Sepsis and Septic Shock

Sepsis and Septic Shock

David Ray Velez, MD

Table of Contents

Definition
Systemic Inflammatory Response Syndrome (SIRS)
Pathophysiology
Sequential Organ Failure Assessment (SOFA) Score
Treatment
Management Concepts

See Also:
*See Fever in Critically Ill

Definition

Modern Definitions (Based on “Sepsis-3”)

  • Sepsis: Life-Threatening Organ Dysfunction Caused by a Dysregulated Host Response to Infection
    • Organ Dysfunction Defined by SOFA Score ≥ 2
  • Septic Shock: Sepsis, Hypotension, and Lactate > 2 mmol/L
    • Hypotension Defined as Requirement of Vasopressors to Maintain MAP ≥ 65 mmHg

Old Definitions No Longer Used (Based on “Surviving SEPSIS”)

  • Systemic Inflammatory Response Syndrome (SIRS):An Exaggerated Proinflammatory Response to Stress
    • *SIRS No Longer Used in the Definition of Sepsis
  • Sepsis: SIRS with a Source of Infection
  • Severe Sepsis: Sepsis with Organ Dysfunction
  • Septic Shock: Sepsis with Hypotension

Systemic Inflammatory Response Syndrome (SIRS)

SIRS is No Longer Used in the Definition of Sepsis

Definition

  • An Exaggerated and Proinflammatory Response to Stressors (Infection, Trauma, Surgery, Ischemia, etc.)
  • Objective Criteria (≥ 2 of):
    • Temperature > 38°C or < 36°C
    • Heart Rate > 90 Beats per Minute
    • Respiratory Rate > 20 Breaths per Minute
    • Leukocyte Count > 12,000, < 4,000 or > 10% Bands

Pathophysiology

  • Initiated By: DAMP or PAMP Binding to TLR
    • Damage-Associated Molecular Pattern (DAMP): On Damaged Tissue
    • Pathogen-Associated Molecular Pattern (PAMP): On Foreign Pathogens
    • Toll-Like Receptors (TLR): Present on Endothelium and Immune Cells
  • Most Potent Stimulus: Endotoxin (Lipid A) – Stimulates TNFα Release
  • Primary Mediators: IL-1 and TNFα
    • Propagates Cytokine Pathway – Dissociation of NF-kB from its Inhibitor Induces Massive Release of Proinflammatory Cytokines (IL-6, IL-8, and Interferon-Gamma)
    • Alters Coagulation, Induces Coagulopathy, and Impairs Fibrinolysis with Microvascular Thrombosis and Increased Capillary Permeability
    • Induces Release of Stress Hormones – Catecholamines, Vasopressin, and RAAS Activation
  • Other Mediators:
    • Activation of Prostaglandin and Leukotriene Pathway
    • Activation of C3a-C5a Complement Pathway

Compensatory Anti-Inflammatory Response Syndrome (CARS)

  • An Exaggerated Response to SIRS in an Attempt to Maintain Immunological Balance
  • May Induce a Relative Immunosuppression – Increases Susceptibility to Infection, Promoting the Sepsis Cascade

Roger Bone Stages

  • Stage 1: Local Pro-Inflammatory Reaction at Site of Infection or Injury to Limit Injury and Prevent Spread
  • Stage 2: Early CARS to Maintain Immunologic Balance
  • Stage 3: SIRS Predominates Over CARS
  • Stage 4: CARS Becomes Excessive Inducing Relative Immunosuppression
  • Stage 5: Multiple Organ Dysfunction (MOD) from Dysregulation of SIRS and CARS

Pathophysiology

In-Hospital Mortality

  • Sepsis: ≥ 10%
  • Septic Shock: ≥ 40%

Impaired End-Organ Oxygen Utilization

  • *Not from Impaired Perfusion
  • Oxygen Consumption Increased in Early Shock
  • Decreased Utilization in Later Shock – Increased SvO2
  • Causes Multisystem Organ Dysfunction/Failure

Hyperglycemia

  • Early Hyperglycemia from Impaired Utilization of Insulin (Low Insulin Levels)
  • Late Hyperglycemia from Insulin Resistance (High Insulin Levels)

Diffuse Vasodilation and Hypotension

  • Mediated by ATP-Sensitive Potassium Channels in Smooth Muscle
    • Hyperpolarization Prevents Contraction
  • From Release of Nitric Oxide (NO), Prostacyclin,and Impaired Secretion of Vasopressin

Other Effects

  • Pulmonary Edema – From Pulmonary Vascular Endothelial Injury and Increased Permeability
  • Bacterial Translocation – Inhibition of Normal GI Barriers Allows Bacterial Translocation into Systemic Circulation
  • Acute Kidney Injury (AKI) – Highest Risk of Mortality of Any End-Organ System Dysfunction in Sepsis
  • Liver Dysfunction
  • Encephalopathy

Gram Negative Sepsis

  • Gram Negative Organisms Have Outer Membranes that Release Lipid A
  • Lipid A is a Lipopolysaccharide – Endotoxin that Induces Septic Shock
  • Most Common Organism: Escherichia coli

Sequential Organ Failure Assessment (SOFA) Score

Sequential Organ Failure Assessment (SOFA) Score

  • Change ≥ 2 Points Required for Modern Definition of Sepsis
  • Score Can Also Be Used to Predict Mortality Risk
  • Includes:
    • PaO2/FiO2 Ratio
    • GCS
    • Hemodynamic Stability – MAP & Vasopressor Requirements
    • Bilirubin (mg/dL)
    • Platelets (x 103/ul
    • Creatinine (umol/L) or UOP (cc/Day)
  PaO2/FiO2 Ratio GCS Hemodynamic Stability Bilirubin Plt Cr or UOP
0 ≥ 400 15 MAP ≥ 70 mmHg < 1.2 ≥ 150 < 1.2
+1 < 400 13-14 MAP < 70 mmHg 1.2-1.9 < 150 1.2-1.9
+2 < 300 10-12 Dopamine ≤ 5 ug/kg/min or Dobutamine Any Dose 2.0-5.9 < 100 2.0-3.4
+3 < 200 & Mechanically Ventilated 6-9 Dopamine > 5 ug/kg/min, Epinephrine ≤ 0.1 ug/kg/min or Norepinephrine ≤ 0.1 ug/kg/min 6.0-11.9 < 50 3.5-4.9 or UOP < 500 cc/d
+4 < 100 & Mechanically Ventilated 3-5 Dopamine > 15 ug/kg/min, Epinephrine > 0.1 ug/kg/min or Norepinephrine > 0.1 ug/kg/min ≥ 12 < 20 ≥ 5.0 or UOP < 200 cc/d

Quick SOFA (qSOFA) Score

  • A Modified SOFA Score to Assist in Identification of Early Sepsis
  • Definition: ≥ 2 of:
    • Systolic Blood Pressure ≤ 100 mmHg
    • Respiratory Rate ≥ 22 Breaths per Minute
    • Altered Mental Status (GCS ≤ 14)
  • Associated with Prolonged ICU Stay, Poor Outcomes, and Increased Mortality

Treatment

Medical Emergency that Requires Immediate Treatment and Resuscitation

Immediate Treatment: IV Fluid Resuscitation and Broad-Spectrum Antibiotics

  • Obtaining Blood Cultures Before Starting Broad-Spectrum Antibiotics
  • Early Source Control is Paramount

Fluid Resuscitation

  • IV Fluid: 30 cc/kg Lactated Ringer Bolus
  • Give within the First 3 Hours
  • May Require Additional Fluid Depending on the Clinical Scenario
  • Restrictive Fluid Strategy is Non-Inferior to Liberal Fluids Strategy
  • Transfuse for a Goal Hgb ≥ 7.0 g/dL

Vasopressor Support

  • Vasopressors Generally Started if Patient Remains Hemodynamically Unstable After the IV Fluid Bolus
  • Goal MAP ≥ 65 mmHg
    • Should Be Individualized to the Patient
    • MAP 60-65 May Not Be Harmful if There are No Signs of End-Organ Hypoperfusion
  • First Line: Norepinephrine (Levophed)
    • *Superior to Dopamine Due to Risk of Tachyarrhythmia
  • Second Line: Vasopressin
    • Started Once Norepineprine Dose Has Increased to 0.20-0.25 mcg/kg/min
    • Given at a Fixed Rate of 0.03-0.04 U/min
    • Reduces Vasopressor Requirements but No Change in Mortality
  • Third Line: Epinephrine (Often Preferred), Phenylephrine, or Dopamine

Steroids

  • Use Early – Often Started if Adding a Second Vasopressor
  • Do Not Need to Confirm Adrenal Insufficiency Before Starting – May Have Additional Benefits in Sepsis Outside of Adrenal Insufficiency
  • Typical Dosing: 200 mg Hydrocortisone Daily (Often 50 mg QID)
  • *Steroids Show Faster Resolution of Shock and Possible Mortality Benefit

Management Concepts

Early Goal Directed Therapy (EGDT)

  • Definition: Intensive Monitoring and Aggressive Management of Specific Circulatory Parameters within the First 6 Hours of Presentation
  • Goal: To Optimize Oxygen Delivery to Tissues
  • Parameters:
    • CVP 8-12
    • MAP ≥ 65
    • Urine Output > 0.5 cc/kg/hr
    • Central Venous Oxygen Saturation (ScvO2) > 70%
    • Hematocrit (Hct) ≥ 30%
  • Therapies:
    • Early Use of Mechanical Ventilation
    • Fluid Resuscitation
    • Vasopressor Support
    • Blood Transfusion
  • Aggressive Therapies Can Increase the Risk of Fluid Overload, Arrhythmia, and Transfusion Reactions
  • Although the Initial RCT (Rivers 2001) Saw Mortality Benefit, Further Studies Have Failed to Show a Clear Benefit

Procalcitonin (PCT)

  • Pathophysiology:
    • Procalcitonin is a Calcitonin Precursor Produced in Thyroid C-Cells at Low Levels (< 0.1 ng/mL)
    • During Sepsis Extra-Thyroidal Production Occurs in Inflamed and Infected Tissues
      • Mostly in Neuroendocrine Cells of the Lung and Intestine
      • Triggered by Inflammatory Cytokines and Bacterial Endotoxins
  • Use:
    • Primarily Used as a Biomarker in Sepsis to Guide Antibiotic Therapy
    • Often Described in the Management of Community-Acquired Pneumonia (CAP)
    • Should Decrease by ≥ 30% Per Day During Resolution of Sepsis
  • Likelihood of Bacterial Infection:
    • ≤ 0.10 ng/mL – Very Unlikely
    • 10-0.25 ng/mL – Unlikely
    • 25-0.50 ng/mL – Likely
    • ≥ 0.50 ng/mL – Very Likely
  • Monitoring Antibiotic Therapy:
    • PCT < 0.25 ng/mL: Stop Antibiotics
    • PCT > 0.25 ng/mL:
      • Decreased > 80% from Peak: Stop Antibiotics
      • Decreased < 80% from Peak: Continue Antibiotics
      • Not Decreased from Peak: Change Antibiotics
    • *In Critically Ill Patients a Target PCT < 0.50 ng/mL May Be Used – Baseline Levels are Generally Higher