What is sepsis in critically ill adult patients?

What is Sepsis?

Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection, not simply the infection itself, but rather the body's harmful overreaction that damages its own organs. 1

Core Definition and Pathophysiology

Sepsis represents a fundamental shift from normal infection response to pathological immune dysregulation. The key distinguishing feature is not the presence of infection alone, but the development of organ dysfunction resulting from the body's abnormal response to that infection 1, 2.

The pathophysiology involves:

• Initial hyperinflammatory phase: Recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) by pattern recognition receptors (including Toll-like receptors) triggers excessive inflammatory signaling through NF-κB and interferon regulatory pathways 1

• Concurrent immunosuppressive phase: Paradoxically occurs alongside inflammation, characterized by lymphocyte apoptosis, T cell exhaustion, expansion of regulatory T cells and myeloid-derived suppressor cells, and M2 macrophage polarization 1, 3

• Cellular and metabolic dysfunction: Altered cellular metabolism leads to lactate accumulation, microcirculatory dysfunction causes tissue hypoperfusion, and profound circulatory abnormalities develop 2, 4

Clinical Identification

Sepsis is operationally identified by an acute increase in Sequential Organ Failure Assessment (SOFA) score of ≥2 points from baseline in the presence of suspected or confirmed infection. 1

For bedside screening outside intensive care units, the quick SOFA (qSOFA) can identify high-risk patients with suspected infection when ≥2 of the following are present 5:

• Altered mental status
• Respiratory rate ≥22 breaths per minute
• Systolic blood pressure ≤100 mmHg

Septic Shock: The Most Severe Form

Septic shock is a subset of sepsis with profound circulatory, cellular, and metabolic abnormalities that substantially increase mortality risk. 1, 2

Septic shock is clinically identified by:

• Vasopressor requirement to maintain mean arterial pressure ≥65 mmHg, AND
• Serum lactate >2 mmol/L (>18 mg/dL) despite adequate fluid resuscitation 2, 4

Hospital mortality exceeds 40% when both criteria are present 2.

Evolution from Historical Definitions

The 2016 Sepsis-3 definition eliminated the systemic inflammatory response syndrome (SIRS) criteria, which previously required ≥2 of: temperature >38°C or <36°C, heart rate >90 bpm, respiratory rate >20 breaths/min, or white blood cell count >12,000 or <4,000 per mL 1, 5. This change occurred because SIRS criteria lacked specificity—many patients with SIRS do not have sepsis, and many with sepsis do not meet SIRS criteria 5.

Clinical Trajectory and Long-Term Implications

Most sepsis mortality now occurs in a delayed immunosuppressive phase rather than from initial hyperinflammation. 1, 6

The modern conceptual model recognizes three potential outcomes 1:

• Early recovery: Successful resuscitation with discharge from hospital
• Early death: Overwhelming inflammatory response causing multiple organ failure within days
• Chronic critical illness: Persistent inflammation, immunosuppression, and catabolism syndrome (PICS) characterized by viral reactivation, nosocomial infections, muscle wasting, and long-term functional/cognitive decline 1, 6

Key Clinical Pitfalls

Common errors in sepsis recognition include:

• Failing to recognize that patients on vasopressors may still have perfusion abnormalities despite normalized blood pressure 2, 4
• Not measuring lactate levels, which are essential for identifying septic shock 4
• Delaying vasopressor initiation while administering excessive fluid resuscitation 2, 4
• Missing subtle presentations in elderly patients who may have attenuated inflammatory responses or only altered mental status as the presenting sign 2, 7

Global Impact

Sepsis affects approximately 48.9 million people globally per year, causing 11 million deaths (nearly 20% of all global deaths) 1. In the United States, sepsis accounts for >1.7 million cases annually with >15% mortality and in-hospital mortality exceeding 30% 1. The condition represents >$20 billion in US hospital costs and is rising due to aging populations 1.