Transcript Diapositiva 1 - metcardio.org

“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.
3
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
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
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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

XIGRIS
(Recombinant)
LILLY

PC

APC

Zymogen

Enzyme

(human) protein C concentrate(s)

Activated protein C

Protein C zymogen (concentrate)

Drotrecogin alfa activated
rhAPC
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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
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ADULT PATIENTS AND CEPROTIN
CASE SERIES SEPSIS
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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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Summary of all published papers reporting on adult
patients receiving protein C concentrates
Author
Landoni G
Year
2009
Journal
Signa Vitae
N
2
Crivellari M
Baratto F
Tuttolomondo A
2008
2008; 2004
2008
Siaarti congr. 2008
Intensive Care Med
Intern Emerg Med
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2
Schellongowski P
Fourrier F
Makris PE
2006
2003
2003
Vox Sang
Intensive Care Med
J Thromb Haemost
<8
<5
7
Vaccarella G
Rintala E
TOTAL
2003
2000; 1998
Minerva Anestesiol
Critical Care Med
1
12
<66
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Summary of all published papers reporting on
adult patients receiving protein C concentrates
Author
Setting
Survival
Landoni G
Sepsis
100%
Crivellari M(18)
Sepsis after cardiac surgery
89%
Baratto F(19)
Sepsis (10 surgical and
medical patients)
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
10 65%
46/66=70%
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Summary of all published papers reporting on
adult patients receiving protein C concentrates
Author
Bolus dose
Following doses
Landoni G
50 IU /kg
3 IU/kg/h
Crivellari M
50 IU /kg
3 IU/kg/h
Baratto F
(100 – PC plasma level) x According to plasma levels
body weight (Kg)
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 STUDIES
ADULT PATIENTS AND CEPROTIN
WWW.CLINICALTRIALS.GOV
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CEPROTIN IN CHILDREN
Author
PATIENTS
dose
Clarke
1
100 IU/kg x 3/day
De Carolis
1
unknown dosage, for 96 hours
De Kleijn
20
Ettingshausen
50, 100, 150 IU/kg 6-12 h
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
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ONGOING STUDIES
PAEDIATRIC 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 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.
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Pathogens
Site 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
?
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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
140
120
100
mean - standard deviation
80
mean
60
mean + standard deviation
40
20
0
T0
T6
T18
T30
T42
Times
T54
T66
T78
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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, eselectin didn’t show any modification.

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Figure 4
250
1200
1000
p = 0.63
IL-6, ng/ml
e-SELECTIN, ng/ml
300
200
150
100
50
0
400
0 12 24 36 48 60 72 84 96
HOURS
600
p = 0.001
150
100
50
500
IL-10, ng/ml
IL-8, ng/ml
600
0
0 12 24 36 48 60 72 84 96
HOURS
200
0
800
200
300
250
p < 0.0001
p < 0.0001
400
300
200
100
0 12 24 36 48 60 72 84 96
HOURS
0
0 12 24 36 48 60 72 84 96
HOURS
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Are you still with me?
All of you?
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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%)
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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


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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
Baratto F(19)
(100 – PC plasma level) x 3 IU/kg/h + adjusting
body weight (Kg)
according to plasma levels
3 IU/kg/h
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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.

15.650 IU (3700 IU)
Baseline values
24 h after bolus
End of treatment
BARATTO ET AL

41+24%
94+18%
90+26%
19.065 IU (bolus 4.500 IU)
Baseline values
24 h after bolus
End of treatment
34+9%
75+26%
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 postoperative 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 MESSAGE
CARDIAC 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 RCTs
TOPICS
HOSPITALS PATIENTS
GRANTS

VOLATILE
ANESTHETICS

4
200
AIFA 2006

FENOLDOPAM

34
1.000
MINISTRY 2008

DESMOPRESSIN

3
200

ESMOLOL
LEVOSIMENDAN
VALVOLE PERCUTANEE

3
10
3
200
1.000
150




[email protected]
www.itacta.org
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