Continuous extracorporeal clearance in metformin-associated lactic acidosis and metformin-induced lactic acidosis: a systematic review

Introduction: Metformin poisoning with lactic acidosis is an uncommon yet clinically serious condition related to the inhibition of normal aerobic metabolism. Toxicity may occur after an acute overdose although it is much more common after a systemic insult, such as acute kidney injury, in the setting of chronic use. Hemodialysis is currently the preferred extracorporeal treatment modality (Grade 1D evidence) although some patients may be too hemodynamically unstable to tolerate it. Continuous renal replacement therapy is considered an alternative if hemodialysis is unavailable but an evaluation of survival amongst this specific treatment class is lacking. Objectives: To assess overall survival and provide an updated review of the toxicokinetic elimination parameters of patients receiving continuous renal replacement therapy for metformin poisoning. Methods: A comprehensive search was performed using the EMBASE and MEDLINE libraries from inception until November 30, 2021. Data was extracted and findings were summarized. Toxicokinetic parameters were analyzed and confirmed for accuracy when data permitted. Results: Eighty-three reports met inclusion criteria. These consisted of only low-quality evidence including 75 case reports, four case series, and four descriptive retrospective reviews. Overall survival among patients suffering from metformin toxicity who received continuous extracorporeal treatment was 85.8%. When stratified between metformin-induced lactic acidosis and metformin-associated lactic acidosis, survival was 75.0% and 87.4%, respectively. Available continuous renal replacement therapy toxicokinetic parameters were quite heterogeneous. Errors in previously published toxicokinetic calculations were noted in only two instances. The overall average and median peak metformin concentrations were 70.5 mg/L and 41.9 mg/L, respectively. The average and median extracorporeal clearance rates were 39.0 mL/min and 42.1 mL/min (range 9.0–58.7 mL/min). The average and median elimination half-life parameters were 27.5 h and median 23.0 h. Elimination half-life ranged from seven to 74 h. There was no meaningful relationship between peak metformin concentration and continuous extracorporeal treatment half-life at lower concentrations, though at very high concentrations (over 200 mg/L), there was a trend towards a half-life below 20 h. There is insufficient data to robustly evaluate overall survival in relation to the extracorporeal clearance rate. Finally, there was no relevant relationship between maximal lactate concentration and survival, nor nadir pH and survival, for patients with either type of metformin toxicity. Conclusions: This retrospective systematic analysis of published cases treating metformin related lactic acidosis with continuous renal replacement therapy notes an overall slightly greater survival percentage compared to previous publications of individuals requiring any modality of renal replacement therapy. Because of publication bias, these results should be interpreted with caution and serve as hypothesis generating for future research. Prospective study focusing on the most clinically meaningful endpoint–survival–will help elucidate if continuous modalities are non-inferior to intermittent hemodialysis in metformin toxicity.