This mixture of sulfated polysaccharides with molecular weights varying between 2kDa and 30kDa is the anticoagulant most commonly used in CRRT. Unfractionated heparin achieves its anticoagulant effect by bonding with antithrombin, favoring its bonding with thrombin (FII), and to a lesser extent by inhibiting activated factor X. To inhibit thrombin, it must bind both with thrombin itself and with antithrombin, although it does not need to bind with antithrombin to inhibit activated factor X. Its half-life ranges from 30min to up to 3h in cases with renal dysfunction. Its major advantages are (a) it is inexpensive; (b) prescribing physicians and the nurses in charge of the procedure are familiar with it; (c) it is easy to administer and to monitor (through aPTT); and (d) its effects can be reversed with protamine. There is no universally accepted protocol for its use, although various algorithms have been proposed for its administration during CRRT.21 It is usually present in the solution primed from the system in variable concentrations (1000–5000IU per liter). Before connection to CRRT and after the evaluation of the patient's coagulation, a bolus (30IU/kg body weight) is usually administered through the arterial line; the recommended maintenance dose is 5–10IU/kg/h.

The main problems associated with heparin are its dosing, bleeding, resistance, and heparin-induced thrombocytopenia. The problem with dosing heparin is that there is no direct relation between the dose of heparin and the aPTT, the duration of the filter, or hemorrhagic complications. Dosage is monitored through the aPTT, targeting levels between 1.5 and 2.0 times the baseline value (45–60s). The dose must be reduced drastically in patients with disseminated intravascular coagulation or thrombocytopenia. Every increase of 10s in the aPTT causes a 25% decrease in clots in the filter. The values of aPTT are partly dependent on the levels of coagulation factors associated with critical illness such as the variable clearing that the heparin itself undergoes when it is administered before filtering. Hemorrhagic events are the most common complication, affecting 10–50% of cases, depending on the type of population and the degree of anticoagulation.22 Hemorrhagic complications are not strictly related to the dose of heparin administered, but they are strictly related to the aPTT. The risk of bleeding increases by 50% for each increment of 10s in the aPTT. The incidence of bleeding complications is underestimated because minor events often go unreported; major bleeding events are defined as intracranial hemorrhage, retroperitoneal hemorrhage, or hemorrhages that result in death or the transfusion of ≥2 units of packed red blood cells.

Resistance to heparin is based on two pillars: (a) On the one hand, low levels of antithrombin III (AT-III), because this protein is consumed when the sepsis coagulation cascade is activated, and greater proteolytic degradation mediated by granulocyte elastase, the effect of which is increased by heparin itself. (b) On the other hand, the expression of heparin-binding proteins decreases heparin's effective concentration and thereby its anticoagulant effect.23 Some centers opt for the administration of AT-III to favor anticoagulation and the durability of the circuit, but the cost-effectiveness remains to be determined. Acquired AT-III deficiency (AT-III <70%) can be supplemented by an initial bolus [AT-III bolus=Weight×(100−initial AT-III activity %)/1.5], following a continuous infusion (40UI/kg/d). The doses should be secondarily adjusted to maintain an AT-III activity level between 80% and 100%.24

The incidence of heparin-induced thrombocytopenia (HIT) in ICU patients is very low, ranging from 0.3% to 0.5%.25 The frequency of HIT in critically ill patients receiving heparin anticoagulation for CRRT still remain to be determined in prospective studies.26,27 It is advisable to determine the levels of antibodies to heparin platelet factor 4 (H/PF4) after calculating the 4T score (Table 1).28 The most susceptible patients are those with a decrease >50% on the fourth day of receiving heparin. HIT should not be confused with the reversible thrombocytopenia that occurs after CRRT is started and ends when CRRT is stopped.26

Low-molecular-weight heparins with 18 saccharide units have a lower molecular weight (3600–6500kDa) than unfractionated heparin; therefore, they cannot simultaneously bond to thrombin and antithrombin, so the antithrombin activity is lost but the anti-factor Xa activity is maintained. Low-molecular-weight heparins are more effective than unfractionated heparin at decreasing fibrin deposits in the filter, and they start to act faster, activating fewer platelets and leukocytes. They are less dependent on antithrombin, bond less with proteins and cells, cause less activation of platelet factor-4, and result in a lower incidence of heparin-induced thrombocytopenia.29 These characteristics, together with more predictable pharmacokinetics, make low-molecular-weight heparins safer and more reliable. Nevertheless, they are more expensive than unfractionated heparin, and monitoring their effects is more complex – not all centers can routinely determine anti-factor Xa levels. The different molecules of low-molecular-weight heparins have distinct pharmacokinetics, which is not interchangeable with their counterparts. The bioavailability, half-life, or clearance in plasma and degree of accumulation in acute kidney failure can vary significantly among the different molecules. A recent systematic review30 concluded than no accumulation effect occurred with tinzaparin and dalteparin, but significant accumulation effects occurred with enoxaparin, bemiparin, and certoparin, even at prophylactic doses. The range of anti-factor Xa for their use has not been defined and is extrapolated from intermittent dialysis (iHD) between 0.2IU/ml and 0.4IU/ml. Unlike in iHD, the studies done in acute patients undergoing CRRT were done a long time ago, included few patients, and had heterogeneous objectives and designs, so it is difficult to draw conclusions. Low-molecular-weight heparins have been compared with unfractionated heparin31,32; different doses of low-molecular-weight heparins have been compared33; and different low-molecular-weight heparins have been compared with each other34 and with different anticoagulation strategies.35 Two recent studies comparing the incidence of bleeding and the duration of the filter between enoxaparin and unfractionated heparin reported contradictory results. Garcés et al.32 found similar filter life and anti-factor Xa ≥1.0IU/ml with enoxaparin, although the incidence of bleeding was higher. On the other hand, in a prospective controlled randomized crossover trial, Joannidis et al.31 with anti-factor Xa levels between 0.25IU/ml and 0.30IU/ml found that the low-molecular-weight heparins (0.15mg/kg pre-filter bolus and 0.05mg/kg/h maintenance perfusion) conferred longer filter life without increasing the incidence of bleeding and were also a cost-effective option. For all these reasons, it is difficult to interpret low-molecular-weight heparins for use in CRRT. Both the dose and the anti-factor Xa target must be tailored in function of the low-molecular-weight heparin chosen and the patient's clinical characteristics.

First reported in the 1960s, regional anticoagulation combines pre-filter unfractionated heparin and post-filter protamine to counteract its effects (1mg protamine/100IU heparin). Its main indication was for patients in whom systemic anticoagulation was contraindicated. Its use has declined in parallel with the rise of citrate and increased knowledge about the side effects of protamine. Regional heparinization exposes patients to the risk of heparin-induced thrombocytopenia and the dose-dependent side effects of protamine: hypotension decreased cardiac output, anaphylaxis, pulmonary vasoconstriction with the risk of right ventricular failure, leukopenia, and a paradoxical effect on coagulation. This paradoxical effect is due to transient thrombocytopenia as well as platelet dysfunction (lower reactivity and thrombin-mediated aggregation). There is also a risk of a rebound anticoagulation effect because the half-life of heparin is longer than that of protamine; this effect is dose dependent and increases slightly with prolonged administration. Heparin-protamine complexes are taken up by the reticuloendothelial system, which fractionates them, rereleasing the heparin. This makes it difficult to titrate the appropriate doses of protamine to reverse its effects. It is more complex to monitor because the aPTT must be measured before and after the administration of the heparin and after reversion with protamine. Protamine should not be used with heparin-lined filters because it reverses the effects of the heparin. For all these reasons, regional anticoagulation with heparin-protamine is not recommended.36

There is a growing body of literature to support favorable results for regional anticoagulation with citrate in CRRT. The strong points of this approach versus other anticoagulation strategies are the increased life of the filter and the decreased number of hemorrhagic complications. Table 2 shows some of the most relevant and most recent studies that compare regional anticoagulation with citrate against other anticoagulation strategies.

Oudemans et al.45 did a comparative analysis of the large randomized multicenter studies published through 2014 (CASH46 from 2014, OVLG47 from 2009, and Hetzel48 from 2011). In the CASH study46 citrate was compared to systemic anticoagulation with heparin in 139 patients. No differences were found in mortality or in recovery of renal function, but citrate was superior in terms of safety (fewer adverse effects, p<0.001), efficacy (longer filter life, p=0.02), and costs (p<0.001). The OLVG study47 compared citrate with nadroparin in 200 patients. The efficacy of the two drugs was similar, but citrate was safer (fewer complications, p<0.001). In a secondary analysis in subgroups, citrate was particularly beneficial after surgery and in sepsis with multiple organ failure, where renal recovery and mortality were improved. The improved survival was attributed to a possible immunomodulating effect of citrate. This hypothesis is supported by experimental data showing that anticoagulation with citrate impedes the degranulation of polymorphonuclear leukocytes and the activation of thrombocytes induced by dialysis; these processes depend on ionic calcium and are blocked by the administration of citrate.49,50 In the Hetzel study,48 citrate was compared against systemic heparin in 170 patients. No significant differences were found in the number of alterations in the acid–base balance or in the reduction of the levels of urea. The group that received citrate had longer filter life and a lower risk of bleeding. No differences in 30-day mortality were found. Hafner et al.51 also compared citrate against systemic heparin. Both modalities were effective in controlling uremia, although the reduction in urea was larger in the citrate group; the authors attributed this difference to longer hemofilter life. The citrate group had slight alterations in the levels of pH, ionic calcium, and sodium; however, these alterations were not associated with adverse events and were all successfully resolved by modifying fluids according to protocol. In the economic analysis, citrate was cost-effective. In a meta-analysis of six randomized controlled trials with a total of 488 patients, Wu et al.52 found that patients receiving citrate had a lower risk of bleeding without an increased incidence of alkalosis compared to patients in whom the circuits were anticoagulated with heparin. The efficacy and filter life were similar in the two groups. The authors concluded that citrate is at least as safe as heparin and significantly cheaper. Gattas et al.53 recently carried out a prospective randomized multicenter trial comparing citrate versus heparin-protamine in 212 patients. The results showed longer filter lifespan and fewer adverse events in the citrate group. There were no differences in the number of transfusions, the duration of CRRT, length of stay, or mortality. There were also no differences in cytokine levels. Stucker et al.54 found that citrate was superior to heparin as a method of anticoagulation in terms of dose and filter lifespan. Alterations in electrolytes and acid–base balance in the citrate group were uncommon, short-lived, and preventable with a strict protocol. There were no differences in short-term survival. Bai et al.55 recently published a meta-analysis including the randomized controlled trials that compared heparin versus citrate in CRRT. The meta-analysis included a total of 992 patients in 11 studies; two of these used regional heparinization, and the rest used systemic heparinization. In the citrate group, there was a significant reduction in the risk of circuit loss and filter failure compared to the groups receiving regional heparinization or systemic heparinization. The risk of bleeding in the citrate group was significantly lower than in the systemic heparinization group and similar to that observed in the regional heparinization group. No differences were observed in survival. These authors concluded that given the low risk of circuit loss and filter failure, regional anticoagulation with citrate should be considered a better method of anticoagulation than heparin in critical patients without contraindications.

In summary, regional anticoagulation with citrate can be considered efficacious and safer than anticoagulation with heparin. Citrate is associated with increased hemofilter lifespan and a lower risk of bleeding and multiple transfusions. Regional anticoagulation with citrate administered under strict protocols by properly trained staff is not associated with significant adverse events. More economic studies are necessary to evaluate its cost-effectiveness. The anti-inflammatory effects of citrate during CRRT and its impact on survival are controversial and should be evaluated in future studies.

This drug is metabolized by the kidneys. In patients with acute kidney failure, the half-life can be prolonged up to 50h, with the risk of the drug accumulating and increasing the risk of bleeding.59 It is usually monitored through the aPTT, although the relationship between the levels of lepirudin and the aPTT is not linear. The most accurate test is ecarin clotting time, but this test is not available in all centers. Some cases of anaphylaxis have been reported. Lepirudin is perfused intravenously (0.005–0.01mg/kg/h) and the dose is adjusted in function of the time to ecarin clotting.60 There is no specific antidote, but factor VIIa can be used in case of bleeding.61 In 2014, Treschan et al.62 published the results of a randomized double-blind study (ALicia) comparing lepirudin and argatroban in 28 critical postoperative patients with suspected heparin-induced thrombocytopenia and need for CRRT. The two drugs were equally efficacious in terms of circuit survival, but the lepirudin group had more episodes of bleeding.

A derivative of l-arginine, argatroban bonds reversibly to the catalytic site of thrombin without the need for a cofactor. It is metabolized by the liver (70%) and has a short half-life (31–59min), so it may be appropriate for critical patients with acute kidney failure without liver failure who need CRRT.63 The recommended dose, based on a prospective study of 30 patients with heparin-induced thrombocytopenia, acute kidney failure, and CRRT, is a bolus of 100μg/kg followed by the perfusion of 1μg/kg/min; the dose is adjusted to reach a target pre-filter aPTT of 1.5–3 times the baseline level.59 In patients with liver dysfunction, the half-life of the drug increased, making it necessary to reduce the dose, as in patients with multiple organ dysfunction (0.2–0.6μg/kg/min). There was an inversely proportional relation between the maintenance dose and severity scales; the closest correlation was with the Sequential Organ Failure Assessment (SOFA) (r=−90, p<0.001, dose μg/kg/min=2.18–0.09×SOFA).59 Argatroban brought about an increase in filter lifespan comparable to that achieved with unfractionated heparin, but argatroban did not increase the risk of bleeding after heart surgery.64 There is no specific antidote for argatroban, but an ex vivo study showed that factor VIIa can be used in cases of bleeding.61 The KDIGO guidelines recommend using argatroban during CRRT before other thrombin inhibitors or factor Xa inhibitors in patients with heparin-induced thrombocytopenia that do not have severe liver failure.5

Bivalidurin reversibly inhibits thrombin. It has a short half-life (25min) and has the additional advantage over argatroban that its metabolism is enzymatic, so it can be used in patients with heparin-induced thrombocytopenia who have hepatic and renal dysfunction. Although the prescribing information does not list this indication, retrospective studies with few patients on the efficacy, safety, and dosing in these patients have shown good results.65 The dose in patients on CRRT is 0.03–0.05mg/kg/h, which is adjusted in function of the pre-filter aPTT (1.5–2.5 times the baseline level). One prospective randomized double-blind study in 10 patients showed that the lifespan of the hemofilter was prolonged significantly compared to unfractionated heparin and to no anticoagulation.66 Although no specific antidote is available, in cases with bleeding, factor VIIa can be administered.61

The vasodilatory effects of this drug are short lasting (half-life 2min) whereas its antiplatelet effects last longer (2h). Some studies have analyzed the use of prostacyclin alone68,69 or combined with unfractionated heparin. The lifespan of the circuits was longer when it was used with unfractionated heparin (PGI2 4–5ng/kg/min with 2–3IU/kg/h unfractionated heparin).70 Herrera et al.71 reported that circuit lifespan was similar with epoprostenol and unfractionated heparin but the risk of bleeding with epoprostenol was lower. Hemodynamic instability was the most common adverse effect associated with PGI2, and it was directly related to the dose used. The main drawback is the risk of arterial hypotension, and this can be minimized by progressively increasing the dose. The cost has come down since a generic version of this drug became available.

Nafamostat, a prostacyclin analog, is a synthetic serine protease inhibitor that inhibits various coagulation factors (thrombin, factor Xa, factor XIIa, kallikrein) and components of the complement system, as well as platelet aggregation. It has a low molecular weight and a short half-life (5–8min). It is eliminated through the circuit, limiting systemic anticoagulation and lowering the risk of bleeding. Few data (only from Japan and Korea) are available about its use in CRRT because it is not available in the United States or Europe. Retrospective72 and prospective73 studies have demonstrated the efficacy and safety of nafamostat (fewer bleeding episodes and transfusions). However, Baek et al.72 founder longer filter lifespan without anticoagulation than with nafamostat (27.5 vs. 19.8h), and Lee et al.73 found a nonsignificant trend toward longer circuit lifespan with nafamostat than with no anticoagulation. Moreover, significant secondary effects such as anaphylaxis, agranulocytosis, and hyperkalemia have been reported.

Finally in Table 3 are summarized the main key points of this review about vascular access and circuit patency in continuous renal replacement therapy.