Massive Transfusion-Associated Hypocalcaemia

Massive transfusion associated hypocalcaemia is a fall in ionised calcium (under 1.1 mmol/L, and severe at under 0.9 mmol/L) caused by citrate in blood components binding calcium during rapid or large volume transfusion. Citrate load can also lower ionised magnesium.

Epidemiology. It occurs in most patients receiving massive transfusion, and is a strong independent predictor of death, need for more transfusion and coagulopathy in trauma. The risk is greatest with fresh frozen plasma and platelets (which contain more citrate), and with rapid infusion.

Risk factors. Transfusion rate over 1 unit every 5 minutes, liver failure (reduced citrate metabolism), hypothermia, shock with poor perfusion, kidney failure, neonates, plasma exchange, and liver transplantation.

Pathophysiology. Citrate (an anticoagulant in stored blood) chelates ionised calcium. The healthy liver metabolises about 3 g of citrate every 5 minutes, but shock, hypothermia and hepatic disease slow clearance. Ionised calcium is essential for coagulation, myocardial contractility and vascular tone.

Presentation is hypotension not responding to fluids and vasopressors, reduced cardiac contractility, prolonged QT, arrhythmia, coagulopathy that does not correct, perioral paraesthesia, tetany, bronchospasm, seizures and cardiac arrest. Features may be masked by anaesthesia.

Red flags.

• Ionised calcium under 0.9 mmol/L.
• QT prolongation, arrhythmia or refractory hypotension during massive transfusion.
• Concurrent liver failure or hypothermia.

Measure ionised calcium on a blood gas analyser every 30 to 60 minutes during massive transfusion (total calcium is unreliable, since citrate bound calcium is included). Also check magnesium, potassium, pH, lactate and ECG for QT interval. Interpret in the context of acidosis (which raises ionised calcium) and alkalosis.

Differential diagnosis. Hypomagnesaemia, hyperkalaemia, hypothermic coagulopathy, hypovolaemia, tension pneumothorax and anaphylaxis.

Calcium replacement (aim for ionised calcium over 1.1 mmol/L, ideally 1.1 to 1.3 mmol/L).

• Calcium chloride 10%: 10 mL (1 g) IV over 5 to 10 minutes, preferably through a central line (peripheral extravasation causes tissue necrosis). It gives three times more elemental calcium than the same volume of calcium gluconate.
• Calcium gluconate 10%: 20 to 30 mL (2 to 3 g) IV over 10 minutes through a large peripheral vein.
• Give another dose after each 4 units of blood components, or earlier if ionised calcium is low, and repeat as directed by repeated measurement. Infusion of calcium chloride 1 to 2 g/h may be needed.
• Do not infuse in the same line as blood components or bicarbonate. In digoxin toxicity give slowly with monitoring.

Magnesium. Magnesium sulphate 2 g (8 mmol) IV over 15 to 20 minutes for low ionised or total magnesium, with reduced dosing in renal impairment.

Support the cause. Warm the patient, correct acidosis by restoring perfusion, keep up with plasma and platelet replacement, and limit non-essential citrate load.

Plasma exchange and liver failure. Pre-emptively replace calcium during plasma exchange, apheresis and liver transplant.

Children and neonates. Calcium chloride 10 to 20 mg/kg IV (0.1 to 0.2 mL/kg of 10%) or calcium gluconate 50 to 100 mg/kg (0.5 to 1 mL/kg of 10%), given slowly through a central line, with ECG monitoring.

Monitoring. Ionised calcium every 30 to 60 minutes, ECG (QT), magnesium, potassium, blood pressure and signs of tetany.

Referral and escalation. Anaesthesia and intensive care teams, and transfusion medicine for large volume use.

Special groups. In liver failure and liver transplantation, expect much greater requirement. In renal failure, avoid over correction. In neonates, extravasation injury is a major risk.