Professor, Critical Care Medicine & Clinical and Translational Science
Chief, Critical Care Medicine |Medical Director, Adult Medical-Surgical ICU | UPMC Magee Womens Hospital
Director, Program for Critical Care Nephrology | CRISMA | University of Pittsburgh School of Medicine
A 58-year-old male presents with septic shock secondary to a perforated bowel. He is intubated, on vasopressor support, and started on continuous renal replacement therapy (CRRT) due to acute kidney injury and fluid overload. Citrate is being used as the anticoagulant for CRRT. Over the past 24 hours, his arterial blood gas shows worsening metabolic acidosis (pH 7.15, HCO3 16), with a recent ionized calcium (iCa) level of 0.85 mmol/L (low). Despite adequate calcium replacement, his blood pressure remains unstable, requiring escalating doses of vasopressors.
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Mechanism of Citrate Anticoagulation: Regional citrate anticoagulation (RCA) in continuous renal replacement therapy (CRRT) involves the infusion of sodium citrate into the arterial limb of the extracorporeal circuit. Citrate chelates calcium ions, preventing blood coagulation. The hemofilter removes most of the calcium citrate complex. The liver, kidneys, and skeletal muscle metabolize the remaining complex to bicarbonate.
Citrate Accumulation vs. Toxicity:
• Citrate accumulation Refers to increased citrate levels in the blood, which can occur due to various factors.
• Citrate toxicity: Specifically refers to the adverse effects caused by excessive citrate levels.
Citrate Toxicity and Management:
A systemic calcium infusion is necessary to replace the calcium lost in the effluent and maintain a normal ionized serum calcium concentration to prevent citrate toxicity. Additionally, dialysate or replacement fluid composition may need to be adjusted.
• Buffer concentration: Reduce the concentration of buffers (e.g., bicarbonate, lactate) to prevent alkalosis, as citrate provides alkali.
• Magnesium concentration: To compensate for citrate binding, use dialysate or replacement fluid with a higher magnesium concentration (0.75 mmol/L).
• Calcium concentration: Ideally, use calcium-free dialysate and replacement fluids to prevent reversal of the citrate effect. If calcium-containing fluids are used, more citrate may be required, but a separate calcium reinfusion might not be necessary.
By carefully managing citrate levels and adjusting the extracorporeal circuit and fluid composition, citrate toxicity can be minimized while maintaining effective anticoagulation during CRRT.
Several factors can predispose patients to citrate toxicity:
• High citrate infusion rates: Rapid infusion of citrate can overwhelm the body’s capacity to metabolize it.
• Impaired hepatic function: The liver plays a crucial role in citrate metabolism. Liver dysfunction can lead to citrate accumulation.
• Hypocalcemia: Low calcium levels can increase the risk of citrate toxicity as the body may compensate by increasing citrate production.
• Hypoalbuminemia: Albumin binds to citrate, reducing its free concentration. Low albumin levels can increase the risk of citrate toxicity.
• Acid-base disturbances: Metabolic acidosis can impair citrate metabolism and increase the risk of toxicity.
• Renal dysfunction: The kidneys play a role in citrate excretion. Impaired renal function can contribute to citrate accumulation.
Clinical parameters that may raise suspicion of citrate toxicity include:
• Hypotension: Citrate-induced hypocalcemia can lead to hypotension.
• Tachycardia: Tachycardia may be a compensatory response to hypotension.
• Neuromuscular irritability: Symptoms like muscle cramps, twitching, or tetany can be indicative of hypocalcemia.
• Arrhythmias: Severe hypocalcemia can lead to cardiac arrhythmias.
• Metabolic acidosis: Citrate metabolism can generate bicarbonate, leading to metabolic alkalosis. However, in patients with severe illness or renal dysfunction, metabolic acidosis may predominate.
The diagnosis of citrate toxicity is primarily based on a combination of clinical findings and laboratory tests:
• Ionized calcium (iCa): A low iCa level is a strong indicator of citrate toxicity.
• Citrate level: Direct measurement of citrate levels can confirm the diagnosis.
• Blood gas analysis: Metabolic acidosis may be present due to citrate metabolism.
• Electrocardiogram (ECG): ECG changes consistent with hypocalcemia (e.g., prolonged QT interval) may be observed.
The effects of citrate toxicity can be severe and include:
• Hypocalcemia: Leading to hypotension, arrhythmias, and neuromuscular irritability.
• Metabolic acidosis: If not managed appropriately.
Preventive measures include:
• Monitoring iCa levels: Frequent monitoring of iCa is essential to detect hypocalcemia early.
• Calcium supplementation: Adequate calcium replacement is crucial to prevent citrate-induced hypocalcemia.
• Adjusting citrate infusion rate: The citrate infusion rate should be adjusted based on the patient’s clinical condition and laboratory parameters.
• Consider alternative anticoagulants: In some cases, alternative anticoagulants (e.g., heparin) may be considered.
Therapeutic interventions for citrate toxicity include:
• Calcium supplementation: Intravenous calcium gluconate or calcium chloride can be administered to correct hypocalcemia.
• Citrate infusion rate reduction or discontinuation: The citrate infusion rate may be reduced or discontinued temporarily.
• Dialysis modality change: If citrate toxicity persists, switching to a different dialysis modality (e.g., bicarbonate-based dialysis) may be considered.
• Correction of underlying conditions: Addressing underlying conditions that contribute to citrate toxicity (e.g., hypoalbuminemia, metabolic acidosis) is important.
Dialysate/effluent rate: A higher dialysate/effluent rate can increase citrate removal, potentially reducing the risk of citrate accumulation. However, excessive fluid removal can lead to hypotension and other complications.
Dialysate composition: The composition of the dialysate can also influence citrate removal. For example, a dialysate with a higher bicarbonate concentration may promote citrate metabolism.
• Citrate toxicity is a potential complication of citrate anticoagulation during CRRT.
• Frequent monitoring of iCa levels is essential.
• Calcium supplementation should be provided as needed.
• The citrate infusion rate may need to be adjusted based on the patient’s clinical condition and laboratory parameters.
• Alternative anticoagulants may be considered in certain cases.
• Early recognition and management of citrate toxicity are crucial to prevent severe complications.
