Calcium-Citrate Anticoagulation during Continuous Renal Replacement Therapy in Patients with Metformin Intoxication: A Case Series, Mathematical Estimation of Citrate Accumulation, and Literature Review

Introduction: Metformin intoxication causes lactic acidosis by inhibiting Krebs' cycle and oxidative phosphorylation. Continuous renal replacement therapy (CRRT) is recommended for metformin removal in critically ill patients. According to current guidelines, regional citrate anticoagulation (RCA) is the first-line strategy. However, since metformin also inhibits citrate metabolism, a risk of citrate accumulation could be hypothesized. In the present study, we monitored the potential citrate accumulation in metformin-associated lactic acidosis (MALA) patients treated with CRRT and RCA using the physical-chemical approach to acid-base interpretation. Methods: We collected a case series of 3 patients with MALA. Patients were treated with continuous venovenous hemofiltration (CVVH), and RCA was performed with diluted citrate solution. Citrate accumulation was monitored through two methods: the ratio between total and ionized plasma calcium concentrations (T/I calcium ratio) above 2.5 and the strong ion gap (SIG) to identify an increased concentration of unmeasured anions. Lastly, a mathematical model was developed to estimate the expected citrate accumulation during CVVH and RCA. Results: All 3 patients showed a resolution of MALA after the treatment with CVVH. The T/I calcium ratio was consistently below 2.5, and SIG decreased, reaching values lower than 6 mEq/L after 48 h of CVVH treatment. According to the mathematical model, the estimated SIG without citrate metabolism should have been around 21 mEq/L due to citrate accumulation. Conclusions: In our clinical management, no signs of citrate accumulation were recorded in MALA patients during treatment with CVVH and RCA. Our data support the safe use of diluted citrate to perform RCA during metformin intoxication.