What are the causes and pathogenesis of Systemic Inflammatory Response Syndrome (SIRS)?

Causes and Pathogenesis of Systemic Inflammatory Response Syndrome (SIRS)

Systemic Inflammatory Response Syndrome (SIRS) is caused by both infectious and non-infectious triggers that activate a dysregulated inflammatory cascade, resulting in the release of pro-inflammatory cytokines and mediators that lead to systemic manifestations including fever/hypothermia, tachycardia, tachypnea, and abnormal white blood cell count. 1, 2

Definition and Diagnostic Criteria

SIRS is defined by the presence of at least two of the following clinical parameters:

• Temperature >38°C (100.4°F) or <36°C (96.8°F)
• Heart rate >90 beats/minute
• Respiratory rate >20 breaths/minute or PaCO₂ <32 mmHg
• White blood cell count >12,000/μL or <4,000/μL or >10% immature (band) forms 1, 2

Causes of SIRS

Infectious Causes

• Bacterial infections leading to sepsis
• Viral infections
• Fungal infections
• Parasitic infections

Non-Infectious Causes

1. Tissue Injury 1

   • Surgery/trauma
   • Hematoma/venous thrombosis
   • Myocardial/pulmonary infarction
   • Burns

2. Therapy-Related 1

   • Blood products
   • Cytokines (especially granulocyte-macrophage colony stimulating factor)
   • Anesthetic-related malignant hyperpyrexia (especially halothane)
   • Neuroleptic malignant syndrome (e.g., caused by haloperidol)
   • Opiates/benzodiazepines

3. Neurological 1

   • Subarachnoid hemorrhage

4. Other Conditions 1

   • Transplant rejection
   • Pancreatitis
   • Erythroderma
   • Thyroid storm
   • Adrenal insufficiency

Pathophysiological Mechanisms

Inflammatory Cascade

1. Initial Trigger

   • Tissue damage releases damage-associated molecular patterns (DAMPs)
   • Pathogens release pathogen-associated molecular patterns (PAMPs)
   • These patterns activate pattern recognition receptors on immune cells 3

2. Cytokine Release

   • Activation of immune cells leads to release of pro-inflammatory cytokines:
     • Tumor necrosis factor-alpha (TNF-α)
     • Interleukin-1 beta (IL-1β)
     • Interleukin-6 (IL-6)
     • Interleukin-8 (IL-8) 1, 3

3. Amplification

   • Cytokines activate more immune cells, creating a positive feedback loop
   • Complement activation (particularly C5a)
   • Release of reactive oxygen species (ROS) and reactive nitrogen species (RNS) 3

4. Endothelial Dysfunction

   • Increased vascular permeability
   • Upregulation of adhesion molecules (ICAM-1)
   • Neutrophil recruitment and activation 3, 4

Surgical Trauma and SIRS

The "trauma of surgery" triggers release of stress hormones and inflammatory mediators, leading to:

• Catabolism of glycogen, fat, and protein stores
• Release of glucose, free fatty acids, and amino acids into circulation
• Support for tissue healing processes 1

Cardiopulmonary Bypass (CPB) and SIRS

CPB during cardiac surgery is a significant trigger for SIRS due to:

• Surgical trauma
• Blood contact with non-physiological surfaces (pump tubing, oxygenator)
• Myocardial ischemia and reperfusion
• Hypothermia
• These factors combine to cause dramatic release of cytokines 1

Progression and Complications

Organ Dysfunction

SIRS can progress to multiple organ dysfunction syndrome (MODS) when the inflammatory response becomes excessive, leading to:

• Acute lung injury/ARDS
• Acute kidney injury
• Cardiovascular dysfunction
• Neurological impairment 3, 4

Risk Factors for Progression

• Age (especially >75 years)
• Malnutrition
• Diabetes
• Smoking
• Obesity
• Prolonged hospitalization
• Shock and hypoxemia
• Hypothermia 1

Clinical Implications

Monitoring and Management

• Regular assessment of vital signs and organ function
• Tracking of laboratory markers (WBC count, lactate)
• Early identification of source if infectious
• Fluid management targeting near-zero balance
• Source control measures when applicable 2

Special Considerations

• Elderly and immunocompromised patients may not exhibit typical SIRS responses despite serious underlying conditions
• Mortality risk increases with the number of SIRS criteria present and with progression to organ dysfunction 2

Preventive Strategies

• Minimizing surgical trauma when possible
• Appropriate perioperative nutrition
• Maintaining near-zero fluid balance during major procedures
• Consideration of specialized CPB circuits to reduce inflammatory activation in cardiac surgery 1

It's important to note that while SIRS was initially developed as a clinical tool to identify patients for sepsis trials, it represents a common pathway of inflammatory response to diverse injuries and remains clinically relevant for early identification of patients at risk for adverse outcomes 5.