Toxicokinetics of metformin overdose treated with CVVHDF

ABSTRACT

Background: Metformin is the most commonly used diabetes medication and at supratherapeutic levels can result in a severe type-A metabolic lactic acidosis known as metformin-associated lactic acidosis (MALA). Treatment of MALA includes aggressive fluid resuscitation, supporting blood pressure and correcting acidosis. Renal replacement therapy (RRT), usually hemodialysis (HD) is recommended in severe cases with refractory acidosis (with elevated lactate), altered mental status, or shock. To our knowledge, this is the second report of metformin half-life during treatment with continuous veno-venous hemodiafiltration (CVVHDF). Case report A 53-year-old man died following a reported acute on chronic ingestion of 80 g of his metformin tablets resulting in severe, refractory shock and MALA. His peak serum metformin concentration was 53mcg/mL (therapeutic range 1-2mcg/mL), peak lactic acid concentration was 49.7 mmol/L, and arterial pH nadir was 7.06. Serial serum metformin concentrations were obtained while on RRT;both HD and CVVHDF. The switch from HD to CVVHDF was done due to staffing shortages during the COVID-19 pandemic. The patient died despite aggressive therapy with renal replacement therapy and multiple vasopressors on hospital day five. Serial metformin concentrations during CVVHDF suggested a half-life of 33-h. Discussion(s) Hemodialysis has been reported to clear metformin at a rate greater than 200mL/min and continuous venous-venous hemofiltration (CVVH) at greater than 50mL/min. In this case, metformin levels appear to follow first-order elimination kinetics during CVVHDF with an estimated half-life of 33 h. Comparatively, metformin has a half-life of 4.7-5.5 h during HD. To our knowledge, this is the second report of estimated metformin half-life while using the CVVHDF form of continuous renal replacement. The previous case report measured a half-life of 16.5 h on CVVHDF. This case report shows CVVHDF decreases half-life of metformin and provides first order elimination in the setting of overdose. Conclusion(s) The early initiation of HD appears warranted but prognostic indicators have not been well established. In the absence of HD availability, other forms of RRT (e.g., CCVHDF) can be used and may provide first-order elimination of metformin.