Toxicology

1. Metformin toxicity
Dr JSDS Lokugalappaththi

2. Introduction
• Oral biguanide
• Anti-hyperglycemic agent
• Inhibits gluconeogenesis.
• Promotes peripheral glucose uptake
• Excreted primarily unchanged in the urine
• Metformin clearance is affected by creatinine clearance
• The classic laboratory finding in metformin toxicity is severe lactic acidosis.

3. Mechanism of lactic acidosis

4. MALA and MILA
• Lactic acidosis associated with metformin can be further subdivided
into two specific clinical entities –
• MALA and MILA

5. Metformin-induced lactic acidosis (MILA)
• Primarily associated with acute accidental or intentional overdoses
• The toxic effect depends on metformin concentration
• In MILA, there is no other identifiable cause of lactic acidosis.
• Death is less common than in MALA, and likely results from
cardiovascular collapse caused by severe refractory acidosis.2,5

6. Metformin-associated lactic acidosis (MALA)
• Occurs from combination of normal or elevated plasma metformin
concentrations and a secondary insult that alters lactate
production/clearance.
• More likely to occur in patients with acute renal impairment from
other medical illnesses
• Have a higher mortality than those with MILA (30-50%).
• The distinction between MALA and MILA is often blurred but
management for both entities is the same

7. metformin-unrelated lactic acidosis
(MULA)
• Metformin is an innocent bystander.
• Metformin levels are low.
• Clinically it may be impossible to differentiate this from MALA.
• Differentiation of MULA from MALA requires measurement of metformin levels

8. Clinical features
• Non specific symptoms
• Nausea ,vomiting, diarrhea
• Abdominal pain
• Dizziness
• Altered mental status
• SOB
• Examination
• Dyspnoea , tachypnea
• Tachycardia ,hypotension
• Altered mental status

9. Laboratory findings
• Severe metabolic acidosis with elevated anion gap
• Elevated lactate
• Hypoglycemia (very rarely

10. How do you make the diagnosis?
• There is not one clearly defined minimum dose of metformin that
leads to toxicity.
• Lethal dose has been associated with greater than 5 g in adults
• greater than 100 mg/kg in pediatrics.
• Suspicion for the diagnosis should be derived from the history, clinical
picture, and lab results.

11. Initial work up
• Glucose
• Arterial or venous blood gas (ABG or VBG), serum lactate
concentration.
• Renal function tests
• Liver function test
• Basic metabolic panel
• Consider acetaminophen and salicylate concentrations to evaluate for
co-ingestion in intentional overdose.
• A serum metformin concentration is unhelpful clinically in most cases,

12. Management
• The mainstay of treatment is good systematic and supportive care.
• Patients should be monitored closely, as clinical worsening can occur
rapidly
• Consider early consultation with toxicologist and nephrologist.

13. Resuscitation
• A- maintain airway patency
• B- optimize oxygenation and ventilation
• C – correct shock with crystalloid and vasopressor ,inotropes
• D – correct Hypoglycemia
• E – Treat Hypothermia

14. Decontamination
• Gastric lavage
• Activated charcoal

15. Supportive care
• Good hydration
• Correction of metabolic acidosis
• Correction of serum electrolytes imbalances
• Organ support

16. Hemodialysis
• Severe metformin toxicity, dialysis can be utilized.
• EXTRIP’s criteria for dialysis include any one of the following4:
• Severely elevated lactate greater than 20 mmol/L
• Severe metabolic acidosis with pH less than or equal to 7.0
• Failure to improve (pH, lactate, clinical status) with standard supportive care
within 2-4 hours

18. salvage therapy if refractory
• Methylene blue
• GIK therapy (Glucose infusion, Insulin infusion, and potassium)

19. •Thank you