Toxicology Talks with Toxijawn

Author:  Mahrukh Choudhary MD, Emergency Medicine Resident, PGY I
Faculty:  Alexis Cates DO, Medical Toxicology/Emergency Medicine Attending

The Case…

You are seeing a 54-year-old female in the Emergency Department (ED) with nausea, vomiting, and epigastric pain. Triage vital signs are as following: T 98.6F, HR 108 bpm, BP 85/48, SaO2 97% on RA. Upon walking into the room, you see an ill-appearing female who appears stated age. She is pale, diaphoretic, and vomiting into an emesis bag. Chart review reveals a past medical history of hypertension, type 2 diabetes, and osteoarthritis. Patient’s current medications include amlodipine, metformin and ibuprofen. You begin to get labs back for this patient and find that she has a profound metabolic acidosis with a lactic acid of 6.8 mmol/L. There is also evidence of acute renal failure with a creatinine of 4.8 mg/dL; records show a normal level two months prior. Fluid resuscitation with intravenous crystalloid is initiated without improvement in blood pressure. A repeat lactic acid is 7.2 mmol/L after two liters of fluids. At this point, you decide to involve toxicology as you are concerned about possible metformin toxicity. 

Learning Point 1: A little bit about metformin…

The active ingredient in metformin is galegine. Galega officinalis or “goat’s rue” is a perennial herb that originated in Southern Europe and West Asia. It was initially used in medieval times to relieve frequent urination associated with diabetes [1]. Over the years, galegine was found to have a hypoglycemic effect in the diabetic population. The most influential study regarding metformin was the UK Prospective Diabetes study which showed that metformin reduced the risk of myocardial infarction and other causes of mortality in the diabetic population [1]. In 2012, diabetes experts in the United States and Europe declared metformin as the drug of first choice in all patients with type II diabetes.

Metformin is hydrophilic and cannot readily pass through the cell membrane. It uses a carrier mediated pathway to enter the cell. Once inside the cell, metformin accumulates in the mitochondrial matrix leading to an overall downstream effect of high AMP-activated Protein Kinase (AMPK)  levels. These higher levels then lead to glucose and lipid metabolism. Metformin also directly inhibits a hepatic enzyme, Glycerol-3-Phosphate Dehydrogenase 2 (GPD2). This enzyme is involved in substrate gluconeogenesis. By blocking this enzyme, there is suppression of gluconeogenesis. 

Figure 1: Metformin mechanism of action

Learning Point 2: Metformin Toxicity

Metformin toxicity can be divided into two categories: metformin-induced lactic acidosis (MILA) and metformin-associated lactic acidosis (MALA). MILA occurs when high levels of metformin is the primary cause of illness, generally due to acute metformin overdose. The exact amount of metformin to result in an acute overdose is unclear, but it is thought to be between 10-20 grams. MALA occurs when patients develop acute renal insufficiency, hypovolemia or other shock states and metformin amplifies the degree of lactic acidosis.

Metformin toxicity results in lactic acidosis due to blockage of pyruvate carboxylase in the gluconeogenesis pathway. This shunts the pyruvate towards lactate production. An increase in lactic acid can be thought of as either an overproduction of lactate in the serum or an underutilization of lactate by the liver. The former most commonly results from an inhibition of oxidative metabolism that decreases the available adenosine triphosphate (ATP) and shunts the reaction to formation of additional lactate. Biguanides also decrease hepatic metabolism of lactate and have a negative inotropic effect on the heart, leading to elevated lactate levels.

Other adverse effects of metformin are hemolytic anemia (more common in G6PD patients), pancreatitis and vitamin B12 deficiency. 

Figure 2: Metformin toxicity – mechanism of action

Learning Point 3: Clinical Presentation of Metformin Toxicity

Metformin toxicity can present in a similar way as many other overdoses or toxidromes. Common symptoms include the following: 

• Gastrointestinal symptoms including nausea, vomiting, and epigastric pain
• Altered mental status with delirium and decreased consciousness

Physical exam findings may include the following: 

• Hypothermia and hypotension
• Vasopressor-refractory shock
• Circulatory instability leading to multi-organ failure.

Initial resuscitation should include fluid resuscitation with intravenous isotonic crystalloid. A fingerstick glucose should be obtained to evaluate for hypoglycemia, as this can cause altered mental status. Workup should include CBC, CMP, lactic acid, beta-hydroxybutyrate (BHB). Acetaminophen and salicylate levels should also be included to evaluate the possibility of other ingestions in cases of intentional overdose. Additionally, sepsis should be considered in patients with fever and hypotension.

In an acute metformin ingestion, labs will show an anion-gap metabolic acidosis with elevated lactic acid. BHB levels will be elevated as metformin promotes catabolism of fats and production of ketoacids.  

The case continued…

Lab results reveal acute renal failure as well as a significant metabolic acidosis. Despite fluid resuscitation, your patient does not appear to be improving. Toxicology is consulted, and the patient is started on norepinephrine through a central venous access. Due to the patient’s mental status and worsening renal function, the decision is made to start dialysis. The patient is also intubated for airway protection in the setting of altered mental status and vomiting to prevent aspiration. Nephrology is consulted, and the patient is admitted to the intensive care unit. 

Learning Point 4: Treatment of Metformin Toxicity

Treatment for metformin toxicity is supportive care as there is no specific antidote. Initial treatment may include decontamination with activated charcoal if the patient presents early after an acute overdose and there are no contraindications such as altered mental status or aspiration risk.  This practice will vary case by case.  Hypoglycemia is corrected with dextrose and then IV fluid resuscitation is recommended. There is no clear consensus on which fluids are best, but D5W with ½ NS and 50 mEq of sodium bicarbonate is a reasonable consideration. Vasopressors are recommended as needed for hypotension refractory to fluid resuscitation. Hemodialysis is the mainstay in treatment of metformin toxicity, particularly in instances of renal insufficiency, as 90% of the drug is renally eliminated. Main indications for hemodialysis are as follows: lactate > 15-20 mmol/L, pH <7, and failure to improve despite standard supportive treatment. Benefit from dialysis is greater for MILA and decreases for MALA as well as metformin unrelated lactic acidosis (MULA) [2]. 

Figure 3: EXTRIP guidelines for MALA treatment

Learning Point 5: Considerations for Methylene Blue in treatment of Metformin Toxicity

There are two main different mechanisms by which methylene blue is thought to be helpful in metformin toxicity. The first is via bypassing complex I in the electron transport chain. Metformin enters the cell by organic cation transporter 1 (OCT1), where it then accumulates in the mitochondria. There, metformin inhibits complex I of the electron transport chain, resulting in decreased NADH oxidation. Decreased electron chain activity suppresses tricarboxylic acid (TCA) cycle flux and decreases mitochondrial ATP synthesis. These actions result in increased AMPK signaling, decreased cAMP/PKA signaling, decreased gluconeogenesis and increased glycolysis.

Methylene blue is capable of accepting electrons from NADH and transferring them to cytochrome c in the mitochondria (bypassing Complex I). The other mechanism is via inhibition of guanylate cyclase (GC). GC leads to smooth muscle relaxation with nitric oxide. By inhibiting GC, it leads to vasoconstriction. There is not enough evidence to support regular use of methylene blue as of now, and it should be considered on a case-to-case basis, particularly in conversation with toxicology. If used, the usual dose is 2 mg/kg loading dose over 15-20 minutes, followed by 0.25 mg/kg/hr infusion.

The case concluded… 

In the intensive care unit, the patient is started on continuous veno-venous dialysis (CVVD) due to her hypotension. Nephrology and toxicology services are following the patient closely. Initially, serial arterial blood gas draws continue to show severe metabolic acidosis. About 12 hours after the initiation of CVVD, the acidosis begins to improve. The patient is extubated on day five, and eventually transferred to a stepdown unit on day nine when there is stabilization of blood pressure and resolution of the acidosis. 

Resources

1.      Alivanis P, Giannikouris I, Paliuras C, Arvanitis A, Volanaki M, Zervos A. Metformin-associated lactic acidosis treated with continuous renal replacement therapy. Clin Ther. 2006 March

2.      Finkle, S Neil. “Should dialysis be offered in all cases of metformin-associated lactic acidosis?.” Critical care (London, England) vol. 13,1 (2009): 110. doi:10.1186/cc7161

3.      Huang et al. Successful Reversal of Meformin-induced shock. Critical Care medicine. Volume 47, Issue 1. Jan 2019.

4.      Jagia, Manish et al. “Metformin poisoning: A complex presentation.” Indian journal of anaesthesia vol. 55,2 (2011): 190-2. doi:10.4103/0019-5049.79890

5.      Moioli A, Maresca B, Manzione A, Napoletano AM, Coclite D, Pirozzi N, Punzo G, Menè P. Metformin associated lactic acidosis (MALA): clinical profiling and management. J Nephrol. 2016 Dec;29)

6.      Wang et al, Review of Biguanude Toxicity. Journal of Intensive Care Medicine. Volume 34, issue 11-12. Aug 2018