A Study on the Efficacy and Safety of Continuous Renal Replacement Therapy (CVVHDF) Using a Commercial Citrate-containing Replacement Fluid (Prismocitrate 18/0)

Acute kidney injury is common in critically ill patients, and continuous renal replacement therapy is the preferable mode of treatment to remove the metabolic waste while avoiding the hemodynamic instability associated with intermittent hemodialysis. Thrombosis frequently occurs in the hemofilter which could reduce the circuit lifespan, jeopardize the efficacy of renal replacement, result in loss of blood cells and increased transfusion requirement. Anticoagulants including conventional heparin and low molecular weight heparin, introduced via the arterial port of the circuit, are widely used to reduce clotting within the extracorporeal circuit. However, significant amount of heparin is not removed in the circuit and will be carried into patient's circulation, which could lead to bleeding complications. Regional citrate anticoagulation (RCA) has been used for intermittent haemodialysis since 1983, and its use has extended to that for continuous renal replacement therapy (CRRT) since 1987. Citrate is introduced at therapeutic level at the arterial limb of the dialysis circuit, where it chelates calcium ions in the blood to prevent clotting within the hemofilter. While some calcium-citrate complex is removed in the filter, the residual will be circulated to the patient and be metabolized in liver. Patient's systemic ionized calcium level remains normal, by hemodilution and also calcium replacement. Therefore, the anticoagulant effect from citrate is regional and confined to the extracorporeal circuit. RCA has the potential to extend circuit life during renal replacement therapy without systemic anticoagulation. In a recent meta-analysis of randomized controlled trials, RCA was as efficacious as heparin anticoagulation in term of maintaining circuit function, and RCA was associated with decreased risk of bleeding with no significant increase in incidence of metabolic alkalosis.(5) Hypocalcemia was more common in patients receiving citrate, but of note, no clinical adverse event was reported in the included studies. Although citrate anticoagulation had repeatedly been demonstrated to prolong filter life, many hospitals still refrained from using it, as a result of limited experience, different patient variety, or other reasons.

The investigators' group has performed a pilot study (HKU/HA HKW IRB No: UW 08-221) to assess the efficacy and safety of continuous venous-venous hemodiafiltration(CVVHDF) using a commercial citrate containing replacement fluid (Prismocitrate 10/2, Gambro) which contains 10mmol/l citrate and 2 mmol/l citric acid. 15 subjects were recruited from July 2008 to June 2011. No serious adverse events were reported, including severe hypocalcemia, hypercalcemia, citrate toxicity and severe acid base disturbances. Metabolic acidosis due to renal failure were only partially corrected by CRRT with citrate anticoagulation in the initial study subjects, the problem was subsequently solved by adding supplemental bicarbonate to the dialysate. Since then, all the patients were able to complete the treatment protocols with adequate kidney lifespan, correction of metabolic abnormalities and fluid imbalance. However, since additional bicarbonate is needed to correct the metabolic acidosis during CRRT, there is room for improvement regarding the formulation of the citrate-containing solution to reduce acid liberation while increasing the alkali bicarbonate production. Prismocitrate 18/0, which contains 18mmol/l citrate (one mmol citrate could be metabolized to produce 3 mmol bicarbonate) and no citric acid, could potentially result in better acid-base control during CRRT.

Inclusion criteria

• The patient requires CRRT as treatment for renal failure, as decided by the attending physician
• The patient fulfils at least one of the following clinical criteria for initiating CRRT:

• According to the RIFLE criteria, (11) patients satisfying the "injury" criteria (increase creatinine by 2 fold or urine output<0.5ml/kg/hr for 12hr) will be considered for CRRT
• Hyperkalemia ([K+] > 6.5 mmol/L).
• Severe acidemia (pH < 7.2).
• Urea > 25 mmol/liter.
• Clinically significant organ oedema in the setting of ARF.

Exclusion criteria