Pathophysiology of Acute Pancreatitis

Etiology (Triggers)

Core Pathogenic Mechanism: Premature Trypsin Activation

Three Initiating Pathways

1. Pancreatic Duct Obstruction

2. Primary Acinar Cell Injury

• Transiently increases exocrine secretion and causes sphincter of Oddi spasm
• Direct oxidative stress on acinar cells causing membrane damage
• Causes secretion of protein-rich pancreatic fluid, forming inspissated protein plugs that obstruct small ducts
• Triggers delivery of proenzymes to the lysosomal compartment (see below)

3. Defective Intracellular Transport of Proenzymes

Trypsin as the Master Activator

• Activates all other digestive proenzymes (chymotrypsinogen, proelastase, prophospholipase A2, prolipase) - triggering a positive feedback loop
• Converts prekallikrein → kallikrein, initiating the kinin system (bradykinin release → vasodilation and pain)
• Activates Factor XII (Hageman factor), triggering the clotting cascade and complement system
• Directly injures blood vessel walls, enabling hemorrhage

Downstream Cascade of Injury

Trypsin activation
       ↓
Proteases → proteolytic destruction of parenchyma
Lipase/Phospholipase A2 → fat necrosis (saponification with Ca²⁺)
Elastase → dissolution of vessel walls → hemorrhage
       ↓
Macrophage/neutrophil recruitment
       ↓
Cytokine storm (IL-1β, IL-6, IL-8, TNF-α)
       ↓
Increased vascular permeability → edema, third-spacing
       ↓
Systemic Inflammatory Response Syndrome (SIRS)

Local Pathological Consequences

1. Microvascular leakage - causing interstitial edema
2. Fat necrosis by lipases - released fatty acids + calcium → chalky white calcium soaps
3. Acute inflammatory reaction - neutrophil/macrophage infiltration
4. Proteolytic destruction of parenchyma and blood vessels → hemorrhage

Systemic Complications (SIRS to MOF)

• Pulmonary: increased microvascular permeability + enzymatic degradation of surfactant (phospholipase A2) → ARDS, pleural effusions (left > right, present in ~50% of severe cases), atelectasis
• Cardiovascular: massive fluid third-spacing + vasodilation → distributive shock, decreased MAP
• Renal: hypoperfusion + inflammatory mediators → acute tubular necrosis / renal failure
• Coagulopathy: cytokine-mediated coagulation cascade activation → DIC
• Sepsis: bacterial translocation across the disrupted gut mucosal barrier → bacteremia and infected pancreatic necrosis
• Metabolic: hypocalcemia (from saponification), hyperglycemia (islet destruction)

Summary Flowchart

Inciting event (gallstone / alcohol / hypertriglyceridemia / drugs)
            ↓
Acinar cell injury (via duct obstruction / direct toxicity / defective transport)
            ↓
Premature trypsinogen → trypsin activation
            ↓
Cascade activation of all digestive enzymes
            ↓
Autodigestion: fat necrosis, proteolysis, hemorrhage
            ↓
Cytokine release (TNF-α, IL-1β, IL-6), complement, kinin activation
            ↓
Local: edema, interstitial pancreatitis → necrotizing pancreatitis
            ↓
Systemic: SIRS → ARDS, renal failure, shock, DIC (multi-organ failure)

• Robbins & Kumar Basic Pathology, Chapter 15 (Pancreas), pp. 640-641
• Rosen's Emergency Medicine, Chapter 77 (Pancreatitis), pp. 1264-1265
• Sleisenger & Fordtran's Gastrointestinal and Liver Disease, Chapter 57

Management of Shock

Classification of Shock

Key concept: Shock can exist with a normal blood pressure. A base deficit more negative than -4 mEq/L or serum lactate >4.0 mmol/L warrants a presumptive diagnosis of shock regardless of BP.

General Principles of Management (All Shock Types)

Step 1: Secure Airway, Breathing, Circulation

• High-flow oxygen; early intubation if respiratory failure or severe obtundation
• Two large-bore IV lines (minimum 16G); intraosseous (IO) access if IV access is delayed - IO can deliver all resuscitation fluids and medications
• If IV/IO unavailable, peripherally-sited vasopressors can be infused via an 18G or larger catheter at the antecubital fossa or more proximally

Step 2: Identify and Treat the Underlying Cause Simultaneously

• Hemorrhagic: control bleeding
• Septic: antibiotics + source control
• Cardiogenic: revascularization / mechanical support
• Obstructive: decompress (needle thoracostomy, pericardiocentesis, thrombolysis)

Step 3: Hemodynamic Monitoring and Targets

• Urine output: target >0.5 mL/kg/h (reliable index of renal perfusion; normal is 1.0 mL/kg/h)
• Serum lactate: trend is more important than single value; lactate clearance >10% per 2h is a positive sign
• Base deficit: target toward 0; base deficit worse than -4 mEq/L = significant shock
• MAP: generally target ≥65 mmHg
• Arterial line for continuous BP monitoring in refractory shock
• Central venous access for vasopressor infusion and CVP monitoring when peripheral access is inadequate

1. Hemorrhagic Shock (Hypovolemic)

ATLS Classification

Caveat: ATLS classes are not rigidly reliable. Tachycardia is neither sensitive nor specific for hemorrhage. Children compensate with large volumes until sudden decompensation; elderly patients decompensate at lower volumes.

Resuscitation Strategy

1. Immediate hemorrhage control: direct pressure, tourniquet, traction splinting for long-bone fractures, REBOA (resuscitative endovascular balloon occlusion of the aorta) for non-compressible torso hemorrhage
2. Fluid resuscitation:
   • Class I-II: judicious isotonic crystalloid (10-20 mL/kg)
   • Class III-IV or suspected massive hemorrhage: balanced transfusion of packed red blood cells (PRBCs) : fresh frozen plasma (FFP) : platelets in a 1:1:1 ratio is preferred over crystalloid alone
   • Avoid large-volume crystalloid resuscitation - causes dilutional coagulopathy, hypothermia, and abdominal compartment syndrome
3. Permissive hypotension (damage control resuscitation): in penetrating trauma with uncontrolled bleeding, target SBP ~80-90 mmHg until hemorrhage control is achieved - prevents "popping the clot"
4. Lethal Triad prevention: Hypothermia + Acidosis + Coagulopathy form a deadly positive-feedback loop:
   • Hypothermia impairs coagulation enzyme activity by 40% even with a drop of a few degrees
   • Warm all IV fluids; use warming blankets; minimize heat loss
   • Transfuse early to correct coagulopathy
5. Transfusion trigger: Hgb <7 g/dL in stable patients; higher thresholds in active hemorrhage or cardiac ischemia

2. Septic Shock (Distributive)

Definition (Sepsis-3)

• Sepsis: suspected/confirmed infection + SOFA score increase ≥2
• Septic shock: sepsis + vasopressor requirement + lactate >2 mmol/L despite adequate volume

Hour-by-Hour Management (Surviving Sepsis Bundle)

• Obtain blood cultures (≥2 sets) before starting antibiotics
• Administer broad-spectrum IV antibiotics within 1 hour of sepsis recognition
• Measure lactate
• Begin IV fluid resuscitation

• Initial bolus: 30 mL/kg IV balanced crystalloid (e.g., lactated Ringer's preferred over 0.9% NaCl, which causes hyperchloremic acidosis) in the first 3 hours
• Reassess frequently with dynamic indices (pulse pressure variation, stroke volume variation) - avoid fluid overload
• Add albumin when large volumes of crystalloid are required
• Do not use hetastarch (HES) - associated with acute kidney injury and increased mortality

• First-line: Norepinephrine (0.01-3 mcg/kg/min) - α1 and β1 agonist; increases SVR and MAP
• Vasopressin: add as fixed-rate adjunct (0.03-0.04 units/min) when norepinephrine dose reaches 0.25-0.5 mcg/kg/min; do not use alone
• Epinephrine: add if hypotension persists despite NE + vasopressin
• Dopamine: avoid in most cases; reserve for highly selected circumstances (e.g., bradycardic patients)
• Dobutamine: add to norepinephrine if low cardiac output state persists despite adequate fluid resuscitation

• Hydrocortisone 200 mg/day IV (as continuous infusion or divided doses) if shock persists despite adequate fluids and vasopressors
• Do not use to treat sepsis without shock

• Target Hgb 7-9 g/dL (higher only in tissue hypoperfusion, CAD, or acute hemorrhage)
• For ARDS: low tidal volume ventilation (6 mL/kg ideal body weight), plateau pressure ≤30 cmH2O, PEEP titration
• Prone positioning ≥12 hours/day for moderate-severe ARDS
• ECMO if severe ARDS fails conventional ventilation (in experienced centers)
• Tight glucose control: avoid hypoglycemia; target <180 mg/dL

3. Cardiogenic Shock

Key Features

• Low cardiac output + elevated filling pressures
• Clinical: cold, clammy extremities; elevated JVP; pulmonary oedema; S3 gallop

Management

1. Oxygen and ventilatory support: non-invasive positive pressure ventilation (CPAP/BiPAP) reduces work of breathing and preload in pulmonary oedema; intubate if needed; apply PEEP
2. Treat the underlying cause urgently:
   • ACS: emergent PCI (percutaneous coronary intervention) - time-critical
   • Cardiac tamponade: pericardiocentesis
   • Tension pneumothorax: needle decompression
   • Massive PE: systemic thrombolysis or catheter-directed therapy
3. Vasopressor/Inotrope selection:
   • Norepinephrine (0.5 mcg/min starting): first-line vasopressor for MAP support
   • Dobutamine (5 mcg/kg/min starting): positive inotrope; reduces afterload - add to NE in low-output states
   • Caution: dopamine increases arrhythmia risk; epinephrine increases myocardial O2 demand; vasodilators (nitroprusside) may be used if adequate MAP maintained to reduce afterload
4. Mechanical circulatory support (MCS) for refractory shock:
   • Intra-aortic balloon pump (IABP): increases coronary perfusion, reduces afterload
   • Impella device / ventricular assist devices (VAD): more powerful LV unloading
   • Veno-arterial ECMO (VA-ECMO): for refractory cardiogenic shock in experienced centers
5. Avoid excessive IV fluids: cardiogenic shock is preload-sensitive but fluid-overload worsens pulmonary oedema

4. Obstructive Shock

5. Neurogenic Shock (Distributive Subtype)

• Caused by loss of sympathetic tone below spinal cord injury (T6 or above)
• Presents with hypotension + bradycardia (distinguishes from other shock types) + warm, dry skin
• Management:
  • IV fluid resuscitation
  • Vasopressors (norepinephrine or phenylephrine) to restore vascular tone
  • Atropine or cardiac pacing if bradycardia is symptomatic
  • Maintain spine immobilization

6. Anaphylactic Shock

• Epinephrine IM (0.3-0.5 mg of 1:1000) into the lateral thigh is the cornerstone - given immediately, not after other drugs
• IV access; 1-2 L crystalloid for hypotension
• H1 + H2 antihistamines (adjuncts only - do not delay epinephrine)
• Corticosteroids (prevent biphasic reaction)
• Nebulized bronchodilators for bronchospasm
• Vasopressors if hypotension refractory to epinephrine

End-Points of Resuscitation

Note: Early Goal-Directed Therapy (EGDT) using strict CVP and ScvO2 targets has not demonstrated mortality benefit over modern protocolized care in large trials (ProCESS, ARISE, ProMISe). Current emphasis is on early recognition, early antibiotics, early fluids, and close monitoring rather than invasive haemodynamic targets.

• Rosen's Emergency Medicine, Chapter 3 (Shock), pp. 59-63
• Sabiston Textbook of Surgery (19e), Chapter 33 (Shock), pp. 563-572
• Goodman & Gilman's Pharmacological Basis of Therapeutics, Chapter - Shock, pp. 285-286
• Barash Clinical Anesthesia (9e), Table 57-4 (Management of Sepsis and Septic Shock), pp. 4831+