Pathophysiology of Cardiopulmonary Bypass (CPB)

MD Anaesthesiology Exam Notes

1. DEFINITION AND PURPOSE

1. Provide a bloodless, motionless operative field
2. Oxygenate blood and remove CO2
3. Maintain organ perfusion and oxygen delivery
4. Enable temperature management (hypothermia for protection, rewarming before weaning)
5. Deliver inhalational or intravenous anesthetic agents

2. BASIC CIRCUIT COMPONENTS

3. PHYSIOLOGICAL ALTERATIONS DURING CPB

3.1 Non-physiological Flow Conditions

• Flow is non-pulsatile (vs. normal pulsatile arterial flow)
• Mean arterial pressure is lower than normal
• Variable degrees of systemic hypothermia are employed
• Normal auto-regulatory mechanisms are bypassed or blunted

3.2 Hemodynamic Changes

• Hemodilution causes a fall in oncotic pressure and hematocrit
• Redistribution of blood volume from patient to circuit
• Systemic vascular resistance changes unpredictably
• At normothermia, required flow ~2.4 L/min/m²; at 18°C, only ~1 L/min/m² is needed (hypothermia reduces O2 consumption by ~50% per 10°C drop)

3.3 Temperature Management

• Hypothermia is the primary mechanism of organ protection during CPB
• Reduces cerebral metabolic rate for oxygen (CMRO2) significantly
• Core temperature of 15-18°C allows up to 60 min of complete circulatory arrest (Deep Hypothermic Circulatory Arrest - DHCA)
• Rewarming must be gradual; rapid rewarming causes cerebral hyperthermia - a major risk for neurological injury

4. SYSTEMIC INFLAMMATORY RESPONSE - THE CORE PATHOPHYSIOLOGY

4.1 Contact Activation (Intrinsic Pathway)

• Complement cascade - via BOTH the alternate pathway (C3 activation) and classical pathway
• Coagulation cascade (factor XII - Hageman factor)
• Kallikrein-bradykinin system
• Plasminogen/fibrinolytic system

4.2 Complement Activation

• Alternative pathway: Direct activation by foreign surfaces (C3 cleavage)
• Classical pathway: Activated by heparin-protamine complexes, endotoxin
• Generates C3a and C5a (anaphylatoxins) - powerful chemotaxic molecules
• C5a activates neutrophils and monocytes → cytokine release, reactive oxygen species (ROS)
• C5b-9 forms the membrane attack complex → direct cellular injury

4.3 Cellular Activation

4.4 Stress Hormone Response

• Catecholamines (epinephrine, norepinephrine) ↑↑
• Cortisol ↑
• Arginine Vasopressin (ADH) ↑
• Angiotensin II ↑
• Glucagon ↑ These are variously influenced by depth of anaesthesia, blood pressure, presence of pulsatile CPB, and type of surgical repair.

4.5 Cytokine Storm

• Pro-inflammatory: TNF-α, IL-1β, IL-6, IL-8, PAF (Platelet Activating Factor)
• Anti-inflammatory (counter-regulatory): IL-10, IL-1Ra
• Reactive oxygen species (ROS) and reactive nitrogen species
• Net effect: vasodilatation, hypotension, increased vascular permeability, edema

5. COAGULATION ABNORMALITIES

5.1 Pre-CPB Anticoagulation

• Unfractionated heparin is mandatory before CPB (contact with circuit surfaces activates thrombogenic cascade)
• Target ACT (Activated Clotting Time) >480 sec before initiating CPB
• Dose: typically 300-400 units/kg IV

5.2 Coagulation Cascade Activation

1. Thrombin generation: Central player in both thrombotic and bleeding phenomena
2. Fibrinogen consumption: Thrombin converts fibrinogen to fibrin; fibrinolytic mechanisms degrade fibrin
3. Endothelial disruption: Normal procoagulant-anticoagulant balance is perturbed

5.3 Platelet Dysfunction

• CPB alters and depletes glycoprotein receptors (GPIb, GPIIb-IIIa) on platelet surfaces
• Platelet count decreases (dilutional + consumption)
• Platelet function is impaired even if count is maintained
• This platelet dysfunction is a major cause of post-CPB bleeding

5.4 Fibrinolysis

• Tissue Plasminogen Activator (tPA) is released from endothelium → plasmin generation
• Fibrinolysis is activated during CPB and persists post-CPB
• Antifibrinolytics (tranexamic acid, epsilon-aminocaproic acid) are used to attenuate this

5.5 Heparin-Induced Thrombocytopenia (HIT)

• Large doses of unfractionated heparin → HIT incidence 1-5%
• Mechanism: Platelet Factor 4 (PF4) + heparin → antigenic heparin-PF4 complex → IgG binding → platelet activation, thrombocytopenia, paradoxical thrombosis
• Earliest sign: >50% drop in platelet count (hours to days post-surgery)
• HITT (with thrombosis): 20-50% of HIT cases
• Diagnosis: ELISA or Serotonin Release Assay (SRA)
• Treatment: Non-heparin anticoagulants (argatroban, bivalirudin)

5.6 Post-CPB Bleeding Causes (Summary)

1. Residual heparin (inadequate protamine reversal)
2. Platelet dysfunction and thrombocytopenia
3. Dilutional coagulopathy (hemodilution from circuit prime)
4. Fibrinolysis
5. Hypothermia-induced coagulopathy
6. Pre-existing antiplatelet drugs

6. END-ORGAN EFFECTS

6.1 Neurological Effects

• Incidence: 1-5% after CABG, higher for valve surgery
• Mechanism: Embolism (dominant cause)
  • Macroembolism from aortic atheromatous plaques (aortic manipulation/cannulation)
  • Air emboli from circuit, cardiac chambers
  • Particulate emboli from calcified valves, intracardiac debris
• Other mechanisms: Hypoperfusion (loss of cerebral autoregulation), cerebral venous obstruction

• Far more common than overt stroke
• Includes: delirium, deficits of memory, concentration, psychomotor speed
• Previously attributed entirely to CPB; now recognized to occur with similar frequency after off-pump surgery, coronary stenting, and non-cardiac surgery
• Risk factors: Pre-existing cerebrovascular disease, age, cerebral hyperthermia on rewarming, microemboli
• Early cognitive loss may persist in up to 40% of patients at 5 years

• Avoid aortic manipulation (epiaortic echo to identify plaque)
• Arterial line filter in CPB circuit
• Cell saver before blood reinfusion (removes lipid/particulate emboli)
• Careful de-airing of cardiac chambers
• Avoid cerebral hyperthermia during rewarming
• pH-stat vs. alpha-stat blood gas management (pH-stat may improve pediatric outcomes)
• Single aortic cross-clamp technique (avoids partial clamping)

6.2 Cardiac Effects (Myocardial Injury)

• Aortic cross-clamping leads to global myocardial ischemia
• Reperfusion on unclamping causes paradoxical injury via:
  • Calcium overload (intracellular Ca²⁺ influx)
  • ROS generation ("oxygen paradox")
  • Neutrophil-mediated injury
  • Mitochondrial permeability transition pore (MPTP) opening

• Hyperkalemic solution (K⁺ ~20-30 mEq/L) - arrests heart in diastole
• Cold (4°C) cardioplegia reduces CMRO2 and metabolism
• Blood cardioplegia: better O2 delivery and buffering
• Antegrade (via aortic root/coronary ostia) or Retrograde (via coronary sinus)
• Retrograde: advantage of uniform distribution in diffuse CAD, not dependent on competent aortic valve

• "Myocardial stunning" - reversible contractile dysfunction after ischemia-reperfusion
• Global hypokinesia requiring inotropic support
• Rhythm disturbances (asystole, conduction blocks from residual cardioplegia potassium)

• Severe refractory vasodilation post-CPB
• Mechanism: Excessive NO production via iNOS, vasopressin depletion, inflammatory cytokines
• Management: Methylene blue (inhibits guanylyl cyclase → blocks cGMP → reduces NO-mediated vasodilation)

6.3 Pulmonary Effects ("Pump Lung" / Post-Perfusion Syndrome)

1. Alveolar collapse and atelectasis (from cessation of ventilation)
2. Pulmonary ischemia-reperfusion injury when pulmonary circulation is restored
3. Neutrophil sequestration in pulmonary capillaries (activated neutrophils from CPB accumulate)
4. Increased vascular permeability → pulmonary edema
5. Surfactant dysfunction from ischemia and inflammatory mediators
6. Complement activation → direct alveolar and endothelial injury

• Severe form: Post-Perfusion Lung (ARDS-like) - now rare with modern membrane oxygenators
• PaO2 is maintained at ~150 mmHg during CPB via oxygenator settings

6.4 Renal Effects

• Incidence of AKI post-CPB: 5-30%; severe requiring dialysis: 1-5%
• Mechanisms:
  1. Ischemia/hypoperfusion: Reduced MAP during CPB, non-pulsatile flow reduces medullary perfusion
  2. Microemboli: Cholesterol, platelet-fibrin emboli in renal microvasculature
  3. Hemolysis: Mechanical hemolysis from roller pumps → free hemoglobin → tubular toxicity
  4. Inflammatory mediators: Cytokines → renal endothelial dysfunction and tubular injury
  5. Nephrotoxic drugs: Contrast, NSAIDs pre-operatively
  6. Longer bypass duration = major independent risk factor for CSA-AKI

6.5 Gastrointestinal Effects

• Gut hypoperfusion during CPB (splanchnic vasoconstriction from catecholamines + non-pulsatile flow)
• Intestinal mucosal ischemia → bacterial translocation → endotoxemia
• Endotoxin enters systemic circulation → amplifies SIRS
• Mucosal necrosis + luminal digestive enzymes → further barrier dysfunction
• Reactive O2 species on reperfusion → aggravate inflammatory cascade
• Complications: GI bleeding (stress ulcers), mesenteric ischemia, pancreatitis, hepatic dysfunction

7. PHARMACOKINETIC EFFECTS OF CPB

• Water-soluble drugs (neuromuscular blockers): plasma concentration falls abruptly at CPB onset
• Lipid-soluble drugs (fentanyl, sufentanil): changes less dramatic initially
• During CPB, constant drug infusions cause progressively increasing blood concentrations (↓ elimination)
• Remifentanil - minimal change, remains ultra-short acting even during CPB; hypothermic CPB reduces clearance by ~20%
• Propofol TCI may be the exception to progressive accumulation

8. HYPOTHERMIA DURING CPB

• Reduces CMRO2 and cellular metabolism
• Provides time for complex surgical repair
• Allows complete circulatory arrest (DHCA) for aortic arch surgery / complex CHD

• Cardiac arrhythmias (including VF at <28°C)
• Coagulopathy (platelet dysfunction, impaired clotting factor function)
• Shifts oxyhemoglobin dissociation curve to the LEFT (↓ O2 unloading)
• Cerebral hyperthermia during rapid rewarming (overshoots)
• Reduced drug metabolism → drug accumulation

• Alpha-stat: pH maintained at 7.40 at 37°C regardless of patient temperature. Used in adults. Maintains cerebrovascular autoregulation.
• pH-stat: pH corrected to 7.40 at actual (cooled) patient temperature by adding CO2. Causes cerebral vasodilation, improved cooling; associated with better neurological outcomes in children undergoing DHCA.

9. BLOOD GAS MANAGEMENT AND ACID-BASE EFFECTS

• CPB causes metabolic acidosis from tissue hypoperfusion, lactic acid production
• Oxygenator is adjusted to maintain PaO2 ~150 mmHg and normocarbia
• Hypothermia shifts oxyhemoglobin curve left (Bohr effect); more O2 bound, less released
• Hematocrit of 22-27% acceptable during hypothermic CPB (lower oxygen carrying capacity offset by increased dissolved O2 and reduced metabolic rate)

10. STRATEGIES TO ATTENUATE CPB PATHOPHYSIOLOGY

11. WEANING FROM CPB

1. Core temperature ≥36°C
2. Sinus rhythm restored (or paced at adequate rate)
3. Adequate ventilation re-established
4. Electrolytes normalized (K⁺, Ca²⁺, glucose)
5. Hematocrit >20-22%
6. Adequate myocardial contractility (TEE guided)

• Gradually reduce venous return to CPB reservoir → heart fills
• Slow pump flow simultaneously
• Assess hemodynamics and cardiac function (TEE)
• Inotropes and vasopressors as needed (epinephrine, dopamine, milrinone, vasopressin)
• Reverse heparin: protamine 1 mg per 100 units heparin given

• Inadequate surgical repair (check with TEE + pressure measurements)
• Undiagnosed lesions
• Myocardial stunning/failure
• Vasoplegic syndrome
• Cardiac tamponade

12. PEDIATRIC CONSIDERATIONS

• Circuit volume is 3× infant blood volume → blood-primed circuit to prevent excessive hemodilution
• Intense inflammatory response due to large artificial surface area relative to body size
• High flow rates needed (up to 200 mL/kg/min)
• pH-stat preferred during DHCA in children (better neurological outcomes)
• Modified ultrafiltration (MUF) post-CPB:
  • Blood from aortic cannula → ultrafilter → returned to right atrium
  • Corrects hemodilution AND removes inflammatory cytokines
• Hemostatic defects from dilution common (FFP + platelets often required)
• Calcium supplementation more important (impaired calcium homeostasis)
• Corticosteroids often given pre-CPB to suppress inflammatory response

EXAMINATION SUMMARY: KEY POINTS TO REMEMBER

1. Core triad of CPB pathophysiology: Inflammatory response + Coagulopathy + End-organ hypoperfusion/embolism
2. Complement activation (both pathways) is the central trigger for SIRS during CPB
3. Platelet dysfunction (not just thrombocytopenia) is the primary cause of post-CPB bleeding coagulopathy
4. Vasoplegia post-CPB: treat with methylene blue (guanylyl cyclase inhibitor)
5. POCD now recognized to be multifactorial, not exclusively due to CPB
6. Heparin: ACT >480 sec; Reversal: Protamine 1 mg per 100 units; HIT incidence 1-5%
7. Hypothermia: 50% reduction in O2 consumption per 10°C drop; DHCA feasible at 15-18°C for up to 60 min
8. Alpha-stat for adults (preserves autoregulation); pH-stat for pediatric DHCA (better neuro outcomes)
9. Cardioplegia: Hyperkalemic (diastolic arrest) + cold + blood; antegrade or retrograde
10. Protamine reversal: 1 mg per 100 units of heparin given; risk of pulmonary hypertension, anaphylaxis