Anticoagulation Strategies for Continuous Renal Replacement Therapy

Venous Access and Circuit

The venous access, the hemofilter, and the venous air trap are the most common sites in the circuit for potential thrombosis. Catheter malfunction leads to intermittent stasis of blood flow, which promotes clotting and subsequent circuit failure. Measures for optimizing catheter function regard the site of insertion and catheter design . Blood flow reductions have been shown to contribute to circuit failure. To minimize blood flow interruptions, the use of a large-bore double-lumen central venous catheter is recommended to be positioned in the right jugular or femoral position (straight course). The length of femoral catheters is preferably 20 to 24 cm and possibly 30 cm in adults, whereas internal jugular catheters are best placed with their tip in the right atrium. The subclavian position is discouraged given the high risk of kinking, the potential for subclavian stenosis, and difficulties with future arteriovenous fistulas. Clinicians should try to avoid inserting a catheter above the diaphragm in case of high intrathoracic pressures and below the diaphragm in patients with intraabdominal hypertension. Attention must be paid to the position of the patient and fixation of the catheter to prevent kinking at the site of insertion. Catheters with side holes should not be used, because turbulent flow initiates clotting. Furthermore, contact of the holes with the vessel wall can inhibit flow, thereby activating clotting and treatment interruption. Temporary catheters for CRRT are made largely of polyurethane or silicone; both are hemocompatible. Polyurethane is a stiffer material, and these catheters are for acute use only (<3 weeks). Silicone is less stressful on the vessel wall and more suitable for long-term use. Finally, during treatment interruption, appropriate measures should be taken to maintain access patency. There is mounting evidence that citrate, as a catheter lock solution, offers better protection against bacteremia and adequate line patency as compared with heparin.

Activation of clotting at the membrane has been reduced greatly with the use of biocompatible membranes. However, modern membranes with a higher adsorptive capacity have a higher tendency to promote clotting. To reduce thrombogenicity of the membrane, surface coating with substances such as heparin or polyethyleneimine has been applied. Studies in patients receiving chronic dialysis have demonstrated the ability to perform dialysis without systemic anticoagulation with these coated membranes (heparin and low-molecular-weight heparin). However, the use of polyethyleneimine-coated membranes has not been shown to prolong circuit life during continuous venovenous hemofiltration (CVVH) without anticoagulation in the critically ill population. Similarly, the addition of heparin to the priming fluid did not reduce thrombogenicity of the membrane in patients with AKI receiving continuous venovenous hemodiafiltration (CVVHDF), neither did intermittent saline flushing, albumin priming, higher blood flow, nor separate heparin administration (prefilter and venous chamber).

Air traps allow for a relatively slow-moving column of blood to have constant contact with air, potentiating the formation of clots. Baldwin et al. examined if providing heparin into a prefilter line and air trap could prolong filter life. As compared with single-site administration, the dual-site administration did not prolong filter life. Gretz et al. achieved a slightly longer circuit life by raising the blood level in the air trap higher than the blood inlet port.

Hemodialysis Versus Hemofiltration

Hemodialysis is associated with longer circuit life than hemofiltration. Reasons are that hemofiltration confers hemoconcentration as ultrafiltrate is removed across the filter. Hemoconcentration promotes clotting because of higher concentrations of cells and coagulation factors in the filter. Furthermore, for a similar dose, hemofiltration requires higher blood flows. To reduce hemoconcentration, a filtration fraction (filtrate/blood flow) below 0.20 is recommended. However, if the venous access is not sufficient to deliver the higher blood flow needed to decrease filtration fraction, repeated stasis of flow may contribute to clotting.

Predilution Versus Postdilution

The use of predilution is another way to reduce hemoconcentration during hemofiltration. During predilution, the fluid lost by ultrafiltration is replaced before the filter rather than after the filter (postdilution). The predilution fluid dilutes the blood in the filter and thereby prevents hemoconcentration. Some studies suggest that delivering replacement fluid in a predilution mode may improve hemofilter life, whereas others show no significant improvement.

Unfractionated Heparin

Unfractionated heparin (UFH) continues to be the most commonly used anticoagulant for CRRT. UFH is a mixture of glycosaminoglycans of varying molecular weight. The higher molecular-weight component reversibly binds to antithrombin (AT), and the lower-molecular-weight heparins predominantly inhibit factor Xa. The molecular weight ranges from 3000 to 30,000 daltons with a mean of around 15,000. The anti-Xa activity occurs predominantly around the 3000 range. Approximately one third of the intravascular heparin binds to AT. By binding to AT, UFH enhances thrombin binding and therefore its anticoagulant activity. The remaining UFH is bound nonspecifically to endothelial cells, macrophages, and plasma proteins such as the acute phase proteins factor VIII and fibrinogen, which often are elevated in critically ill patients. For this reason the anticoagulant response to UFH among critically ill patients is unpredictable and often reduced, a phenomenon known as heparin resistance .

Conventional dosing includes a heparin bolus of 2000 to 5000 IU being injected into the circuit at commencement of the CRRT procedure, followed by a continuous heparin infusion at the arterial side of the circuit at 5 to 10 IU per kilogram body weight per hour to maintain an APTT 1.5 to 2 times the upper limit of normal. Currently, a lower APTT target, 1 to 1.4 times normal, is recommended to prevent serious bleeding. Observational studies show that filter clotting decreases and the risk of bleeding increases at higher APTT. In clinical practice, the APTT target depends on the balance between the risk of bleeding and the need for systemic anticoagulation.

The use of heparin has several advantages: its half-life is relatively short (0.5–3 hours), its anticoagulant effect can be reversed with protamine, it has been used in clinical practice for more than 75 years, and heparin is cheap. However, drug resistance and bleeding are common, and heparin carries a risk of heparin-induced thrombocytopenia (HIT), a potentially life-threatening condition (see later in this chapter). Current data comparing heparin to alternate forms of anticoagulation reveal that the risk-benefit ratio of heparin in critically ill patients is unfavorable (see later in this chapter).