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Anticoagulation for Continuous Renal Replacement Therapy
Continuous renal replacement therapy (CRRT) has evolved as the preferred form of dialysis in hemodynamically unstable critically ill patients with acute kidney injury (AKI). It is applied continuously and achieves solute clearance and fluid removal by convection, as in continuous venovenous hemofiltration (CVVH), diffusion, as in continuous venovenous hemodialysis (CVVHD), or a combination of both, as in continuous venovenous hemodiafiltration (CVVHDF). CRRT requires anticoagulation for the prevention of clotting of the extracorporeal circuit. Clotting of the hemofilter reduces total therapy time and leads to decreased dialysis efficacy, blood loss in the extracorporeal circuit, and increased cost because of frequent hemofilter replacements. Hemofilter survival without anticoagulation can be prolonged by facilitating a well-functioning vascular access, maintaining higher blood flow rates, using pre-dilution replacement fluid to reduce the filtration fraction in convective CRRT to less than 20 to 25%, decreasing the blood-air contact in the bubble trap, and assuring prompt reaction to device alarms. Although observational studies have demonstrated that CRRT without anticoagulation is feasible in patients with coagulopathy, most critically ill patients require some form of anticoagulation to achieve adequate dialysis. The ideal anticoagulant for CRRT should have a short half-life and provide optimal antithrombotic activity with low bleeding risk and minimal systemic adverse effects. It should be inexpensive and readily available with simple monitoring methods and have an antidote for easy reversal. This chapter discusses the anticoagulation options available for CRRT with their advantages and disadvantages.
Selecting Anticoagulation Approaches for Continuous Renal Replacement Therapy
The most common anticoagulant options for CRRT include unfractionated heparin (UFH), regional citrate anticoagulation (RCA), and no anticoagulation. Less common anticoagulation options include UFH with protamine reversal, low-molecular-weight heparin (LMWH), thrombin antagonists, and platelet-inhibiting agents. The anticoagulant choice should be determined by the bleeding risk of the patient and the presence of liver failure or heparin-induced thrombocytopenia (HIT) ( Table 68.1 ). The Kidney Disease: Improving Global Outcomes (KDIGO) AKI guidelines recommend using RCA rather than UFH in patients who do not have contraindications to citrate and are with or without increased risk of bleeding. In patients who have contraindications to citrate and are without increased bleeding risk, they recommend using UFH or LMWH rather than other anticoagulants. KDIGO also recommends avoiding regional heparinization during CRRT in patients at increased risk of bleeding. They recommend no anticoagulation in patients with contraindications to citrate use and who are at increased risk of bleeding.
Table 68.1
Anticoagulation Choice Based on Clinical Characteristics
| Clinical Characteristics | Choice of Agent | |
|---|---|---|
| No Liver Failure | Severe Liver Failure | |
| Low risk of bleeding | UFH, citrate | UFH, No anticoagulation |
| High risk of bleeding | Citrate | No anticoagulation |
| Heparin-induced thrombocytopenia | Citrate, argatroban | Bivalirudin |
UFH , Unfractionated heparin.
Specific Agents and Anticoagulation Techniques ( Table 68.2 )
Unfractionated Heparin
In patients at low risk of bleeding, minimal-dose UFH is preferred because it is easy to use, inexpensive, and readily accessible, and has an antidote (protamine). UFH is a mixture of glycosaminoglycans with molecular weights between 5000 and 30,000 Da. It acts by binding to antithrombin III and inhibiting factors IIa and Xa. The larger heparin fragments mainly have anti-IIa activity, while the smaller fragments principally inhibit Xa. An anticoagulant effect from the inhibited Xa can occur in the setting of a normal activated plasma prothrombin time (aPTT) as the smaller fragments have delayed clearance compared to the larger heparin fragments.
Table 68.2
Specific Agents and Anticoagulation Techniques
| Agent | Dosing | Monitoring | Comments |
|---|---|---|---|
| Heparin | Bolus: 2000–5000 IU (25–50 IU/kg) Maintenance: 5–15 IU/kg/h |
aPTT goal: 45–60 seconds or 1.5 to 2 times normal or anti-Xa activity 0.3–0.6 IU/mL | Contraindicated in high bleeding risk patients Increased risk of HIT |
| Citrate | Depends on the CRRT operating characteristics and citrate solution composition Infused to achieve a postfilter ionized calcium < 0.35 mmol/L or citrate blood concentration of 3–6 mmol/L |
Postfilter ionized calcium, blood electrolytes, and calcium ratio (total calcium to ionized calcium) | Requires IV calcium and frequent electrolyte monitoring Contraindicated in severe liver failure or lactic acidosis |
| Argatroban | Bolus 100 mcg/kg followed by infusion to achieve a target aPTT of 1.5–3.0 Doses range between 0.7 and 1.7 μg/kg/min |
aPTT 1.5–3 times baseline | No antidote Initial dose reduction to 0.5 μg/kg/min in the setting of liver failure |
| Regional UFH with protamine | UFH is infused prefilter at 1000–1500 U/h Protamine is infused at 10–12 mg/h postfilter to neutralize heparin |
Circuit and systemic aPTT | Regional anticoagulation reduces risk of systemic bleeding Technically complicated HIT risk |
| Enoxaparin Nadroparin Dalteparin |
Loading dose 0.1 5 mg/kg and maintenance dose of 0.05 mg/kg/h Loading dose of 15–25 IU/kg followed by a maintenance dose of 5 IU/kg/h |
Anti-Xa levels with target levels between 0.25 and 0.35 units/mL | High risk of bleeding Expensive Less reversal with protamine |
aPTT , Activated partial thromboplastin time; CRRT , continuous kidney replacement therapy; HIT , heparin-induced thrombocytopenia; IV , intravenous; UFH , unfractionated heparin.
A single optimal regimen for UFH administration during CRRT has not been identified. Typical heparin protocols recommend administering UFH into the arterial limb of the dialysis circuit as a bolus of 1000 to 5000 IU (25–30 IU/kg), followed by a continuous infusion of 5 to 15 IU/kg/h. Anticoagulation is monitored by maintaining an aPTT goal between 45 and 60 seconds (1.5 to 2.0 times normal) or anti-Xa activity between 0.3 and 0.6 IU/mL. However, the optimal target aPTT is not known with certainty, and the therapeutic benefit of preventing clotting in the extracorporeal circuit must be balanced with the risk of systemic bleeding. Disadvantages of UFH include dosing variability arising from complex and unpredictable pharmacokinetics, risk of heparin resistance caused by low patient antithrombin levels, the development of HIT, and the risk of hemorrhage. UFH is contraindicated in patients at high risk of bleeding (e.g., recent surgery, coagulopathy, thrombocytopenia).
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