National Toxicology Information Centre - Pavia Poison Control Centre, IRCCS Fondazione Salvatore Maugeri and University of Pavia , Pavia , Italy.
Clin Toxicol (Phila). 2014 Feb;52(2):129-35. doi: 10.3109/15563650.2013.860985. Epub 2013 Nov 28.
OBJECTIVE. The relationship between metformin accumulation and lactate increase is still debated. This observational case series aims to evaluate the correlation of metformin plasma levels with the pH, lactate and creatinine levels, and with the mortality rate in selected patients with metformin accumulation confirmed through metformin plasma concentration detection at hospital admission. MATERIAL AND METHODS. All cases of lactic acidosis (pH, ≤ 7.35; arterial lactate, ≥ 5 mmol/L) related to metformin accumulation (plasma level ≥ 4 mcg/mL) from 2007 to 2011 were retrospectively reviewed. Erroneous ingestion and voluntary overdoses were excluded. Epidemiological, medical history, clinical and laboratory data were evaluated in all cases. RESULTS. Sixty-six patients were included. Thirty-one patients (47%) had contraindication to therapy with metformin. All patients showed severe lactic acidosis (pH, 6.91 ± 0.18; lactate, 14.36 ± 4.90 mmol/L) and acute renal failure (creatinine, 7.24 ± 3.29 mg/dL). The mean metformin plasma concentration was 40.68 ± 27.70 mcg/mL. Metformin plasma concentrations showed a correlation, statistically significant even if not strong, with creatinine (p = 0.002, R = 0.37), pH (p < 0.0001, R = - 0.43) and plasma lactate levels (p = 0.001, R = 0.41). Sixty-two (94%) underwent dialysis. Early mortality (before discharge from ICU) was 26% (17 cases). Lactate and metformin concentrations had mean levels not statistically different in surviving and deceased patients. CONCLUSIONS. Patients on chronic therapy with metformin may develop a mitochondrial-related toxicity that should be considered when patients present with lactic acidosis, renal failure, and frequently, a medical history of gastrointestinal manifestations during the days preceding the hospital admission. The correlation between metformin plasma concentrations and creatinine, pH, and lactate levels seems to be related to the mechanism of action (inhibition of complex I of the mitochondrial respiratory chain) and to the kinetic properties (high distribution volume and low protein binding) of the drug. The relevant early mortality seems not correlated with the levels of metformin or lactates: this could be due to the possible role of concurrent illness even if, such as for the relationships with lactate and creatinine, a more proper toxicological evaluation could be obtained by assessing metformin erythrocyte concentrations instead of the plasmatic ones.
二甲双胍蓄积与乳酸升高之间的关系仍存在争议。本观察性病例系列旨在评估在选定的经入院时检测证实存在二甲双胍蓄积的患者中，二甲双胍血药浓度与 pH 值、乳酸和肌酐水平以及死亡率之间的相关性。
回顾性分析了 2007 年至 2011 年期间与二甲双胍蓄积相关的所有乳酸酸中毒（pH 值≤7.35；动脉乳酸值≥5mmol/L）病例（二甲双胍血药浓度≥4μg/mL）。排除错误摄入和自愿过量。评估了所有病例的流行病学、病史、临床和实验室数据。
共纳入 66 例患者。31 例（47%）存在使用二甲双胍的禁忌证。所有患者均出现严重乳酸酸中毒（pH 值为 6.91±0.18；乳酸值为 14.36±4.90mmol/L）和急性肾衰竭（肌酐值为 7.24±3.29mg/dL）。二甲双胍血药浓度平均为 40.68±27.70μg/mL。二甲双胍血药浓度与肌酐（p=0.002，R=0.37）、pH 值（p＜0.0001，R=-0.43）和血浆乳酸水平（p=0.001，R=0.41）具有相关性，尽管相关性不强，但仍具有统计学意义。62 例（94%）接受了透析治疗。早期死亡率（入住 ICU 前死亡）为 26%（17 例）。存活患者和死亡患者的乳酸和二甲双胍浓度的平均值无统计学差异。
长期接受二甲双胍治疗的患者可能会发生与线粒体相关的毒性反应，当患者出现乳酸酸中毒、肾衰竭且常常在入院前数日有胃肠道表现的病史时，应考虑这种毒性反应。二甲双胍血药浓度与肌酐、pH 值和乳酸水平之间的相关性可能与药物的作用机制（抑制线粒体呼吸链复合物 I）和动力学特性（高分布容积和低蛋白结合）有关。相关的早期死亡率似乎与二甲双胍或乳酸水平无关：这可能是由于并发疾病的可能作用，即使如此，与乳酸和肌酐的关系一样，通过评估红细胞中的二甲双胍浓度而不是血浆中的浓度，可能可以获得更适当的毒理学评估。
