What is the definition of sepsis?

Sepsis Definition

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, clinically identified by an increase in the Sequential Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with in-hospital mortality exceeding 10%. 1

Core Diagnostic Framework (Sepsis-3 Criteria)

The current definition framework, established by the Society of Critical Care Medicine, represents a fundamental shift from previous inflammation-focused criteria:

• Organ dysfunction is the defining feature, operationalized as a SOFA score increase of ≥2 points from baseline 1
• The previous concepts of SIRS (Systemic Inflammatory Response Syndrome) and "severe sepsis" are no longer used in current clinical practice 1
• This definition emphasizes the pathophysiological reality that sepsis involves a dysregulated inflammatory response that can lead to multi-organ failure, not simply the presence of infection plus inflammation 1

Evolution from Previous Definitions

Prior to 2016, sepsis definitions relied heavily on SIRS criteria (temperature >38°C or <36°C, heart rate >90 bpm, respiratory rate >20/min or PaCO₂ <32 mmHg, and WBC >12,000/mm³ or <4,000/mm³) 1. This approach was abandoned because inflammation alone does not capture the organ dysfunction that drives mortality in sepsis 1.

Septic Shock Definition

Septic shock represents a subset of sepsis with particularly profound circulatory, cellular, and metabolic abnormalities associated with substantially higher mortality risk. 1

Clinical identification requires both of the following criteria despite adequate fluid resuscitation:

• Vasopressor requirement to maintain mean arterial pressure (MAP) ≥65 mmHg 1, 2
• Serum lactate level >2 mmol/L (>18 mg/dL) in the absence of hypovolemia 1, 2

This dual-criterion approach captures both the hemodynamic instability (requiring vasopressors) and the cellular metabolic dysfunction (elevated lactate) that characterize this severe phenotype 2.

Rapid Bedside Identification: qSOFA

For rapid identification of patients at risk outside the ICU setting, the quick SOFA (qSOFA) consists of three clinical variables 1:

• Respiratory rate ≥22 breaths/min
• Altered mental status (Glasgow Coma Scale score ≤13)
• Systolic blood pressure ≤100 mmHg

Presence of at least 2 of these criteria suggests higher risk of poor outcomes typical of sepsis and should prompt urgent evaluation 1. Recent evidence suggests combining qSOFA with lactate levels may modestly improve risk stratification, with an area under the ROC curve of 0.724 versus 0.706 for qSOFA alone 3.

Risk Stratification Using NEWS2

The 2024 NICE guidance introduced NEWS2 (National Early Warning Score 2) for stratifying risk of severe illness or death from sepsis in acute hospital, mental health, and ambulance settings 4:

• NEWS2 incorporates six physiological parameters: respiratory rate, oxygen saturation, supplemental oxygen requirement, systolic blood pressure, pulse rate, level of consciousness, and temperature 4
• Risk categories based on aggregate scores determine the urgency of antibiotic prescribing and monitoring frequency 4
• Score interpretation: 0 (very low risk), 1-4 (low risk), 5-6 (moderate risk), with higher scores indicating greater urgency 4

This approach standardizes early recognition of patient deterioration nationally and helps mitigate the risk of delayed treatment, which can be life-threatening 4.

Pathophysiological Mechanisms

Understanding the underlying biology clarifies why the definition focuses on organ dysfunction rather than inflammation alone:

• Initial phase: Pathogen-associated molecular patterns (PAMPs) trigger inflammatory signaling pathways, activating nuclear factor-κB and producing pro-inflammatory cytokines 5
• Endothelial dysfunction: The endothelium converts from an anticoagulant to a procoagulant state, with increased vascular permeability causing fluid leakage and tissue edema 5
• Microcirculatory failure: Tissue hypoperfusion occurs despite potentially normal macrocirculatory parameters, leading to cellular metabolic dysfunction and lactate accumulation 5, 2
• Immunosuppressive phase: Following initial inflammation, patients develop profound immunosuppression characterized by lymphocyte apoptosis, reduced HLA-DR expression on monocytes, and impaired neutrophil function 5, 6

Clinical Implications for Practice

Early recognition is crucial for improving outcomes, as the pathophysiology involves concurrent inflammatory and immunosuppressive responses that vary by patient 1, 6:

• Patient factors including age, comorbidities, and immune status significantly affect the clinical course 1
• Elderly patients may present with attenuated inflammatory responses and fewer clinical signs despite severe infection 1
• Immunocompromised patients (e.g., HIV-positive) have increased susceptibility due to pre-existing immune system activation and exhaustion 1

Common Pitfalls to Avoid

• Failing to measure lactate levels, which are essential for diagnosing septic shock according to current definitions 2
• Overlooking perfusion abnormalities in patients receiving vasopressors who may still have tissue hypoperfusion despite normalized blood pressure 5, 2
• Confusing septic shock with other forms of distributive shock (e.g., anaphylactic, neurogenic), which require different management approaches 2
• Delaying vasopressor initiation while continuing excessive fluid administration, which may worsen outcomes through fluid overload 2

Microbiological Considerations

More than 90% of sepsis cases are caused by bacteria, with Gram-negative and Gram-positive organisms occurring with approximately equal frequency 1. Fungi, particularly Candida species, account for a significant minority of cases 1. Blood cultures remain the cornerstone of microbiological diagnosis, though prior antibiotic therapy may yield negative cultures despite ongoing infection 1.