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Citrate pharmacokinetics and metabolism in cirrhotic and noncirrhotic critically ill patients

Kramer, Ludwig; Bauer, Edith; Joukhadar, Christian; Strobl, Wolfram; Gendo, Alexandra; Madl, Christian; Gangl, Alfred

doi: 10.1097/01.CCM.0000084871.76568.E6

Objectives To investigate pharmacokinetics and metabolism of sodium citrate in critically ill patients. To determine the risk of citrate accumulation in the setting of liver dysfunction (cirrhosis, hepatorenal syndrome).

Design Prospective cohort study.

Setting Intensive Care Unit, Department of Medicine IV, University Hospital Vienna.

Patients Consecutive critically ill cirrhotic (n = 16) and noncirrhotic patients (n = 16).

Interventions Infusion of sodium citrate (0.5 mmol·kg−1·hr−1) and calcium chloride (0.17 mmol·kg−1·hr−1) for 2 hrs. Analysis of serial arterial blood samples.

Measurements and Main Results Total body clearance of citrate was normal in noncirrhotic critically ill patients but significantly reduced in cirrhotic patients (710 vs. 340 mL/min, p = .008). Citrate peak concentrations and concentration over time were increased by 65% and 114% in cirrhotic patients (p < .001), respectively; volumes of distribution were similar. Net metabolic changes were quantitatively similar, with pH and plasma bicarbonate concentrations increasing more slowly in cirrhotic patients. No citrate-related side effects were noted. Citrate clearance could not be predicted by standard liver function tests and was not appreciably influenced by renal function and Acute Physiology and Chronic Health Evaluation II scores.

Conclusions This first systematic study on citrate pharmacokinetics and metabolism in critically ill patients confirms a major role of hepatic citrate metabolism by demonstrating reduced citrate clearance in cirrhotic patients. Pharmacokinetic data could provide a basis for the clinical use of citrate anticoagulation in critically ill patients. Provided dose adaptation and monitoring of ionized calcium, citrate anticoagulation seems feasible even in patients with decompensated cirrhosis. Metabolic consequences of citrate infusion were not different between groups in this study but may be more pronounced in prolonged infusion.

From the Department of Medicine IV (LK, AG, CM, AG) and Department of Clinical Pharmacology (CJ), University of Vienna Medical School, Vienna, Austria; and the Christian Doppler Laboratory for Specific Adsorption Technologies (WS), Krems, Austria.

Supported, in part, by the Christian Doppler Laboratory for Specific Adsorption Technologies, Krems, Austria, which performed citrate analysis.

Provided citrate infusion rates are adapted and ionized calcium is monitored, citrate anticoagulation seems feasible in patients with advanced cirrhosis, where the advantages compared with heparin are obvious.

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