Bench-to-bedside review: Citrate for continuous renal replacement therapy, from science to practice

To prevent clotting in the extracorporeal circuit during continuous renal replacement therapy (CRRT) anticoagulation is required. Heparin is still the most commonly used anticoagulant. However, heparins increase the risk of bleeding, especially in critically ill patients. Evidence has accumulated that regional anticoagulation of the CRRT circuit with citrate is feasible and safe. Compared to heparin, citrate anticoagulation reduces the risk of bleeding and requirement for blood products, not only in patients with coagulopathy, but also in those without. Metabolic complications are largely prevented by the use of a strict protocol, comprehensive training and integrated citrate software. Recent studies indicate that citrate can even be used in patients with significant liver disease provided that monitoring is intensified and the dose is carefully adjusted. Since the citric acid cycle is oxygen dependent, patients at greatest risk of accumulation seem to be those with persistent lactic acidosis due to poor tissue perfusion. The use of citrate may also be associated with less inflammation due to hypocalcemia-induced suppression of intracellular signaling at the membrane and avoidance of heparin, which may have proinflammatory properties. Whether these beneficial effects increase patient survival needs to be confirmed. However, other benefits are the reason that citrate should become the first choice anticoagulant for CRRT provided that its safe use can be guaranteed.


Introduction
Anticoagulation is required to prevent clotting in the extra corporeal circuit during continuous renal replacement therapy (CRRT). Heparin is still the most commonly used anticoagulant to maintain circuit patency, especially since it is eff ective, instantaneous in its anticoagulation and cheap. However, bleeding is the main side eff ect, especially in critically ill patients [1]. Furthermore, the use of heparin is hampered by complex interactions with acute phase proteins and cells and by the potential development of heparin-induced thrombocytopenia. Heparin can also inhibit the anti-infl ammatory eff ects of antithrombin and trigger the release of infl ammatory mediators from blood and endothelial cells. Th is can lead to an unpredictable dose-eff ect relationship and an uncontrollable and potentially deleterious interference with pro-and anti-infl ammatory pathways [2]. Regional anticoagulation with citrate off ers an attractive alternative, but is still not standard care. Although citrate is primarily used for extracorporeal anticoagulation, it also has an eff ect on acid-base balance, energy supply and membraneinduced infl ammation, and indirectly on parathyroid hormone (PTH) secretion. Th e aim of this narrative review is to describe the complexity of citrate anti coagulation, to review the science underlying clinical decision-making and to summarize the clinical benefi ts of citrate.

Mechanism of regional anticoagulation with citrate
Citrate acts by chelating calcium and therefore inhibits the clotting cascade at several levels. It provides regional anticoagulation, virtually restricted to the extracorporeal circuit. Citrate systems work on simple and shared modalities: a) pre-fi lter infusion of citrate, which chelates ionized calcium (ionCa 2+ ; aiming for an ionCa 2+ concentra tion <0.35 mmol/L); b) a replacement infusion of calcium at the end of the extracorporeal circuit or via a separate venous access to correct for the calcium loss into fi ltrate or calcium-free dialysate; and c) preferable use of calcium-free dialysis or fi ltration fl uids. Some authors report the use of calcium-containing solutions. However, when used in hemodialysis or pre-dilution

Abstract
To prevent clotting in the extracorporeal circuit during continuous renal replacement therapy (CRRT) anticoagulation is required. Heparin is still the most commonly used anticoagulant. However, heparins increase the risk of bleeding, especially in critically ill patients. Evidence has accumulated that regional anticoagulation of the CRRT circuit with citrate is feasible and safe. Compared to heparin, citrate anticoagulation reduces the risk of bleeding and requirement for blood products, not only in patients with coagulopathy, but also in those without. Metabolic complications are largely prevented by the use of a strict protocol, comprehensive training and integrated citrate software. Recent studies indicate that citrate can even be used in patients with signifi cant liver disease provided that monitoring is intensifi ed and the dose is carefully adjusted. Since the citric acid cycle is oxygen dependent, patients at greatest risk of accumulation seem to be those with persistent lactic acidosis due to poor tissue perfusion. The use of citrate may also be associated with less infl ammation due to hypocalcemia-induced suppression of intracellular signaling at the membrane and avoidance of heparin, which may have proinfl ammatory properties. Whether these benefi cial eff ects increase patient survival needs to be confi rmed. However, other benefi ts are the reason that citrate should become the fi rst choice anticoagulant for CRRT provided that its safe use can be guaranteed.
hemo fi ltration, a higher citrate concentration in the fi lter (mmol citrate/L blood fl ow) is required to attain a similar degree of hypocalcemia in the circuit [3][4][5][6][7][8], and when administered for post-dilution in the venous chamber, the risk of local clotting is increased [9,10].
Whereas citrate causes a dose-dependent decrease of ionCa 2+ concentration, the relationship between ionCa 2+ concentration and the degree of anticoagulation is more complex. Citrate has almost no anticoagulant eff ect when ionCa 2+ levels remain >0.50 mmol/l [11] or >0.56 mmol/L [12]. However, clotting times steeply increase when ionCa 2+ levels decrease further. Below 0.25 [11] or 0.33 mmol/L [12] there is near total inhibition of coagulation.
Anticoagulation can be monitored by measuring postfi lter ionCa 2+ with adjustment of citrate dose according to the desired calcium target. Other protocols are less complex and use a fi xed citrate dose proportional to blood fl ow targeting a citrate concentration in the fi lter of about 3 mmol/L [13,14].
Citrate is partially removed by fi ltration or dialysis. Its sieving coeffi cient is about one for both dialysis and hemofi ltration [8]. Th e removed fraction varies between 0.20 and 0.50 depending on the relationship between blood and effl uent fl ow and on CRRT modality. Citrate requirements are lower with dialysis because, to achieve similar effl uent doses, dialysis is possible with lower blood fl ows. Furthermore, dialysis removes a higher fraction of the infused citrate due to the higher ratio of effl uent to blood fl ow [15]. In case of hemofi ltration, removal approaches fi ltration fraction. Th e remaining citrate enters the patient where coagulation is restored because a) the circuit blood is diluted in the patient's circulation and b) citrate is rapidly metabolized in the mitochondrial citric acid cycle in liver, kidney and muscle, liberating the bound calcium. As a result, citrate has anticoagulant properties only within the circuit and not in the patient.

Citrate solutions and acid base eff ects
Th ere are numerous citrate solutions for daily practice. Th e choice depends on local availability, preferences regarding CRRT modality (pre-or post-dilution, diff usion versus convection), legislation and available software. None of the solutions have proven clinical superiority, but the individual type of solution can have diff erent metabolic consequences [13,14].
In principle, citrate is infused either as a separate trisodium citrate (TSC) [9,[16][17][18][19][20], acid-citrate-dextrose (ACD) solution [4][5][6][7]21,22], or as a component of an isotonic citrate in saline with [23] or without citric acid [18] or of a balanced pre-dilution replacement fl uid [24][25][26][27][28][29] (Table 1). Although citrate is primarily used for extracorporeal anticoagu lation, it has profound eff ects on acid-base balance as well. Anticoagulant and acid-base eff ects are not directly related. Th e degree of anticoagulation depends on citrate dose and hypocalcemia (see above), while the eff ect on acid base state depends on metabolism of citrate and the 'apparent strong ion diff erence' of the solution (SIDa = [Na + +K + +Ca 2+ +Mg 2+ ] -[Cl -+citrate 3-]) [30], that is, the type of cations opposing the citrate anion. For example, only two thirds of the cations in ACD solution are strong ions (that is, Na + ). Th e buff er stre ngth of ACD is therefore lower than that of the pure TSC solution. Within the body, citrate is rapidly metabolized and the eff ective SID (SIDe) of the solution is [Na + + K + + Ca 2+ +Mg 2+ ] -[Cl -]. Th us, the alkalizing eff ect of the citrate solution depends on the metabolism of citrate. In clinical practice, the citrate dose is primarily titrated according to its anticoagulant eff ects (hypocalcemia). Th erefore, the buff er strength can be best compared between solutions when expressing SIDe per mmol citrate (Table 1).
Th e accompanying dialysis or replacement solutions should compensate for the sodium load and buff er strength of the citrate solution used and for the loss of calcium and magnesium. For this reason, the composition of the dialysis or replacement fl uids and their metabolic side eff ects diff er in the various citrate anticoagulation protocols [13,14]. Depending on the modality used, metabolic acidosis can be corrected by increasing citrate dose, effl uent dose (removal of metabolic acids) or bicarbonate replacement, and metabolic alkalosis vice versa. It should be noted that when using the isotonic balanced citrate-containing pre-dilution replacement solution, anticoagulant dose and CRRT dose (effl uent fl ow) cannot be adjusted separately [29,31]. When using a low-bicarbonate dialysis solution, acidosis is corrected by increasing citrate dose and decreasing dialysis fl ow [19]. To date, no studies have compared the diff erent modalities on clinical endpoints.

Clinical benefi ts of citrate
Clinical benefi ts of citrate are primarily related to less bleeding, a better circuit survival and lower requirement for blood products. A recent meta-analysis, including 6 randomized controlled trials (RCTs) with a total of 488 patients and data on 658 circuits, with a focus on safety and effi cacy of citrate anticoagulation, found a longer circuit survival time and a reduced risk of bleeding [32]. Control anticoagulation used in the six diff erent studies was unfractionated heparin [10,17,20], low molecular weight heparin [9] or regional heparinization [33]. Metabolic derangements were similar to control anticoagulation and could be controlled easily. Notably, in the largest clinical trial, citrate anticoagulation was better tolerated than heparin [9]. It should also be noted that patients with an increased bleeding risk -that is, those who are likely to benefi t most from citrate anti coagu lation -were not included in the randomized studies. Similarly, patients with liver failure were excluded and therefore results do not apply to this population either. In contrast to the above-mentioned meta-analysis, a repeat meta-analysis including the same six RCTs concluded that the effi cacy of citrate and heparin for CRRT was similar, but citrate decreased the risk of bleeding with no signifi cant increase in the incidence of metabolic alka losis [34]. Th e main reason for the discrepant results related to circuit life was the diff erent way the authors handled the study by Betjes and colleagues [10], which did not report interquartile ranges of circuit survival. Zhang and colleagues [32] estimated the survival times by scaling the Kaplan-Meier curve. In contrast, Wu and colleagues [34] did not include this study in their circuit survival analysis.
Most of the studies on citrate anticoagulation are too small to evaluate patient outcome [13]. However, the largest (single center) trial (performed by one of the authors), including 200 critically ill patients, unexpectedly showed a 15% absolute increase in 3-month survival using an intention to treat analysis [9]. Among the higher proportion of surviving patients, there was a trend towards better renal recovery with more patients free from chronic dialysis in the citrate group (P = 0.08). Of note, the benefi t of citrate on survival could not be fully explained by less bleeding. Although citrate did not perform worse in any post hoc subgroup, it appeared particularly benefi cial in surgical patients, younger patients, patients with sepsis and in patients with more organ failure, suggesting either a protective role of citrate or harmful eff ects of heparin during infl ammation. A subsequent multi-centre RCT did not confi rm the survival benefi t with citrate [35]. However, this trial was smaller, included a younger patient population with less severe organ failure, used a diff erent citrate protocol, and had a short follow-up period and a high proportion of drop outs.

Bioenergetic consequences
Potential sources of CRRT-derived energy consist of citrate, glucose (in ACD) and lactate. Th eir respective caloric equivalents are 2.48 kJ (0.59 kcal), 3.06 kJ (0.73 kcal) and 1.37 kJ (0.33 kcal) per millimole. Net energetic gain depends on the dose infused and the amount removed by CRRT. Th e dose of citrate infused during hemodialysis is lower compared to hemofi ltration, not because of a better clearance with dialysis (sieving coeffi cients approach 1 for both), but because hemodialysis is feasible with lower blood fl ow rates [15]. Table 2 shows an estimate of the daily energy delivery when using diff erent modalities and citrate solutions for CRRT at a dose of 2 L/h. During continuous venovenous hemodialysis (CVVHD), energy delivery is lowest with TSC as citrate source and during pre-dilution CVVH using an isotonic citrate-containing replacement fl uid. ACD contains 139 mmol glucose/L. When used as citrate source, it provides about 350 kcal/day (1,466 kJ) during CVVHD and about 500 kcal/day (1,294 kJ) during postdilution CVVH. Lactate-containing replacement fl uids together with citrate [6,7] during CRRT at 2 L/h add about 550 kcal (2,303 kJ) to daily energy delivery ( Table 2).
Th e question is whether this energy delivery is benefi cial or harmful. First, some energy provision may be useful since it compensates for the losses of amino acids and small peptides during CRRT. Second, both citrate and lactate may be easy fuel under stress [36][37][38][39][40]. Neither rely on insulin to enter the cell and citrate can replenish the Krebs cycle when intermediates are scarce [41]. Substrate availability is a crucial regulator of the Krebs cycle. Citrate enters cells directly providing intermediates to the cycle. Th ereby, citrate can restore  [42] or limited substrate availability [43]. Lactate enters the mitochondria, where it is converted to pyruvate generating ATP, or enters the liver for gluconeogenesis. Th ird, glycolysis requires an initial investment of ATP before more ATP is produced [44]. Th erefore, when energy stores are depleted, citrate and lactate may be preferable over glucose [36][37][38]. On the other hand, using ACD as citrate source means that 90 to 150 g of glucose is infused per day, because the solution provides 1.23 mmol glucose for each millimole of citrate. Th is degree of energy delivery may pose an unnecessary strain, especially when using ACD in combination with lactate-buff ered replacement fl uids [7]. It is important to be aware of the metabolic consequences of any type of fl uid used and to adjust nutritional intake when necessary [45].

Hypocalcemia and reduction of infl ammation
Activation of neutrophils and platelets and the subsequent release of mediators from intracellular granules are regulated by cytosolic Ca 2+ , which acts as an intracellular messenger [46][47][48][49]. Cytosolic Ca 2+ is maintained through mobilization from intracellular stores and an infl ux of extracellular Ca 2+ via plasma membrane channels. Th erefore, citrate-induced changes of the extracellular calcium concentration may have a direct eff ect on intra cellular Ca 2+ signaling. Hypocalcemia in the fi lter not only downregulates membrane-induced infl ammation [50][51][52][53], but seems to reduce systemic infl ammation as well [54,55]. Several pro-infl ammatory actions of neutrophils are calcium-dependent. Among them are superoxide genera tion, adhesion, degranulation, phospholipase-A2 activa tion and interleukin-8 synthesis [46]. We stimulated isolated leukocytes under diff erent extra cellular calcium conditions with and without citrate, and found that inhibition of the cytosolic Ca 2+ increase after stimulation with N-formyl-L-methionyl-L-leucyl-Lphenyl alanine (fMLP) depends on the degree of extracellular hypo calcemia and not on the presence of citrate. Typical results of a single experiment are presented in Figure 1. Th e eff ects of citrate on complement activation, especially seen when using the old unsubstituted Table 2 cupro phane membranes, are not uniform; some studies found no eff ect [47,52,55], whereas others reported suppression of the complement cascade [50]. Complement activation and associated neutropenia seem to be mediated by a diff erent membrane receptor, not related to degranulation.

Avoidance of the non-anticoagulant eff ects of heparins on infl ammation
In addition to their anticoagulant eff ects, heparins have both pro-and anti-infl ammatory eff ects elicited by their binding to numerous proteins and cells. Th e balance of these eff ects likely depends on the site of heparin binding, on heparin dose and on the presence, type and severity of sepsis [56][57][58] and may be benefi cial [59][60][61], neutral [62], but totally unpredictable and potentially deleterious [58,[63][64][65][66][67]. Anti-infl ammatory eff ects may be due to inhibition of the formation of thrombin. In addition, heparins may attenuate neutrophil-induced endothelial damage by inhibiting leukocyte adherence to the endothelial cells as well as mast-cell activation by prevention of intracellular calcium release [56]. Pro-infl ammatory eff ects may primarily be due to the binding and inhibition of endothelial antithrombin, thereby preventing local prostacyclin formation (summarized in [2]) and hampering the microcirculation [66,67]. Furthermore, during sepsis, heparin may contribute to the inactivation of antithrombin by elastase on vascular surfaces where neutrophils are sequestered [68]. Second, heparin can mobilize infl ammatory mediators, such as myeloperoxidase, lactoferrin, elastase and platelet factor-4, not only from circulating neutrophils, platelets and cells adhered to and activated by the dialysis membrane, but also from heparan sulfate like substances on the endothelial surface [64,65]. Th ird, heparin binds to lipopolysaccharidebinding protein, and this process facilitates the transfer of lipopolysaccharide to the CD-14 receptor and augments endotoxin-induced activation of monocytes [58,67]. Finally, heparin avidly binds to discrete domains released from the nucleus onto the membrane of apoptotic or necrotic cells. Th ese heparin-binding sites on apoptotic cells signal phagocytotic clearance and heparin may thus actually delay such clearance [63]. Th erefore, by its binding to numerous proteins and cells, heparin induces unpredictable eff ects on many body functions and some of these may be harmful, especially during infl ammation.

Intoxication
Th e main risk of citrate anticoagulation is the unintended infusion of large amounts of citrate into the patient's circu lation, which can lead to severe hypocalcemia, hypo tension due to decreased myocardial contractility and vascular tone, and eventually cardiac arrest. Th is poten tially severe adverse event can be instantaneously counter acted by calcium infusion. Unintended continued citrate infusion during the change of bags is usually not associated with clinical side eff ects, mainly because this amount is relatively low. However, the nursing staff should be aware of this potential risk. Fortunately, integrated software takes care of discontinuation of the citrate pump when bags are changed.

Accumulation
Th e main limitation of citrate anticoagulation is accumulation as a result of reduced mitochondrial citrate metabolism. Reduced metabolism is seen in patients with liver failure due to decompensated chronic liver disease and also in those with ischemic hepatitis and poor muscle perfusion as seen in prolonged cardiogenic shock. Th e citrate molecule itself is not toxic, but the symptoms of citrate accumulation are due to secondary hypocalcemia and acidosis. Monitoring of the patient's Ca 2+ is therefore crucial. Ionized hypocalcemia is the most sensitive indicator of citrate accumulation [69]. While decreasing Ca 2+ , citrate accumulation concomitantly increases total calcium concentration, due to an increase in citratebound calcium as well as calcium supplementation in response to ionized hypocalcemia. Th e total to ionized calcium ratio, therefore, is a useful marker to detect citrate accumulation [3,69,70] and seems the most speci fi c [69]. A rise in total to ionized calcium ratio >2.25 should trigger the clinician to consider citrate accu mulation. A recent prospective observational study in 208 critically ill medical patients receiving CRRT with regional citrate anticoagulation for acute kidney injury found that a ratio ≥2.4 independently predicted a 33.5-fold increase in 28-day mortality [71]. Failure to metabolize citrate therefore seems to indicate a high risk of dying. Citrate accumulation due to metabolic failure can lead to metabolic acidosis. How ever, measurement of the anion gap is not helpful in this setting, mainly because citrate accumulation due to metabolic failure tends to occur in situations where lactic acid accumulates too, that is, in the context of advanced liver disease or tissue hypoxia. In contrast, increased citrate infusion in patients with adequate metabolism (that is, in the context of inadvertent protocol error or after polytransfusion) can lead to metabolic alkalosis. Management of citrate accumulation includes a) decreas ing both citrate fl ow and blood fl ow if feasible, b) increasing citrate clearance (effl uent fl ow), c) reducing or discontinuing citrate fl ow at the cost of anticoagulant activity (when citrate is part of the pre-dilution replacement, reduction of citrate dose is not an option, because the dose of anticoagulation and CRRT are coupled, and citrate should be replaced by bicarbo nate with or without heparin), d) administration of intravenous calcium to correct hypocalcemia, and e) titrated replacement of bicarbonate to correct acidosis.

Other electrolyte disturbances
Systemic hypocalcemia during citrate anticoagulation may also be due to insuffi cient replacement -for example, when calcium replacement is lower than calcium loss. In that case, both total and ionized calcium decrease. Th e risk of calcium loss across the membrane is particularly high when calcium-free dialysate or replacement fl uids are used. Although it may be rational to replace the lost amount of calcium, calcium replacement dose is generally adjusted according to actual systemic Ca 2+ concen trations, which additionally refl ect trans-cellular shifts, such as the infl ux of extracellular Ca 2+ upon infl ammatory stimuli [46,48]. Furthermore, the optimal ionCa 2+ concentration during critical illness is not known. Critically ill patients often have low ionCa 2+ concentrations [72] and supplementation of calcium might be harmful [73]. An alternative target for calcium replacement might be normalization of the PTH concentration. Citrate also binds to magnesium and this may cause hypomagnesemia due to increased magnesium loss. Th e use of highly concentrated trisodium citrate solutions may lead to hypernatremia if the sodium content of the replacement solutions is not proportionally reduced.

Citrate in liver failure
Th e metabolism of citrate is diminished in patients with liver failure [74,75]. Unfortunately, citrate clearance cannot be reliably predicted from standard liver function tests. However, adjustment of dose and intensifi ed monitoring of ionized calcium levels seem to allow the safe use of citrate in patients with decompensated cirrhosis. Two recent studies showed the feasibility of citrate anticoagulation in patients with liver failure receiving treatment with a molecular absorbent recirculating system (MARS) [76,77]. In the observational study, the median citrate infusion rate was 3.1 mmol/L blood fl ow and median duration of treatment was 20 h [76]. Although the total to ionized calcium ratio increased signifi cantly, treatment was well tolerated. Th e second study was a randomized cross-over study comparing citrate anticoagulation with no anticoagulation. Out of 27 sessions, 4 had to be terminated prematurely but all 4 were in the no anticoagulation group [77]. Th e use of citrate was associated with a lower ionized calcium concentration, albeit without adverse events. It should be noted that the MARS treatments are intermittent. However, in a large prospective observational study includ ing 133 patients treated with citrate-based continuous venovenous hemodialysis for 72 hours, citrate anticoagulation was well tolerated in 86 patients with liver dysfunction as defi ned by a bilirubin >2 mg/dl [78]. Only 2% of patients developed an increased total to ionized calcium ratio (≥2.5).

Citrate in shock with lactate acidosis
Citrate metabolism occurs primarily in liver and muscle. A high lactate concentration in patients with shock at the start of CRRT should raise awareness of the risk of citrate accumulation, because this may indicate mitochondrial dysfunction. Nevertheless, clinical practice shows that a considerable proportion of patients with shock do tolerate citrate anticoagulation, especially those with septic shock and high lactate levels if circulation improves. In the randomized controlled trial by one of the authors, only one patient developed signs of citrate accumulation [9]. However, citrate is likely to accumulate in patients with persistent severe heart failure, ischemic hepatitis and poor muscle perfusion, because the Krebs cycle only operates under aerobic conditions. In these cases, intensifi ed monitoring of the total to ionized calcium ratio and acid base balance is advised (2-hourly at start), and citrate infusion should be reduced or discontinued when calcium ratio increases above 2.25 to 2.5.

Eff ects on bone metabolism
Systemic hypocalcemia is a potent stimulus for PTH secretion. In normal subjects, a decrease in serum ionized calcium of as little as 0.025 mmol/L leads to release of preformed PTH within minutes, followed by an increased production of biologically active PTH. Th e immediate eff ect of PTH is to mobilize calcium from skeletal stores. In patients with normal kidney function, PTH also increases tubular calcium reabsorption and stimulates the conversion of 25-hydroxyvitamin D3 to 1.25-dihydroxyvitamin D3. In critically ill patients with acute kidney injury, the renal eff ects of PTH may be negligible, but concern about the potential harmful eff ects on bone metabolism has been expressed [79]. Th ree studies in critically ill patients with acute kidney injury reported a negative calcium balance and signifi cant rise in intact PTH levels during citrate-based CRRT when aiming for systemic ionized calcium levels between 0.8 and 1.1 mmol/L [79][80][81]. Th e exact signifi cance of PTH secretion during critical illness remains uncertain but severe bone reabsorption has been described during prolonged citrate-based CRRT. Adequate calcium replace ment may be crucial for preventing bone loss.

Strategies to increase the safety of citrate
Th e full advantage of citrate can only be realized if its risks are well appreciated and controlled. Safe introduction of citrate starts with the choice of a well-designed and fl exible protocol with proven effi cacy, adjusted to the preferences for CRRT modality and dose, and availability of fl uids and devices. Strict adherence to the protocol and its algorithms can prevent metabolic derangement. Safe implementation of citrate requires focused training of all staff involved, the availability of ionized calcium measure ment 24 h a day and attention to detail. Th e risk of citrate intoxication can be avoided by using CRRT machines with integrated software that interrupt citrate infusion when the blood pump stops and also by preventing the unintended mix-up of citrate bags and crystalloid infusion bags by markedly diff erent labeling. Intensifi ed monitoring of ionized calcium is needed in patients with risk of accumulation. Patient safety can be improved by 'pop-up' alerts in the patient data management system, continuous monitoring of citrate and ionized calcium concentrations, and computerized algorithms predicting systemic and post-fi lter total or ionized calcium concentrations [82][83][84].

Conclusion
Evidence is accumulating that regional anticoagulation of the CRRT circuit with citrate is feasible and safe in critically ill patients. Compared to heparin, citrate anticoagulation reduces the risk of bleeding and associated blood transfusion, not only in patients with an increased risk of bleeding but also in those without. Metabolic complications depend on the type of fl uids used and are largely prevented by the use of a strict protocol, training and integrated citrate software. Recent studies indicate that citrate can even be used in patients with (acute-onchronic) liver failure when monitoring is intensifi ed and dose is carefully adjusted. Patients at greatest risk of accumulation are those with persistent poor tissue perfusion and lactic acidosis, since citrate metabolism is oxygen dependent. Th e use of citrate may additionally be associated with less infl ammation due to hypocalcemia at the membrane and also by avoiding the therapeutic use of heparin. Whether these benefi cial eff ects increase patient survival needs to be confi rmed. However, its other benefi ts are reason enough [85] to make citrate the fi rst choice anticoagulant for CRRT provided that its safe use can be guaranteed.