Pathophysiology of Cardiopulmonary Bypass (CPB)

MD Anaesthesiology Exam Notes

1. DEFINITION AND PURPOSE OF CPB

• CPB diverts venous blood away from the heart (via cannulae in right atrium/vena cava), adds O₂, removes CO₂, and returns blood through an arterial cannula (ascending aorta or femoral artery)
• Nearly all blood bypasses the heart and lungs during established CPB
• CPB provides both artificial ventilation and circulation simultaneously
• Mean arterial pressure is usually below normal and flow is non-pulsatile - both profoundly non-physiological
• Goals: bloodless/motionless surgical field; oxygenation and ventilation; organ perfusion and O₂ delivery; temperature management (hypothermia for protection); delivery of anesthesia

2. THE CPB CIRCUIT - BASIC COMPONENTS

• Venous reservoir - receives blood via right atrial/caval cannulae by gravity drainage; if the reservoir empties, air is pumped into the patient (catastrophic)
• Oxygenator - membrane oxygenator (modern standard); gas exchange by diffusion across a semi-permeable membrane; replaced bubble oxygenators which caused more microemboli
• Heat exchanger - integral to oxygenator; allows cooling (hypothermia) and rewarming
• Main pump - roller pump (occlusive, non-pulsatile) or centrifugal pump (preferred increasingly; less trauma to blood cells)
• Arterial line filter - removes microemboli from the arterial outflow before return to patient
• Ancillary pumps - cardiotomy suction (blood salvage), left ventricular vent, cardioplegia delivery

3. PUMP PRIME AND HEMODILUTION

• CPB circuit must be primed with fluid before use (typically 1200-1800 mL for adults) to eliminate bubbles
• Prime composition: balanced crystalloid (Lactated Ringer's) ± albumin, mannitol, heparin, bicarbonate
• Hemodilution at onset of CPB typically drops hematocrit to 22-27% in adults
• Blood is added to prime for neonates/infants and severely anemic adults to prevent excessive hemodilution
• Hemodilution reduces blood viscosity - beneficial for microcirculatory flow; but reduces O₂-carrying capacity
• Hemodilution also dilutes clotting factors and platelets, contributing to coagulopathy

4. ANTICOAGULATION DURING CPB

• Contact of blood with artificial surfaces of circuit initiates thrombogenic cascade
• Heparin (300-400 units/kg IV) required before cannulation; target ACT > 400-480 seconds
• Activated Clotting Time (ACT) is standard monitoring; normal ACT is 90-120 sec; CPB requires > 400 sec
• ACT may be prolonged by hypothermia, hemodilution, and pre-existing coagulopathies (falsely reassuring)
• Some subclinical coagulation may progress despite acceptable ACT
• Protamine reverses heparin after weaning from CPB (1-1.3 mg protamine per 100 units heparin)
• Heparin-Induced Thrombocytopenia (HIT) occurs in 1-5% of patients; triggered by IgG antibodies against heparin-PF4 complex; platelet count drops >50%; 20-50% develop HITT (thrombosis); treat with non-heparin anticoagulants (argatroban, bivalirudin)

5. SYSTEMIC INFLAMMATORY RESPONSE (SIRS) - KEY PATHOPHYSIOLOGY

Triggers of Inflammatory Response:

• Contact of blood with non-physiological surfaces of the CPB circuit
• Surgical trauma, ischemia-reperfusion injury, endotoxin release
• Non-pulsatile flow, hypothermia, hemodilution

Complement Activation:

• Both classical and alternate pathways are activated
• Contact with CPB circuit activates C3 (alternate pathway) and the classical pathway
• Generates anaphylatoxins (C3a, C5a) - powerful chemotactic molecules
• C5a activates neutrophils and causes histamine release, increased vascular permeability

Coagulation Cascade Activation:

• Contact activation (Factor XII/Hageman factor activation) triggers intrinsic coagulation pathway
• Thrombin generated in large amounts - converts fibrinogen to fibrin
• Fibrinolytic mechanisms (activated endothelium) degrade fibrin - hyperfibrinolysis
• Antifibrinolytics (tranexamic acid, epsilon-aminocaproic acid) used to reduce bleeding
• Aprotinin (a protease inhibitor) was used but withdrawn in North America due to increased mortality

Platelet Activation and Dysfunction:

• Mechanical trauma from CPB apparatus activates platelets and leukocytes
• CPB alters and depletes glycoprotein receptors on platelet surface
• Results in platelet dysfunction - increases perioperative bleeding
• Hypothermia further reduces platelet aggregation

Cellular Immune Activation:

• Monocytes, platelets, and neutrophils activated - release acute inflammatory mediators and cytokines (IL-1, IL-6, IL-8, TNF-α) that persist even after CPB ends
• Activated cells produce reactive oxygen species (ROS)/free radicals - cytotoxic and cardiovascular effects (vasodilation, hypotension)
• Kallikrein system activation - contributes to vasodilation

Result: Post-CPB SIRS

• Systemic inflammatory response resembling sepsis and trauma
• Can lead to multiorgan dysfunction/failure (MODS/MOF)

6. HORMONAL AND STRESS RESPONSES

• Massive stress hormone surge at CPB initiation
• Elevated: catecholamines, cortisol, arginine vasopressin (AVP), angiotensin II, aldosterone
• Plasma renin activity increases - sodium and water retention
• Insulin resistance and hyperglycemia are common
• Growth hormone and glucagon also elevated
• Magnitude influenced by depth of anesthesia, blood pressure management, and presence of pulsatile flow

7. EFFECTS ON COAGULATION

• Multiple mechanisms act in concert:

• Post-CPB bleeding is multifactorial; TEG/ROTEM guided therapy is most effective
• Hypothermia during CPB: reduces platelet aggregation AND plasma-mediated coagulation by decreasing clotting factor production and enzymatic activity; hyperfibrinolysis may also occur

8. CARDIOVASCULAR EFFECTS

Non-pulsatile Flow:

• Normal arterial flow is pulsatile; CPB flow is steady/non-pulsatile
• Non-pulsatile flow reduces lymphatic drainage, impairs microcirculation
• Increases peripheral vascular resistance (baroreceptor-mediated)
• May reduce organ perfusion despite adequate mean pressures
• Some circuits attempt to simulate pulsatile flow (controversial benefit)

Vasoplegia:

• Profound vasodilation/vasoplegia post-CPB - systemic vascular resistance dramatically falls
• Mechanisms: NO release, complement-mediated vasodilation, catecholamine depletion, cytokines
• Methylene blue (inhibits guanylyl cyclase, interrupts cGMP pathway) used to restore blood pressure in refractory vasoplegia

Myocardial Protection Failure:

• Aortic cross-clamping causes complete global ischemia of the heart
• Cardioplegia (potassium-rich ± blood) arrests the heart in diastole - reduces O₂ demand
• Cold cardioplegia reduces metabolic rate (~7% reduction per 1°C cooling)
• Ischemia-reperfusion injury on cross-clamp removal - generates ROS, calcium overload, cell death
• Ventricular fibrillation increases O₂ demand dangerously
• Ventricular distension increases O₂ demand and reduces subendocardial blood flow

9. NEUROLOGICAL EFFECTS

• Most feared complication of CPB; mechanisms are multifactorial:

Types of Neurological Injury:

• Type I (focal): stroke, TIA, stupor, coma - from macroemboli (air, atherosclerotic debris, thrombus, fat)
• Type II (diffuse): cognitive dysfunction, delirium, memory impairment, seizures - from microemboli and hypoperfusion

Mechanisms:

• Macroembolism - air emboli (from open cardiac chambers; air preferentially enters right coronary ostium due to position in supine patient), calcified atherosclerotic debris from aortic manipulation, thrombus
• Microembolism - platelet-fibrin aggregates, fat globules, silicone particles
• Cerebral hypoperfusion - from low MAP, non-pulsatile flow, CPB tubing improperly placed
• Inflammatory cerebrovascular injury - cytokine-mediated neuronal damage
• Hyperthermia during rewarming - cerebral metabolic demand exceeds supply
• EEG changes during CPB from: hypothermia, hemodilution, altered drug concentrations, altered PaCO₂

Post-op Cognitive Dysfunction (POCD):

• Cognitive changes detectable in >50% of patients after cardiac bypass surgery
• Incidence decreases with time but may persist in a subset of patients
• Risk factors: age, duration of CPB, degree of hemodilution, embolic load

10. PULMONARY EFFECTS

• Lung excluded from perfusion during CPB (bronchial circulation provides minimal perfusion)
• Post-CPB pulmonary dysfunction is common - ranges from mild hypoxemia to frank ARDS
• Mechanisms:
  • Atelectasis - from cessation of ventilation and surgical retraction
  • Surfactant dysfunction - ischemia impairs type II pneumocyte surfactant production
  • Complement-mediated neutrophil sequestration in pulmonary capillaries - releases proteases and ROS causing endothelial injury and capillary leak
  • Interstitial edema from increased capillary permeability (systemic inflammatory response)
  • Reperfusion injury when pulmonary circulation restored
  • Hemodilution lowers colloid oncotic pressure - promotes transudation
• "Post-pump" pulmonary syndrome reflects complement anaphylatoxin effects on pulmonary vasculature

11. RENAL EFFECTS

• Acute Kidney Injury (AKI) is a significant post-CPB complication
• Three main mechanisms:
  1. Hypoperfusion/ischemia - low MAP, non-pulsatile flow, renal vasoconstriction from catecholamines and angiotensin
  2. Embolization - macro and microemboli to renal vasculature
  3. Whole-body inflammatory response - cytokine-mediated microvascular injury and tubular damage
• Hemoglobinuria from hemolysis (mechanical trauma to RBCs in roller pumps) deposits in tubules
• Risk factors: longer duration of CPB, pre-existing renal disease, diabetes, low hematocrit on bypass, age

12. HYPOTHERMIA IN CPB

• Mild hypothermia (32-34°C), moderate (25-32°C), deep (15-25°C)
• Deep Hypothermic Circulatory Arrest (DHCA) at 15-20°C - allows up to 60 min of total circulatory arrest for complex repairs (e.g., aortic arch surgery, pediatric congenital heart surgery)
• Protective mechanisms:
  • Reduces O₂ consumption (Q10 effect - every 10°C drop halves metabolic rate)
  • Slows enzymatic reactions and ionic pumping
  • Reduces neurotransmitter release
• Ice packing around the head during DHCA - delays rewarming and promotes brain cooling
• Hypothermia complications: coagulopathy, arrhythmias (VF common below 30°C), increased SVR, left shift of oxyhemoglobin curve (impairs O₂ delivery), impaired drug metabolism, cold-induced diuresis
• pH management during hypothermia:
  • Alpha-stat (pH corrected for 37°C, not actual temperature) - preferred in adults; maintains cerebral autoregulation
  • pH-stat (maintain pH 7.4 at actual temperature; adds CO₂) - better outcomes in children undergoing circulatory arrest; improves cerebral perfusion

13. PHARMACOKINETIC EFFECTS OF CPB

• Plasma concentrations of water-soluble drugs (e.g., neuromuscular blockers) abruptly decrease at onset of CPB due to hemodilution
• Lipid-soluble drugs (e.g., fentanyl, sufentanil) are less affected
• Mechanisms of altered drug levels:
  • Sudden increased volume of distribution (hemodilution)
  • Decreased protein binding (hemodilution reduces plasma proteins)
  • Altered perfusion and redistribution between compartments
  • Some drugs bind CPB components (opioids)
• Heparin causes lipoprotein lipase release → hydrolyzes triglycerides → free fatty acids → competitively inhibit drug-protein binding
• Hypothermia reduces hepatic and renal clearance → drugs accumulate during CPB
• Constant infusions during CPB tend to produce progressively increasing blood concentrations (except propofol TCI which may be the exception)

14. END-ORGAN DYSFUNCTION - SUMMARY TABLE

15. STRATEGIES TO ATTENUATE CPB PATHOPHYSIOLOGY

• Heparin-bonded circuits - reduce contact activation and complement activation
• Leukocyte depletion filters - reduce inflammatory cell-mediated injury
• Ultrafiltration/hemofiltration - removes inflammatory cytokines (especially beneficial in pediatric patients; modified ultrafiltration [MUF] post-CPB removes vasoactive substances)
• Corticosteroids - modulate inflammatory response (methylprednisolone); benefit on outcomes controversial
• Antifibrinolytics - tranexamic acid (TXA), epsilon-aminocaproic acid (EACA) - reduce hyperfibrinolysis and blood loss
• Pulsatile perfusion - may improve organ perfusion (benefit remains controversial)
• Warm/tepid CPB vs. cold - avoids hypothermia complications; raises concern about losing protective effects
• Off-pump CABG (OPCAB) - eliminates CPB entirely; reduces inflammatory response and blood transfusion requirements; use limited to CABG procedures
• Mini-CPB circuits - smaller surface area; reduce post-CPB inflammatory response
• Mannitol in pump prime - promotes diuresis and acts as free radical scavenger
• Cerebral protection: alpha-stat pH management, maintaining adequate MAP, avoiding hyperthermia during rewarming

HIGH-YIELD EXAM POINTS SUMMARY

1. CPB generates a SIRS-like state via complement activation (both classical via contact activation and alternate via C3), platelet/leukocyte activation, cytokine release, and ROS generation
2. Three mechanisms of end-organ dysfunction: hypoperfusion, embolization, systemic inflammatory response
3. Hemodilution at onset of CPB lowers Hct to 22-27%; dilutes clotting factors and platelets
4. Hypothermia provides organ protection (reduces metabolic rate) but causes coagulopathy, arrhythmias, and impaired drug metabolism
5. Non-pulsatile flow increases SVR and impairs microcirculatory perfusion
6. Cardioplegia (high-K+ ± blood) arrests the heart in diastole; cold temperature reduces metabolic demand
7. Ischemia-reperfusion injury on cross-clamp release - ROS generation, calcium overload
8. POCD occurs in >50% after CPB; embolic and inflammatory mechanisms
9. ACT monitoring for heparin adequacy; target >400 sec during CPB
10. Protamine reverses heparin post-CPB; methylene blue treats refractory vasoplegia
11. pH-stat preferred in children/DHCA; alpha-stat preferred in adults
12. DHCA at 15-20°C allows up to 60 minutes of circulatory arrest for complex repairs