for AKI recommend the use of RCA as the preferred anticoagulation modality for CRRT in patients without contraindications for citrate, even in the absence of increased bleeding risk or impaired coagulation [6].
Citrate: Mechanism of the Anticoagulant Action
Sodium citrate, infused before the filter, chelates calcium, essential to the coagulation process. The ensuing regional hypocalcemia in the filter inhibits thrombin generation. Citrate is partially removed by filtration or dialysis [7], and the remaining amount, infused into the patient, is rapidly metabolized in the citric acid (Krebs) cycle, especially in the liver, muscle, and renal cortex. The calcium previously chelated is released into the patient’s blood as a result of citrate metabolism, whereas the calcium lost with the effluent needs to be replaced by calcium solution administered to the patient. Systemic coagulation is thus unaffected (Fig. 1).
Fig. 1. Schematic representation of the regional citrate anticoagulation implemented in an extracorporeal circuit of CRRT. The citrate solution is infused before the dialyzer, at a flow rate proportional to blood flow, citrate dose, and solution citrate concentration. Citrate chelates calcium: the resulting effect is the extreme reduction of ionized calcium (iCa) in blood (ideal target 0.3–0.4 mmol/L). Calcium must be administered to the patient to restore the physiological level (1.1–1.25 mmol/L). A specific infusion line is needed either downstream of the dialyzer or directly to the patient. The calcium-citrate complexes are partially lost in the effluent, depending on the dialysis dose. The metabolic load of citrate to the patient will be the difference between citrate infused into the circuit and citrate lost with the effluent (correlation between the effluent volume and the amount of citrate lost).
For anticoagulation, the citrate dose is adjusted to blood flow so as to achieve an ionized calcium (iCa) concentration <0.3–0.5 mmol/L in the filter [4]; the lower the calcium concentration, the higher the degree of anticoagulation [8]. Some protocols use a fixed dose of citrate in relation to blood flow according to an algorithm, with the target of about 3 mmol citrate/L blood flow. Other protocols adjust the citrate dose by measuring the post-filter iCa, which complicates the intervention but optimizes anticoagulation [2, 4].
RCA versus Heparin: Incidence of Bleeding
Two recent meta-analyses [10] confirmed the advantage of RCA over heparin in terms of incidence of bleeding during CRRT.
In particular, all studies considered by Wu et al. [9] assessed the incidence of bleeding, and a significant difference was found between the 2 groups (RCA vs. heparin), with fewer patients in the citrate group suffering from major bleeding (RR 0.34; 95% CI 0.17–0.65). The number of people needed to receive the treatment before one person would experience a beneficial outcome (number needed to treat) was 6.87.
Again, in a small study that randomized 48 patients for continuous veno-venous hemofiltration (CVVH) with RCA or systemic heparin anticoagulation, Betjes observed a significantly higher incidence of bleeding and highlighted that the mean need for red blood cell transfusion was more than double in patients receiving unfractioned heparin (0.88 vs. 0.43 units of packed red blood cell per day of CVVH) [11]. More recently, in a larger study, Morabito et al. [12] likewise showed a lower transfusion rate during RCA-CVVH than with heparin (0.29 vs. 0.62, p = 0.017) or no-AC (0.29 vs. 0.64 blood units/day, p = 0.019), probably in part due to the significantly lower need for filter set replacement during RCA-CVVH. In addition, RCA was associated with an increase in the platelet count and antithrombin-III activity, thus avoiding platelet concentrate administration and antithrombin-III supplementation.
If the use of citrate is associated with a lower hemorrhagic risk (compared to heparin) and a reduction in blood loss for technical reasons (lower number of filters replaced), it would be reasonable to expect an indirect positive effect on the survival as well, but no strong evidence is presently available about any such possible favorable effects of RCA. Only in one large single-center randomized trial, including 200 critically ill patients on CRRT using nadroparin or citrate anticoagulation, was RCA associated with a surprising 15% absolute increase in 3-month survival, which was not fully clarified by the lower incidence of bleeding. Moreover, post-hoc analysis revealed that RCA might be particularly advantageous in specific clinical conditions (e.g., surgery, sepsis, severe multiple organ dysfunction syndrome, and younger age). To explain this survival advantage of RCA, the authors called into question the possible positive effect of citrate in the “inflammation network” (less polymorphonuclear and platelet degranulation due to hypocalcemia inside the filter, more substrate availability for citric acid cycle maintaining redox state) [13].
Two subsequent multicenter randomized trials, as large as the previous one, comparing unfractioned heparin with RCA in 170 [14] and 212 [15] patients undergoing CRRT, disconfirmed the RCA survival benefit. Finally, the recent meta-analysis by Liu et al. [10] clarified that there was no significant difference in mortality between the citrate and heparin groups.
RCA and Circuit Life Span
The circuit life span is affected by many factors, such as the patient’s clinical condition, coagulation status, patency of vascular access, modality of CRRT, and filtration fraction. The various confounding factors may cause a high heterogeneity among trials but the recent meta-analysis by Liu et al. [10] suggested that the choice of anticoagulant between heparin and citrate may play a pivotal role. In particular, RCA may have an advantage in prolonging the circuit life span. Thirteen trials that investigated the circuit life span of citrate versus heparin groups during CRRT were taken into consideration. The circuit duration before clotting was significantly longer in the citrate group than in the heparin group, with a mean difference (MD) of 15.69 h (95% CI 9.30–22.08, p < 0.01). Due to the remarkable heterogeneity mentioned above, subgroup analyses were performed by the authors studying CVVH, CVVHDF, pre-dilution, and post-dilution groups separately. Overall, in the CVVH (MD 8.18, 95% CI 3.86–12.51, p < 0.01) and pre-dilution subgroups (MD 17.51, 95% CI 9.85–25.17, p < 0.01), the circuit life span was significantly longer in the citrate group than in the heparin group [10].
In our experience (we started using citrate in 2010), in the 5 years from 2011 to 2015, we performed a total of 7,316 twenty four hour-treatments (CRRT) with a progressively increasing proportion of treatments using RCA (from 2.9% in 2011 to 49.5% in 2015). We observed a progressive reduction in the number of filters used for every 72 h of treatment (from 2.4 in 2011 to 1.3 in 2015). Although we did not directly collect these data, because the analysis is retrospective, we are in agreement with the reports by authors (Schilder et al. [18])
