Transcript Protein C in children with sepsis

C protein
concentrates in
paediatric septic
patients
Giacomo Monti, MD
University Vita – Salute S.
Raffaele Milano
Department of
Anesthesia and Intensive
Care
[email protected]
2
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
3
Protein C
• CEPROTIN
(Human)
BAXTER
• XIGRIS
(Recombinant)
LILLY
• PC
• APC rhAPC
• Zymogen
• Enzyme
•
(human) protein C concentrate(s)
•
Activated protein C
•
Protein C zymogen (concentrate)
•
Drotrecogin alfa activated
4
5
PC in literature
• Extensive literature scan by PubMed, Embase,
Google Scholar
• Contact with expert
• Update to January 2009
6
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
Sepsis in children: US - 2
• Sepsis is the 2nd cause of death among children, 4th
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
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
9
Care Med 2008; 34:1690-7
“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.”
10
The “RESOLVE”
study
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).
Drotrecogin alfa (activated) in children with
severe sepsis: a multicentre phase III
randomised controlled trial. Nadel S et al.
Lancet 2007; 369: 836–43
11
Summary of all published papers
reporting on children patients
receiving protein C concentrates
Author
Gerson
Rivard
Smith
Rintala
Ettingshausen
Clarke
Leclerc
White
De Kleijn
Fourrier
Pettenazzo
Silvani
De Carolis
TOTAL
Year
1993
1995
1997
1998
1999
2000
2000
2000
2003
2003
2004
2005
2008
Journal
Pediatrics
J Pediatr
Lancet
Crit Care Med
Semin Thromb Hemost
Intensive Care Med
Crit Care Med
Blood
Crit Care Med
Intensive Care Med
Minerva Anestesiol
Minerva Anestesiol
Turk J Pediatr
N
1
4
12
3
8
1
2
36
30
15
8
11
1
131
12
Summary of all published papers
reporting on children patients
receiving protein C concentrates
Author
Gerson
Rivard
Smith
Rintala
Ettingshausen
Clarke
Leclerc
White
N
1
4
12
3
8
1
2
35
De Kleijn
Fourrier
Pettenazzo
Silvani
De Carolis
TOTAL
30
15
8
11
1
131
Setting
Meningococcal purpura fulminans
Meningococcal septic shock
Meningococcal septic shock
Meningococcal septic shock
Meningococcal septic shock
Meningoccal severe sepsis
Meningococcal septic shock
Septic shock and presumptive
meningococcemia
Severe sepsis or meningococcal disease
Meningococcal purpura fulminans
Septic shock
Severe sepsis or septic shock
Severe sepsis
Survival
1
4
12
2
6
1
2
33
23
6
6
8
1
103
(79%)
13
• Few papers account for
more than half of
published – treated
patients
• 3 “major” papers 78
children (59%)
14
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
Mean time to PC infusion begin in non amputated:
Mean time to PC infusion begin in amputated:
12 (3.1) h
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
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
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
De Kleijn, Crit Care Med 2003
• Only RCT, double blinde, • Fase two study (dose
PC vs placebo
findings, safety)
• 40 patients (10 placebo, • 1 placebo group
30 treatment)
• 3 treatment groups
• Meningoccemia and
incremental doses (50,
septic shock
100, 150 IU/kg/6h
19
Main findings
Mortality
Not powered to achieve a
significant result
No linear trend comparing
predicted versus
observed mortality
Fascinating result
compared to predicted
mortality
Group
PRISM
predicted
mortality
Actual
mortality
placebo
67%
20%
50 IU/kg
35%
9%
100 IU/kg
26%
11%
150 IU/kg
60%
50%
Overall
(drug)
40%
23%
Adapted from:
De Kleijn et al. Crit Care Med 2003; 31:1839-47
20
Main findings - 2
Dose response - PC
• Supplementation of PC is
effective
• Concentration is dose –
dependant
• 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
21
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
Main findings - 4
Safety
• 4 amputations (not
attributed to study
drugs)
• 1 not serious bleeding
event in a patient with
severe DIC
23
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
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
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
PC pathways
DYSFUNCTION OF ENDOTHELIAL PROTEIN C ACTIVATION IN
SEVERE MENINGOCOCCAL SEPSIS . Faust el al. NEJM 2001;
27
345:408-16
A-PC effect
2007
28
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
30
PC and endothelium
Three possible pathways:
• Lack of PC – EPCR interaction
• EPCR binds to
– Activated PC
– Not-activated PC
31
Lack of PC – EPCR interaction
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 etpatients
with
Liaw, PC
al. Patients
withsepsis.”
severe sepsis vary markedly in their ability
to generate
activatedR
protein
Blood.
2004;104:3958-3964
Lauterbach
et al.C.Eur
J Pediatr.
2006;165:585-9
Protein C concentrations in severe sepsis: an early directional change
in plasma levels predicts outcome. Shorr F et al. Crit Care. 2006; 10:
R92.
32
PC and endothelium
Three possible pathways:
• Lack of PC – EPCR interaction
• EPCR binds to
– Activated PC
– Not-activated PC
33
EPCR binds to a-PC
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
34
PC and endothelium
Three possible pathways:
• Lack of PC – EPCR interaction
• EPCR binds to
– Activated PC
– Not-activated PC
35
EPCR binds to PC (and thrombin)
The ligand occupancy of EPCR couples PAR-1 to
Gi protein
The ligand occupancy of endothelial protein C receptor
switches the protease-activated receptor 1-dependent
signaling specificity of thrombin from a permeabilityenhancing to a barrier-protective response in endothelial
cells. Jong-Sup et al. Blood 2007; 110: 3909–3916.
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
36
wild type PC
Modified, non anticoagulant PC
Unfortunately, up to now, just in mice !
37
Thanks !
[email protected]
38
39
39
For these and further slides on these
topics please feel free to visit the
metcardio.org website:
http://www.metcardio.org/slides.html