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Questions and Answers
What is the earliest stage of sepsis as per the revised classification?
Which cytokine response is primarily responsible for causing systemic illness in sepsis?
What characterizes severe sepsis compared to regular sepsis?
Which of the following is the most common cause of sepsis?
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What is a potential consequence of the anti-inflammatory response during sepsis?
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What is a key feature of early diffuse alveolar damage?
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Which of the following is a characteristic finding in patients with COVID-19 related complications?
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What pathological change occurs due to cytokine-induced myocardial dysfunction in sepsis?
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In severe sepsis, which mechanism is primarily responsible for contributing to shock?
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What role does the liver play in metabolic processes during sepsis?
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Which type of infection is most frequently associated with septic shock in the US?
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What molecules are recognized by the innate immune system as part of the sepsis response?
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What is the primary transcription factor activated during the sepsis inflammatory response?
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Which type of bacteria is commonly associated with the release of superantigens that can induce septic shock?
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What systemic effect results from the production of inflammatory cytokines during sepsis?
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Which complement component is mentioned as playing a role in further enhancing the proinflammatory state during sepsis?
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What kind of damage can trigger the release of DAMPs associated with sepsis?
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What is the primary factor that induces coagulation in Sepsis-Induced Coagulopathy (SIC)?
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What happens to endothelial anticoagulant factors during SIC?
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What is a key consequence of excessive consumption of coagulation factors during SIC?
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Which process contributes to organ damage in the context of SIC?
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Which clinical manifestation results from the presence of fibrin nets within the microvasculature?
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What results from the simultaneous activation of coagulation and fibrinolysis in SIC?
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What is the role of leukotrienes in the context of SIC?
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Which condition is a direct result of diffuse alveolar damage due to sepsis?
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How does the activation of coagulation systems during SIC lead to organ hemorrhage?
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What activates the coagulation pathways in smaller vessels during SIC?
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Which type of bacterial infection is most frequently associated with septic shock in the United States?
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What are PAMPs primarily recognized as by the innate immune system?
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What is the primary function of NF-κB during the sepsis inflammatory response?
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Which component is mentioned as a proinflammatory mediator that can further activate endothelial cells during sepsis?
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What type of molecules are DAMPs, and what triggers their release?
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What is the primary distinction between sepsis and severe sepsis?
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What is a result of the internal civil war between pro-inflammatory and anti-inflammatory forces during sepsis?
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Which stage of sepsis is characterized by multi-organ damage and the need for pressors to maintain blood pressure?
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Which factor contributes to the systemic illness associated with sepsis?
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What is the most common initial infection leading to sepsis?
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Study Notes
Sepsis Definition
- Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection.
- The body's response to infection with release of pro-inflammatory and anti-inflammatory cytokines, mediators and adaptive bioenergetic changes.
Stages of Sepsis
- Early stage (SIRS): Non-specific symptoms like fever and malaise.
- Severe stage (Sepsis): Hypotension and organ dysfunction.
- Septic shock: Severe hypotension requiring pressors to maintain blood pressure and multi-organ damage.
Sepsis Causes
- Most common: Bacterial pneumonia, followed by UTI and intra-abdominal infections.
- Caused by both gram-positive and gram-negative bacteria.
- Gram-positive bacteria most commonly trigger septic shock in the US, followed by gram-negative bacteria and fungi.
Sepsis Pathogenesis
- The innate immune system responds to PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns).
- PAMPs recognize parts of pathogens, like LPS in gram-negative bacteria or peptidoglycan in gram-positive bacteria.
- DAMPs are released from necrotic cells due to infection, trauma, chronic disease, or infarction.
- Superantigens are bacterial proteins that cause massive cytokine release, leading to polyclonal T-cell activation, examples include toxic shock syndrome toxin from Staphylococcus aureus and streptococcal pyrogenic exotoxin from Streptococcus pyogenes.
- PAMPs and DAMPs activate receptors like TLRs and NLRs.
- This activation triggers neutrophils and monocytes to produce NF-κB, a transcription factor that initiates the production of inflammatory cytokines such as IL-1, TNF-α, IL-6, IFN-γ.
- Inflammatory cytokines cause direct systemic effects, vasodilation, increased permeability, decreased perfusion, and immunosuppression due to secondary anti-inflammatory mediators.
- Some organisms activate complement.
- Complement components like C3a cause endothelial activation and proinflammatory state.
- Other components upregulate immune cells and act as chemoattractants.
- PAMPs also induce factor XII for coagulation, leading to microvascular thrombus, DIC/SIC, and tissue ischemia.
- TGF-β and leukotrienes are produced to modulate and turn down inflammation.
Sepsis-Induced Coagulopathy (SIC)
- Similar to DIC but induced by sepsis.
- TNF-α activates endothelial cells, stimulating coagulation pathways in smaller vessels.
- Endothelial anticoagulant factors like TFPI, thrombomodulin, and protein C are decreased.
- Fibrinolysis is also decreased due to increased PAI-1 expression.
- Systemic activation of coagulation systems leads to widespread thrombosis and fibrinolysis.
- Consumption of coagulation factors due to fibrinolysis results in bleeding.
- Thrombosis, bleeding, petechiae, purpura, and organ hemorrhage can occur.
Neutrophil Extracellular Traps (NETs)
- Neutrophils release NETS to trap and contain microorganisms.
- NETS can damage endothelial cells and stimulate coagulation through both intrinsic and extrinsic coagulation pathways.
- NETS can traumatize blood cells, leading to schistocytes (torn up red blood cells) and microangiopathic hemolytic anemia.
Sepsis and Acute Respiratory Distress Syndrome (ARDS)
- Diffuse alveolar damage leads to ARDS.
- Damage is caused by neutrophil and cytokine-induced damage to pulmonary endothelium and epithelium.
- Clinical respiratory failure occurs with decreased PaO2/FiO2 and pulmonary infiltrates.
- Stages:
- Early: Increased vascular permeability and marked pulmonary edema.
- Intermediate: Type 1 pneumocyte epithelium is lost, forming hyaline membranes and type two pneumocyte hyperplasia.
- Late: Fibrosis.
COVID-19 and Sepsis
- Hypercoagulative state skewed towards thrombosis.
- Multiple thrombi in small pulmonary arteries.
- System deep venous thromboses.
- Pulmonary emboli.
- Consumption of coagulation factors and low platelet count.
- Bleeding less frequently found compared to ordinary DIC.
- Very high D-dimers are characteristic.
Sepsis and Cardiac Dysfunction/Failure
- Cytokine-induced damage, hypoperfusion, mitochondrial dysfunction, and myocardial cell adaptation.
- Cardiac cells may shut down to conserve energy, leading to decreased contractility and peripheral vasodilation, exacerbating hypoperfusion and ischemia.
- Myocardial ischemia, necrosis, and infarction can occur.
- Coagulative necrosis (ischemic).
- Contraction band necrosis (pressor effect).
- Reperfusion injury with oxygen free radicals.
- Contributes to shock.
- Nitric oxide plays a major role in the development of septic shock, acting as an antimicrobial and anti-inflammatory agent, but also a potent vasodilator.
Sepsis and Liver Dysfunction/Failure
- Liver is important for gluconeogenesis and Acetyl-CoA production.
- Early sepsis: Hyperglycemia.
- Late sepsis: Liver failure and hypoglycemia.
- Hepatic enzymes release from necrotic cells, leading to elevated lactic dehydrogenase (LDH).
- Centrilobular necrosis (Zone 3 necrosis) is prominent.
Sepsis and Kidney Dysfunction/Failure
- Multi-organ failure is caused by cytokine and neutrophil-induced injury, ischemia, cell adaptive changes, and mitochondrial functional changes.
- Blood flow shunting occurs.
- Acute tubular necrosis with coagulative necrosis of the proximal tubule can be seen.
- Profound hypotension contributes to kidney damage.
- Edema and clinical renal failure occur.
Lactic Acidosis
- Lactic acidosis (>2 mmol/L) is not specific for sepsis.
- Other factors such as medications, liver failure, severe exercise, toxins, trauma, and various others can cause lactic acidosis.
- Lactic acidosis (>= 4 mmol/L) indicates a critically ill patient with a poor prognosis, but not specific for sepsis.
- Utility of serial lactate measurements and therapy targeting specific levels is controversial.
Shock
- Systolic BP is determined by the pressure built up during contraction.
- Diastolic pressure is the pressure remaining when the heart relaxes.
- Mean arterial pressure (MAP) is calculated as 1/3 (systolic - diastolic) + diastolic.
Sepsis Definition & Stages
- Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection.
- Sepsis is not the same as SIRS (Systemic Inflammatory Response Syndrome) and severe sepsis terms are no longer utilized.
- Three stages of sepsis:
- Early stage (SIRS): Non-specific symptoms like fever and malaise.
- Severe stage (Sepsis): Hypotension and organ dysfunction.
- Septic shock: Severe hypotension requiring pressors to maintain blood pressure and multi-organ damage.
- The body's reaction to infection involves a combination of pro-inflammatory and anti-inflammatory cytokines, mediators, and adaptive bioenergetic changes.
- Pro-inflammatory forces can lead to systemic illness, multi-organ dysfunction, and shock if not treated promptly.
- Anti-inflammatory forces can help control inflammation, but can also lead to immunosuppression and superinfection.
Sepsis Triggers & Mechanisms
- Common causes of sepsis:
- Bacterial pneumonia (most common).
- Urinary tract infections.
- Intra-abdominal infections.
- Gram-positive bacteria are more common in the US, while gram-negative bacteria are more common in Europe.
- The innate immune system recognizes different molecular patterns:
-
PAMPs (Pathogen-Associated Molecular Patterns): Recognize parts of the pathogen.
- Examples: LPS (gram-negative bacteria), peptidoglycan (gram-positive bacteria), microbial toxins.
-
DAMPs (Damage-Associated Molecular Patterns): Molecules derived from necrotic cells.
- Damage can come from: infection, trauma, chronic disease, infarct.
-
Superantigens: Bacterial proteins (usually toxins) that cause polyclonal T-cell activation leading to massive cytokine release.
- Examples: Staph aureus (toxic shock), Strep pyogenes.
-
PAMPs (Pathogen-Associated Molecular Patterns): Recognize parts of the pathogen.
- PAMPs and DAMPs bind to their respective receptors (TLR, NLRs, etc.)
- This activates neutrophils and monocytes, leading to the creation of NF-κB.
- NF-κB initiates the production and secretion of inflammatory cytokines like IL-1, TNF-alpha, IL-6, IFN-gamma, and others.
- These cytokines cause systemic effects, vasodilation, increased permeability, and immunosuppression.
- Some organisms (PAMPs) activate the complement system.
- Complement components (like C3a) can cause endothelial activation and induce a proinflammatory state.
- Other complement components stimulate various immune cells and act as chemoattractants.
- PAMPs can also induce factor XII for coagulation through altered endothelial function.
- This leads to microvascular thrombus (DIC/SIC) and tissue ischemia.
- To counter excessive inflammation, TGF-beta and leukotrienes are produced.
Sepsis-Induced Coagulopathy (SIC)
- This is like DIC (Disseminated Intravascular Coagulation) but induced by sepsis.
- Pro-inflammatory cytokines (like TNF-alpha) activate endothelial cells and stimulate coagulation pathways, particularly in smaller vessels.
- They decrease production of endothelial anticoagulant factors (TFPI, thrombomodulin, protein C).
- They also decrease fibrinolysis by increasing PAI-1 expression.
- SIC results in systemic activation of coagulation systems with widespread thrombosis and fibrinolysis.
- Fibrinolysis leads to consumption of coagulation factors and bleeding.
- Depletion of clotting factors and platelets in small vessels can lead to hemorrhaging in other areas.
- Clinical signs of SIC include: thrombosis, bleeding, petechiae, purpura, and organ hemorrhage.
Role of Neutrophil Extracellular Traps (NETS)
- Neutrophils are the first line of defense in phagocytizing pathogens.
- NETs are released to trap and contain microorganisms, but they also contribute to tissue damage.
- NETs are believed to damage endothelial cells and stimulate coagulation through both intrinsic and extrinsic coagulation pathways.
- As blood cells try to navigate through the fibrin mesh nets, they get damaged, resulting in schistocytes (torn red blood cells).
- Ultimately, this can lead to microangiopathic hemolytic anemia.
Sepsis and Respiratory Failure
- Sepsis can cause diffuse alveolar damage leading to Adult Respiratory Distress Syndrome (ARDS).
- Neutrophil and cytokine-induced damage to pulmonary endothelium and epithelium contribute to respiratory failure.
- Clinical features of respiratory failure include: decreased PaO2/FiO2 ratio and pulmonary infiltrates.
- Diffuse alveolar damage occurs due to:
- Direct injury to the pulmonary endothelium.
- Cytokine and neutrophil-mediated endothelial and epithelial lung damage.
- Coagulation-induced inflammation and neutrophil adhesion.
- Stages of diffuse alveolar damage:
- Early: Increased vascular permeability and marked pulmonary edema.
- Intermediate: Loss of type 1 pneumocyte epithelium, hyaline membranes, and type 2 pneumocyte hyperplasia.
- Late: Fibrosis.
Sepsis and COVID-19
- COVID-19 is associated with a hypercoagulative state, leading to:
- Multiple thrombi within small pulmonary arteries.
- Systemic deep venous thromboses.
- Pulmonary emboli.
- Consumption of coagulation factors and low platelet counts, but bleeding is less common than in typical DIC.
- Very high D-dimer levels are characteristic.
Sepsis and Cardiac Dysfunction
- Cytokine-induced damage, hypoperfusion, mitochondrial dysfunction, and myocardial cell adaptation contribute to cardiac dysfunction in sepsis.
- Cardiac cells may shut down to conserve energy, leading to:
- Decreased cardiac contractility.
- Peripheral vasodilation.
- These factors worsen hypoperfusion and ischemia.
- Severe sepsis can lead to:
- Myocardial ischemia, necrosis, and infarction (similar to atherosclerotic myocardial infarction).
- Coagulative necrosis.
- Contraction band necrosis.
- Reperfusion injury with oxygen free radicals.
- Cardiac dysfunction contributes to shock.
- Nitric oxide, while beneficial in antimicrobial and anti-inflammatory roles, can also be a potent vasodilator and contribute to septic shock.
Sepsis and Liver Dysfunction
- The liver is crucial for gluconeogenesis (converting lactate to glucose) and Acetyl-CoA for oxidative metabolism.
- Liver failure can lead to lactic acid accumulation.
- Stages of liver dysfunction:
- Early sepsis: Hyperglycemia.
- Late sepsis: Major liver failure and hypoglycemia.
- Severe liver dysfunction can lead to:
- Release of hepatic enzymes from necrotic cells, elevating lactic dehydrogenase (LDH).
- Centrilobular necrosis (Zone 3 necrosis).
Sepsis and Kidney Dysfunction
- Multi-organ failure in sepsis is likely due to cytokine and neutrophil-induced injury, ischemia, cell adaptive changes, and mitochondrial functional changes.
- Sepsis can lead to acute tubular necrosis with coagulative necrosis of the proximal tubule of the kidney.
- Renal dysfunction is often a result of profound hypotension.
- Clinical signs include: edema and clinical renal failure.
Lactic Acid in Sepsis
- Lactic acidosis (>2mmol/L) is not specific to sepsis.
- Hypoxia/hypoperfusion might not be the primary cause of lactic acidosis in sepsis.
- Lactic acidosis can be caused by various factors including medications (e.g., metformin), liver failure, severe exercise, toxins, trauma, and others.
- Lactic acidosis (>=4mmol/L) indicates a critically ill patient with a poor prognosis, but is not specific to sepsis.
- Serial measurement of lactate and therapy targeting lactic acid levels is controversial and its utility has been questioned.
Shock and Mean Arterial Pressure (MAP)
- Systolic blood pressure is determined by the pressure during contraction.
- Diastolic blood pressure is the pressure when the heart relaxes.
- MAP is calculated as: (Systolic - Diastolic) / 3 + Diastolic.
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Description
This quiz explores the definition, stages, causes, and pathogenesis of sepsis. Test your knowledge on how the body's response to infection leads to life-threatening conditions. Understand the critical differences in each stage of sepsis and its implications.
