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].
Recent data on RCA in patients with liver failure undergoing CRRT have provided important information. In spite of substantial increases in citrate levels, the metabolic consequences were less significant than expected: a trend towards metabolic alkalosis was found instead of acidosis, and no significant electrolyte disturbances (including hypocalcemia) were observed [26]. Blood citrate levels were related to the calcium ratio; prothrombin activity <26% and lactate level >3.4 mmol/L proved to be acceptable predictors of citrate accumulation. However, a more recent retrospective study suggested that we may further restrict the exclusion criteria for RCA, describing the association between the incidence of citrate accumulation and more elevated lactate levels (>7.5 mmol/L) [23]. Most of these issues can be deemed valid in the case of extracorporeal liver support treatments usually adopted as a “bridge” to liver transplantation or liver recovery, such as the Molecular Adsorbent Recirculating System and Prometheus System. In our experience with Prometheus, RCA was a safe and effective anticoagulation modality [27, 29, 30].
Conclusion
The use of citrate represents a valid alternative to traditional anticoagulation with heparin during CRRT since it reduces the bleeding risk and increases the efficiency of the treatment. The increase of filter life span in fact, is not a goal to be pursued in itself, but the reduction of the filter clotting events within the first 48–72 h reduces the discrepancy between the prescribed and delivered dialysis doses. With recent technological innovations, the RCT during CRRT can be conducted safely with minimal risk of complications even in patients at the highest risk of citrate accumulation such as patients with liver dysfunction.
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