Episode 102: Tox files #1 with Andrew Sheen and Jerry Snow

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We hear a mystery tox case from Jerry Snow, director of the toxicology fellowship at Banner University Medical Center in Phoenix, and one of his med tox fellows Andrew Sheen.

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Takeaway pearls

  1. Truly severe metabolic acidosis (single digit serum bicarb), with anion gap causes including but not limited to an elevated lactate (>20 or so), has a fairly limited differential and tox should be strongly considered. Lactates here can run into the 60s. Consider DKA, cyanide, and metformin.
  2. Metformin levels can be checked, though there isn’t one level clearly linked with morbidity. Levels >20 are generally associated with morbidity and mortality, however, and single digit levels are rarely fatal.
  3. The mechanism: a cytotoxic-type cellular shock by poisoning the electron transport chain, despite adequate oxygen delivery. As this causes dysfunction in smooth muscle, cardiac muscle, etc, other forms of shock develop secondarily, namely distributive and sometimes cardiogenic. But the initial lactate elevation (not actually a lactic acidosis) is purely a metabolic phenomenon.
  4. Be very cautious intubating such patients, as a common pitfall is to fail to match their prior spontaneous minute ventilation on the vent and tank their pH.
  5. Renal replacement therapy is the treatment of choice, both to manage the severe acidemia, and to clear the offending drug. (You can give bicarb in the meanwhile but it won’t be enough.) The latter effect is limited, as while metformin is dialyzable, it has a high volume of distribution. This may mean either CRRT or prolonged/multiple sessions of IHD are needed as the drug redistributes back from the tissues. In reality, most severe cases are too hemodynamically unstable for IHD, though if they can tolerate it, it may be superior. Patients with working kidneys will eventually clear the rest of the compound themselves, and those with anuria will probably need more renal replacement.
  6. Whatever the case, start early; RRT within 6 hours is associated with better outcomes. A barrier to this can be diagnostic delays, however.
  7. RRT can probably stop when lactate is <3, pH >7.35 or thereabouts.
  8. Intentional metformin overdose is fairly common.
  9. Activated charcoal is indicated with early presentations, but most patients present too late, particularly because symptoms can take some time to develop. Many sick patients will have vomiting or diarrhea, leading to some degree of spontaneous GI decontamination too. However, whole bowel irrigation should certainly be considered in severe earlier cases.
  10. Acute overdoses are often actually somewhat less ill than more chronic ingestions as well.
  11. Development of shock is strongly predictive of mortality, along with pH <7, lactate >20, encephalopathy. Without any of these (per EXTRIP), mortality is almost zero. These are good things to evaluate (or trend) when you’re unsure about how worried to be.
  12. Most chronic cases are associated with renal insufficiency, eg a new AKI. However, decompensation can also be kicked off by drug interactions; common ones are the new use of cetirizine or trimethoprim (inhibit the organic cation transporter than excretes metformin).
  13. There is ongoing research on innovative therapies, such as methylene blue, or succinate prodrugs, but nothing definitive.
  14. Mortality is high, upwards of 30-50%.
  15. Calling poison control with a specific diagnostic question (“is this metformin?”) will always increase the odds of a right answer, over the open-ended (“is this some tox thing?”).
  16. Most toxicities can be resumed on metformin down the road; it is unclear whether some patients have some greater inherent vulnerability to the drug. A sound approach is to take “sick days,” however, holding your drug when coming down with some other illness that could provoke an AKI.

References

PATHOPHYSIOLOGY & CLASSIFICATION

1. Lalau JD, Kajbaf F, Protti A, et al. Metformin-associated lactic acidosis (MALA): Moving towards a new paradigm. Diabetes, Obesity & Metabolism. 2017;19(11):1502-1512. doi:10.1111/dom.12974

2. Anwar KR, Khan MM, Badruddeen, et al. Metformin-associated lactic acidosis: Bridging pharmacokinetic determinants, metabolic pathways, and clinical outcomes. European Journal of Pharmacology. 2026;1029:179017. doi:10.1016/j.ejphar.2026.179017

3. Piel S, Ehinger JK, Elmér E, Hansson MJ. Metformin induces lactate production in peripheral blood mononuclear cells and platelets through specific mitochondrial complex I inhibition. Acta Physiologica. 2015;213(1):171-80. doi:10.1111/apha.12311

EXTRACORPOREAL TREATMENT

4. Calello DP, Liu KD, Wiegand TJ, et al. Extracorporeal treatment for metformin poisoning: Systematic review and recommendations from the Extracorporeal Treatments in Poisoning Workgroup. Critical Care Medicine. 2015;43(8):1716-30. doi:10.1097/CCM.0000000000001002

5. Roberts DM, Ghannoum M. Expanding the evidence for managing metformin poisoning to support decision-making. Clinical Toxicology. 2023;61(4):203-206. doi:10.1080/15563650.2023.2196372

6. Correia MS, Horowitz BZ. Continuous extracorporeal clearance in metformin-associated lactic acidosis and metformin-induced lactic acidosis: A systematic review. Clinical Toxicology. 2022;60(11):1198-1212. doi:10.1080/15563650.2022.2117453

7. De Simone E, Pozzato M, Marchisio M, et al. Efficacy of continuous venovenous hemodiafiltration in patients with metformin associated lactic acidosis and acute kidney injury. Scientific Reports. 2025;15:8537. doi:10.1038/s41598-025-92889-x

PROGNOSIS & OUTCOMES

8. Corchia A, Wynckel A, Journet J, et al. Metformin-related lactic acidosis with acute kidney injury: Results of a French observational multicenter study. Clinical Toxicology. 2020;58(5):375-382. doi:10.1080/15563650.2019.1648816

9. Thammavaranucupt K, Phonyangnok B, Parapiboon W, et al. Metformin-associated lactic acidosis and factors associated with 30-day mortality. PLoS One. 2022;17(8):e0273678. doi:10.1371/journal.pone.0273678

10. Bennis Y, Bodeau S, Batteux B, et al. A study of associations between plasma metformin concentration, lactic acidosis, and mortality in an emergency hospitalization context. Critical Care Medicine. 2020;48(12):e1194-e1202. doi:10.1097/CCM.0000000000004589

METFORMIN SAFETY & PREVENTION

11. Lazarus B, Wu A, Shin JI, et al. Association of metformin use with risk of lactic acidosis across the range of kidney function: A community-based cohort study. JAMA Internal Medicine. 2018;178(7):903-910. doi:10.1001/jamainternmed.2018.0292

12. Connelly PJ, Lonergan M, Soto-Pedre E, et al. Acute kidney injury, plasma lactate concentrations and lactic acidosis in metformin users: A GoDarts study. Diabetes, Obesity & Metabolism. 2017;19(11):1579-1586. doi:10.1111/dom.12978

13. de Boer IH, Khunti K, Sadusky T, et al. Diabetes management in chronic kidney disease: A consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO). Kidney International. 2022;102(5):974-989. doi:10.1016/j.kint.2022.08.012

ADJUNCTIVE THERAPY & LAB PEARLS

14. Godo S, Yoshida Y, Fujita M, et al. The dramatic recovery of a patient with biguanide-associated severe lactic acidosis following thiamine supplementation. Internal Medicine. 2017;56(4):455-459. doi:10.2169/internalmedicine.56.7754

15. Deville M, Charlier C. Ethylene glycol determination in serum: Comparison between enzymatic assay and GC-MS on real samples. Clinical Toxicology. 2026;1-7. doi:10.1080/15563650.2026.2628956

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