Fatal Metformin Intoxication with Markedly Elevated Blood and Liver Concentrations

Journal of Analytical Toxicology 2012;36:657 –659 doi:10.1093/jat/bks076 Advance Access publication September 19, 2012 Case Report Fatal Metformin Intoxication with Markedly Elevated Blood and Liver Concentrations F. Lee Cantrell1*, Craig L. Nelson2, Ray D. Gary2 and Iain M. McIntyre2 1 California Poison Control System, San Diego Division and Clinical Pharmacy, University of California San Francisco School of Pharmacy, 200 W. Arbor Dr., San Diego, CA 92103, and 2San Diego County Medical Examiner’s Office—Toxicology, 5555 Overland Ave., Suite 1411, San Diego, CA 92123 *Author to whom correspondence should be addressed. Email: . The highest postmortem metformin concentrations are recorded utilizing a sensitive and specific analytical procedure. The peripheral blood metformin concentration was 240 mg/L, the liver concentration was 240 mg/kg and the gastric concentration was 1,700 mg. Additionally, an antemortem blood sample collected shortly after admission revealed a metformin concentration of 210 mg/L. These data, revealing a liver to peripheral blood ratio of 1.0, provide additional support that metformin is not subject to postmortem redistribution. Intentional self-poisonings with metformin can result in death, despite multiple medical interventions. potassium, 5.2 mmol/L; chloride, 106 mmol/L; blood glucose, 463 mg/dL; and carbon dioxide, 18 mmol/L with an anion gap of 10. No indications of liver or kidney dysfunction were present. Over the course of the next two hours, the decedent was administered intravenous fluids and antiemetics, but subsequently developed a decreased level of consciousness and hypotension. She was admitted to the intensive care unit and treated with sodium bicarbonate, mechanical ventilation, multiple vasopressors, hemodialysis and continuous renal replacement therapy, but ultimately expired within 36 h from the ingestion. Introduction Autopsy The autopsy documented a well-developed, well-nourished woman with no apparent oral or esophageal injuries. The stomach contained approximately 600 mL of watery, brown fluid with irregular, tan mucoid fragments without grossly recognizable food, visible pills or pill residue. Her gastric mucosa had broad areas of hyperemia; however, the mucosa was generally intact. As suggested by her clinical course and confirmed by the autopsy findings of intact esophageal and gastric mucosa and walls, any ingestion of drain cleaner that may have occurred could not have been sufficient to cause or contribute to her death. Despite her medical history, she had little evidence of pre-existing natural disease. She had no significant trauma. Since being approved by the United States Food and Drug Administration in 1995, metformin, a member of the biguanide class of oral hypoglycemics, has become one of the most popular medications prescribed in the United States (1). Because of its widespread use, it is not surprising that over 7,500 cases of metformin exposures were reported to United States poison control centers in 2010 (2). Despite this large number of exposures, only five reported fatalities occurred where metformin was detected during postmortem analysis. Upon reviewing the literature, the highest reported postmortem metformin concentrations in central blood and the liver are 77.3 mg/L (3) and 146 mg/kg (4), respectively. This study reports the highest peripheral blood and liver metformin concentrations on record. Case Report The decedent was a 57-year-old woman who had a medical history of hypertension, hypercholesterolemia, diabetes mellitus, depression and anxiety. Her regular medications included mirtazapine, atorvastatin, metformin, glipizide, pioglitazone/glimepiride, trazodone, losartan, clonazepam, ubidecarenone, aspirin and vitamins. One evening while visiting relatives, the decedent developed persistent vomiting and diarrhea. When questioned, she admitted to ingesting some of her medication with drain cleaner. Emergency medical services were immediately contacted and the patient was transported to a hospital by paramedics. Upon arrival, she complained of oral irritation, but refused to give further information to staff. Initial vital signs were: blood pressure, 116/85 mm/Hg; heart rate, 120 beats per min; respiratory rate, 19; temperature, 99.08F; oxygen saturation, 99% on room air. An admission urine toxicology screen was negative for opiates, methadone, barbiturates, phencyclidine, amphetamines, benzodiazepines, cocaine, marijuana and ethanol. Additional testing detected no salicylate or acetaminophen. An initial electrolyte panel revealed: sodium, 134 mmol/L; Specimens An admission blood sample collected approximately 24 h before her death was obtained from the hospital, and all postmortem specimens analyzed were collected at autopsy at the San Diego County Medical Examiner’s Office. Peripheral blood was drawn from the iliac veins and stored in standard glass tubes containing sodium fluoride (25 mg) and potassium oxalate (20 mg). The upper right lobe of the liver was sampled, and gastric contents were also collected. All samples were stored at 48C until analysis. Methods Toxicological analyses Screening Drug screening of the antemortem blood included alcohol and simple volatiles by gas chromatography–flame ionization detection (GC–FID) headspace analysis, enzyme-linked immunoassay (ELISA) (Immunalysis, Pomona, CA) for drugs of abuse (cocaine metabolites, methamphetamine, opiates, benzodiazepines, fentanyl and cannabinoids), alkaline extractable drugs by # The Author [2012]. Published by Oxford University Press. All rights reserved. For Permissions, please email: GC–mass spectrometry (MS) following solid-phase extraction, and high-performance liquid chromatography (HPLC) with photodiode array detection for acid/neutral compounds. Because metformin was not detected with this routine screening, it was subsequently determined by minor modification of a previously validated and published extraction procedure by Drummer et al. (5) together with the chromatographic conditions described previously for metformin by Kar and Choudhury (6). of the specimen was injected at a flow rate of 0.8 mL/min. Detection of eluent was monitored at 230 nm. Total run time was 10 min, with metformin and MPPH eluting at 1.38 and 1.57 min, respectively. The calibration curve was linear from 0 –50 mg/L with a correlation coefficient of 0.99971. The limit of detection and quantitation was 2.0 mg/L (the lowest calibration standard utilized). Results Materials Metformin HCL was purchased from Grace (Deerfield, IL). The stock metformin was dissolved in methanol at a concentration of 1.0 mg/mL. The internal standard was 5-(4-methylphenyl)5-phenylhydantoin (MPPH), which was purchased from Sigma-Aldrich (St. Louis, MO). The stock MPPH was dissolved in acetonitrile at a concentration of 1.0 mg/mL. HPLC grade acetonitrile (Omnisolv), HPLC-grade methanol (Omnisolv) and potassium phosphate, dibasic (BDH) were purchased through VWR (Radnor, PA (...truncated)