Citrate Anticoagulation During Continuous Renal Replacement Therapy in Pediatric Critical Care

T. Keefe Davis, MD; Tara Neumayr, MD; Kira Geile, RN, CPNP; Allan Doctor, MD; Paul Hmeil, MD, PhD

Disclosures

Pediatr Crit Care Med. 2014;15(5):471-485. 

In This Article

Potential Complications

Hypocalcemia

The potential electrolyte disturbances and the complexity of calcium monitoring have hampered some institutions from implementing RCA. The most dangerous complication of RCA is hypocalcemia.[32] Two mechanisms contribute to hypocalcemia. The first is removal of calcium across the hemofilter with inadequate calcium replacement. The citrate infusion increases the dialyzable calcium fraction by decreasing protein bound calcium, thereby increasing removal.[32] Second, hypocalcemia can occur because of citrate infused into the patient. Citrate infused prefilter is not completely removed across the hemofilter. Measurements of postfilter citrate levels are not routinely performed, and therefore, the exact amount of citrate removed during CRRT is usually not available. Studies using conventional hemodialysis with high-flux filters have shown removal rates of greater than 80% for citrate.[32] However, CRRT provides lower clearance rates compared with conventional hemodialysis. An adult CRRT study reported citrate clearance rates of 35–50%,[33] and one pediatric study reported an average clearance of only 20%.[9] The excess citrate infused into the patient binds the patient's free iCa, producing a low patient iCa value. A total calcium test measures both free and citrate/protein-bound calcium. Therefore, a practical approach for citrate toxicity is monitoring the total to iCa ratio. A total calcium as compared to an iCa is directly proportional to the concentration of citrate in the blood.[34] An elevated total to iCa ratio of greater than 2.5 indicates citrate toxicity and is sometimes referred to as "citrate lock".[27]

Citrate Toxicity (Lock)

Upon entering the body, citrate is able to diffuse beyond the intravascular space and distribute throughout the total extracellular fluid. Citrate can be metabolized by most cells within the body, but the major sites of metabolism are the liver, renal cortex, and skeletal muscle.[35] Functional mitochondria are necessary to metabolize citrate via the tricarboxylic acid/Kreb's cycle.[36] Citrate toxicity has been associated with increased mortality.[34,37] It should be appreciated that citrate itself is not toxic.[38] Rather, it is the hypocalcemia that results in depressed myocardial function, vasoplegia, and prolonged QT interval that lead to fatal arrhythmias.[38] Citrate toxicity rarely occurs in patients with normal liver function as the liver is capable of metabolizing 100 times the normal citrate concentration.[34,39] The elimination half-life of citrate in adults with normal liver function has been shown to be 33 minutes.[35] However, liver dysfunction and lactic acidosis are risk factors for decreased metabolism and citrate toxicity.[34,40–42] Elimination half-life was increased to 50 minutes in patients with liver failure.[35] This is not to say that liver dysfunction or lactic acidosis are absolute contraindications to RCA. Citrate anticoagulation has been safely used in patients with severe liver dysfunction.[43] However, an additional factor places children at increased risk for citrate toxicity. Citrate infusions are often administered at much higher rates as compared to adults on a mg per kg basis. This is because citrate infusion rates are based on blood flow and not the patient's weight per se. As discussed earlier, blood flow rates, especially in small children, are disproportionately high as compared to adults when calculated in mL/min/kg, and therefore, citrate infusion rates likewise are high. The clinical team must remain vigilant for the possibility of citrate toxicity and intervene appropriately.

Citrate toxicity is treated by increasing citrate clearance as well as by increasing the calcium infusion to maintain normal iCa levels. Maneuvers to clear citrate include increasing convective clearance (by increasing replacement fluid and the ultrafiltration rate); increasing diffusion (by increasing dialysate rates); and pausing the citrate infusion. The exact amount of time to hold the citrate infusion if other clearance measures do not work has not been defined and should be guided by frequent reassessment of patient iCa and total to iCa ratio. We have successfully managed citrate toxicity by holding the citrate infusion for 30 minutes and then restarting at 70% of the previous rate. Others have reported holding the citrate infusion for 4 hours and restarting at 50% of the previous rate.[26] Three additional options are to decrease blood flow which allows a proportional decrease in citrate delivery, accept a higher circuit iCa, or change the proportional dosing of citrate relative to blood flow. The last approach has been used in newborns with inborn errors of metabolism treated with CRRT.[44] The authors report starting citrate anticoagulation at 50% of the normal rate (0.75 mL/hr × the blood flow in mL/min) per the protocol previously reported by Bunchman et al.[7,8]

Other Divalent Cations: Magnesium and Phosphorous

Citrate does not bind calcium exclusively and chelates other divalent cations such as magnesium (Mg) and phosphorous (Pi). A decrease of greater than 50% in ionized Mg was shown to occur in healthy adults receiving pheresis with citrate anticoagulation although measurements of total magnesium (the standard laboratory test) did not change.[45] Therefore, replacement is necessary, but typically provided via dialysate and replacement fluids. Phosphorous is also chelated by citrate potentiating hypophosphatemia. Unlike magnesium, Pi supplementation is often provided separately due to incompatibility with other solutes in the dialysate and replacement fluids. However, recently, the addition by providers/pharmacy of phosphate to commercial fluids has been safely performed in both pediatrics and adults.[46,47] Furthermore, there are now four commercially available dialysate and replacement fluids containing phosphate.[48] Therefore, it is important to be aware of the composition of the fluids prescribed. Regardless of method of phosphate and magnesium replacement interval, laboratory studies should include phosphate and magnesium levels (ionized magnesium studies are not normally measured).

Source of Calories, Hyperglycemia, and Acidosis Versus Alkalosis

Citrate solutions provide additional sources of energy and may require an adjustment of nutritional intake (citrate is an endogenous metabolic intermediate and in multiple foods). Caloric equivalents per millimole are citrate 0.59 kcal, glucose 0.73 kcal, and lactate 0.33 kcal. The net energetic gain depends on the amount infused and the amount removed.[49] Energy delivery is lower with TSC compared with ACD-A. For example, a typical prescription with a blood flow of 100 mL/min and a 33% removal of citrate across the hemofilter would provide approximately 1,100 kcal in 24 hours when using ACD-A compared with 750 kcal in 24 hours for a TSC solution. The use of ACD-A as a citrate source (which also contains glucose as compared to no glucose in TSC solution) means that 90–150 g of additional glucose is infused per day and may result in hyperglycemia if insulin resistance or deficiency is present.[49]

Acid-base balance can be affected by citrate. Protocols that use TSC may be more likely to result in hypernatremia (due to its high sodium content of 420 mmol/L) and alkalosis as sodium citrate is metabolized to bicarbonate by the following reaction: Na3Citrate + 3H2CO3[left right arrow]Citric acid + 3NaHCO3.[50] Theoretically, ACD-A solution has less risk for causing alkalosis because ACD-A contains only 67% TSC (33% citric acid) and therefore generates 33% less bicarbonate.[9] However, alkalosis is one of the most common electrolyte disturbances to develop regardless of citrate formulation ( Table 3 and Table 4 ). Paradoxically, if citrate cannot be metabolized, it accumulates and can result in a high anion gap acidosis. The measurement of the anion gap as a marker of citrate accumulation is typically not helpful as lactic acid is often present and responsible for decreased metabolism.[49] The best way to monitor for citrate toxicity is to be aware of risk factors and to routinely calculate the total calcium to iCa ratio ensuring it remains less than 2.5.

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