meningococcal septic shock12 Rintala3Meningococcal septic shock2 Ettingshausen8Meningococcal septic shock6 Clarke1Meningoccal severe sepsis1 Leclerc2Meningococcal septic shock2 White35Septic shock and presumptive meningococcemia 33 De Kleijn30Severe sepsis or meningococcal disease23 Fourrier15Meningococcal purpura fulminans6 Pettenazzo8Septic shock6 Silvani11Severe sepsis or septic shock8 De Carolis1Severe sepsis1 TOTAL131103 (79%) 13 Summary of all published papers reporting on children patients receiving protein C concentrates

14. 14 Few papers account for more than half of published – treated patients 3 “major” papers 78 children (59%) 14

15. 15 Smith, Lancet 1997 12 patients Meningoccemia and septic shock GMSPS score predicted mortality: 80% PRISM predicted mortality: 57% Dose: titrate to concentration of 0.8-1.2 IU/ml (normal) 100% survival 2 (17%) lower limb amputation No drug – related adverse event 15

16. 16 Mean time to PC infusion begin in non amputated:12 (3.1) h Mean time to PC infusion begin in amputated:60 (17.0) h p<0.01 Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus-induced purpura fulminans. Smith OP et al. Lancet 1997; 350: 1590–93 16

17. 17 White, Blood 2000 36 patients (some adults, mean age 12) Meningococcemia and septic shock GMSPS score predicted mortality: 50% Dose: bolus 100 IU/kg and infusion 10 IU/kg/h 92% survival 4 (12%) amputation No drug – related adverse event 17

18. 18 Four amputation: 2 patients received PC after 24 hours to admission An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia. White B et al. Blood 2000 96: 3719-3724 18

19. 19 De Kleijn, Crit Care Med 2003 Only RCT, double blinde, PC vs placebo 40 patients (10 placebo, 30 treatment) Meningoccemia and septic shock Fase two study (dose findings, safety) 1 placebo group 3 treatment groups incremental doses (50, 100, 150 IU/kg/6h 19

20. 20 Main findings Mortality Not powered to achieve a significant result No linear trend comparing predicted versus observed mortality Fascinating result compared to predicted mortality GroupPRISM predicted mortality Actual mortality placebo67%20% 50 IU/kg35%9% 100 IU/kg26%11% 150 IU/kg60%50% Overall (drug) 40%23% Adapted from: De Kleijn et al. Crit Care Med 2003; 31:1839-47 20

21. 21 Main findings - 2 Supplementation of PC is effective Concentration is dose – dependant 21 50 IU/kg/6 h restore normal PC value (0.8-1.2 IU/ml) 100 – 150 IU/kg/6h obtain 2-2.5 folds normal value Effect on concentration is stable in the 6 hours beetwen doses Dose response - PC

22. 22 Main findings - 3 Dose response – aPC PC is activated by patients Activation is dose – dependant With a 100 - 150 IU/kg/6 h schedule, peak aPC is significantly higher Effect of activation is not mantained in the 6-hours “window” 22

23. 23 Main findings - 4 Safety 4 amputations (not attributed to study drugs) 1 not serious bleeding event in a patient with severe DIC 23

24. 24 Lessons from literature - 1 Real efficacy –mortality reduction– is not definitively established, quality of evidence is poor Safety is high We need a RCT trial 24

25. 25 Lessons from literature - 2 If you decide to use PC, do use preferably within 24 hours from admission A “suggested” schedule: – Test dose of 10 IU/kg – From 100 to 150 UI/kg first bolus dose – Begin a perfusion that gives up a daily cumulative dose of 400-600 IU/kg or use bolus at least every 6 hours 25

26. 26 Hot topics From 131 patients published, just 8 children were not affected by meningococcal disease PC is always activated ? Should we really need activation ? 26

27. 27 PC pathways DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN SEVERE MENINGOCOCCAL SEPSIS. Faust el al. NEJM 2001; 345:408-16 27

28. 28 A-PC effect 28 2007

29. 29 A-PC anticoagulative properties The A-PC / PS complex binds to VIIIa and Va and inactivate them Decreased Thrombin Generation Decreased Fibrin Formation and reduced amplification of inflammatory pathway A-PC Side effects 29

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31. 31 PC and endothelium Three possible pathways: Lack of PC – EPCR interaction EPCR binds to – Activated PC – Not-activated PC 31

32. 32 Protein C concentrations in severe sepsis: an early directional change in plasma levels predicts outcome. Shorr F et al. Crit Care. 2006; 10: R92. Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newborns. “The differences between survivors and non-survivors were statistically significant (respectively, for ATIII P=0.003 and for PC P=0.00002). A highly statistically significant correlation (P=0.0016) between plasma PC functional level and risk of death was found in patients with sepsis.” Lauterbach R Lauterbach R et al. Eur J Pediatr. 2006;165:585-9 Liaw, PC et al. Patients with severe sepsis vary markedly in their ability to generate activated protein C. Blood. 2004;104:3958-3964 Lack of PC – EPCR interaction 32

33. 33 PC and endothelium Three possible pathways: Lack of PC – EPCR interaction EPCR binds to – Activated PC – Not-activated PC 33

34. 34 APCs direct effects on cells include: (i)alteration of gene expression profiles; (ii)anti-inflammatory activities; (iii)Antiapoptotic (iv)endothelial barrier stabilization. Mediated by a Gi protein intracellular pathway EPCR binds to a-PC 34

35. 35 PC and endothelium Three possible pathways: Lack of PC – EPCR interaction EPCR binds to – Activated PC – Not-activated PC 35

36. 36 Bae, JS et al. Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand. Thromb Haemost 2008; 100: 101–109 The ligand occupancy of EPCR couples PAR-1 to G i protein The ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability- enhancing to a barrier-protective response in endothelial cells. Jong-Sup et al. Blood 2007; 110: 3909–3916. EPCR binds to PC (and thrombin) 36

37. 37 wild type PC Modified, non anticoagulant PC Unfortunately, up to now, just in mice ! 37

38. 38 monti.giacomo@hsr.it Thanks !

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