1 “protein c zymogen as adjuvant treatment of severe sepsis in heart surgery patients.” 9°...

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“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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BACKGROUND IN ADULT SEPTIC PATIENTS

XIGRIS (activated C protein) reduces mortality in adult patients with APACHE score >24 or double organ failure.

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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

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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

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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

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ADVERSE REACTIONS

6 modest allergic reactions among 21.988 doses of ceprotin

Bleeding complication: NEVER REPORTED

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NAMES

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

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ADULT PATIENTS AND CEPROTIN

CASE SERIES SEPSISCrivellari M et al. Safe administration of protein C concentrate in patients with sepsis at high risk

for bleeding. SMART 2008 submittedBaratto 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

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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

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Author Year Journal N

Landoni G 2009 Signa Vitae 2

Crivellari M 2008 Siaarti congr. 2008 9

Baratto F 2008; 2004 Intensive Care Med 20

Tuttolomondo A 2008 Intern Emerg Med 2

Schellongowski P 2006 Vox Sang <8

Fourrier F 2003 Intensive Care Med <5

Makris PE 2003 J Thromb Haemost 7

Vaccarella G 2003 Minerva Anestesiol 1

Rintala E 2000; 1998 Critical Care Med 12

TOTAL <66

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

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Author Setting SurvivalLandoni G Sepsis 100%

Crivellari M(18) Sepsis after cardiac surgery 89%

Baratto F(19) Sepsis (10 surgical and 10 medical patients)

65%

Tuttolomondo A(20) Meningitis 100%

Schellongowski P(21) Purpura fulminans 75%

Fourrier F(22) Purpura fulminans 40%

Makris PE(23) DIC 71%

Vaccarella G(24) Purpura fulminans 100%

Rintala E(25, 26) Purpura fulminans 58%

TOTAL 46/66=70%


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Author Bolus dose Following dosesLandoni G 50 IU /kg 3 IU/kg/h

Crivellari M 50 IU /kg 3 IU/kg/h

Baratto F (100 – PC plasma level) x body weight (Kg)

According to plasma levels

Tuttolomondo A Various Various

Schellongowski P Various Various

Fourrier F 100 IU/Kg 100 IU/Kg/day

Makris PE Various Various

Vaccarella G 80 IU/kg 2000 IU every 4h * 4days

Rintala E 100 IU/Kg 100 IU/Kg every 6 hours

TOTAL


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ONGOING STUDIESADULT PATIENTS AND CEPROTIN

WWW.CLINICALTRIALS.GOV

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Author PATIENTS doseClarke 1 100 IU/kg x 3/day

De Carolis 1 unknown dosage, for 96 hours

De Kleijn 20 50, 100, 150 IU/kg 6-12 h

Ettingshausen 8

Fourrier 100 IU/kg bolus x4/die

Leclerc 2 100 IU/kg day

Pettenazzo 8 100 IU/kg bolus, 80-100 IU/kg every 6-12 h upon plasma dosing PC

Rintala 3 100 UI/kg x4/die

Rivard 4 100 UI/kg x4/die

Silvani 11 mean 324 UI/kg/day (66-400)

Smith 30 100 IU/kg bolus, 10-15 IU/kg/h continuously

White 36 100 IU/kg as loading dose and continous infusion 10 IU/kg/h. After 24h titrated to a plasma PC level 80-120 IU/ml

TOTAL 124

CEPROTIN IN CHILDREN

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ONGOING STUDIESPAEDIATRIC PATIENTS AND CEPROTIN

WWW.CLINICALTRIALS.GOV

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CARDIAC SURGERY

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CARDIAC OUTPUT AFTER CARDIAC SURGERY

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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

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9 PATIENTSBaseline 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.

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Pathogens Site of infection

negative blood culture ?

Enterobacter Cloacae PNEUMONIA

Acinetobacter Baumanii, Klebsiella Pneumofila PNEUMONIA

Acinetobacter Baumanii, Citrobacter Braakii PNEUMONIA


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


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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.

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

PROTEIN C

0

20

40

60

80

100

120

140

T0 T6 T18 T30 T42 T54 T66 T78

Times

mean - standard deviation

mean

mean + standard deviation

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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.

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Figure 4

0 12 24 36 48 60 72 84 96HOURS

0

50

100

150

200

250

300e-

SE

LE

CT

IN, n

g/m

l

0 12 24 36 48 60 72 84 96HOURS

0

200

400

600

800

1000

1200

IL-6

, ng/

ml

0 12 24 36 48 60 72 84 96HOURS

0

50

100

150

200

250

300

IL-8

, ng/

ml

0 12 24 36 48 60 72 84 96HOURS

0

100

200

300

400

500

600

IL-1

0, n

g/m

l

p = 0.63 p < 0.0001

p = 0.001 p < 0.0001

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Are you still with me?

All of you?

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RESULTSPredicted mortality of 68%. APACHE II (24+3) SAPS II (60+5)

In our case series mortality at 30 days was 1/9 (11%)

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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

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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

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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.

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PCc DOSES IN ADULTS

Crivellari M(18) 50 IU /kg 3 IU/kg/h

Baratto F(19) (100 – PC plasma level) x body weight (Kg)

3 IU/kg/h + adjusting according to plasma levels

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PCc DOSES IN ADULTSThe 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

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%

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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

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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.

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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

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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.

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ITACTA ONGOING RCTsTOPICS HOSPITALS PATIENTS GRANTS

VOLATILE ANESTHETICS

FENOLDOPAM

DESMOPRESSIN

ESMOLOL LEVOSIMENDAN VALVOLE PERCUTANEE

[email protected]

4 200 AIFA 2006

34 1.000 MINISTRY 2008

3 200

3 200 10 1.000 3 150

For these and further slides on these topics please feel free to visit the

metcardio.org website:

http://www.metcardio.org/slides.html

1 “protein c zymogen as adjuvant treatment of severe sepsis in heart surgery patients.” 9°...

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