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Sepsis — Comprehensive Overview

1. Definition (Sepsis-3, 2016)

• Respiratory rate ≥22/min
• Altered mentation
• Systolic BP <100 mmHg

Note: The old "SIRS criteria" (fever, tachycardia, tachypnea, leukocytosis) were abandoned in Sepsis-3 due to poor sensitivity and specificity. "Severe sepsis" as a term is also obsolete.

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2. Epidemiology

• >48 million cases estimated globally per year; >11 million deaths
• Accounts for 6% of adult U.S. hospitalizations
• Causes as many deaths as acute MI; leading cause of death in non-cardiac ICUs
• Incidence is increasing (more immunosuppressed patients, resistant organisms, aggressive surgery)
• Disparities: African Americans have higher incidence (6.0 vs. 3.6/1,000 population) and ICU mortality (32% vs. 29%) vs. Whites
• Cost: ~$20 billion/year in the U.S.

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3. Pathogens & Sources of Infection

1. Urinary tract (48.9%)
2. Respiratory tract (32.9%)
3. Intra-abdominal (13.6%)
4. Skin/soft tissue (10.3%)

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4. Pathophysiology

Immune Activation

• Pathogen-associated molecular patterns (PAMPs — e.g., LPS, peptidoglycan) are recognized by pattern recognition receptors (e.g., TLR-4 on myeloid cells)
• This activates neutrophils, monocytes, macrophages, dendritic cells, NK cells, and lymphocytes
• Massive release of pro-inflammatory mediators: TNF-α, IL-1, IL-6, IL-8, reactive oxygen species, nitric oxide, histamine, prostaglandins, bradykinin

Vascular & Endothelial Effects

• Systemic vasodilation → decreased SVR and MAP
• Capillary leak → interstitial fluid accumulation, decreased intravascular volume
• Endothelial activation → upregulation of adhesion molecules, leukocyte trafficking into tissues

Coagulation

• Activation of the clotting cascade and complement system → prothrombotic state
• Platelet and clotting factor consumption → risk of DIC (Disseminated Intravascular Coagulation)

Cardiovascular

• Vasodilation + hypovolemia + decreased ventricular contractility = distributive shock
• Sepsis-induced cardiomyopathy is common and generally reversible

Immune Suppression

• Paradoxically, an immunosuppressed state can develop (lymphocyte apoptosis, T-cell exhaustion), exceeding the pro-inflammatory phase — contributing to secondary infections and late deaths

Organ Dysfunction (MODS — Multi-Organ Dysfunction Syndrome)

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5. Diagnosis & Workup

• CBC: leukocytosis or leukopenia, thrombocytopenia, bandemia (≥5–10%)
• Metabolic panel: elevated creatinine (AKI), low bicarbonate/elevated anion gap (lactic acidosis)
• Lactate: key marker — lactate >2 mmol/L (with hemodynamic instability) = septic shock
• Blood cultures (×2 sets) — before antibiotics if possible but don't delay antibiotics
• LFTs: elevated bilirubin, alkaline phosphatase; aminotransferases usually mild
• Coagulation: PT/PTT, fibrinogen, D-dimer (for DIC screening)
• Procalcitonin: useful to guide antibiotic de-escalation

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6. Management (Surviving Sepsis Campaign 2021 Guidelines)

The "Hour-1 Bundle" (initiate within 1 hour of recognition)

1. Measure lactate (remeasure if initial >2 mmol/L)
2. Blood cultures before antibiotics
3. Broad-spectrum IV antibiotics — within 1 hour of shock recognition
4. 30 mL/kg IV crystalloid for hypotension or lactate ≥4 mmol/L
5. Vasopressors if patient remains hypotensive during/after fluid resuscitation (target MAP ≥65 mmHg)

Antibiotics

• Septic shock: immediate empiric therapy within 1 hour — every 1-hour delay increases mortality ~7–8%
• Sepsis without shock: initiate within 3 hours if no alternative diagnosis found
• Antibiotic selection (site- and risk-guided):

• De-escalate based on culture results and clinical improvement (guided by procalcitonin)

Fluids

• Initial: 30 mL/kg IV crystalloid (normal saline or balanced crystalloids — LR preferred to reduce hyperchloremic acidosis)
• Reassess after each bolus; dynamic measures of fluid responsiveness (pulse pressure variation, passive leg raise) preferred over static CVP
• Avoid fluid overload — associated with worse outcomes

Vasopressors

• Norepinephrine = first-line vasopressor (target MAP ≥65 mmHg)
• Vasopressin (0.03 units/min) can be added to reduce norepinephrine dose
• Dopamine — only in select patients (bradycardic, low cardiac output); higher arrhythmia risk
• Epinephrine — add-on for refractory shock
• Phenylephrine — avoid in most septic shock (decreases CO)

Corticosteroids

• Hydrocortisone 200–300 mg/day IV recommended in patients with septic shock not responding to adequate fluids and vasopressors (vasopressor-refractory)
• Speeds hemodynamic recovery; no clear mortality benefit but reduces ICU length of stay

Source Control

• Critical and urgent — drainage of abscesses, debridement of necrotizing fasciitis, relief of biliary obstruction, repair of perforated viscus
• Remove infected catheters/devices as rapidly as possible

Ventilation (ARDS)

• Low tidal volume ventilation: 6 mL/kg ideal body weight
• Plateau pressure <30 cmH2O
• Prone positioning for severe ARDS (PaO2/FiO2 <150)
• Conservative oxygen strategy: SpO2 target 92–96%

Glycemic Control

• Target blood glucose 140–180 mg/dL
• Avoid hypoglycemia

Other Supportive Care

• DVT prophylaxis (LMWH preferred)
• Stress ulcer prophylaxis in high-risk patients
• Early enteral nutrition (if tolerated)
• Early mobilization
• Remove unnecessary catheters as soon as possible

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7. Complications

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8. Post-Sepsis Syndrome & Long-Term Outcomes

• 50% of survivors are rehospitalized within 1 year; 1 in 6 die within the first year
• Long-term sequelae ("Post-Intensive Care Syndrome"):
  • Physical: fatigue, muscle wasting, weakness, decreased functional capacity
  • Cognitive: cognitive decline, dementia
  • Psychological: depression, PTSD, decreased QoL
• Increased risk of subsequent MI, stroke, recurrent infections
• The 2021 Surviving Sepsis Campaign recommends structured discharge planning with follow-up for physical, cognitive, and psychological support

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Risk Factors for Poor Prognosis

• Age (especially >75)
• Male sex
• Diabetes, obesity, COPD, cancer
• Renal or hepatic insufficiency
• High SOFA score at presentation
• Lactate >4 mmol/L
• Delay in antibiotic administration

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• Harrison's Principles of Internal Medicine, 22E (2025) — Chapter 315: Sepsis and Septic Shock
• Goldman-Cecil Medicine, International Ed. — Chapter 94: Shock Syndromes Related to Sepsis
• Rosen's Emergency Medicine — Laboratory and diagnostic approach
• Sleisenger & Fordtran's GI and Liver Disease — Hepatic involvement in sepsis