Sepsis Overview and Stages

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 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.