Overview of Management of RCA
The use of citrate as an anticoagulant for human blood was first discovered in the early 1900s. It inhibits the clotting cascade by chelating ionized calcium (iCa). The loss of functional calcium affects a number of cofactors, preventing the propagation of the coagulation cascade (Figure 1), with the ultimate effect being inhibition of thrombin formation. Regional anticoagulation, only inhibiting the clotting cascade within the extracorporeal circuit, is an ideal option in the critically ill child with multiple organ failure at high risk for bleeding. Citrate is a small molecule with a molecular weight of 191 Da. As a comparison, unfractionated heparins are 3,000–30,000 Da and LMWHs are 2,000–9,000 Da. The chemical formula for citrate is C6H7O7; it is a tricarboxylic acid and carries a negative charge. There are four commercially available citrate formulations, of which only two are available in North America ( Table 1 ). These solutions differ in buffering capacity and osmolarity so it is important to know which citrate solution is being used. Of the available acid citrate dextrose (ACD-A or ACD-B) solutions, ACD-A is the most commonly used. ACD-A is made up of 3.22% citrate (74.8 mmol/L of citrate and 38 mmol/L of citric acid) and contains glucose (123.6 mmol/L) and sodium (224.4 mmol/L). Therefore, 100 mL of ACD-A contains 2.45 g of dextrose, 2.2 g of sodium citrate, and 0.73 g of citric acid. In comparison, trisodium citrate (TSC) is 4% citrate (136 mmol/L), does not contain glucose, and has a high sodium concentration of 420 mmol/L. Despite widespread use, citrate is not a Food and Drug Administration (FDA)-approved anticoagulant for CRRT.
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Figure 1.
Calcium-dependent factors in the clotting cascade. Citrate acts immediately to chelate divalent cations. The chelation of calcium inhibits the function of calcium-dependent cofactors: IXa, VIIIa, and VIIa, disrupting both the intrinsic and extrinsic pathways of the clotting cascade. Ultimately, loss of calcium inhibits the formation of thrombin.
Citrate should be infused into the access line of the extracorporeal circuit as proximally as possible because blood contacting the plastic tubing induces thrombogenesis. In order for citrate to be an effective anticoagulant, the iCa concentration within the circuit should be maintained below 0.5 mmol/L (2 mg/dL). Numerous protocols have been developed in both pediatric and adult patients, and typically, the citrate infusion is begun at a set ratio relative to blood flow (for sample of different protocols see Table 2 ). In most protocols, the prefilter iCa levels are checked within 1 hour of initiation to ensure a goal of less than 0.5 mmol/L is achieved and every 6–12 hours thereafter. There is a direct dose-effect relationship between citrate and calcium, enabling the titration of citrate to maintain the desired low extracorporeal circuit iCa level.
The calcium chelated blood enters the filter and these small-molecular-weight iCa-citrate complexes are removed relatively efficiently (20–50% removal) across the filter (Figure 2). Therefore, the blood returning to the patient is calcium deplete, and the remaining calcium is chelated by the remaining unfiltered citrate. The patient must be given supplemental IV calcium to avoid life-threatening arrhythmias from hypocalcemia. Ideally, calcium replacement occurs through a separate central catheter and not within the extracorporeal circuit. This is because calcium repletion reactivates the clotting cascade and calcium infused into the return line increases the risk of clotting within the catheter and the loss of the circuit due to catheter malfunction. The amount of calcium repletion is dependent on the amount of calcium removed across the hemofilter. Therefore, similar to monitoring the circuit calcium for effective extracorporeal anticoagulation, monitoring of the patient's iCa is performed every hour until a steady state of removal has been established and thereafter every 6–8 hours to ensure appropriate calcium replacement. The calcium replacement rate may need to be adjusted independently of the citrate rate to ensure the patient's iCa is maintained within the normal range. No data support superiority of one calcium salt (gluconate vs chloride) over the other.
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Figure 2.
Regional citrate anticoagulation. Inhibition of the clotting cascade is limited only to the extracorporeal circuit. Citrate is infused into blood entering the extracorporeal circuit at a site proximal to the hemofilter. Citrate chelates calcium making it biologically unavailable. This inhibits the propagation of the coagulation cascade. Calcium citrate complexes are removed at a rate of 20–50% across the hemofilter. The remaining free citrate posthemofilter is available to chelate any remaining calcium. Therefore, the blood returning to the patient is calcium poor. Calcium replacement must be provided to the patient (ideally via a separate infusion) to avoid life-threatening hypocalcemia. Blood upon returning to the body is reexposed to free ionized calcium, and the clotting cascade is no longer inhibited.