What is the pathophysiology and treatment of sepsis?

Sepsis Pathophysiology and Treatment

Pathophysiology

Sepsis is a dysregulated host response to infection causing life-threatening organ dysfunction through microvascular dysfunction, inflammatory mediator damage, and cellular metabolic failure. 1

Core Pathophysiological Mechanisms

Inflammatory Cascade and Tissue Damage:

• Pathogen-associated molecular patterns (PAMPs) trigger widespread inflammatory reactions causing direct cytotoxic effects from inflammatory mediators and microbial toxins 1
• Recruitment of inflammatory cells, endothelial damage, and increased vascular permeability contribute to organ dysfunction 1
• The process involves both hyperinflammatory and immunosuppressed states, with substantial heterogeneity between patients 2

Microcirculatory Dysfunction:

• Interstitial edema, capillary microembolization, microthrombi formation, and loss of microvascular blood flow regulation lead to perfusion mismatch 1
• If microvascular dysfunction is not corrected, it progresses to global tissue hypoxia, direct tissue damage, and ultimately organ failure 1
• Decreased peripheral vascular resistance occurs despite compensatory increases in heart rate 1

Cardiac Dysfunction (Septic Cardiomyopathy):

• Myocardial depression prevents adequate cardiac output increases despite compensatory mechanisms 1
• Caused by myocardial depressant factors including toxins, cytokines, metabolic defects of myocytes, and beta-receptor down-regulation 1
• Decreased preload from altered ventricular compliance and reduced right ventricular venous return (venous pooling, fluid sequestration) 1

Tissue Oxygenation Failure:

• Inadequate regional oxygen supply due to perfusion mismatch is a critical factor beyond global oxygen transport restrictions 1
• Respiratory failure, decreased cardiac output, and anemia compound the oxygen delivery problem 1

Treatment Approach

Immediate Recognition and Resuscitation

Early Fluid Resuscitation:

• Prompt administration of intravenous crystalloid solutions is critical and should be titrated to clinical response, not predetermined protocols 1
• Crystalloid solutions are first choice because they are well tolerated and cost-effective 1
• Infuse rapidly to induce quick response but avoid artificial stress response; interrupt when no improvement in tissue perfusion occurs 1
• Monitor for fluid overload (basal lung crepitations indicate overload or impaired cardiac function) 1
• Ultrasound measurement of inferior vena cava diameter can guide resuscitation 1

Target Parameters:

• Mean arterial pressure (MAP) ≥65 mmHg 1
• Urine output ≥0.5 mL/kg/h 1
• SpO2 ≥95% 1
• Central venous oxygen saturation >70% 1

Vasopressor Therapy

Initiation Criteria:

• If adequate MAP >65 mmHg cannot be achieved despite adequate intravascular filling, vasoconstrictors must be used 1
• Early vasopressor use reduces organ failure incidence 1

Agent Selection:

• Noradrenaline (norepinephrine) should be used first-line as a potent vasoconstrictor 1
• Vasopressin (0.01-0.04 units/min) or terlipressin (boluses of 1-2 mg) are rescue therapies for refractory shock 1

Inotropic Support

Indication:

• Not routinely recommended; only indicated when low cardiac output is accompanied by central venous oxygen saturation <70% despite optimal fluid resuscitation, anemia correction, and vasopressor use 1
• Titrate to targeted response: improvements in central venous oxygen saturation, myocardial function indices, and lactate reduction 1

Agent Selection:

• Combination of dobutamine and noradrenaline (stimulates α1 and β2 receptors) is first-line treatment 1
• Adrenaline is equally efficacious but not routinely used due to metabolic side effects 1

Corticosteroid Therapy

Specific Indication:

• Steroids should only be initiated in septic shock requiring vasopressor support despite adequate fluid resuscitation 3
• Hydrocortisone 200-300 mg/day for at least 5 days, followed by tapering 1
• Do not use corticosteroids in sepsis without shock—no evidence of benefit and potential for harm 3

Evidence Quality:

• Weak recommendation with approximately 2% absolute reduction in 28-day mortality 3
• Patients with high SOFA scores and refractory shock derive greatest mortality benefit 3

Monitoring and Prognostic Assessment

Clinical Monitoring:

• Serial SOFA score monitoring to detect deterioration 3
• Lactate measurement is important for initial evaluation, though elevated lactate is now only used to define septic shock, not sepsis 1
• Early warning scores using physiological parameters (blood pressure, pulse, respiratory rate, temperature, oxygen saturation, consciousness level) 1

Mortality Risk Stratification:

• No sepsis: 1.2% mortality 1
• Sepsis only: 4.4% mortality 1
• Severe sepsis: 27.8% mortality 1
• Septic shock: 67.8% mortality 1

Critical Pitfalls to Avoid

• Do not delay fluid resuscitation or antibiotic administration—speed of treatment initiation directly influences prognosis 1
• Do not use predetermined fluid protocols; titrate to individual clinical response 1
• Do not initiate steroids based on elevated inflammatory markers (e.g., CRP) alone without vasopressor-dependent shock 3
• Do not continue fluid loading when no improvement in tissue perfusion occurs 1