**Citrate Anticoagulation in Hemodialysis**

Stephan Thijssen *Renal Research Institute USA* 

### **1. Introduction**

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Plushch, M., Samsonova, N. (2009). Preliminary report regarding the use of selective sorbents in complex cardiac surgery patients with extensive sepsis and In hemodialysis, the patient's blood is flown through an extracorporeal circuit containing a hemodialyzer. This process stimulates coagulation for several reasons, most notably the blood's contact with the artificial surfaces of the tubing and dialyzer membrane and with air in the venous bubble trap, turbulent and stagnant blood flow, shear stress and hemoconcentration during the treatment [1]. Technological advances, e.g., the development of air-free blood circuits and more biocompatible materials for both tubing and dialyzer membranes, may eventually help reduce thrombogenicity of the extracorporeal circuit but are unlikely to eliminate this problem anytime soon. As a result, anticoagulation is (and will be, for the years to come) generally required for hemodialysis in the vast majority of patients.

In most cases in the United States, unfractionated heparin is the agent of choice to provide dialysis anticoagulation. While this is usually well-tolerated and relatively safe, there are significant drawbacks. The most obvious of these is that the anticoagulation is systemic in nature, which translates into an increased bleeding risk. This is certainly undesirable in endstage renal disease patients, who are already afflicted with uremic thrombocytopathy, and it is particularly dangerous for patients with additionally increased bleeding risk, e.g., patients after surgery or trauma, and patients with active (e.g., gastro-intestinal) bleeding. Another possible complication related to heparin use, albeit rare in dialysis patients, is heparininduced thrombocytopenia (HIT) type II [2], a potentially life-threatening condition associated with a mortality rate of 8 to 20 percent. Other possible side-effects of heparin use include osteoporosis, hair loss, and hyperlipidemia. Starting in late 2007, a series of severe anaphylactoid reactions had caused serious injuries and deaths. These reactions were later linked to heparin contaminated with oversulfated chondroitin sulfate [3, 4].

Several alternatives to heparin anticoagulation are potentially available, each of them accompanied by specific disadvantages. Intermittent saline flushes, i.e., flushing of the extracorporeal circuit with 25 to 50 mL of 0.9% sodium chloride solution every 15 to 30 minutes, is often used during acute dialysis in patients with increased bleeding risk or in patients with HIT type II. Since the procedure, surprisingly, is not automated, it is very laborious. Furthermore, its capacity to prevent clotting is rather limited, with partial clotting occurring in approximately 20 percent, and complete clotting of the extracorporeal circuit in about 7 percent of treatments [1]. Clotting of the extracorporeal system, of course, is associated with blood loss to the patient, and even with partial clotting, solute clearances will be impaired. Other agents used for systemic anticoagulation in hemodialysis are fondaparinux, danaparoid, and direct thrombin inhibitors. These have other downsides,

Citrate Anticoagulation in Hemodialysis 219

as not to compromise anticoagulation due to calcium influx from the dialysate [6]. This

A question of central importance is how plasma citrate concentrations relate to iCa concentrations. We analyzed the data from 21 regional citrate anticoagulation treatments performed at Renal Research Institute facilities in New York, USA, in 10 patients, during which 4% trisodium citrate (136 mmol/L) was infused into the arterial line and iCa measured before the dialyzer. Blood flow rates were 350 mL/min in 4 treatments, 400 mL/min in 13 treatments, and 450 mL/min in 4 treatments. Hematocrit and iCa were measured 13 minutes into the treatment using an Abbott i-Stat point-of-care analyzer. Hematocrits ranged from 28% to 39% (average, 33.6%). Citrate infusion rates ranged from 140 to 480 mL/h, and iCa ranged from 0.27 to 0.68 mmol/L (average, 0.38 mmol/L). Plasma citrate concentrations were calculated based on citrate infusion rates and calculated plasma flow rates. **Figure 2** illustrates the relationship between pre-dialyzer blood iCa activity and plasma citrate concentration. As can be seen, a plasma citrate concentration of >3.5 mmol/L is typically required to bring iCa levels to below 0.3 mmol/L. The exact citrate concentration necessary depends mainly on the individual patient's plasma calcium and protein (primarily albumin) concentrations. Total calcium in the serum comprises a protein-bound and a free (ionized) fraction, and the equilibrium concentrations of each can be estimated based on the respective dissociation constant [7-10]. Likewise, free citrate reacts with free calcium to form calcium-citrate complexes, again with a known dissociation constant [11]. Strictly, the multi-ionic milieu of the plasma should be considered, but reducing the relationships to calcium, protein, and citrate is a fair approximation. In clinical practice, these relationships are, however, not calculated. Instead, the citrate infusion rate is generally based on empirical knowledge and in most cases only tailored to the patient's blood flow rate. As can be expected, this may occasionally lead to citrate concentrations that are either too low to provide sufficient anticoagulation, or unnecessarily high. To assess the individual situation, pre-dialyzer (some groups use post-dialyzer) iCa levels can be measured in the plasma to ascertain that they are within the desired target range of approximately 0.25 to 0.35 mmol/L. If they are not, adjustments to the citrate infusion rate can be implemented and the iCa levels reassessed. Likewise, the post-dialyzer iCa concentrations are not known in clinical practice, and the rate of calcium substitution is based on empirical knowledge. Routinely, systemic iCa levels are measured in the patient at multiple time points during the treatment, and the calcium substitution rate is adjusted to counter drops or rises in systemic iCa concentration. Each adjustment usually necessitates a reassessment of iCa levels after 15

setup of regional citrate anticoagulation is depicted in **Figure 1**.

to 30 minutes to monitor its effect.

Fig. 1. Conventional setup of regional citrate anticoagulation in hemodialysis.

such as long half-life, lack of an antidote, or high cost, and all of them increase the bleeding risk as they are administered systemically.

The primary purpose of anticoagulation during hemodialysis is to prevent clotting of the blood while it is traveling through the blood tubing and dialyzer. Against this background, the cornerstones of optimal anticoagulation for hemodialysis are complete suppression of the activation of the clotting cascade, strict limitation to the extracorporeal circuit, absence of serious side-effects, and low cost.

Limitation of anticoagulation to the extracorporeal circuit, also known as regional anticoagulation, is important because it eliminates the increased bleeding risk associated with systemic anticoagulation. Originally, this was accomplished by infusing heparin into the arterial line of the blood circuit and antagonizing its anticoagulant effect by infusing its antidote protamine into the venous line. Since protamine's half-life is shorter than heparin's, the anticoagulant effect may return after the dialysis procedure, increasing the bleeding risk. Also, this mode of anticoagulation is not suitable for HIT type II patients because of the heparin administration. Regional anticoagulation by infusing the arachidonic acid derivative prostacyclin into the arterial line is based on this molecule's inhibitory effect on thrombocyte aggregation and its short half-life of only a few minutes. The downsides are its vasodilatatory properties, which can cause significant hypotension during the treatment, and its prohibitive cost. Regional citrate anticoagulation is an alternative to these two methods that also confines anticoagulation to the extracorporeal circuit but does not come with the disadvantages mentioned above. In fact, it conveys a set of additional advantages that go above and beyond merely providing regional anticoagulation.
