The citrate metabolic load to the patient is the difference between the citrate infused into the CRRT circuit and the quantity of citrate lost in the effluent. In fact there is a direct positive correlation between the effluent volume and the amount of citrate lost [7]. With the more commonly reported citrate protocols, the citrate load is approximately 10–20 mmol/h. This citrate load to the patient is quickly metabolized through the aerobic pathways of the Krebs cycle in the liver, skeletal muscle, and kidney. For each 1 mmol citrate metabolized in the Krebs cycle, 3 mmol hydrogen ions are consumed and 3 mmol bicarbonate is generated, assuming that the citrate is completely metabolized. The resulting bicarbonate produced from citrate metabolism along with bicarbonate in replacement/dialysis fluids provides the buffer supply to the patient [8].
But the buffer power of a citrate solution also depends on the proportion of strong cations in the fluid counterbalancing the citrate anion. Generally, citrate is available at various concentrations of trisodium salt, but in some commercial solutions hydrogen is used (citric acid) instead of sodium. Hydrogen does not act as a buffer. The Stewart approach to the acid-base equilibrium [21] provides an interesting tool for a deeper comprehension of the buffering effect of citrate. After metabolism of citrate, the remaining sodium increases the strong ion difference (SID) in body fluids: SID = (Na+ + K+ + Ca2+ + Mg2+) – (Cl− + lactate−). An increased SID produces alkalosis, while the infusion of a zero-SID fluid (such as saline) decreases the SID of body fluids and causes acidosis. As the citrate anion contrasts the cation load, the citrate solution has per se a zero SID (SID = [Na+ + K+ + Ca2+ + Mg2+] – [Cl− + citrate3−]) and is therefore potentially acidifying. As a result of citrate metabolism, there appears an alkalizing effect due to the strong cation load.
Fig. 2. Change in the CRRT anticoagulation modality from 2011 to 2015 in our Nephrological Department and relative change in the difference between the prescribed and delivered dialysis doses. Columns represent the ratio of different anticoagulation modalities per each year (light grey stands for no anticoagulation; medium grey for heparin; dark grey for citrate). Over the years, we progressively increased the number of treatments with regional citrate anticoagulation modality, which, in 2015, reached near half of the overall number of CRRT performed in the intensive care units. Thanks to the reduction of the down-time due to filter clotting, the discrepancy between the prescribed and delivered dialysis doses (arrows) could be progressively reduced, from 22% in 2011 to 7% in 2015. For the same reason, we could effectively increase the prescribed dose.
Indeed, in conditions where citrate metabolism is reduced (severe liver failure, severe tissue hypoxia/hypoperfusion) even trisodium citrate can first cause some acidosis as a zero SID solution, but if citrate is metabolized, free strong cations produce their alkalinizing effect.
So, by the same anticoagulant effect, commercial solutions containing citric acid at least in part will have a lower alkalizing effect, and need to be taken into account in the prescription. In addition, the Stewart approach to acid-base equilibrium, is able to offer an explanation of the fact that different citrate formulations, although infused at similar flow rates and thus giving the patient the same citrate load, may exhibit divergent capacity and speed in correcting acidosis because of a substantial difference in solution SID, and in particular in the chloride content [22].
Metabolic and Electrolyte Disarrangements Due to Citrate Anticoagulation
Despite the reported problems that citrate may induce hypernatremia or hyponatremia, hypercalcemia or hypocalcemia, hypermagnesemia or hypomagnesemia, these complications are quite uncommon when there is strict adherence to the RCA protocols. In particular, hypernatremia is an infrequently observed complication associated with the use of hypertonic solutions without low-sodium concentration dialysate and/or replacement fluids. Calcium and magnesium imbalances might be caused by effluent losses in the form of citrate complexes not adequately corrected by systemic supplementation [8].
Impaired liver function, arterial hypoxia, and reduced tissue perfusion are described in the literature as risk factors for citrate accumulation [23]. Citrate is an intermediate of energy metabolism and is not toxic, but accumulation of it with consecutive reduction of iCa could decrease the cardiac contractility or cause arrhythmias, and symptoms of systemic ionized hypocalcemia. However, there is increasing evidence that at least impaired liver function need not be considered as an absolute contraindication for RCA [24]. Several studies have reported that RCA can be safely used even in this population [25–27].
Monitoring Citrate Anticoagulation during CRRT
Measurement of citrate concentration in the blood is not available in the daily routine, so the most commonly accepted clinical markers for citrate accumulation [8] are as follows:
• An increased ratio of total calcium (tCa) to iCa (tCa/iCa),
• Metabolic acidosis with or without an increased anion gap, and
• Elevated demand for calcium substitution.
A calcium ratio (tCa/iCa) of 2.5 is often indicated as the critical threshold for enhanced risk of metabolic complications due to impaired citrate metabolism. Nevertheless, it has been reported that a lower cutoff of 2.1 appears to accurately predict the citrate accumulation (systemic citrate concentration 1 mmol/L) with high sensitivity and specificity (89 and 100%, respectively) [28].
However, the incidence of metabolic disarrangements resulting from citrate accumulation has been found to be rather low since it generally affects less than 3% of all CRRT patients on RCA, and clinical diagnosis of citrate accumulation is found exclusively in severely ill patients with multiorgan failure and severe lactic acidosis [24].
RCA in Patients with Liver Failure as a Safety Paradigm
The use of RCA in patients with liver dysfunction is often considered hazardous due to deranged liver metabolism and increased risk of citrate accumulation. However, many of the potential risks related to the use of citrate in these patients have been overcome, thanks to the recent evolution in dialysis machine engineering technology [24]. The new software is in fact able to adapt citrate infusion to blood flow changes, thus limiting the risk of an inappropriate citrate/blood flow ratio. Moreover, with CRRT monitors the citrate dose can be modified at any time during the treatment in the event of a documented or suspected citrate overload. Last, modulation of the convective and/or diffusive CRRT dose may prevent the development of citrate accumulation, due to the substantial removal of citrate with the effluent fluid [7].