The circuit is a large foreign surface with a low-shear, high-contact geometry. Without intervention it clots. The entire art of CRRT anticoagulation is confining that intervention to the circuit.
5.1 Why Circuits Clot
Contributing factors, roughly in order of practical importance:
- Access dysfunction — intermittent flow interruption is the commonest cause of premature clotting, and no anticoagulant compensates for a poorly functioning catheter.
- High filtration fraction — haemoconcentration along the fibre (Ch. 1, Ch. 4).
- Air–blood interface in the deaeration chamber.
- Turbulence and stasis at connectors, kinks and the venous chamber.
- Patient factors — sepsis-associated hypercoagulability, antiphospholipid syndrome, high platelet count, high haematocrit.
💡 Before escalating anticoagulation, interrogate the access. A circuit clotting every four hours with recurrent access-pressure alarms is a catheter problem, not a heparin-dose problem.
5.2 Guideline Anchoring
KDIGO 2012 AKI, Section 5.3 — Anticoagulation:
• In a patient without increased bleeding risk or impaired coagulation and not already receiving systemic anticoagulation, use anticoagulation during RRT. (1B)
• For CRRT, use regional citrate anticoagulation rather than heparin in patients who do not have contraindications for citrate. (2B)
• In a patient with increased bleeding risk who is not receiving anticoagulation, use regional citrate anticoagulation rather than no anticoagulation during CRRT. (2C)
• Avoid regional heparinisation during CRRT in a patient with increased bleeding risk. (2C)
• In a patient with heparin-induced thrombocytopenia (HIT), all heparin must be stopped and a direct thrombin inhibitor or Factor Xa inhibitor is recommended. (1A)
💡 KDIGO's citrate preference is graded 2B — a suggestion, not a strong recommendation — and is explicitly conditional on the absence of citrate contraindications. It is not a mandate, and it does not survive severe hepatic failure or shock with impaired citrate metabolism.
5.3 Regional Citrate Anticoagulation (RCA)
Mechanism
Citrate is infused into the access limb, immediately post-catheter and pre-filter. It chelates ionised calcium, driving post-filter iCa into the range of roughly 0.25–0.35 mmol/L, at which the calcium-dependent steps of the coagulation cascade cannot proceed. The circuit is anticoagulated; the patient is not.
Calcium is then restored — either by a separate calcium infusion returned to the patient (usually via the venous limb or a dedicated central line), or partially by calcium-containing replacement fluid, depending on protocol.
Citrate itself is partly removed in the effluent; the remainder enters the patient and is metabolised, principally in the liver, and also in skeletal muscle and renal cortex, via the tricarboxylic acid cycle. Each metabolised citrate anion yields three bicarbonate equivalents.
The two calcium measurements — the core discipline of RCA
Measurement | Where sampled | Target | What it tells you |
Post-filter (circuit) iCa | Circuit, after the filter | ~0.25–0.35 mmol/L | Whether the circuit is adequately anticoagulated → titrate the citrate rate |
Systemic (patient) iCa | Arterial/venous patient sample | Normal physiological range | Whether the patient is adequately calcium-replete → titrate the calcium infusion |
💡 The single most important operational rule in RCA: these two numbers control two different pumps and must never be conflated. A low circuit iCa is the goal. A low patient iCa is a complication. Confusing them — for example, giving calcium because the post-filter value is low — defeats the anticoagulation entirely.
Exact targets and titration steps are protocol- and device-specific. Follow your unit's validated protocol; do not transplant numbers between machines.
Metabolic consequences
1. Metabolic alkalosis — the commonest metabolic effect. Citrate delivered to the patient in excess of what is removed in the effluent generates bicarbonate (3 mEq per citrate). Managed by reducing citrate load relative to effluent, adjusting the bicarbonate content of the replacement/dialysate solution, or increasing dose.
2. Citrate accumulation — occurs when hepatic metabolism cannot keep pace: severe liver failure, shock with hepatic hypoperfusion, severe lactic acidosis. Accumulated citrate continues to chelate calcium systemically.
The classic signature:
- Rising total calcium (chelated citrate–calcium complexes are measured as total calcium)
- Falling or hard-to-maintain ionised calcium (escalating calcium infusion requirement)
- Rising total-to-ionised calcium ratio — a ratio above roughly 2.5 is the commonly cited alert threshold, with some protocols using 2.1
- Widening anion gap with worsening metabolic acidosis — because unmetabolised citrate is itself an unmeasured anion, and the expected bicarbonate generation fails to materialise
⚠️ Declared gap: the total/ionised calcium ratio thresholds in circulation (2.1, 2.25, 2.5) derive from small observational studies and consensus practice, not from randomised validation. Treat a rising ratio as a trend-based warning to reassess citrate load and hepatic function, not as a validated diagnostic cut-off.
3. "Citrate lock" / gap acidosis — the paradoxical combination of metabolic acidosis with a widened anion gap in a patient on citrate, which is the opposite of the expected alkalosis and should prompt immediate assessment for accumulation.
4. Hypernatraemia — with hypertonic trisodium citrate formulations, sodium loading can be significant. Formulation-dependent.
5. Hypocalcaemia and hypomagnesaemia — citrate chelates magnesium as well as calcium. Magnesium is not routinely replaced by the calcium infusion and requires separate monitoring and repletion.
Contraindications and cautions
Setting | Concern |
Severe hepatic failure / acute liver failure | Impaired citrate metabolism → accumulation. Relative contraindication; some centres use RCA with reduced dose and intensive monitoring. |
Shock with severe tissue hypoperfusion / lactic acidosis | Impaired TCA-cycle metabolism → accumulation |
Pre-existing severe metabolic alkalosis | Will be worsened |
Inability to monitor iCa frequently | RCA is unsafe without reliable, frequent calcium measurement |
5.4 Systemic Heparin
Unfractionated heparin remains the most widely available alternative: familiar, inexpensive, reversible with protamine, and monitorable by aPTT or anti-Xa.
- Cost: systemic anticoagulation of a critically ill patient, with the attendant bleeding risk, and the risk of HIT.
- Regional heparinisation (heparin pre-filter, protamine post-filter) is technically possible but KDIGO suggests avoiding it in patients with increased bleeding risk (2C), and protamine carries its own reaction risk.
- Low-molecular-weight heparin is used in some centres; monitoring requires anti-Xa, and clearance is altered in renal failure.
5.5 Head-to-Head Evidence
RICH (Zarbock et al., JAMA 2020)
- Design: multicentre RCT, regional citrate vs systemic heparin anticoagulation in CVVHDF for severe AKI. Terminated early.
- Co-primary outcomes: filter lifespan and 90-day mortality.
- Result: filter lifespan was significantly longer with citrate (approximately 47 hours vs 26 hours). No statistically significant difference in 90-day mortality.
- Safety: fewer bleeding complications with citrate; more infections were observed in the citrate group — a finding that has not been consistently reproduced and warrants caution rather than firm conclusion.
✅ What is supported: citrate reliably prolongs circuit life and reduces bleeding compared with systemic heparin.
⚠️ What is not supported: a mortality benefit for citrate over heparin has not been demonstrated. RCA is preferred for circuit performance and bleeding safety — not because it saves lives.
5.6 Comparison Table
Regional Citrate (RCA) | Systemic Heparin | |
Site of anticoagulation | Circuit only | Patient and circuit |
Mechanism | Ionised calcium chelation | Antithrombin-mediated inhibition of thrombin/Xa |
Monitoring | Post-filter iCa and systemic iCa | aPTT or anti-Xa |
Bleeding risk | Low | Elevated |
Filter life | Longer (RICH: ~47 h vs ~26 h) | Shorter |
Key metabolic hazards | Alkalosis, accumulation, hypocalcaemia, hypomagnesaemia, hypernatraemia | — |
Key non-metabolic hazards | Requires intensive monitoring and protocol discipline | HIT |
Fails in | Severe hepatic failure, profound shock | Antithrombin deficiency, HIT |
KDIGO position | Preferred for CRRT (2B) when not contraindicated | Alternative |
5.7 No Anticoagulation
A legitimate strategy in active bleeding, profound coagulopathy, or immediately post-operatively. Mitigations that genuinely help:
- Maximise pre-dilution (Ch. 4) — lowers filtration fraction, the most effective non-pharmacological measure
- Optimise access and minimise flow interruptions
- Reduce filtration fraction by raising Qb or lowering Q_uf
- Accept shorter filter life and prescribe a higher dose to absorb the downtime (Ch. 4, KDIGO 2B)
💡 Note that KDIGO suggests RCA rather than no anticoagulation even in patients with increased bleeding risk (2C) — the regional nature of citrate means high bleeding risk is an argument for it, not against it, provided citrate metabolism is intact.
5.8 Chapter Summary
- Interrogate the access before escalating anticoagulation.
- KDIGO suggests RCA over heparin for CRRT (2B), conditional on no citrate contraindication.
- RCA's discipline is two calcium numbers controlling two pumps — post-filter iCa titrates citrate; systemic iCa titrates calcium.
- Alkalosis is expected; acidosis with a widening gap and a rising total/ionised calcium ratio signals accumulation — think liver, think perfusion.
- RICH: citrate roughly doubles filter life and reduces bleeding — with no demonstrated mortality benefit.