THE METFORMIN GAP

Abstract

SESSION TITLE: Fellows Critical Care Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Metformin is a biguanide widely used as first line therapy for type 2 diabetes mellitus. It improves glycemic control by decreasing glucose production by the liver and increasing the peripheral sensitivity of insulin. A rare but life-threatening toxicity of metformin is lactic acidosis. We present a case of metformin associated lactic acidosis (MALA) with an osmolar gap. CASE PRESENTATION: A 56 year old female with a history of type 2 diabetes mellitus and hypertension, on lisinopril, metoprolol and metformin, presented with altered mental status and abnormal breathing. She had no history of alcohol or other illicit drug use. CT head showed no acute changes and urine drug screen was negative, but blood work was significant for acute renal failure with lactic acidosis and an elevated osmolar gap (Table 1). Her mentation continued to worsen, and arterial blood gas showed pH <6.95, pCO2 68 and pO2 219. She was intubated and mechanically ventilated but remained in shock requiring three high dose vasoactive medications to maintain a MAP of 60mmHg. A sodium bicarbonate infusion was started until continuous renal replacement therapy was able to be initiated. She was started on empiric antimicrobials and was also empirically treated with fomepizole. Serum methanol and ethylene glycol levels later resulted as negative. She improved rapidly with renal replacement therapy; she was weaned off vasopressors within 48 hours, extubated on day 4 of admission and was discharged from hospital 5 days later with normal renal function. DISCUSSION: MALA is a rare but well described entity which can occur with both therapeutic use and overdose states. It is associated with high mortality rate (up to 45% in some case series) without consistent correlation between plasma metformin concentration or lactic acid levels and predicted mortality. The exact mechanism by which metformin induces lactic acidosis is complex (Figure 1). Serum osmolality is determined by plasma solutes, primarily sodium salts, glucose and urea. An increase in the osmolar gap reflects additional plasma solutes, most commonly ethanol or toxic alcohol ingestion (e.g. methanol, ethylene glycol). Ketoacids and lactic acid do not directly raise the serum osmolality but along with chronic renal failure, can cause a mild elevation. No etiology was found for this patient’s osmolar gap. While MALA with an elevated osmolar gap without other etiology has been described in case reports, its frequency and mechanism have not been defined. CONCLUSIONS: Owing to the multiple and often nonspecific signs and symptoms of MALA, it can be difficult to predict or diagnose. Conditions and medications that can predispose a patient to lactic acidosis need to be excluded prior to making a diagnosis of MALA. Early consideration of MALA in patients receiving metformin is important, as early institution of renal replacement therapy can improve survival. Reference #1: Rajasurya V, Anjum H, Surani S (May 23, 2019) Metformin Use and Metformin-associated Lactic Acidosis in Intensive Care Unit Patients with Diabetes. Cureus 11(5): e4739 Reference #2: Ralph DeFronzo, G. Alexander Fleming, Kim Chen, Thomas A. Bicsak. Metformin-associated lactic acidosis: Current perspectives on cause and risk. Metabolism 65 (Feb 2016) p20-29 Reference #3: W.L. Eppenga, A. Lalmohamed, A.F. Geerts, H.J. Derijks, M. Wensing, A. Egberts, et al. Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study Diabetes Care, 37 (2014), pp. 2218-2224 DISCLOSURES: No relevant relationships by Kathryn Lai, source=Web Response