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Questions and Answers
What are fibrin microvascular thrombi?
They are thrombi within capillary blood vessels that can contribute to tissue ischemia and necrosis.
What condition can result from the passage of erythrocytes through fibrin nets?
What is one of the earliest pathological features of Diffuse Alveolar Damage?
COVID-19 findings in the lung at autopsy are common in bacterial and other types of viral sepsis.
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What does sepsis often trigger?
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Which organ is crucial for gluconeogenesis and converting lactate back to glucose?
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What is a potential consequence of acute tubular necrosis?
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Lactic acidosis is specific for sepsis.
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What indicates a critically ill patient with poor prognosis related to lactic acidosis?
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What is the potential consequence of sepsis-induced coagulopathy (SIC)?
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What is Systemic Inflammatory Response Syndrome (SIRS)?
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Which of the following is true regarding Sepsis?
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What is septic shock?
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SIRS and Severe Sepsis are still commonly used terms.
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What does the anti-inflammatory response aim to do?
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The successful treatment of sepsis relies on its early recognition and management of symptoms that are often ______.
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What is the main cause of sepsis?
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Immunosuppressive therapies such as glucocorticoids have been proven consistently beneficial for sepsis treatment.
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What do PAMPs stand for?
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What commonly triggers the process of sepsis?
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Sepsis is defined in the Third International Consensus Definitions for Sepsis as life-threatening organ dysfunction caused by a ______ response to infection.
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Match the following terms with their correct definitions:
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Study Notes
Systemic Inflammatory Response Syndrome (SIRS) and Sepsis
- The body's response to infection involves both pro-inflammatory and anti-inflammatory cytokines.
- Pro-inflammatory forces can lead to systemic illness and even death if untreated.
- Anti-inflammatory forces can also cause immunosuppression and superinfection.
- Sepsis-3 definitions were established in 2016 by the third international consensus conference, with SIRS and severe sepsis terms no longer being used.
- Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.
- Sepsis-3 uses the SOFA score to predict the risk of mortality.
- Early recognition of sepsis is crucial for successful treatment, but symptoms can be nonspecific.
- Sepsis involves a complex interplay of both pro-inflammatory and anti-inflammatory immune system activation, as well as cell adaptive responses.
- Mortality rates for sepsis vary depending on location and population, but generally range from 20% to 50%.
- The overuse of antibiotics in sepsis cases can lead to the emergence of drug-resistant microorganisms.
- There is no gold standard for sepsis diagnosis and many non-infectious conditions can mimic its symptoms.
- Bacterial pneumonia is the most common cause of sepsis, followed by intra-abdominal and urinary tract infections.
- Both Gram-positive and Gram-negative bacteria cause sepsis.
- Sepsis is initiated by the innate immune system's response to either PAMPs (Pathogen-associated molecular patterns) from microbes or DAMPS (Damage-associated molecular patterns) from necrotic cells.
- Superantigens, like those produced by Staphylococcus aureus and Streptococcus pyogenes, can cause massive cytokine release.
- Inflammation in sepsis can lead to neutrophil activation, which can cause organ damage and promote coagulation.
- Sepsis-induced coagulopathy (SIC) can progress to disseminated intravascular coagulation (DIC), resulting in widespread thrombosis and bleeding.
- The damage to the endothelium in sepsis leads to the formation of fibrin thrombi in microvessels, which can cause ischemia and necrosis in organs.
- Microangiopathic hemolytic anemia can occur when erythrocytes are traumatized by fibrin thrombi, leading to petechiae and purpura.
- Diffuse alveolar damage (DAD) can occur in sepsis, leading to acute respiratory distress syndrome (ARDS) characterized by decreased PaO2/FiO2 and pulmonary infiltrates.
- Early stage DAD is marked by increased vascular permeability and pulmonary edema.
- Late stage DAD involves fibrosis.
Diffuse Alveolar Damage
- Early stage: intra-alveolar edema, hyaline membrane formation
- This leads to: failure to oxygenate blood, widespread tissue hypoxia
COVID-19 Lung at Autopsy
- Findings are uncommon in bacterial and other types of viral sepsis.
Sepsis: Hypercoagulative State
- Multiple thrombi within small pulmonary arteries
- System deep venous thromboses
- Pulmonary emboli
- Consumption of coagulation factors, low platelet count and bleeding less frequently found than in ordinary DIC
- Very high D-dimers are present
Sepsis and Cardiac Dysfunction/Failure
- Combination of:
- Cytokine-induced damage
- Hypoperfusion
- Mitochondrial dysfunction
- Myocardial cell adaptation
- Decreased cardiac contractility and peripheral vasodilation contribute to systemic organ hypoperfusion and ischemia
Impaired Myocardial Function
- Impaired myocardial contractility
- Evidence of: myocardial ischemia, necrosis and infarction similar to atherosclerotic myocardial infarction
- Coagulative necrosis (ischemic)
- Contraction band necrosis (pressor effect)
- Reperfusion injury
- Contributes to: Shock
### Hepatic Changes in Sepsis
- Functional role of liver: conversion of lactate back to glucose (gluconeogenesis) and Acetyl-CoA for entrance into oxidative metabolism
- Liver failure leads to: Lactic acid accumulation
- Early sepsis: hyperglycemia
- Late sepsis: hypoglycemia
Massive Hepatic Necrosis
- Release of hepatic enzymes from necrotic cells
- Elevated lactic acid dehydrogenase (LDH)
- Patient liver enzyme elevations: Aspartate aminotransferase (AST) 800 IU/L (normal 10-40), alanine aminotransaminase ALT–936 IU/L (normal 7-56)
- Centrilobular necrosis (Zone 3 necrosis) releases hepatic enzymes into the blood
### New Ideas About Acute Renal Injury in Sepsis
- Multi-organ failure in sepsis likely owing to:
- Cytokine and neutrophil-induced injury
- Ischemia
- Cell adaptive changes
- Mitochondrial functional changes
- Shunting of blood flow
- Pathologist may see acute tubular necrosis but often no pathologic changes at autopsy of patients with clinical renal failure
Pathology of Classic Acute Tubular Necrosis
- Coagulative necrosis of proximal tubules
Effect of Profound Hypotension on Kidneys
- Acute tubular injury
- Edema
- Clinical renal failure
Lactic Acid Measurement
- Lactic acidosis (>2mmol/L) is not specific for sepsis
- Other causes: medications (e.g. metformin), liver failure, severe exercise, toxins, trauma
- Lactic acidosis (=>4mmol/L) indicates a critically ill patient with poor prognosis
- Serial measuring of lactate and therapy directly targeting lactic acid levels is controversial
Sepsis Conundrum
- Defining sepsis, recognizing it early enough for a good outcome and treating it is difficult
- Aggressively treating non-septic patients with sepsis protocols may be harmful
Sepsis: Definition & Stages
- Life threatening organ dysfunction caused by a dysregulated host response to infection
- Three stages:
- Early stage (SIRS)
- Severe stage (Sepsis)
- Septic shock
Sepsis: Body's Response to Infection
- Release of a combination of pro-inflammatory and anti-inflammatory cytokines, other mediators and adaptive bioenergetic changes
- Pro-inflammatory forces and cell bioenergetic changes cause:
- Systemic illness
- Multi-organ dysfunction/failure
- Shock
- Death
- Anti-inflammatory forces can help:
- Halt the deleterious effects of inflammation
- However, these forces can lead to immunosuppression and superinfection
### Causes of Sepsis
- Bacterial pneumonia is the most common cause
- Followed by urinary tract infections and intra-abdominal infections
- Infections are from both gram-positive and gram-negative bacteria
- Septic shock is most frequently triggered by gram-positive bacterial infections, followed by gram-negative bacteria and fungi
What Starts Off Sepsis?
- Innate immune system responds to:
- PAMPs (Pathogen-associated molecular patterns)
- DAMPs (Damage-associated molecular patterns)
- Superantigens
PAMPs
- Recognize parts of the pathogen
- Examples:
- Gram-negative bacteria with lipopolysaccharide (LPS)
- Gram-positive bacteria with peptidoglycan
- Microbial toxins
DAMPs
- Damage can be from:
- Infection
- Trauma
- Chronic disease
- Infarct (anoxia)
### Superantigens
- Bacterial proteins, usually toxins, that cause polyclonal T-cell activation resulting in massive cytokine release
- Examples:
- Staphylococcus aureus (toxic shock)
- Streptococcus pyogenes
Sepsis: Pathogen Recognition and Activation
- PAMPs and DAMPs bind to their respective receptors (TLR, NLRs, etc)
- Binding activates neutrophils and monocytes, leading to NF-κB creation
- NF-κB initiates production and secretion of inflammatory cytokines (IL-1, TNF-alpha, IL-6, IFN-gamma)
- These cytokines lead to: direct systemic effects, vasodilation, increased permeability, decreased perfusion and immunosuppression
- Certain organisms (PAMPs) activate complement
- Complement components (like C3a) cause endothelial activation and induce proinflammatory state
- Other complement components upregulate different immune cells and act as a chemoattractant
- PAMPS induce factor XII for coagulation through altered endothelial function, leading to: Microvascular thrombus (DIC/SIC), tissue ischemia
### Modulation of Inflammation
- TGF-beta and leukotrienes are produced to modulate and turn down inflammation
Sepsis-Induced Coagulopathy (SIC)
- Proinflammatory cytokines like TNF-alpha activate endothelial cells, stimulating coagulation pathways especially in smaller vessels.
- Decrease production of endothelial anticoagulant factors (TFPI, thrombomodulin, protein C)
- Decrease fibrinolysis by increasing PAI-1 expression
- DIC/SIC: Systemic activation of coagulation systems with widespread thrombosis & fibrinolysis.
- Consumption of coagulation factors resulting in bleeding
### Neutrophil Extracellular Traps (NETS)
- Neutrophils are the 1st line of defense to phagocytize pathogens
- NETS trap and contain microorganisms, but also damage endothelial cells and stimulate coagulation.
- As blood cells try to get through fibrin mesh nets, they get traumatized, resulting in: Schistocytes (torn up RBCs), microangiopathic hemolytic anemia
Consequences of Sepsis & DIC/SIC
- Diffuse alveolar damage:
- Direct injury to pulmonary endothelium
- Cytokine and neutrophil-mediated endothelial and epithelial lung damage
- Coagulation-induced inflammation and neutrophil adhesion
- Results in: Clinical respiratory failure, decreased PaO2/FiO2, pulmonary infiltrates
COVID-19 and DIC/SIC
- Hypercoagulative state skewed toward thrombosis
- Multiple thrombi within small pulmonary arteries
- System deep venous thromboses
- Pulmonary emboli
- Consumption of coagulation factors, low platelet count and bleeding less frequently found than in ordinary DIC
- Very high D-dimers characteristic
Sepsis and Cardiac Dysfunction/Failure
- Cytokine-induced damage, hypoperfusion, mitochondrial dysfunction and myocardial cell adaptation
- Decreased cardiac contractility & peripheral vasodilation worsen hypoperfusion and ischemia
Worst Case Scenario: Sepsis and Cardiac Dysfunction/Failure
- Myocardial ischemia, necrosis and infarction similar to atherosclerotic myocardial infarction
- Coagulative necrosis (ischemic)
- Contraction band necrosis (pressor effect)
- Reperfusion injury
- Contributes to shock
### Hepatic Changes in Sepsis
- Liver is important for:
- Conversion of lactate back to glucose (gluconeogenesis)
- Acetyl-CoA for entrance into oxidative metabolism
- Liver failure leads to: Lactic acid accumulation
- Early sepsis: hyperglycemia
- Late sepsis: hypoglycemia
### Massive Hepatic Necrosis
- Release of hepatic enzymes from necrotic cells
- Elevated lactic acid dehydrogenase (LDH)
- Patient liver enzyme elevations: Aspartate aminotransferase (AST) 800 IU/L (normal 10-40), alanine aminotransaminase ALT–936 IU/L (normal 7-56)
- Centrilobular necrosis (Zone 3 necrosis) releases hepatic enzymes into the blood
### New Ideas About Acute Renal Injury in Sepsis
- Multi-organ failure in sepsis likely owing to:
- Cytokine and neutrophil-induced injury
- Ischemia
- Cell adaptive changes
- Mitochondrial functional changes
- Shunting of blood flow
- Pathologist may see acute tubular necrosis but often no pathologic changes at autopsy of patients with clinical renal failure
### Pathology of Classic Acute Tubular Necrosis
- Coagulative necrosis of proximal tubules
Effect of Profound Hypotension on Kidneys
- Acute tubular injury
- Edema
- Clinical renal failure
Lactic Acid Measurement
- Lactic acidosis (>2mmol/L) is not specific for sepsis
- Other causes: medications (e.g. metformin), liver failure, severe exercise, toxins, trauma
- Lactic acidosis (=>4mmol/L) indicates a critically ill patient with poor prognosis
- Serial measuring of lactate and therapy directly targeting lactic acid levels is controversial
### SHOCK: Blood Pressure
- Systolic blood pressure: determined by the pressure built up during contraction
- Diastolic blood pressure: when the heart relaxes, but pressure remains up
- Mean arterial pressure (MAP): Systolic-diastolic and take 1/3 of that and add it back onto the diastolic
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Description
Test your knowledge about sepsis, its complications, and the systemic inflammatory response syndrome (SIRS). This quiz covers key concepts, potential consequences, and early management strategies essential for critical care. Dive into the mechanisms and implications of these serious medical conditions.
