Transcript Acitvated Protein C in Severe Sepsis

Severe Sepsis and
Activated Protein C
Jeff Hurley MD
Perspective
• Most common cause of death in
medical and surgical ICUs (20-60%).
Approximately 225,000 cases of sepsis
which are fatal annually.
• Sepsis Syndrome represents a
systemic inflammatory response to
various insults.
• Severity is determined by alteration in
normal physiological parameters,
etiology, and response to treatment
Spectrum
SIRS
Severe Clinical insult manifested by 2 or more of the
following:

Temperature > 38°C or <36°C

Tachycardia > 90 beats/minute

Respiratory rate > 20 or PaCO2 < 32 mm Hg

White blood count > 12,000 or < 4,000 or > 10%
Bands
Sepsis
SIRS due to an infection (known or suspected—not
obligatory). Considered SEVERE if hypotension or
systemic manifestations of hypoperfusion (lactic acidosis,
oliguria, changes in mental status, ARDS, hypoxemia PaO2
< 72 on RA) is present.
Septic
Shock
Sepsis induced hypotension (SBP < 90, reduction of > 40
mm Hg from baseline) despite adequate fluid resuscitation
that requires pressors to maintain normotension, along
with perfusion abnormalities that may induce lactic
acidosis, oliguria, or changes in mental status.
MODS
The presence of altered organ function in an acutely ill
patient such that homeostasis cannot be maintained
without intervention.
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Pathophysiology
Normal responses to insults result in the development of:
1.
2.
3.
Inflammatory response
Thrombotic response
Anti-Fibrinolytic response
Pathophysiology
• Infectious process
• Mobilization of
PMNs and Monos
• Creation of
inflammatory
cytokines
triggering a
casade. Noteably:
IL-1, TNF, IL-6.
• Innappropriate
regulation or
ongoing stimulation
of pathway (LPS,
peptidoglycan,
lipotoeichoic acid,
super antigens)
• Resulting in Sepsis
Treatment
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Many therapeutic interventions
have been attempted.
1.
2.
3.
4.
5.
6.
Anti-endotoxin
Mabs against TNF
Bradykinin antagonists
PAF antagonists
Prostaglandin antagonists
IL-ra
None have shown a benefit over
placebo.
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Activated Protein C
Protein C is a vitamin K dependent endogenous protein that is a
regulator of the inflammatory, coagulation, and fibrinolytic
pathways.
Under normal conditions, the generation of Thrombin (IIa) is
balanced by the combination of thrombin with thrombomodulin. This
combination converts the inactive precursor to the activated from of
the protein. Evidence suggests that in sepsis, then is a cytokine
induced decrease in thrombomodulin.
APC then degrades factors VIIIa and Va, both cofactors in the
coagulation cascade. Hence, APC acts as an antithrombotic.
APC, through decreased Thrombin levels, decreases the release of
Plasminogen activator inhibitor-1 resulting in an increase in plasmin
generation. Hence, APC acts an a pro-fibrinolytic.
APC, through in vitro studies, has also shown to decrease the
production of inflammatory cytokines such as IL-1, IL-6, and TNF.
Hence, APC acts as an anti-inflammatory. Also shown to decrease
selectin-mediated adhesion.
Other avenues: Factor XII activation leads to kallikrein activation.
Kallifrein then cleaves kininogen to the vasoactive peptite
bradykinin which has been related to the iNOS (inducible nitric oxide
system) system.
Sepsis also is suspected to alter mitochondrial function.
Study Summary
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Randomized, double-blinded, placebo-controlled, multicenter
trial.
1690 enrolled patients
Inclusion criteria: 3 out of 4 SIRS plus 1 out of 5 of the
following:
1.
2.
3.
4.
5.
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Hypotension unresponsive to fluids
Oliguria
ARDS criteria Pao2 to FiO2 < 250
Hematologic disorder platelets < 80,000 or 50% decrease in 3 days
Metabolic acidemia < 7.30 or base deficit > 5 with plasma lactate >
1.5 normal levels
Exclusion criteria: Pregnancy, age <18, Platelets < 30,000,
conditions that increased risk of bleeding, others.
Randomized to APACHE II
Measure: Survival at 28 days.
Delivery: 96 hour infusion of APC at 24 ug/kg/hr. No dosage
adjustment of age, gender, hepatic or renal dysfunction.
Results
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Study stopped early.
Relative risk reduction of 19.4% with an absolute reduction of 6.1%
Number needed to treat: 16.4
Physiology
• Reduction in D-Dimer, a measure of intravascular
thrombus formation.
• Reduction in IL-6 levels.
Complications
• Bleeding was the most serious complication 3.5%
in study group versus 2.0% in placebo.
• Occurred predominately in those predisposed to
bleeding.
• 1 serious bleeding event for every 66 patients
treated.
• Contraindications: Internal bleeding, recent
hemorrhagic stroke, recent brain surgery or severe
head trauma, trauma, epidural catheter,
intracranial neoplasm or mass lesion.
• Predisposed: INR > 3.0, platelets < 30,000, heparin
infusion, recent GI bleed, recent thrombolytic use,
recent G IIb/IIIa inhibitors, recent aspirin or other
antiplatelet, recent ischemic stroke, AVM or
aneurysm, severe hepatic disease.
Legal Isssues in Sepsis
• Failure to recognize SIRS criteria or potential
sources of infection.
• Failure to take unstable patients to surgery to treat
infectious processes.
• Insufficient fluid resuscitation or failure to institute
vasoactive drugs or mechanical ventilation.
• Incorrect sequence of pressors such as single use
epinephrine that impairs splanchnic blood flow and
perfusion.
• Excessive use of pressors to supranormal cardiac
output that has shown to increase morbidity and
mortality.
• Administration of bicarbonate therapy that worsens
intracellular acidosis.
Summary
• APC (drotrecogin alfa) indicated
for the reduction of mortality in
Severe Sepsis who have a high
risk of death.
• Absolute reduction in mortality
of 6.1%
• Standard of Care?