Inflammation and Shock - Foundations of Tissue Perfusion and Cellular Response

What is tissue perfusion?

The process of delivering oxygenated blood to tissues and removing waste products via the circulatory system

Importance of Tissue Perfusion

• Maintains cellular metabolism and ATP production

• Essential for organ function - brain, heart, kidneys are most sensitive

  • “muscles”

• Impaired perfusion → ischemia, cell death, organ failure

  • “ischemia = reduced blood flow to a specific area leading to insufficient oxygen perfusion in that area”

What is the formula for cardiac output (CO)?

Cardiac Output (CO) = Stroke Volume x Heart Rate

Cardiac Output

Volume of blood pumped by the heart per minute (normal: 4-8 L/min)

Stroke Volume

• Preload: ventricular filling (end-diastolic volume)

  • “end-diastolic volume = the amount of blood in the heart's ventricles (left and right) at the end of the relaxation phase (diastole)”

• Contractility: Strength of ventricular contraction

• Afterload: Resistance the ventricle must overcome to eject blood

Heart Rate

Controlled by autonomic nervous system:

• Sympathetic: ↑HR (β1 receptors)

  • “Fight or Flight, ↓SV”

• Parasympathetic: ↓HR (vagus nerve)

  • “Rest and Digest, ↑SV”

Definition of Systemic Vascular Resistance (SVR)

• Resistance blood encounters in systemic circulation (mainly arterioles)

  • “blood → get to tissues”

  • “arterioles = small branch of an artery leading into capillaries”

Analogy of Systemic Vascular Resistance (SVR)

SVR acts like a vise grip on the aorta - tight grip = harder for blood to flow

Impact of Systemic Vascular Resistance (SVR)

• ↑SVR → ↑Afterload → ↑Cardiac workload

  • “vasoconstriction”

• ↓SVR → ↓Afterload → easier ejection but risk of hypotension

  • “vasodilation”

  • “during hypotension: fluid is hanging out in the tissues, not going back to the heart”

Venous System

Stores 70-80% of total blood volume (acts as reservoir)

Venous Return

Influences preload and therefore stroke volume

Regulation of Venous Return & Blood Reservoir

• Vasoconstriction: ↑Venous return  →  ↑Preload  →  ↑CO

• Vasodilation: ↓Venous return  →  ↓Preload  →  ↓CO

What is Inflammation?

A protective response to injury, infection, or irritation

Goals of Inflammation

• Eliminate the initial cause of cell injury

• Clear out necrotic cells and tissues

• Initiate tissue repair

Clinical Relevance of Inflammation

Seen in infections, trauma, autoimmune conditions

Acute Inflammation

• Rapid onset, short duration

• Predominantly neutrophil response

• Examples: Appendicitis, cellulitis

Chronic Inflammation

• Persistent, long-term

• Involves macrophages, lymphocytes

• Examples: Rheumatoid arthritis, Crohn’s disease

Cardinal Signs of Inflammation

• Redness (rubor)

• Heat (calor)

• Swelling (tumor)

• Pain (dolor)

• Loss of function (functio laesa)

Cardinal Signs of Inflammation: Redness (rubor)

Due to vasodilation and increased blood flow

Cardinal Signs of Inflammation: Heat (calor)

Increased blood flow and metabolic activity

Cardinal Signs of Inflammation: Swelling (tumor)

Accumulation of fluid from increased vascular permeability

Cardinal Signs of Inflammation: Pain (dolor)

Release of chemical mediators stimulating nerve endings

Cardinal Signs of Inflammation: Loss of function (functio laesa)

Result of pain and swelling limiting movement

Cellular & Chemical Mediators: Neutrophils

First responders, phagocytose pathogens

Cellular & Chemical Mediators: Macrophages

Clean up debris, release cytokines

• “cytokines → big inflammatory mediators, raise temperature”

Cellular & Chemical Mediators: Mast Cells

Release histamine, trigger vasodilation

• “seen earlier in inflammatory processes”

Cellular & Chemical Mediators: Cytokines

IL-1, TNF-alpha promote inflammation and fever

Cellular & Chemical Mediators: Histamine

Increases vascular permeability

Cellular & Chemical Mediators: Prostaglandins

Mediate pain and fever

Systemic Effects of Inflammation: Fever

Triggered by cytokines acting on hypothalamus

Systemic Effects of Inflammation: Leukocytosis

↑ Elevated white blood cell count

Systemic Effects of Inflammation: Increased CRP and ESR

Markers of systemic inflammation

Systemic Effects of Inflammation: Link to SIRS

Systemic inflammatory response can progress to septic shock

• “SIGNS: fever, tachycardia, hypotension, decreased urine output”

Inflammation & Shock Connection

• Inflammatory mediators cause vasodilation and increased capillary permeability

• Fluid shifts from intravascular to interstitial space

• ↓Preload → ↓Cardiac output → ↓Tissue perfusion

• Seen in septic shock and other distributive shock states

Distributive Shock

Often results from systemic inflammation

• (e.g., sepsis, anaphylaxis)

Cytokine Storm

Excessive release of inflammatory cytokines

• (e.g., IL-1, TNF-alpha)

• “seen in autoimmune diseases”

Effects of Inflammation (Cytokine Storm) and (Distributive) Shock

• Vasodilation

• Increased capillary permeability

• Fluid shifts →  ↓Preload and ↓Perfusion

What is Stress Hyperglycemia triggered by?

Critical illness, trauma, or infection

What are the hormonal drivers of Stress Hyperglycemia?

Catecholamines, cortisol, glucagon → ↑gluconeogenesis and insulin resistance

What is the clinical impact of Stress Hyperglycemia?

Hyperglycemia can impair immune function and wound healing

What are the blood glucose targets in a patient with Stress Hyperglycemia?

140-180 mg/dL in critically ill patients (per ADA guidelines)

Clinical Pearls: What does Stroke Volume (SV) depend on?

• Preload

• Contractility

• Afterload

Clinical Pearls: Pump vs. Volume

Evaluate both myocardial function and intravascular volume status

• “Heart innate function vs. fluid status”

Definition of Shock

A life-threatening condition where the circulatory system fails to deliver adequate oxygen and nutrients to meet tissue metabolic demands

Common Pathophysiologic Thread of Shock

Inadequate tissue perfusion → cellular hypoxia → anaerobic metabolism → lactic acidosis → organ dysfunction

Key Consequences of Shock

• ↓ATP production

• Cell membrane dysfunction

• Multi-organ failure if untreated

Cause of Hypovolemic Shock

• Absolute fluid loss: hemorrhage (trauma, GI bleed), severe dehydration

• Relative fluid loss: Third spacing (burns, peritonitis)

Pathophysiology of Hypovolemic Shock

↓Intravascular volume →  ↓Venous return (preload) →  ↓Stroke volume →  ↓Cardiac output  →  ↓Tissue perfusion

Clinical Clues of Hypovolemic Shock

• Tachycardia

• Hypotension

• Cool, clammy skin 

  • “due to vasoconstriction”

• ↓ Urine output 

Cause of Cardiogenic Shock

• Myocardial infarction (most common)

• Severe heart failure

• Arrhythmias

Pathophysiology of Cardiogenic Shock

Pump failure → ↓Stroke volume despite adequate volume → ↓Cardiac output → ↓Tissue perfusion

Clinical Clues of Cardiogenic Shock

• Pulmonary edema

  • “fluid in lungs → swelling”

• Jugular venous distension

• Hypotension

• Weak pulses

Cause of Obstructive Shock

• Cardiac tamponade

• Massive pulmonary embolism

• Tension pneumothorax

Pathophysiology of Obstructive Shock

Physical obstruction to blood flow  →  ↓Venous return or ↓Outflow  →  ↓Cardiac output  →  ↓Tissue perfusion

Clinical Clues of Obstructive Shock

• Distended neck veins

• Muffled heart sounds (tamponade)

• Sudden dyspnea (PE)

Subtypes of Distributive Shock

• Septic

• Neurogenic

• Anaphylactic

Pathophysiology of Distributive Shock

Massive vasodilation → ↓SVR → relative hypovolemia → ↓Tissue perfusion

Cause of Septic Shock

Severe infection leading to systemic inflammatory response

Pathophysiology of Septic Shock

Inflammatory mediators → vasodilation and capillary leak → ↓SVR and preload → ↓Tissue perfusion

Clinical Features of Septic Shock

• Fever

• Warm, flushed skin (early)

• Hypotension

• Tachycardia

Cause of Neurogenic Shock

Spinal cord injury disrupting sympathetic tone

Pathophysiology of Neurogenic Shock

Loss of sympathetic tone → vasodilation → ↓SVR → ↓Tissue perfusion

Clinical Features of Neurogenic Shock

• Bradycardia

• Hypotension

• Warm, dry skin

Cause of Anaphylactic Shock

Severe allergic reaction (e.g., food, insect stings, medications)

Pathophysiology of Anaphylactic Shock

Histamine release → massive vasodilation and increased capillary permeability → ↓SVR and preload → ↓Tissue perfusion

Clinical Features of Anaphylactic Shock

• Hypotension

• Tachycardia

• Airway compromise

• Urticaria

Anaerobic Metabolism in Shock

• In shock, reduced oxygen delivery forces cells into anaerobic glycolysis

• Anaerobic metabolism yield only 2 ATP per glucose (vs. 36 in aerobic)

• Lactic acid accumulates → metabolic acidosis → impaired cellular function

What are the clinical signs of anaerobic metabolism in shock?

• Elevated lactate

• low pH

• Tachypnea

Mitochondrial Dysfunction

• Mitochondria are essential for ATP production via oxidative phosphorylation

• In shock, hypoxia and toxins impair mitochondrial function

• Analogy: ‘Canaries in the coal mine’ - mitochondria fail early in stress

Consequences of Mitochondrial Dysfunction

↓ATP  →  cell death, organ failure

Electrolyte Derangements

• Na+/K+ pump failure due to ATP depletion

• Sodium and water enter cells → cellular edema

• Potassium leaks out → hyperkalemia

• Membrane permeability increases → risk of cell lysis

Why CRP Increases in Shock States

• CRP (C-reactive protein) is an acute-phase reactant made by the liver

• Triggered by cytokines like IL-6 during systemic inflammation

• Shock (septic, cardiogenic, hypovolemic) causes tissue hypoxia and injury

• Cytokine release stimulates CRP production 

• CRP binds to damaged cells, activates complement, and enhances phagocytosis

Clinical Significance of Increased CRP in Shock States

• Elevated CRP reflects inflammation and tissue damage

• In septic shock, CRP correlates with severity and prognosis

• Normal: <10 mg/L | Moderate: 10-100 mg/L | Severe: >100 mg/L

What are normal lactate levels?

0.5-2.2 mol/L

What do elevated levels of serum lactate indicate?

They indicate tissue hypoxia and anaerobic metabolism

What is the prognostic marker for serum lactate?

Higher levels correlate with worse outcomes

What is serum lactate as a marker used for?

Used to guide resuscitation and monitor response to therapy

Procalcitonin (PCT)

• Precursor of calcitonin, elevated in bacterial infections

• Rises early in sepsis and septic shock

• Helps differentiate bacterial vs. viral infections

• Levels > 2 ng/mL suggest severe systemic infection

D-dimer

• Fibrin degradation product, elevated in coagulation activation

• Increased in septic shock, DIC, and thromboembolic events

• Non-specific but useful in ruling out PE/DVT

• High levels may indicate poor prognosis