Sepsis

Definition (Sepsis-3, 2016)

• Persistent hypotension requiring vasopressors to maintain MAP ≥65 mmHg, AND
• Serum lactate >2 mmol/L despite adequate volume resuscitation
• Mortality in septic shock is approximately 40%

qSOFA (quick SOFA) - a bedside screening tool: altered mentation, RR ≥22/min, SBP ≤100 mmHg. Score ≥2 should prompt further organ dysfunction assessment.

Epidemiology

• ~88% of sepsis cases are community-onset (detected within 48 h of hospitalization); ~12% are hospital-onset
• ~53% of U.S. sepsis cases are bacterial culture-positive, split roughly evenly between gram-positive and gram-negative organisms
• Most common organisms: S. aureus, Streptococcus spp., E. coli, Klebsiella, Pseudomonas aeruginosa
• Most common primary infection sites: urinary tract (49%), respiratory tract (33%), intra-abdominal (14%), skin/soft tissue (10%)
• Mortality has been declining over time despite stable or rising incidence, as shown below:

Harrison's Principles of Internal Medicine 22e - Sepsis incidence (stable ~5-6%) vs. mortality (declining from ~19% to ~15%), 2009-2014

Pathophysiology

Trigger: PAMPs and DAMPs

• PAMPs (Pathogen-Associated Molecular Patterns): bacterial LPS (gram-negatives), cell wall components, pathogen nucleic acids
• DAMPs (Damage-Associated Molecular Patterns): histones, HMGB1, oxidized phospholipids, ATP released from injured host cells
• Both are recognized by Pattern Recognition Receptors (PRRs) - including Toll-like receptors (TLRs, 10 human subtypes), NOD receptors, RAGE, and RIG-I receptors

Cellular Responses

• Neutrophils: upregulate CD11b, adhere to endothelium, release Neutrophil Extracellular Traps (NETs) - web-like DNA structures with antimicrobial proteins (cathepsin-G, myeloperoxidase, neutrophil elastase)
• Monocytes/Macrophages: release proinflammatory cytokines - IL-6, IL-18, TNF-α, and activate inducible nitric oxide synthase (iNOS)
• Endothelial cells and platelets: activated, promoting a prothrombotic state with microvascular thrombosis

Net Result

• Systemic vasodilation (NO-mediated)
• Capillary leakage - interstitial fluid accumulation
• Microvascular thrombosis - consuming platelets and clotting factors (risk of DIC)
• Impaired oxygen delivery, uptake, and utilization at the cellular level
• End-organ dysfunction: AKI, ARDS, hepatic dysfunction, encephalopathy, cardiovascular collapse

Hemodynamic Pattern

Clinical Presentation

Laboratory Evaluation

Hematology

• CBC: Leukocytosis or leukopenia; thrombocytopenia in severe sepsis/DIC; bandemia (≥5-10% bands) suggests immature cell release
• Coagulation: Elevated PT/aPTT, decreased fibrinogen, increased fibrin split products - hallmarks of DIC

Chemistry

• Lactate: Key prognostic marker. Lactate 0-2.5 mmol/L = 5% mortality; 2.5-4 = 9%; >4 mmol/L = 28% mortality
• Creatinine/GFR: AKI signals organ failure and worse prognosis
• Bicarbonate: Low bicarb suggests metabolic acidosis from inadequate perfusion
• Anion gap: Elevated AG acidosis in sepsis - usually lactic acidosis

Biomarkers

• Procalcitonin (PCT): PCT >0.5 ng/mL suggests bacterial infection; PCT <0.1 ng/mL makes it less likely. Useful for antibiotic stewardship (serial measurements to guide de-escalation). A low PCT does NOT exclude severe bacterial infection.
• C-reactive protein (CRP): Less specific; useful in serial measurements

Microbiology

• Blood cultures (x2 sets), urine, sputum, CSF, wound cultures - obtain before antibiotics if possible, but do NOT delay antibiotics waiting for cultures
• Only 30-40% of clinical sepsis cases yield positive cultures

Imaging

• CXR: pneumonia, ARDS (bilateral infiltrates)
• CT abdomen/pelvis: intra-abdominal source (abscess, diverticulitis, appendicitis, pancreatitis)
• Echo: endocarditis vegetations, sepsis-induced cardiomyopathy
• MRI: necrotizing fasciitis, epidural abscess

Management

1. Initial Resuscitation (First Hour - "Hour-1 Bundle")

• IV crystalloid: at least 30 mL/kg IBW within the first hour
• Balanced crystalloids (lactated Ringer's) preferred over normal saline - associated with lower rates of AKI and potentially improved mortality
• Albumin does not show significant benefit over crystalloid
• Monitor volume responsiveness to prevent overload (dynamic parameters: pulse pressure variation, stroke volume variation, passive leg raise response)

2. Vasopressors

• Norepinephrine - first-line agent (α1 + β1 agonist; dopamine shown to have more adverse events)
• Vasopressin - second-line adjunct; weak evidence of mortality benefit in less severe septic shock (norepinephrine 5-14 μg/min)
• Epinephrine - used in anaphylactic shock; also in cardiogenic shock
• Angiotensin II - adjunct in refractory vasodilatory shock
• Phenylephrine - selective α1 agonist; limited evidence in septic shock

3. Antibiotics

• Initiate broad-spectrum empirical antibiotics immediately after blood cultures - delays in appropriate antibiotics are associated with increased mortality
• Tailor to suspected source and local resistance patterns (e.g., MRSA coverage if high risk, antipseudomonal if immunocompromised)
• De-escalate based on culture results and PCT guidance

Recent evidence (JAMA 2024 meta-analysis, PMID 38864162): prolonged/extended infusion of β-lactam antibiotics is associated with improved outcomes in sepsis/septic shock compared to intermittent bolus dosing.

4. Source Control

• Identify and eliminate the anatomical infection source as soon as possible
• Examples: surgical drainage of abscess, debridement of necrotizing fasciitis, removal of infected central line, cholecystectomy for gangrenous cholecystitis

5. Lactate Clearance

• Target normalization of elevated lactate levels as a resuscitation endpoint
• Lactate clearance is associated with improved mortality

6. Steroids

• Hydrocortisone (200-300 mg/day): consider in septic shock refractory to vasopressors (adrenal insufficiency) - per Surviving Sepsis Guidelines

7. Glycemic Control

• Target blood glucose 140-180 mg/dL; avoid hypoglycemia

8. Mechanical Ventilation (if ARDS develops)

• Low tidal volume ventilation (6 mL/kg IBW)
• Target plateau pressure <30 cmH2O
• Prone positioning for severe ARDS

9. Early Goal-Directed Therapy (EGDT) - Historical Context

• Originally proposed by Rivers et al. (2001): targeted CVP 8-12, MAP ≥65, UO ≥0.5 mL/kg/hr, ScvO2 ≥70%
• Three large multicenter RCTs (ProCESS, ProMISE, ARISE) showed no mortality benefit of formal EGDT over usual care - mainly because usual care had already incorporated early antibiotics and fluid resuscitation
• The principles of early identification and aggressive resuscitation remain valid; the specific EGDT protocol is no longer recommended

Organ-Specific Complications

Surviving Sepsis Campaign (SSC) 2021 Summary

Recent Evidence Updates

• PMID 38864162 (JAMA 2024 Meta-Analysis): Prolonged vs. intermittent infusion of β-lactam antibiotics in sepsis/septic shock - prolonged infusion shows improved clinical cure and potentially mortality benefit
• PMID 39961104 (Ann Intern Med 2025, Systematic Review): SEP-1 bundle compliance associated with improved outcomes, though implementation challenges exist
• PMID 39037814 (JAMA Network Open 2024, Meta-Analysis): Sepsis alert systems in EDs are associated with reduced mortality and improved bundle adherence