Citrate anticoagulation of the CRRT circuit

This has appeared in many previous papers. The college love citrate, and have dedicated some SAQs to it:

• Question 18 from the first paper of 2021
• Question 22 from the first paper of 2015
• Question 29 from the second paper of 2013
• Question 17 from the first paper of 2007
• Question 3.3 from the second paper of 2013

Mechanism of anticoagulation by citrate

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). This has been used to preserve the fluidity of blood samples for many decades, being first discovered around 1890.

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.

The net effect is the inhibition of thrombin formation.

In order to work, the citrate dose must be adjusted to achieve an ionised calcium concentration less than 0.4mmol/L within the filter.

Metabolic fate of citrate

A good overview of this is available from an article by Bellomo and Kellum. Of the infused citrate, some proportion is actualy removed by the CRRT circuit (as it is a small molecule), and the rest is rapidly metabolized in the Krebs cycle reactions - particularly in the liver, muscle and renal cortex. The chelated calcium is released by this process.

As a metabolic substrate, citrate has a measurable nutritional value: about 3kcal/g, or 0.59kcal/mmol (in case you are wondering, 1g citrate = 5mmol). And because it is consumed in Krebs cycle, it has the advantage of increasing the strong ion difference by being a strong anion which disappears without a trace. For each molecule of citrate burned in the Krebs furnace, three sodium ions are left behind, which has the equivalent effect of adding 3 HCO₃^- molecules.

A non-Stewartian explanation is also often given for this phenomenon. It describes the process of metabolism as something which consumes 3 H⁺ ions, and therefore has the equivalent effect of adding 3 HCO₃^- molecules. Even more crudely, 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.

Evidence for the safety and efficacy of citrate as a regional anticoagulant in dialysis

Is it any good, you ask.

The answer is, probably yes.

Here are a few papers:

• Monchi et al (2004): 49 circuits; single-centre RCT looking at circuit lifespan.
  • Conclusion: "Regional citrate anticoagulation seems superior to heparin for the filter lifetime and transfusion requirements". The haemofilters lasted 70 hours on average with citrate, and 40 hours on average with heparin.
• Oudemans-van Straaten et al (2009):215 patients, naldoparin vs. citrate: single centre RCT.
  • Unexpectedly, 3-month mortality was found to be decreased by 15% with citrate.
  • Authors hypothesised that some sort of interference with inflammation improved the SIRS response. Unfortunately, the population was elderly (average age was 73), and their all-cause mortality was high (43-68%).
• Hetzelet al (2010): 174 patients, heparin vs. citrate: multicentre RCT.
  • "Use of citrate resulted in less systemic anticoagulation, a lower risk of bleeding and a longer haemofilter patency. Episodes of hypercalcaemia, hypocalcaemia and the need for additional bicarbonate infusions occurred more often under citrate."
  • No influence on mortality. Neither any safer nor more effective than heparin, all things considered. Conclusion: "neither citrate nor heparin anticoagulation should be regarded as a therapeutic standard, since there is no advantage of one of these substances with regard to patient mortality."
• Bellomo and Kellum scraped the literature for opinions in 2011:
  • Generally the tone of the paper suggests that heparin has been elevated unfairly to a high pedestal, and that perhaps it should not be viewed as a gold standard. Much is made of various little-known idiosyncrasies of heparin action in the critically ill, for instance proinflammatry effects and the resistance to heparin induced by critical illness. Intelligent use of citrate is cautiously urged as a valid alternative.
• Schilder et al (2013): 139 patients, heparin vs citrate: multicenter RCT.
  • Conclusion: "Renal outcome and patient mortality were similar for citrate and heparin anticoagulation during CVVH in the critically ill patient with AKI. However, citrate was superior in terms of safety, efficacy and costs"
  • However, the number was small; the study was powered for 360 patients but enrolment was slow and the authors got bored of it after 6 years, terminating the trial. With less than ghalf of the expected patient numbers, the study was not powered to detect subtle differences in mortality.
• Fiaccadori et al (2015): An Italian position statement.
  • A strongly pro-citrate statement:  "regional citrate anticoagulation (RCA) could represent the most promising strategy" provided one is cautiously protecting their patient from complications.