What is the pathophysiology of sepsis?

From the Guidelines

Sepsis is a life-threatening condition caused by a dysregulated host response to infection, leading to organ dysfunction and potentially death if left untreated. The pathophysiology of sepsis begins when pathogens enter the bloodstream, triggering an overwhelming immune response 1. Initially, pattern recognition receptors identify pathogen-associated molecular patterns, activating immune cells to release pro-inflammatory cytokines like TNF-α, IL-1, and IL-6. This cytokine storm leads to widespread inflammation, endothelial damage, and microvascular dysfunction. Blood vessels become leaky, causing fluid to shift from blood vessels into tissues, resulting in edema and hypotension. Simultaneously, the coagulation system becomes dysregulated, with both excessive clotting (microvascular thrombosis) and bleeding tendencies. Cellular metabolism shifts to anaerobic pathways due to tissue hypoxia, producing lactic acid and contributing to metabolic acidosis. Organ dysfunction follows as tissues receive inadequate oxygen and nutrients, potentially progressing to multiple organ failure. The heart, lungs, kidneys, liver, and brain are commonly affected, with cardiac output initially increasing but eventually decreasing as the condition worsens. If untreated, this cascade leads to refractory hypotension, profound tissue hypoxia, and ultimately death. Early recognition and treatment with appropriate antibiotics, fluid resuscitation, and supportive care are essential to interrupt this pathological process.

Some key points to consider in the pathophysiology of sepsis include:

• The importance of early recognition and treatment, as delayed intervention can lead to increased morbidity and mortality 1
• The role of the immune response in sepsis, including the release of pro-inflammatory cytokines and the activation of immune cells 1
• The impact of sepsis on organ function, including the heart, lungs, kidneys, liver, and brain 1
• The need for prompt administration of intravenous fluids and vasopressors to restore adequate blood pressure and perfusion 1

Overall, the key to managing sepsis is early recognition and treatment, with a focus on restoring adequate blood pressure and perfusion, and providing supportive care to prevent organ dysfunction and death. This approach is supported by the most recent and highest quality evidence, including the 2017 guidelines for the management of intra-abdominal infections 1 and the 2012 Surviving Sepsis Campaign guidelines 1.

From the Research

Pathophysiology of Sepsis

The pathophysiology of sepsis is a complex process involving a dysregulated host response to infection, leading to organ dysfunction 2, 3, 4. The key aspects of this process include:

• An initial exaggerated inflammatory-immune response triggered by the pathogen, which activates or suppresses multiple downstream pathways 2
• The activation of endothelial, hormonal, bioenergetic, metabolic, immune, and other pathways, leading to circulatory and metabolic perturbations and resulting in organ dysfunction 2
• A dysregulated innate and adaptive immune response, resulting in excessive inflammation, immunosuppression, and failure to re-establish immune homeostasis 3

Organ Dysfunction in Sepsis

Organ dysfunction is a hallmark of sepsis, with multiple organ systems affected, including:

• Cardiovascular dysfunction, producing vasodilation, reduced cardiac output, and hypotension/shock 5
• Respiratory dysfunction, which may require mechanical ventilation and attention to volume status 5
• Renal dysfunction, a frequent manifestation of sepsis 5
• Hematologic dysfunction, producing low platelets and either elevation or reduction of leukocytes 5
• Hepatic dysfunction, manifesting as elevated bilirubin, often a late finding in sepsis 5
• Neurologic dysfunction, resulting from local endothelial injury and systemic inflammation 5

Immune Response in Sepsis

The immune response in sepsis is characterized by:

• A hyperinflammatory state, together with impaired innate immune functions of phagocytes, immunosuppression, and complement activation 6
• A loss of redox balance, associated with the development of systemic inflammatory response syndrome (SIRS) 6
• The potential for immunotherapy to modulate the immune response, causing excessive inflammation or enhancing immunity 3