The college love citrate toxicity, and have asked about it in the past; one can find it in Question 3.3 from the second paper of 2013 and Question 22 from the first paper of 2015

The cardinal features of citrate toxicity are:

  • High anion gap metabolic acidosis OR metabolic alkalosis
  • Low ionised calcium with a high (or normal) total calcium

The predisposing factors include:

  • Liver disease (unable to metabolise the lactate)
  • Coagulopathy (requirement for regional anticoagulation of the CRRT circuit)
  • HITTS (or any other contraindication to the use of heparin)
  • Hypocalcemia
  • Decreased hepatic blood flow (eg. in sepsis or other shock states)

Citrate as a cause of high anion gap metabolic acidosis, followed by metabolic alkalosis

Citrate is an anion. In solution, it is a weak acid, a concept familiar to those of us who have ever rubbed their eyes with a lemon. The presence of citrate in solution may give rise to a degree of acidosis. Even though it is co-administered with lots of cations (trisodium citrate is the most common formulation), the total strong ion difference (SID) of the solution is 0, and so - like all 0-SID fluids (eg. normal saline) - the net effect on the whole-body acid base balance is to produce a degree of acidosis. Furthermore, over the course of a CRRT session the rate of sodium removal may outstrip the rate of citrate removal by the circuit, resulting in the widening of the anion gap.

Citrate is then metabolised (mainly in the liver, though all tissues could theoretically make use of it). The result is that now you have an excess of cations and a deficit of anions, giving rise to an increased strong ion difference. Thus, alkalosis ensues. Intensivists from Berlin reported that in their single-centre experience over 50% of the patients developed a metabolic alkalosis (and none of them had any metabolic acidosis).

Influence of citrate on ionised and total calcium

The ionised calcium in acidosis normally increases. Well, in respiratory acidosis it probably increases more than in lactic acidosis (because lactate forms calcium-lactate complexes), but still - it should be high, not low.

If one is acidotic with a low ionised calcium, one should look to citrate. Its influence is confirmed by the presence of a high total to ionised calcium ratio (i.e. the total calcium is normal, but the ionised fraction is low) - this is because measurement instruments which detect calcium will also measure citrate-calcium complexes in the serum, but the ion-selective electrode which measures ionised calcium will only measure the free fraction, which decreases with citrate toxicity.

Furthermore, as the citrate is metabolised, the chelated calcium is released, resulting in a rebound hypercalcemia.

A massively overengineered temple dedicated to ionised calcium can be found among the largely apocryphal ABG interpretation chapters.

What conditions may increase the risk of citrate toxicity?


LITFL have an excellent point-form summary of citrate toxicity. Much of what we know about it is derived from the sorry experience of patients who were recipients of massive transfusions.

Uhl, L., et al. "Unexpected citrate toxicity and severe hypocalcemia during apheresis." Transfusion 37.10 (1997): 1063-1065.

Bushinsky, David A., and Rebeca D. Monk. "Calcium." The Lancet 352.9124 (1998): 306-311.

Schaer, H., and U. Bachmann. "Ionized calcium in acidosis: differential effect of hypercapnic and lactic acidosis." British journal of anaesthesia 46.11 (1974): 842-848.

Dzik, Walter H., and Scott A. Kirkley. "Citrate toxicity during massive blood transfusion." Transfusion medicine reviews 2.2 (1988): 76-94.

Tolwani, Ashita J., et al. "Simplified citrate anticoagulation for continuous renal replacement therapy." Kidney international 60.1 (2001): 370-374.

Bakker, Andries J., et al. "Detection of citrate overdose in critically ill patients on citrate-anticoagulated venovenous haemofiltration: use of ionised and total/ionised calcium." Clinical Chemical Laboratory Medicine 44.8 (2006): 962-966.

Forni, Lui G., et al. "Circulating anions usually associated with the Krebs cycle in patients with metabolic acidosis." Critical Care 9.5 (2005): R591.

Morgera, Stanislao, et al. "Metabolic complications during regional citrate anticoagulation in continuous venovenous hemodialysis: single-center experience." Nephron Clinical Practice 97.4 (2004): c131-c136.