Severe Sepsis and Activated Protein C

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Severe Sepsis and Activated Protein C

• Jeff Hurley MD

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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

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Spectrum
SIRS Severe Clinical insult manifested by 2 or more of the following Temperature gt 38C or lt36C Tachycardia gt 90 beats/minute Respiratory rate gt 20 or PaCO2 lt 32 mm Hg White blood count gt 12,000 or lt 4,000 or gt 10 Bands
Sepsis SIRS due to an infection (known or suspectednot obligatory). Considered SEVERE if hypotension or systemic manifestations of hypoperfusion (lactic acidosis, oliguria, changes in mental status, ARDS, hypoxemia PaO2 lt 72 on RA) is present.
Septic Shock Sepsis induced hypotension (SBP lt 90, reduction of gt 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
• Inflammatory response
• Thrombotic response
• Anti-Fibrinolytic response

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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

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(No Transcript)
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Treatment

• Many therapeutic interventions have been
  attempted.
• 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.

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Study Summary

• 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
• Hypotension unresponsive to fluids
• Oliguria
• ARDS criteria Pao2 to FiO2 lt 250
• Hematologic disorder platelets lt 80,000 or 50
  decrease in 3 days
• Metabolic acidemia lt 7.30 or base deficit gt 5
  with plasma lactate gt 1.5 normal levels
• Exclusion criteria Pregnancy, age lt18,
  Platelets lt 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.

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Results

• Study stopped early.
• Relative risk reduction of 19.4 with an absolute
  reduction of 6.1
• Number needed to treat 16.4

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Physiology

• Reduction in D-Dimer, a measure of intravascular
  thrombus formation.
• Reduction in IL-6 levels.

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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 gt 3.0, platelets lt 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.

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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.

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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?