Regarding regional citrate anticoagulation for continuous renal replacement therapy (CRRT):
- What is the mechanism by which citrate provides anticoagulation?
- What is the metabolic fate of the citrate?
- What are the features of citrate toxicity?
- What conditions may increase the risk of citrate toxicity?
- What alternative(s) to citrate could you use in a patient with severe HITS?
Forms a calcium – citrate complex which drops the serum ionized calcium level. Calcium is necessary for IX ® IXa, X ® Xa and PT ® thrombin.
Citrate complexed with calcium is partially removed by the filter, but some enters the circulation. Citrate is largely metabolized in the liver, entering the tricarboxylic acid pathway (Krebs cycle) generating NADH. Also generates bicarbonate (at a rate of 3 bicarb per 1 citrate).
2 sorts of problems:
First (most commonly described), due to inadequate calcium replacement, are those of low ionized calcium, i.e. chilliness, anxiety, perioral paraesthesias, carpopedal spasm, tetany, QT prolongation and arrhythmias. Associated with metabolic alkalosis from citrate metabolism, and possibly with sodium overload from the hypertonic sodium citrate.
Secondly (less common), due to citrate load in excess of hepatic ability to metabolise it, i.e. accumulation of citrate-calcium complex. Metabolic acidosis with high anion gap from citrate; raised ratio of total to ionized calcium from complexed calcium in circulation (normal total:ionized ratio 1.9-2.2:1, toxic ratio > 2.5:1.
Hypocalcaemia Liver failure
Low cardiac output (i.e. poor hepatic perfusion)
Prostacyclin (PGI2) Argatroban Danaparoid Bivalirudin Fondaparinux Lepirudin
Summaries exist, covering some of these topics:
What is the mechanism by which citrate provides anticoagulation?
Citrate is a calcium chelator, and by robbing the clotting cascade of its ionised calcium it disables the steps of the cascade in which calcium plays a role (many people dont realise that calcium used to be Factor IV). The following are clotting cascade proteins which require calcium to function:
- Factor VIIa
- Factor IXa
- Factor X
- Factors Xa
- Factor II (prothrombin)
So, 2, 7 9 and 10. Same as the Vitamin K-dependent factors.
What is the metabolic fate of the citrate?
The words "metabolic fate" are music to my ears.
In brief, citrate - in the course of its metabolism via the Krebs cycle - removes 3 H+ ions from the body, which has the equivalent effect of adding 3 HCO3- molecules. Thus, it is generally said that "citrate generates three bicarbonate molecules". It is true - its metabolism is the equivalent of buffering, and in excess citrate can cause a metabolic alkalosis. Thankfully, some of the citrate ends up being removed by the dialysis circuit, as it is a very small molecule.
What are the features of citrate toxicity?
Citrate toxicity - or rather, its biochemical features - is touched upon in the answer to Question 3.3 from the second paper of 2013.
In brief, the main features of citrate toxicity are as follows:
- High anion gap metabolic acidosis
- Potentially, also a metabolic alkalosis
- Low ionised calcium
- Normal total calcium (thus, a high total to ionised calcium ratio)
What conditions may increase the risk of citrate toxicity?
- 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)
- Decreased hepatic blood flow (eg. in sepsis or other shock states)
Citrate is mainly metabolised in the liver.
What alternative(s) to citrate could you use in a patient with severe HITS?
The list offered by the college is hardly all-inclusive:
- Prostacyclin (PGI2)
One might also mention using higher flow rates and pre-dilution as non-pharmacological means of increasing filter lifespan. In general, a massive list of strategies used to improve filter lifespan is also available somewhere around here, and it contains many options which don't involve citrate.
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