Sepsis and Septic Shock

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Sepsis is a systemic, life-threatening condition caused by body’s dysregulated immune response to an infection, leading to widespread inflammatory activation, microvascular dysfunction, and progressive impairment of organ systems.

Septic shock is the most severe form of sepsis in which profound circulatory, cellular, and metabolic abnormalities lead to:

• Persistent hypotension requiring vasopressors to maintain MAP ≥ 65 mmHg despite adequate fluid resuscitation
• Serum lactate > 2 mmol/L, indicating tissue hypoperfusion

Infections that lead to sepsis commonly arise from pneumonia (lungs), urinary tract infections, abdominal infections such as peritonitis or biliary tract disease, soft-tissue infections, or contaminated medical devices. The microorganisms involved are often:

• Gram-negative bacteria like E. coli and Klebsiella
• Gram-positive bacteria like Staphylococcus aureus and Streptococcus pneumoniae
• Anaerobes like Bacteroides
• Fungi like Candida in immunocomporomised or ICU patients

Pathophysiology

The process begins when components of microorganisms, called PAMPs, and molecules released from damaged tissues, called DAMPs, bind to pattern-recognition receptors—especially Toll-like receptors—on immune and endothelial cells. This recognition activates intracellular pathways, particularly those involving NF-κB, which then stimulate an intense release of inflammatory cytokines, including TNF-α, IL-1β, IL-6, and others. The cytokine storm and immune dysregulation no longer serve to control the infection but instead injure the patient’s own tissues.

Once the cytokine response begins to escalate, the endothelium throughout the body becomes leaky and dysfunctions, allowing fluid to escape into tissues (resulting in edema) and becomes strongly pro-coagulant (microthrombi form), causing maldistribution of blood flow. Cytokines also produce large quantities of nitric oxide, decreasing systemic vascular resistance, causing widespread vasodilation and hypotension. These combined effects lead to a mix of low blood pressure, inadequate microvascular perfusion, and the formation of tiny clots that further obstruct blood flow in small vessels.

At the same time, cytokines trigger the coagulation cascade, elevating tissue factor expression and thrombin generation, plus decreasing fibrinolysis. These conditions lead to microvascular thrombosis (inducing organ ischemia), consumption of clotting factors and platelets, increasing bleeding risk, and causing disseminated intravascular coagulation.

Cells themselves begin to experience mitochondrial dysfunction and impaired oxygen use, forcing them into anaerobic metabolism and increasing lactate production. The lactate elevation becomes an important clinical marker of tissue hypoperfusion and cellular metabolic failure.

As the inflammatory, vascular, and metabolic dysfunction progresses, multiple organs begin to fail.

• The lungs develop non-cardiogenic pulmonary edema and severe hypoxemia (ARDS)
• The kidneys experience reduced perfusion, microvascular injury, and inflammatory damage, leading to oliguria and rising creatinine
• The heart often develops a reversible form of myocardial depression called septic cardiomyopathy, in which the ejection fraction drops due to cytokine-mediated impairment of contractility
• The liver may fail to process bilirubin and synthesize clotting factors, causing jaundice and coagulopathy
• The brain is extremely sensitive to the inflammatory and perfusion abnormalities of sepsis, often resulting in confusion, agitation, or a depressed level of consciousness
• The gastrointestinal tract becomes hypoperfused and can lose its mucosal barrier, increasing the risk of secondary infection

When two or more organ systems are significantly impaired, the condition is referred to as multi organ dysfunction syndrome (MODS), the main cause of death in septic patients.

Clinical features

• Fever or hypothermia (may be present in elderly or in immunocompromised individuals)
• Tachycardia
• Tachypnea
• Warm skin early and later cool skin
• Persistent hypotension

Laboratory Findings

• Elevated CRP and procalcitonin
• Elevated lactate (due to hypoperfusion)
• Leukocytosis or leukopenia
• Abnormal liver/kidney values
• Low platelets

Organ Dysfunction signs

• Brain: confusion, decreased consciousness
• Lungs: low oxygen levels, respiratory failure
• Kidneys: decreased urine output, Elevated creatinine
• Liver: Elevated bilirubin, abnormal coagulation
• Heart/circulation: hypotension, poor perfusion
• Blood: thrombocytopenia

References

Johnson, R. L. (2003). Robbins Basic Pathology. *Archives of Pathology & Laboratory Medicine*, 127(11), 1532. https://doi.org/10.5858/2003 127 1532 rbp

Sattar, H. A. (2025). Fundamentals of Pathology: Medical Course and Step 1 Review.