Filippo MARIANO, MD
Nephrology and Dialysis Unit, Department of Medicine Area,
CTO Hospital, Turin, Italy
Filippo Mariano, MD
Nephrology and Dialysis Unit,
Department of Medicine Area,
10126 Turin, Italy
Continuous renal replacement therapies (CRRT) are popular techniques which are, at present, easy to carry out in intensive care unit (ICU) settings. However, the key point of the success of these therapies is based on the feasibility of this treatment in patients who are critically ill, and very often with septic or surgical complications. The main challenge in the application of CRRT remains the requirement of anticoagulation therapy in order to prevent clotting of the extracorporeal circuit. In these patients, anticoagulation is in many instances an invasive procedure, not free from severe complications such as active bleeding.
Unfractionated heparin is still the most commonly used anticoagulant therapy for extracorporeal treatments in ICUs and considered the gold standard. However, apart from unfractionated heparin and low molecular weight heparin (LMWH), several alternative methods to heparin have been proposed and applied in the last 40 years.
These alternative approaches are either systemic or regional, which are virtually restricted to the extracorporeal circuit without involving patient circulation.
As shown in Figure 1, they include low molecular weight heparin, prostacyclin, thrombin inhibitors, the serine proteinase inhibitor nafamostat, hirudin, regional heparinization, saline flushes and other technical variations, and regional citrate anticoagulation. Amid these alternative approaches, regional citrate anticoagulation is the most promising method in terms of safety, efficiency and feasibility.
In the history of extracorporeal circulation, hirudin extracted from leaches was the first anticoagulant, and only in the late 1920s was heparin adopted as an anticoagulant in humans (1).
As matter of fact, heparin is quite similar to the theoretical features of an ideal anticoagulant (Fig. 2).
Unfractionated heparin is cheap, efficacious, quite safe, easily monitored and with a possible complete inhibition by antagonists (Fig. 3).
Therefore, up till now heparin has been the drug of choice for preventing clotting in chronic patients undergoing hemodialysis as well as patients treated by CRRT. Apart from heparin induced thrombocytopenia (HIT), the main adverse side effect of heparin is the risk of bleeding (2). In patients at a high risk of bleeding CRRT is often a harmful balance between the circuit clotting rate and hemorrhagic complications. In those dialyzed patients whose anticoagulation was more severe with PTT ranging from 45 to 55 sec, both bleeding episodes and filter life were present at a significantly higher rate than in patients with PTT ranging only from 15 to 35 sec (2). The incidence of bleeding episodes during CRRT, bearing in mind all the administration methods, ranged from 10% to 30%, with mortality due to bleeding as high as 15%. In addition, clinically important bleeding significantly increases the risk of death in ARF patients (3-9).
Low molecular weight heparin
Experience in the use of low molecular weight heparin as an anticoagulant instead of unfractionated heparin during CRRT led to inconsistent results in terms of safety or efficiency (10-12). In a prospective randomized controlled clinical trial performed in order to compare the efficacy, safety, and cost of fixed-dose low-molecular-weight heparin (dalteparin) with adjusted-dose unfractionated heparin, patients in predilution CVVHDF received dalteparin (initial bolus of 20 units/kg + infusion at 10 units/kg/hr, with an anti-factor-Xa activity of 0.49 ± 0.07) or heparin (initial bolus of 2000-5000 units + continuous infusion at 10 units/kg/hr, activated partial thromboplastin time of 79±4.3 secs)(7). Kaplan-Meier mean time to failure of the hemofilter was 46.8±5.03 hrs in dalteparin and 51.7±7.51hrs in heparin treated patients (p = 0.75), with no significant difference in reduction of platelet count, heparin-induced thrombocytopenia, bleeding episodes (5 episodes for dalteparin and 7 episodes for heparin, p = 0.53.49) and mean packed-cell transfusion volume (p = 0.90). However, daily costs, including coagulation assays, of hemofiltration were approximately 10% higher using dalteparin than with heparin. The authors concluded that "unfractionated heparin remains our anticoagulant of choice for continuous hemofiltration in intensive care" (11).
Heparinoids are molecules similar to heparin, but different both immunologicaly and in its substrate activity. They include danaparoid and dermatan sulphate, both used in cases of suspected HIT for their low cross reactivity with heparin induced antibodies (< 10%). Danaparoid is a mixture of heparan sulfate, dermatan sulfate and chondroitin sulfate. Its antithombotic activity is due to inhibition of factor Xa (mediated by anti-thrombin III) and partial inhibition of thrombin. Elimination is by renal route, with a half-life (anti-Xa activity) of 25 h. In a retrospective analysis on danaparoid anticoagulation in 13 ICU thrombocytopenic patients with ARF and HIT who underwent renal replacement therapies (RRT), mean filter life was 37.5 hrs, with reached anti-Xa levels of 0.4 U/ml. However, major bleeding in 6 out of 13 patients was observed (13). Dermatan sulphate selectively catalyzes inactivation of thrombin by Heparin Cofactor II and does not interact with antithrombin III or other coagulation factors. Dermatan sulphate has been used in chronic hemodialyzed patients suffering from HIT with safety and efficacy (14). In patients undergoing RRT extracorporeal filter clotting was observed in 19.9% (n 294 slow hemofiltration sessions) during anticoagulation with dermatan sulphate and in 19% during anticoagulation with unfractionated heparin (n 572 slow hemofiltration sessions)(15).
Thrombin inhibitors include hirudin and its analogs (lepirudin and others), and argatroban, the first molecule of a new class of thrombin inhibitors. In patients treated with lepirudin, no specific antidotes are available, aPTT is not a reliable monitoring parameter and bleeding was the most frequent adverse event which was observed (half-life up to 2 days in anuric patients treated by RRT)(16). Argatroban, a low molecular weight peptidomimetic (arginomimetic) drug, has a hepatic metabolism and biliary elimination with half-life of 39-51 min. No dosage changes are needed in renal failure, and no significant clearance has been observed in CVVH. In a retrospective review of 50 RRT treatment courses with argatroban in patients suffering from HIT, no patient died due to thrombosis and 2 patients (4%) developed new thrombosis while on argatroban. Major bleeding occurred in 3 (6%) of 50 treatment courses (17).
Prostacyclin and its analogs
Available experience with prostacyclin analogs and serine esterase inhibitors are limited (18-20). Iloprost has been used in HIT patients undergoing cardiopulmonary both in combination with heparin at low dosage (18) and as the sole anti-hemostatic agent in CRRT (19).
In order to prolong extracorporeal circuit life in high risk bleeding patients, mechanical measures such as increasing blood flow and flushing the filter with saline (21,22), priming hemofilter and lines with heparinized human albumin instead of heparinized saline (23), use of flat plate configuration, administrating heparin into the air chamber and using a larger membrane surface (24), manipulating heparin dilution and point of administration (25) were not associated with a significant increase in circuit life. On the contrary, it has been demonstrated that predilution is a key factor in prolonging filter life in RRT (26). By comparing the use of predilution vs postdilution, Uchino et al observed that median filter life was significantly shorter in the post-dilution period (13.0 vs. 18.0 h, p = 0.021). Multivariate linear regression analysis showed that the pre-dilution mode was a significant independent predictor of increased filter life (p = 0.029), together with well known other factors such as platelet count (p = 0.0035) and heparin dose (p = 0.046)(26).
Heparin protamine is an old regional alternative method. Despite some favourable reports in CRRT, regional anticoagulation with heparin and protamine has not been widely adopted because of concerns regarding the need for frequent and careful monitoring of coagulation parameters and meticulous dosage adjustments. In a group of patients with ARF after cardiac surgery, at a high risk of bleeding and with a mean filter life shorter than 24 hours without an anticoagulant, mean filter life was increased to 37.8 h by applying regional heparinization (27). In a recent article by van der Voort et al. (28) the role of pre- and postdilution and of nadroparin vs heparin protamine were evaluated on filter run time in CVVH in two consecutive prospective randomised crossover studies. Median filter run time was 45.7 vs 16.1 h in pre- and in post-dilution mode (p = 0.005), respectively, and 39.5 vs. 12.3 h in nadroparin and heparin protamine CVVH (p = 0.045), respectively. Pre-dilution CVVH result in important in filter run time, and regional anticoagulation with systemic nadroparin resulted in a significantly longer filter life compared to heparin-protamine anticoagulation (28).
Citrate as an anticoagulant in hemodialysis was first reported in the1960s by Morita et al. (29). Thirty years later, citrate was applied by Mehta et al as a regional anticoagulation in critically ill patients treated by RRT (30).
Citrate exerts a regional anticoagulation activity that is restricted to the extracorporeal circuit by chelating ionized calcium (iCa++) in the blood circuit. After mixing with citrate at the beginning of the extracorporeal circuit, iCa++ is partially chelated, its free ionized concentration falls from a blood systemic value of 1-1.2 mmol/L to 0.3-0.5 mmol/L, rendering circuit blood non coagulable. In the filter, a larger portion of the citrate–calcium complex is freely filtered and lost with the spent dialysate. The remaining amount of citrate which returns to the patient is rapidly metabolized to bicarbonate by entering the tricarboxylic pathway, mainly the liver, kidney and skeletal muscles. In addition, citrate calcium in the patient blood returns free due to citrate metabolism and the patient is preserved by systemic anticoagulation. Calcium is lost in the ultrafiltered fluid or in spent dialysate since membranes with a sieving coefficient near to unit are largely permeable to free calcium or citrate calcium complex. Lost calcium is usually replaced by an infusion of calcium at the end of extracorporeal circuit (Fig. 4).
In the last few years, citrate has become increasingly popular. This interest reflects the real impact this method currently has on extracorporeal treatments in ICUs in North America and Europe. For instance, in all adult ICUs in the Calgary Health Region, a standardized protocol in CRRT which includes options of regional citrate or systemic heparin has been implemented since August 1999 (31). From these and other data, citrate anticoagulation seems to act as a practical alternative to heparin. There are many reasons for the citrate popularity, but the primary benefit is the citrate ability to provide dialysis without a systemic anticoagulation to ICU patients. This issue is very important in ongoing continuous RRT patients, when systemic anticoagulation is often the limitation factor of the “continuous” treatment and where the bleeding risk is more relevant compared to intermittent treatment.
Regional citrate anticoagulation has been applied to several RRT modalities including SLED, CVVHD, CVVHDF, CVVH, CPFA-HF and fractioned plasma separation and adsorption. Different modalities of citrate administration have been described, such as trisodium citrate, ACD-solution A and predilution with citrate-containing replacement fluid (8,30-39). On the whole most of these studies seemed to prove the superiority of citrate in comparison to heparin in filter and circuit life, and no life-threatening complications were apparent. In the case of administration of an excessive citrate load (> 20 mmol/hour) in patients suffering from hepatic failure, some well-recognized biochemical alterations due to citrate metabolism (increased total- to iCa++ ratio, metabolic alkalosis, increased anion gap) occurred. Reduction of citrate load or increase of dialysate flow rate could reverse these metabolic abnormalities (8,30-38).
We implemented the classical scheme of regional citrate anticoagulation on Multifiltrate (Fresenius Medical Care, Bad Homburg, Germany), and performed continuous veno-venous hemodiafiltration (CVVHDF) in the predilution mode. As a matter of fact, we chose to maximally simplify the methodology using the available hardware without adding any external devices, by employing commercial solutions and applying the predilution as much as possible. Our protocol is described in the schema of Figure 4.
Figure 4: We performed CVVHDF by infusion in predilution of a citrate containing and Ca++ free solution. This solution was prepared by adding a commercial 1000 ml ACD-A solution (Fresenius Kabi Italia) to a 4500 ml Ca++ free bag (HDF/501, Pierrel Medical Care). As dialysate, we used a Ca++ free commercial solution (HDF/501), and a commercial 10% calcium chloride solution was infused via the heparin pump, connected to the end of the extracorporeal circuit.
So far we performed more than 100 CVVHDF sessions with this simple and feasible operative protocol, with good clinical results and no apparent complications (Figure 4).
The positive results obtained with regional citrate anticoagulation were confirmed in 3 recently published large studies involving 251 patients (9,31,38). In the prospective randomized study by Kutsogiannis DJ et al (38) involving 30 patients not at high risk of hemorrhagic complications, the median hemofilter survival time was 124.5 hours in the citrate group, the time being significantly longer than the 38.3 hours in the heparin group (P < 0.001). As regards adverse effects, no definite hemorrhage occurred in the citrate group whereas seven instances did in the heparin group. Occult hemorrhage was once present in both the citrate and heparin group. After adjustment for antithrombin-III levels and illness severity score, the relative risk of hemorrhage with citrate anticoagulation was still significantly lower than that with heparin (0.14 vs 0.96). In the second considered large multi-center study involving seven US centers, 138 patients and 442 CRRT circuits were utilized to assess filter life span and anticoagulation complications in patients receiving CRRT with heparin, citrate or no anticoagulation (9). Mean circuit survival was no different for circuits receiving heparin (42.1 +/-27.1 h) and citrate (44.7 +/-35.9h), with similar clotting rates and without any significant difference by Kaplan-Meier analyses of survival between the two groups. No anticoagulation circuits showed a significantly lower survival (27.2+/-21.5 h, P<0.001). Life-threatening bleeding complications due to the anticoagulant were present in the heparin group, and absent in the citrate group (9). The third study refers to results obtained with a standardized protocol for CRRT implemented at all adult intensive care units in the Calgary Health Region, Canada. Of 87 patients with acute renal failure requiring CRRT, 54 were initially treated with citrate (212 filters), 29 with heparin (97 filters), and 4 with saline flushes. Median filter life span was significantly higher with citrate than with heparin (40 vs 20 h), with a median time to spontaneous filter failure greater with citrate in comparison with heparin (>72 vs 33 hours). In addition, citrate anticoagulation was well tolerated, and no treatment was discontinued for hemorrhagic episodes, hypernatremia, metabolic alkalosis, or hypocalcemia (31).
On the basis of these preliminary data, citrate could be considered the most promising anticoagulant alternative to heparin now available.
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