• non specific insult
• must have two of following
  • fever or hypothermia (temp >38 or <36)
  • tachycardia (HR > 90)
  • tachypnea (RR > 20 or PaCO₂<32 or mechanical ventilation)
  • WBC > 12000 or <4000 or >10% immature forms

• infection with SIRS (usually positive blood cultures)

• altered organ function in an acutely ill pateints
• homeostasis cannot be maintained without intervention

• violate mechanical barriers
  • IV, intraarterial catheters
  • endotracheal intubation
  • urethral catheters
  • surgical wounds
  • invasive procedures
• obstruction of a viscus- prolif. usually proximal to obstruction with escape into blood stream
  • GI
  • biliary
  • urinary
• impaired host defense mechanisms
  • cytotoxic chemotherapy
  • immunodeficiencies
• prior antibiotic therapy changing microbial flora

• gram positive has become more common than gram negative
  • Staph the most common
  • coagulase negative staph cause bactermia in patients with indwelling IV catheters

• E coli
• other enterobacteria
  • Klebsiella
  • Enterobacter
  • Serratia
  • antibiotic resistant enterobacter species
    • Pseudomonas
    • Acinetobacter

• urinary tract
• lung (most common for severe infection)
• intraabdomnial source (second most common source for severe infection)

1. drop in afterload aka drop in systemic vascular resistance (due to vasodilation)
   • characteristic hemodynamic feature in septic shock
2. allows heart to pump greater volume, so CO and EF increase
3. however, vascular bed so dilated that the heart cant keep up with the demand
4. endotoxins will also decrease myocardial contractility
5. In the end, the CO cant keep up with the increased demands caused by the drop in SVR, leads to hypotension

Mech. of action of endotoxin causing humoral effects

1. endotoxin initiate complement cascade via the O polysac. (alternative path) or lipid A (classical pathway) leading to inflammation
2. initiates kinin pathway to produce bradykinin leading to hypotension
3. activates Hageman factor (via TNF damaged endothelial cells or directly) initiates coagulation pathway and fibrinolytic pathway leading to disseminated intravascular coagulation (DIC)

• macrophages and monocytes
• lymphocytes
• neutrophils
• endothelial cells

• IL-1- cause fever
• IL-6
• NO- vasodilator

• prostaglandins
• leukotrienes
• superoxide

• IL-1
• IL-6
• IL-8
• IL-12
• TNF alpha
• IFN alpha
• G-CSF
• beta chemokines

• IL-2
• IL-3
• IL-4
• IL-6
• IL-10
• IL-13
• IFN gamma
• GM-CSF

• TNF
• IL-1

• bone marrow transplants between endotoxin sensitive and resistant mice can change endotoxin sensitivity
  • endotoxin sensitive mice can be made endotoxin resistant via bone marrow transplant
• reticuloendothelial hyperplasia leads to increased endotoxin sensitivity
  • remember, TNF produced by endothelial cells
• supernatant from bone marrow cell culture of endotoxin stimulated macrophages obtained from endotoxin sensitive mice will cause shock and death in endotoxin resistant mice
• direct TNF injection lead to shock
• TNF produced by macrophages is in bone marrow

• toxins are superAg
• they will stimulate T cells to release cytokines

• sensed by TLR's as a mechanism for recognition of pathogens and presentation to cells
• ligands can be LPS, techoic acid, or any conserved microbial molecule
• Process
  1. LPS bind to LPS binding protein which binds to CD14 on phagocytic cells
  2. CD14 passes LPS to TLR, leading to activating the transcription factor nF-κB, signal transduction, and cytokine synthesis

• C5a will cause neutrophil agglutination and trapping of these clumps in the lungs
• in the lung, they cause production of oxygen radicals and lysosomal enzyme release that can damage endothelial cells
• if there is damage to the lung capilaries, we get ARDS

Remember, this is pulmonary complication of severe sepsis/shock

• TNF
  • increase capillary permeability
  • increased ICAM expression (increase adhesion molecules) on pulm. endotehlium
  • promote neutrophil sequestration through CD18 binding
• adhesion molecules (activate via TNF, IL-1, IL-8) promote neutrophils sticking to pulm. endothelial cells

• low- beneficial
• high- detrimental

Control the cytokine storm to take care of sepsis.

1. beginning of infection
   • eradicate microorganism
2. blood stream infection
   • neutralize microbial toxins
3. activation of mediators
   • modulate host response
4. shock and multiorgan failure
   • intensive life support

• anti-endotoxin Ab's
• monoclonal Ab's directed against TNF
  • TNF antagonists
• soluble TNF R's
  • bind TNF and prevent it from reaching bioactive receptors on cell

• glucocorticosteroids (high and low dose)
• IL-1 R antagonist
• monoclonal antibody to TNF
• anti CD14
• NO antagonists
• ibuprofen

• systemic activation of coagulation
• leads to:
  • intravascular depostion of fibrin causing microvascular thrombosis of small and midsized vessels causing organ failure (ischemia, infarction)
  • depletion of platelet and coagulation factors, causing bleeding

• antithrombin 3
  • inh. vitamin K dependent proteases (factors IX, X)
• activated protein C
  • inactivate factors V, VII

This is caused by a prolonged consumption leading to sustained procoagulant effect, causing inh. of fibrinolysis.

• treat with activated protein C
• prognosis- improvement in DIC and reduced mortality

• overproduction of proinflam. cytokines leads to an immunosuppresed response
• we keep failing because we also will produce an immunosuppressive response 
  • dominant cytokines in blood of septic pateints are antiinflammatory such as
    • IL-4 (makes Th2 and produced by Th2)
    • IL-10 (downregulates IL-1, 6, TNF alpha, IFN gamma, and promotes Th2 response)

THIS IS WHY THESE BACTERIA SURVIVE

• primary role of cytokines and chemokines is to localize and contain infection
• sepsis represents a system that is out of control
• the primary generalized host response is an attempt to down regulate inflammation

• anti-infective (release complement, PRM's, sequester Fe)
• anti-inflam (cytokine antagonists, steroids, antioxidants, protease inh.)
• procoagulant (wall of infection
• metabolic (mobilize fatty acids, maintain normal glucose)

• cellular SOS signal
  • epi induce IL-6 production in vivo
• infusion of IL-6 raise blood levels of IL-4, IL-1, cortisol
• IL-6 stimulate hypothalamic pit. axis
• IL-6 knockout mice have exagerated responses to bacterial challenge

• at normal concentrations, it allows for synthesis of acute phase pro-inflam. proteins
• at high conc., it suppreses these proteins and stimulates anti-inflam proteins like IL-10
  • downreg. IL-1, IL-6, TNF, and IFN gamma

• in later stages of sepsis, there is a shift from proinflam. Th1 response to anti inflam. Th2 response

• state of anergy
• promotes apoptosis, leading to an anti inflammatory response
  • if necrosis, this would enhance antimicrobial defenses
  • evidence- protease inhibitors will inhibit caspases, hence inhibit apoptosis, leading to improved survival in experimental sepsis by modulating production of pro and anti inflammatory cytokines (everything calms down)

• resp.- acute lung injury w/tachypnea and resp. alkalosis which can become ARDS
• renal- acute tubular necrosis secondary to hypotension
• GI- bacterial translocation due to apoptosis of mucosal cells
• hepatic dysfunction in two forms
  • cholestasis with decreased billirubin excretion
  • if shock severe, hepatocellular cell necrosis and liver failure
• hematologic
  • leukocytosis (if leukopenia, more severe)
  • thrombocytopenia (due to DIC or IgG)
  • coagulopathy

• myocardial dysfunction w/decreased contractility
• decreased vascular resistance

• glucose increased (increased gluconeogenesis in liver)
• lipids
  • decrease syn. of cholesterol
    • decrease LDL, HDL
  • TNF inh. of lipoprotein lipase
    • increased VLDL's, TG's
• increased lactate due to decreased tissue perfusion and acidosis