By Dr Hojat Bahadori, Zheng Cheng Zhu
Key Reference
Iglesias, I. Kaplan’s Cardiac Anesthesia: Perioperative and Critical Care, 8th Edition.
Can J Anesth/J Can Anesth 71, 1438–1439 (2024)
Background on Cardiac Bypass
Cardiopulmonary bypass (CPB) maintains systemic circulation and oxygenation during cardiac surgeries while the heart is stopped and isolated. In short, venous blood is diverted to an external oxygenator and returned to the body via large cannulae traditionally inserted in the right atrium and ascending aorta. The heart is isolated from systemic circulation via aortic cross clamping, and cardioplegia delivered to achieve cardiac arrest and provide cooling to minimise ischaemic injury for the duration of bypass. These steps allow surgeons to operate on a motionless and blood-free heart in a controlled environment, whilst systemic perfusion and anaesthesia can be maintained via an extracorporeal system.
Cardiac bypass is an essential component of procedures such as
-
Coronary artery bypass grafting (CABG).
-
Heart valve repair or replacement.
-
Repair of congenital heart defects.
-
Heart transplants.
By ensuring uninterrupted circulation, CPB allows complex surgeries to be performed safely. However, because blood comes into contact with artificial surfaces in the bypass circuit, anticoagulation is critical to prevent clotting. Heparin, in light of its predictability, reversibility and ease of administration, has become the anticoagulant-of-choice for CPB.
What Is Heparin?
Heparin is widely used in medical and surgical settings in the prevention and management of blood clot formation. It is available in two forms, unfractionated heparin (UFH) which contains unfiltered mixture of glycoaminoglycan polymers with molecular weights between 3000 to 30,000D, and low molecular weight heparin (LMWH) with only small-chain polymers with molecular weights ranging 3,000 to 6,000D.
Pharmacodynamics
Heparin exerts its anticoagulant effect through indirect agonism of endogenous antithrombin III (ATIII), causing a conformational change that enhances the affinity and inhibitory activity of ATIII to clotting factor proteases, predominantly thrombin and factor Xa. The anticoagulant effectiveness of UFH demonstrates interpersonal variability partly due to heterogeneity in polymer composition, and must be monitored using laboratory activated partial thromboplastin time (APTT) or point-of-care activated clotting time (ACT) when administered at high doses.
Pharmacokinetics
UFH can be administered intravenously or subcutaneously, with distribution primarily within intravascular space as largely protein-bound molecules. UFH follows a biphasic elimination pattern, combining rapid sequestration by the saturatable reticuloendothelial system with slower non-saturatable first-order renal clearance. As such, UFH half-life is dose-dependent and non-linear. Alternatively, UFH is rapidly bound and reversed with protamine at a 1mg(protamine):100IU(UFH) ratio
Why Do You Need Heparin During Cardiac Bypass?
During CPB, blood comes into contact with artificial non-endothelial surfaces, which activates inflammatory and clotting mechanisms, leading to thrombus formation. Exposure of tissue factor via surgical wound further adds clotting burden. UFH prevents these clots from forming in the extracorporeal circuit, ensuring smooth blood flow and preventing catastrophic complications like embolism or stroke.
How Do We Dose and Measure Heparin?
Dosing:
The standard initial dose is 300–400 units/kg administered intravenously. This may require individualised adjustment given variable dose-responsiveness. As such, clear evidence of anticoagulation through ACT measurement is required before CPB initiation.
Monitoring:
ACT is used to measure heparin’s efficacy. While APTT correlates with heparin concentrations at lower therapeutic concentrations (e.g. for existing thrombus management), APTT demonstrates a logarithmic relationship with poorer sensitivity at higher heparin doses, whereas ACT shows a linear relationship. Moreover, ACT is more logistically feasible as a point-of-care test than laboratory APTT or anti-Xa assays that have substantial time delays. However, ACT becomes unreliable with increasing CPB duration, as ACT is non-heparin specific and prolonged from hypothermia and haemodilution.
An ACT greater than 480 seconds is typically required during bypass to ensure adequate anticoagulation. Close communication is required with the cardiac surgeon to ensure the correct timing of heparin and the correct ACT.
Reversal:
After surgery, the effects of heparin are reversed with protamine sulfate.
-
Dose: 1mg of protamine for every 100 units of heparin
-
This may be reduced if >1hr since last heparin dose
Anaesthetists must entertain the risk of postoperative bleeding when reversing heparin. Protamine not only neutralises heparin through direct ionic bonding, but also impairs platelet adhesion and aggregation, paradoxically increasing bleeding risk. Patients may exhibit “heparin rebound” with redistribution of heparin from sequestered stores, where patients may require repeated protamine dosing for larger initial heparin boluses. Individualised dosing based on predicted heparin concentration is recommended to reduce bleeding risk.
In addition, protamine is associated with arterial hypotension, pulmonary vasoconstriction and anaphylaxis. These deleterious haemodynamic effects must be considered when managing patients with brittle compensatory reserves intraoperatively during cardiac surgery.
What Happens If Heparin Fails?
Heparin resistance is defined as an inability to achieve ACT > 480s despite adequate heparin dosing (300-400 unit/kg)
Although rare, heparin resistance can result in clot formation in the bypass circuit, potentially leading to severe complications such as
-
Blockage of the oxygenator or pump.
-
Embolic events causing stroke, myocardial infarction, or organ damage.
Heparin resistance may be due to ATIII deficiency, ATIII-independent mechanisms, or pseudo-resistance.
ATIII deficiency
This can be acquired from impaired production secondary to critical illness or liver injury, and increased ATIII clearance from preoperative heparin use, nephrotic syndrome and sepsis. CPB itself can lead to consumptive reduction in ATIII by activating coagulation cascade, while the patient cohort requiring CPB often presents with vascular endothelial abnormalities and inflammatory states that are prothrombotic.
Congenital ATIII deficiency is a rare autosomal dominant disorder due to mutation of the SERPINC1 gene. These patients invariably develop profound thrombophilia and require haematology input.
ATIII-independent mechanisms
Intravascular heparin concentration may be reduced when there is a greater proportion of positively-charged extracellular molecules present, such as during sepsis when there is an upregulation of pro-inflammatory cytokines, platelets and acute phase reactants. As heparin is highly negatively charged, they bind to heparin and reduce effective heparin concentration.
Pseudo-resistance
Upregulation of factor VIII and fibrinogen in cases of endothelial dysfunction may blunt the apparent effectiveness of heparin through low APTT and ACT without impacting anti-Xa or ATIII levels. This may cause underestimation of heparin effect and lead to heparin overdose,
Management of heparin resistance
Therapeutic options include additional heparin dosing, ATIII supplementation (through fresh frozen plasma (FFP) or ATIII concentrates), and/or use of alternative anticoagulants.
Heparin resistance is commonly overcome with adding further heparin up to 4U/ml, where a ceiling effect is reached corresponding with saturation of ATIII. Care must be taken to appropriately dose protamine to reduce the risk of protamine-induced platelet dysfunction and heparin rebound.
FFP and ATIII concentrates aim to rectify ATIII deficiency and augment heparin effectiveness. The addition of adjunct anticoagulants, such as bivalirudin, has been trialled in isolated case reports with promising results. Emergency interventions, including switching anticoagulants or circuit components, may be necessary.
What Do You Do If Heparin is Contraindicated?
Heparin-Induced Thrombocytopenia (HIT): HIT is an immune-mediated reaction where heparin causes a drop in platelets and paradoxical clotting.
Alternatives: In patients with HIT or allergy, anticoagulants like bivalirudin, argatroban, or fondaparinux are used. These agents provide anticoagulation without cross-reactivity with heparin.
Other Interesting Facts About Heparin?
Origin: Heparin was first isolated in 1916 from liver cells (hence the name, derived from “hepar,” Greek for liver).
Dual Role: Besides anticoagulation, heparin has anti-inflammatory properties, which may reduce complications during surgery.
Re-exposure: Heparin can safely be reused in most patients without HIT, as long as precautions are taken.
Reference
Cartwright B, Mundell N. Anticoagulation for cardiopulmonary bypass: part one. BJA Educ. 2023;23(3):110-116. doi:10.1016/j.bjae.2022.12.003
Deranged Physiology. Unfractionated and low molecular weight heparin. From https://derangedphysiology.com/main/cicm-primary-exam/haematological-system/Chapter-221/unfractionated-and-low-molecular-weight-heparin. Last Accessed 01/01/2025
Iglesias, I. Kaplan’s Cardiac Anesthesia: Perioperative and Critical Care, 8th Edition. Can J Anesth/J Can Anesth 2024; 71, 1438–1439
