Venk Septic Shock

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Systemic inflammatory response syndrome (SIRS)

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any two of the following conditions or symptoms:
• T > 38°C or T < 36°C
• HR > 90 (bpm)
• Respiratory rate > 20 bpm or PaCO2 < 32 mm Hg
• White blood cell count > 12,000/µL, < 4000/µL is a clinical response or systemic response due to unknown reasons leading to inflammation.

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sepsis levels

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1. sepsis: Systemic inflammatory response syndrome due to infection
2. severe sepsis: Sepsis leading to multi-organ failure
3. septic shock: Sepsis resulting in hypotension which cannot be corrected by IV fluids

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septic shock

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1. Sepsis and septic shock are major health problems worldwide; death toll in 6 figure numbers.
2. In recent years increased incidence of sepsis or septic shock due to increases in numbers of
a. elderly people
b. immuno-compromised individuals arising due to AIDS and immunosuppressive drugs.
c. extended stay in the hospital
d. indwelling catheters and implants.
3. 50% deaths in Intensive care units; more than 200, 000 people die ; much more than deaths due to AIDS or mycoardial infarction.

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endotoxin VS exotoxin

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To a great extent sepsis is due to infection by GN bacteria; endotoxin or LPS that forms an important cell wall of GN bacteria
1. ENdotoxin by gram negative bacteria VS EXotoxins by gram positive bacteria. Endotoxin: cell wall constituent
2. ENdotoxins: lipopolysaccharide VS EXotoxins: polypeptides.
3. genes for ENdotoxins/LPS in chromosomal DNA VS EXotoxins by genes in the plasmid
4. ENdotoxins are weakly immunogenic; LPS released during infection with GN bacteria may not induce a protective B cell or T cell response; chances of recurrent infection. EXotoxins: immunogenic; given as vaccines.
5. In septic shock: bacteria can be detected in the blood VS exotoxin mediated shock: toxin that is detected in the blood
6. TX of septic shock patients with antibiotics control the infection but cannot be subdue the inflammation completely. b/c the inflammation is mediated by TNF-α, other cytokines by LPS.

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LPS or endotoxin

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1. LPS or endotoxin: part of the cell wall of GN bacteria.
2. The lipid A: phospholipid; inflammatory events that result in septic shock; one common fatty acid: myristic acid.
3. The polysaccharide core protrudes from the bacterial surface and has five sugar molecules. Bacteria in same species have similar sequence of sugars in the polysaccharide core.
4. The O antigen: component of LPS and is similar in bacteria belonging to the same strain

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Pathogenesis in septic shock (by lipid A) part 1

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1. During infection with GN bacterial breaks epithelial barrier, LPS binds to LPS binding protein released by host. LPS + LPS-binding protein complaex, now binds to the toll like receptor 4 (TLR-4) that is expressed on the surface of monocytes and macrophages
2. TLR are pattern recognition receptors (PRR) on the cell surface of monocytes, macrophages and dendritic cells; PRR help the innate immune system to distinguish self from foreign. T cells vs B cells that are highly specific
3. more than 10 different toll like receptors
4. TLR4 is co-expressed w/ CD14: specific for LPS; TLR4 and
5. CD14 connected to a cytoplasmic adaptor molecule called MD2
6. LPS binds to LPS binding protein
7. LPS-LPS binding protein binds to CD14 expressed on monocytes.
8. activation and signaling of MD2
9. MD2 in turn activates TLR4

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Pathogenesis in septic shock (by lipid A) part 2

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1. Activation of TLR 4 leads to downstream signaling --> expression of NFκB
2. NFκB binds to the nucleus and induces the synthesis of TNF-α
3a. normal concentrations TNF-α protects the host by inducing granuloma formation during M. TB
3b. Excess production of TNF-α in conjunction with other cytokines such as IL-1 and IL-6 induce septic shock; cause cachexia (muscular wasting), anorexia (lack of appetite) and inflammation;
4. in conjunction with IL-1 causes hyperpyrexia (that is elevating the body temperature). These cytokines act on hypothalamus and induce prostaglandin synthesis leading to increase in body temperature

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other effects of TNF-α: NO production

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1. enhance nitric oxide production and nitric oxide causes hypotension
2. Nitric oxide produced from precursor L-arginine. by nitric oxide synthase
3. Nitric oxide synthase exist in three isoforms:
a. endothelial nitric oxide synthase (eNOS); endothelial cells
b. neuronal nitric oxide synthase (nNOS)
c. inducible nitric oxide synthase (iNOS or NOS2); in Mphage
4. In septic shock, increased levels of TNF-α activates iNOS and eNOS
5. This result in nitric oxide production: vasorelaxation and hypotension
6. TNF-α also induces synthesis of bradykinins; induce hypotension by enhancing nitric oxide production

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TNF- α (DIC)

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1. TNF- α enhances the expression of tissue factor (TF) on monocytes and neutrophils
2. Tissue factor triggers clotting by extrinsic pathway
3. Tissue factor + factor VIIa --> entire complex activates factor X; prothrombin --> thrombin; fibrinogen --> fibrin
4. Protein C: enhances fibrinolytic activity by
a. neutralizing the effects plasminogen activator inhibitor and
b. enhancing the activity of plasminogen activator (a serine protease) that converts plasminogen --> plasmin: fibrinolytic activity. They break the clot and hence prevent disseminated intravascular coagulation
5. TNF-α REduces the levels of protein C and plasminogen activator and ENhances the levels of plasminogen activator inhibitor; favoring disseminated intravascular coagulation, vascular collapse, multi-organ failure and death

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Changes in the endothelial cells (part 1)

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1. During septic shock; substantial changes under the influence of cytokines and contribute to the development of hypotension, DIC, vascular permeability and inflammation
2. impacted by the cytokines such as TNF- α and IL-6 that are released during endotoxemia
3. induces the expression and synthesis of endothelial nitric oxide synthase enzyme in endothelial cells; Nitric oxide released causes hypotension; bradykinin is released induce endothelial nitric oxide synthase expression
4. TNF-α also induces the expression of P-selectin and E-selectin on endothelial cell surface; binding of leukocytes to the selectin --> rolling and leaving the blood vessels to the site of infection to induce inflammation; by the following mechanism
a. LPS can directly activate the complement by alternate pathway
b. Complement are series of serum proteins or serine proteases that contribute to innate defenses, inflammation, opsonization and vascular permeability

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changes in the endothelial cells part 2:
alternate pathway of complement by LPS

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1. directly binding to the a. C3 b. Factor B.
2. Factor D then acquires proteolytic activity and acts on C3-Factor B complex generating C3Bb
3. This complex keeps adding C3b, acquires C5 convertase activity; C5 --> C5a, C5b
4. C5b + C6,7, 8, 9 form membrane attack complex creating small pores on the cell wall causing osmotic imbalance and cell lysis
5. dead endothelial cells found in the circulation during septic shock; histology show endothelial cells swollen due to inflammation
6. C5a functions as an anaphylotoxin. It acts on mast cells and basophils and induce the release of histamine
a. Histamines enhance vascular permeability; allowing leukocytes to leave the circulation and to the extravascular spaces to induce inflammation
b. endothelial cells express P-selectin and E-selectin on surface by TNF-α
c. This facilitates binding of leukocytes and gentle rolling while being attached

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changes in the endothelial cells part 3

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1. endothelial cells die --> clotting factor XII + collagen along with prekallikrien initiation intrinsic pathway of clotting cascade
2. Factor XII x/ kallikrein convert factor XI --> XIa acts on IX w/ VIIIa to generate IXa
3. IXa activates factor X which converts prothrombin --> thrombin
4. Thrombin converts fibrinogen --> fibrin; intravascular coagulation
5. TNF-α DEcreases the levels of Protein C and plasminogen activator and INcreases the levels of plasminogen activator inhibitor; MORE coagulation and LESS fibrinolytic activity
6. Small fibrin particles called D-Dimers can be detected in the circulation
7. multi-organ failure and death if untreated
8. characteristics of septic shock

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Toxic shock syndrome

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1. Infection with some GP bacteria; mimic septic shock: toxic shock syndrome instead of septic shock
2. GP bacteria; no LPS: peptidoglycan on their cell wall
3. toxic shock syndrome are caused by peptidoglycan and lipotechoic acid, a product of peptidoglcan
4. During infection with Gram positive bacteria; peptidoglycan or techoic acid will bind to toll receptor 2; downstream signaling leading to TNF-α production
5. TNF-α, super-antigen mediates the inflammatory events that culminate in shock; Super-antigens are produced by S. aureus and other microbes
6. super-antigen does not require processing by antigen presenting cells
7. Super-antigens superficially bind to the MHC class II molecules expressed on the cell surface of the antigen presenting cells
8. The other end of the super-antigen will bind to the Vβ−region of T cell receptor and trigger the immune response
9. The immune response is so robust that it can lead to death. The inflammatory events are similar to that of septic shock
10. Small quantities of super-antigen is sufficient