Pathophysiology of Cardiopulmonary Bypass (CPB)

Introduction

I. The CPB Circuit - Basic Components

1. Oxygenator - removes CO₂ and adds O₂ (bubble or membrane type; modern circuits use membrane oxygenators to reduce foaming and blood trauma)
2. Roller pump - provides non-pulsatile flow; flow ~2.4 L/min/m² at normothermia, reduced to ~1 L/min/m² at 18°C hypothermia
3. Heat exchanger - controls body temperature
4. Arterial line microfilter - pore size 20-30 µm to remove debris and microemboli

II. Haemostatic Derangements

A. Contact Activation (Intrinsic Pathway)

• Factor XII → Kallikrein → activates the intrinsic coagulation pathway
• Kallikrein also activates complement and the angiotensin system
• High-molecular-weight kininogen (HMWK) stimulates endothelial release of tissue plasminogen activator (t-PA), initiating fibrinolysis

B. Thrombin Generation

• Converts fibrinogen → fibrin (consumes fibrinogen rapidly)
• Activates Factors V, VIII, XI - perpetuating coagulation
• Also activates protein C → anticoagulant feedback

C. Platelet Dysfunction

• Plasma proteins (von Willebrand factor, fibrinogen) rapidly adsorb onto circuit surfaces and become conformationally altered
• Platelets adhere via GpIb/IX/V (to vWF) and GpIIb/IIIa (to fibrinogen)
• Platelet activation causes degranulation: release of platelet factor 4 (PF4), β-thromboglobulin, ADP
• Shear forces detach activated, degranulated platelets → circulate in a dysfunctional state or form microaggregates
• Net result: thrombocytopenia + platelet dysfunction → post-CPB coagulopathy

D. Fibrinolysis

• Plasminogen is converted to plasmin by both t-PA (from endothelium) and kallikrein
• Plasmin degrades fibrin, Factors V and VIII, and platelet surface glycoproteins
• Fibrin degradation products (FDPs) further impair platelet function
• The net result is a consumptive coagulopathy with both clotting and bleeding tendencies

III. Systemic Inflammatory Response

A. Complement Activation

• Both the classical and alternative complement pathways are activated
• Contact of blood with circuit surfaces generates C3a and C5a (anaphylatoxins) - these are powerful chemotactic molecules
• C5a triggers neutrophil activation, degranulation, and superoxide production

B. Leukocyte Activation

• Monocytes, neutrophils, and platelets release acute-phase inflammatory mediators and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8)
• This response persists even after CPB is terminated

C. Reactive Oxygen Species (ROS)

• Activated neutrophils and monocytes produce reactive oxidants (superoxide, hydrogen peroxide)
• These cause cytotoxic damage to endothelium, leading to:
  • Microvascular injury
  • Interstitial oedema
  • Vasodilation and hypotension (vasoplegia)

D. Ischaemia-Reperfusion Injury

• Non-pulsatile flow, hypothermia, and aortic cross-clamping produce global ischaemia
• Reperfusion on weaning from CPB floods tissues with neutrophils and ROS → reperfusion injury worsening endothelial damage

IV. End-Organ Dysfunction

A. Neurological

• Stroke from macroembolism (aortic plaque, air)
• Neurocognitive dysfunction ("pump head") - subtle deficits in memory and concentration; caused by microemboli + cerebral hypoperfusion
• More severe with longer bypass times and advanced age

B. Renal

• Acute kidney injury (AKI) from renal hypoperfusion, microemboli, and inflammatory mediators
• Haemoglobin from haemolysis (caused by pump shear forces) is directly nephrotoxic

C. Pulmonary

• Post-pump lung (acute lung injury): complement-activated neutrophils aggregate in pulmonary capillaries
• Increased capillary permeability → interstitial oedema, reduced compliance, impaired gas exchange
• May manifest as ARDS in severe cases

D. Myocardial

• Despite cardioplegia, ischaemia during aortic cross-clamping causes some degree of myocardial stunning
• Reperfusion injury worsens this; volatile anaesthetics (e.g., isoflurane, sevoflurane) provide ischaemic preconditioning that is partially protective

E. Gastrointestinal

• Splanchnic hypoperfusion → gut mucosal ischaemia → bacterial translocation → amplifies the systemic inflammatory response (SIRS)

V. Heparin-Induced Thrombocytopenia (HIT)

• Large doses of unfractionated heparin required for CPB predispose to HIT (incidence 1-5%)
• PF4 released from platelets binds heparin → heparin-PF4 complex becomes antigenic → IgG antibody formed
• IgG-heparin-PF4 complex binds platelets → further PF4 release → positive feedback loop
• Earliest sign: platelet count drop >50% within hours to days post-surgery
• 20-50% of HIT patients develop arterial or venous thrombosis (HITT)
• Diagnosis: ELISA or serotonin release assay (SRA)
• Treatment: stop heparin; switch to non-heparin anticoagulant (argatroban, bivalirudin)

VI. Physiological Effects of Hypothermia

• Oxygen consumption falls 50% per 10°C drop in temperature
• At 18°C, complete deep hypothermic circulatory arrest (DHCA) can be tolerated for up to 60 minutes
• Hypothermia itself contributes to:
  • Platelet dysfunction and coagulopathy
  • Reduced drug clearance (e.g., remifentanil clearance reduced ~20% per degree below 37°C)
  • Metabolic acidosis on rewarming
  • Dysrhythmias (especially on rewarming)

VII. Haemodilution

• The CPB circuit must be primed with fluid (~1.5-2 L crystalloid in adults; blood in neonates/infants as prime volume may be 3x the infant's blood volume)
• Results in acute normovolaemic haemodilution:
  • Decreased haematocrit (target nadir Hct ~21-25%)
  • Decreased plasma protein concentration → reduced drug binding → altered pharmacokinetics
  • Dilution of clotting factors and platelets → contributes to post-CPB coagulopathy

VIII. Anticoagulation and Reversal

• Heparin given before cannulation: 300-400 units/kg to achieve ACT >400-480 seconds
• Monitored by activated clotting time (ACT)
• After CPB: reversed with protamine sulphate (1 mg per 100 units of heparin)
• Protamine-heparin complex can itself trigger anaphylaxis and complement activation

Summary Table

Conclusion