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Sepsis and Septic Shock¶

Chapter 315 | Part 8: Critical Care Medicine: Sepsis and Septic Shock · Part 8 – Critical Care Medicine · Chapter 315

Key Clinical Points¶

Sepsis-3 Definition: Life-threatening organ dysfunction caused by a dysregulated host response to infection.
Septic Shock Definition: A subset of sepsis in which profound circulatory, cellular, and metabolic abnormalities increase mortality risk beyond sepsis alone.
Antibiotic Timing: Immediate empiric antimicrobial therapy within 1 h of shock recognition is recommended for bacterial septic shock.
qSOFA Score: Respiratory rate ≥ 22 breaths/min, Glasgow Coma Scale (GCS) < 15, and systolic blood pressure (SBP) ≤ 100 mmHg; a score ≥ 2 is associated with poor outcomes.
SOFA Score: An increase of ≥ 2 from baseline in any organ system defines sepsis.
Pathogen Prevalence: Approximately 88% of sepsis cases are community-onset; 53% of U.S. cases are bacterial culture positive.
Source Control: Identification and elimination of the source of infection (e.g., abscess, perforation) is imperative.
Fluid Resuscitation: Initial management includes administering appropriate intravenous crystalloid, ~30 mL/kg.
Mortality Risk: In patients with bacterial septic shock, there is an estimated 7–8% increase in mortality for every 1-h delay in appropriate antibiotic administration.
Neurologic Complications: Sepsis-associated encephalopathy occurs in over half of septic patients and is associated with increased mortality.

DEFINITION & OVERVIEW¶

• Sepsis Definition: - Sepsis-3 (Current): Life-threatening organ dysfunction caused by a dysregulated host response to infection. - Septic Shock: A subset of sepsis in which profound circulatory, cellular, and metabolic abnormalities increase mortality risk beyond sepsis alone. • Historical Context & Evolution: - Sepsis-1 (1992): Defined as the body's systemic response to infection; used SIRS criteria (Temp ≥ 38°C, HR > 90 bpm, RR > 20 breaths/min, PaCO_2 < 40 mmHg, WBC ≤ 12,000/μL or > 10% bands). - Sepsis-2 (2003): Acknowledged clinical complexity beyond SIRS; expanded criteria to include hypoperfusion or end-organ dysfunction. - Sepsis-3 (2016): Current standard; abandoned SIRS in favor of organ dysfunction markers.

Sepsis Mimics¶

• Noninfectious Inflammatory Febrile Syndromes: - Connective tissue diseases - Vasculitides • Respiratory/Pulmonary Mimics: - Heart failure - Noninfectious causes of pneumonitis or lung injury (e.g., noninfectious COPD) • Abdominal Mimics: - Mesenteric ischemia - Inflammatory bowel disease • Noninfectious Hypotension: - Hypovolemia - Autonomic dysfunction - Adrenal insufficiency

EPIDEMIOLOGY¶

• Global and U.S. Burden: - 48.9 million cases globally/year; 1.7 million in the U.S. - ~6% of hospitalized adults develop sepsis (stable incidence). - 11 million deaths globally/year (1 in 5 total global deaths); 85% occur in low- and middle-income countries. • Mortality Rates: - 15% overall mortality among U.S. hospitalized adults with sepsis. - Up to 40% mortality in patients with septic shock. • Risk Factors: - Age: Mortality increases with age; significantly higher in males across all age groups. - Comorbidities: Diabetes, obesity, neurologic/respiratory/cardiac conditions, renal or hepatic insufficiency, cancer, or other immunosuppressing conditions. - Recent Admission: Any hospital admission for any reason within 90 days is associated with a 3x increased risk of developing sepsis.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Pathogen Dynamics: - Community-Onset: ~88% (detected within 48h of admission). - Hospital-Onset: ~12% (higher risk of comorbidities, intraabdominal infections, and mortality). - Bacterial Prevalence: 53% of U.S. cases are bacterial culture positive. - Gram-Positive: S. aureus, Streptococcus spp., Enterococcus spp. (13.6% were antibiotic-resistant). - Gram-Negative: E. coli, Klebsiella spp., Pseudomonas aeruginosa (13.2% resistant to carbapenems/fluoroquinolones). - Primary Sites: Urinary tract (48.9%), Respiratory tract (32.9%), Intraabdominal (13.6%), Skin/Soft tissue (10.3%). • Immune Triggers: - PAMPs (Pathogen-Associated Molecular Patterns): e.g., bacterial lipopolysaccharide (LPS), cell wall/membrane components, nucleic acids. - DAMPs (Damage-Associated Molecular Patterns): e.g., histones, S100 proteins, oxidized phospholipids. - PRRs (Pattern Recognition Receptors): TLR (10 types), CLR, RAGE, RIG-I, and NOD receptors. • Myeloid & Lymphoid Responses: - Neutrophils: Release NETs (DNA + antimicrobial proteins like cathepsin-G, myeloperoxidase) → microvascular thrombosis; release ROS/RNS → tissue injury. - Monocytes: Transition to M1 pro-inflammatory macrophages; cause glycocalyx breakdown and endothelial activation (ICAM, VCAM-1, Tissue Factor). - Lymphoid Cells: NK cells contribute to pathogen clearance but can also mediate inflammatory responses; T/B cells may suffer from exhaustion or apoptosis in sepsis. • Coagulopathy & Complement: - Clotting: Increased Tissue Factor (TF) on endothelium/leukocytes → clotting cascade; increased PAI-1 → impaired fibrinolysis. - Complement: C3a and C5a activate platelets/myeloid cells; C5b-9 (MAC) promotes endothelial injury. • Cellular Injury: - Endothelial Dysfunction: Loss of VE-cadherin, increased permeability, and interstitial fluid accumulation. - Metabolic Failure: Disruption of mitochondrial function and ATP production leads to cellular injury and tissue hypoperfusion.

CLINICAL FEATURES¶

• General Presentation: - Non-specific: Fever, tachycardia, lethargy. - Localizing signs: Cough (respiratory), pyuria (urinary), abdominal pain. • Neurologic Complications: - Encephalopathy: Occurs in >50% of septic patients; associated with increased mortality. - Manifestations: Altered consciousness, cognition, or attention; seizure, stroke, or meningism.

DIAGNOSTIC APPROACH¶

Initial Screening:
qSOFA Score: RR ≥ 22; GCS < 15; SBP ≤ 100 mmHg. (Score ≥ 2 indicates high risk of poor outcome).
Confirmatory Diagnosis:
SOFA Score: Identify an increase of ≥ 2 from baseline in any organ system.
Septic Shock Identification:
Sepsis-induced hypotension (SBP < 90 mmHg or reduction ≥ 40 mmHg from baseline) despite adequate volume resuscitation.
Laboratory & Imaging:
Labs: CBC, BMP, LFTs, serum lactate, coagulation panel, UA.
Cultures: Blood, urine, sputum, wound (obtain before antibiotics).
Imaging: X-ray/ultrasound for lung; CT/ultrasound for abdomen.
Neurological Evaluation:
EEG for seizures; MRI/CT for stroke; Lumbar puncture for suspected meningitis.

MANAGEMENT & TREATMENT¶

Source Control:
Identify and eliminate the source of infection (e.g., abscess, perforation) immediately.
Fluid Resuscitation:
Initial: Crystalloid ~30 mL/kg.
Monitoring: Dynamic assessment of volume status; invasive blood pressure monitoring.
Antibiotic Therapy (Table 1):
Timing: Initiate within 1 hour of shock recognition.
Pulmonary (CAP):
Standard: β-lactam (ampicillin/sulbactam, ceftriaxone, or ceftaroline) + macrolide (azithromycin or clarithromycin).
Monotherapy: Respiratory fluoroquinolone (levofloxacin or moxifloxacin).
Additions: Vancomycin/linezolid for MRSA; Piperacillin-tazobactam, cefepime, meropenem, or imipenem for P. aeruginosa.
CNS (Meningitis/Ventriculitis):
Vancomycin + cefepime, ceftazidime, or meropenem; OR Vancomycin + ceftriaxone.
Skin and Soft Tissue:
Vancomycin/linezolid + piperacillin-tazobactam, a carbapenem, OR ceftriaxone + metronidazole.
Intraabdominal (Extrabiliary):
Imipenem-cilastin, meropenem, doripenem, or piperacillin-tazobactam.
Community: Cefazolin, cefuroxime, or ceftriaxone.
Intraabdominal (Biliary/Cholangitis):
Imipenem-cilastin, meropenem, or piperacillin-tazobactam + levofloxacin or cefepime + metronidazole.
Organ-Specific Management (Table 2):
Respiratory: Target SpO_2 90–96%; high-flow nasal cannula (if neurologically stable); target plateau pressure <30 cmH_2O; tidal volume 6–8 mL.
Gastrointestinal/Liver:
Avoid hypotension and hepatoxic agents; stress ulcer prophylaxis.
Enteral feeding if shock controlled within 48 h; Parenteral if not met within 7 days.
Insulin if blood glucose ≥ 180 mg/dL.
Neurologic:
Early recognition, supportive care, correct metabolic/electrolyte abnormalities; limit neurotoxic agents and sedatives.

PROGNOSIS & COMPLICATIONS¶

• Mortality Risk: - 7–8% increase in mortality for every 1-hour delay in appropriate antibiotic administration. • Organ Failure Prevalence: - Respiratory: 7% develop ARDS. - Renal: 67% develop acute kidney injury (AKI). - Liver: 50% of septic shock patients have liver dysfunction. - Coagulation: 35% of septic shock patients have DIC. • Neurological Sequelae: - Over half of patients experience encephalopathy; associated with long-term functional and neuropsychiatric sequelae.

KEY PEARLS & CLINICAL TRAPS¶

• Sepsis vs. Shock: Sepsis is the infection/dysregulation; Shock is the specific addition of circulatory/metabolic collapse. • Timing is Critical: The 1-hour window for antibiotics is a primary driver of survival. • Source Control: Must be performed concurrently with medical management. • Sepsis Mimics: Always rule out heart failure, COPD, and other noninfectious causes of hypotension/hypoxia.

Reference Tables¶

TABLE 315-1 Site-Specific Empiric Antibiotic Recommendations¶

Harrison's 22e, p.2321

SITE OF INFECTION	INITIAL EMPIRIC THERAPY	OTHER CONSIDERATIONS
Pulmonary
CAP	Multidrug therapy with a β-lactam (ampicillin + sulbactam, ceftriaxone, or ceftaroline) and a macrolide (azithromycin or clarithromycin) Monotherapy with a respiratory fluoroquinolone (levofloxacin or moxifloxacin)	Risk factors for MRSA and/or Pseudomonas aeruginosa: add vancomycin or linezolid for MRSA coverage; replace standard CAP therapy with antipseudomonal coverage such as piperacillin- tazobactam, cefepime, meropenem, or imipenem. Recommendation based on “local validation” of risk factors for community-onset MRSA or P. aeruginosa or prior isolation of these organisms in the previous year, particularly from respiratory specimens.
	Multidrug therapy with vancomycin or linezolid and piperacillin-tazobactam, cefepime, ceftazidime, imipenem, meropenem, or aztreonam
Central Nervous System
Health care–associated ventriculitis and meningitis	Vancomycin and cefepime, ceftazidime, or meropenem	β-Lactam choice based on local in vitro susceptibility patterns. If carbapenem-resistant Acinetobacter is suspected, addition of meropenem and colistin or polymyxin B.
	Vancomycin and ceftriaxone
Skin and Soft Tissue
Necrotizing fasciitis including Fournier gangrene	Multidrug therapy with vancomycin or linezolid and piperacillin-tazobactam, a carbapenem, or ceftriaxone and metronidazole	Prompt surgical consultation is recommended for patients with aggressive infections associated with signs of systemic toxicity or suspicion of necrotizing fasciitis or gas gangrene.
	Vancomycin and piperacillin-tazobactam
Purulent furuncle/ carbuncle/abscess (severe)	Vancomycin, daptomycin, linezolid, telavancin, or ceftaroline	Incision and drainage as indicated.
Intraabdominal
	Cefoxitin, ertapenem, moxifloxacin, or tigecycline
Community-onset extrabiliary (severe)	Imipenem-cilastatin, meropenem, doripenem, or piperacillin-tazobactam	Health care associated: imipenem-cilastatin, meropenem, or piperacillin-tazobactam, levofloxacin, or cefepime each along with metronidazole, vancomycin added to each regimen.
	Cefazolin, cefuroxime, or ceftriaxone
Community-onset biliary (severe) or cholangitis	Imipenem-cilastatin, meropenem, or piperacillin-tazobactam, levofloxacin, or cefepime each in combination with metronidazole
Genitourinary

TABLE 315-2 Organ-Specific Clinical Findings and Management Neurologic¶

Harrison's 22e, p.2322

	EPIDEMIOLOGY	CLINICAL FINDINGS	DIAGNOSIS	TREATMENT
Neurologic	54% of septic patients develop encephalopathy	Altered consciousness, cognition, or attention; seizure, stroke, or meningism	EEG, brain imaging (MRI or CT), lumbar puncture	Early recognition and supportive care; treat underlying cause; correct metabolic and electrolyte abnormalities; limit neurotoxic agents and sedatives
	25% of septic patients develop shock and half have myocardial dysfunction	Tachycardia, hypotension, skin mottling, prolonged capillary refill, oliguria, altered mental status	Invasive blood pressure monitoring, dynamic assessment of volume status, echocardiogram
Respiratory	7% of septic patients develop ARDS	Tachypnea, hypoxia, increased work of breathing	Chest x-ray or ultrasound with noncardiogenic bilateral infiltrates and Pao/Fio 2 2 <300 mmHg or Spo/Fio ≤315 2 2	Maintain Spo 90–96%; use high-flow nasal canula 2 in patients with adequate neurologic status; target plateau pressure <30 cmHO and tidal volume of 2 6–8 mL; consider rescue therapies in patients with refractory hypoxia
	67% of septic patients have acute kidney injury	Oligura or anuria	Elevated serum creatinine and blood urea nitrogen, acidemia, hyperkalemia
Gastrointestinal	50% of septic shock patients have liver dysfunction	Right upper quadrant pain, asterixis, jaundice	Elevated bilirubin, alkaline phosphatase, and transaminases; right upper quadrant ultrasound	Treat underlying infection, avoid hypotension and hepatoxic agents; stress ulcer prophylaxis for high- risk patients; enteral feeding if shock controlled within 48 h; parenteral feeding if nutrition goal not met within 7 days; insulin if blood glucose ≥180 g/dL
	35% of septic shock patients have disseminated intravascular coagulation	Clinical or subclinical thrombosis or hemorrhage	Thrombocytopenia, increased fibrin split products, decreased fibrinogen, prolonged PT/INR