Metformin is a first-line agent for type 2 diabetes mellitus often used as monotherapy or in combination with oral diabetic medications. It is a member of the biguanide class and its main intended effect is expressed by the inhibition of hepatic gluconeogenesis. In addition, metformin increases insulin sensitivity, enhances peripheral glucose utilization and decreases glucose uptake in the gastrointestinal tract. Phenformin, a previously used biguanide, as withdrawn from the market in the 1970’s due its association with numerous cases of lactic acidosis. Metformin is currently used extensively in the management of diabetes and is the most commonly prescribed biguanide worldwide. The therapeutic dosage of metformin ranges from 850 mg to a maximum of 3000 mg daily and is typically divided into twice daily dosing. It is primarily used in the treatment of diabetes but has been used in other conditions associated with insulin resistance such as polycystic ovarian syndrome. MALA is a rare but well reported event that occurs with both therapeutic use and overdose states.
A 22-year-old female presents to the Emergency Department after being found alongside a suicide note by her family. She was thought to have taken an unknown, but large amount of her husband’s metformin. She arrives at the ED nearly 10 hours after ingestion. She was agitated, but conversant. She reports having nausea and vague feelings of being unwell and is very distraught over the state of her critically ill husband. She has some self-inflicted superficial lacerations over her left anterior forearm. Her vital assigns upon arrival were: T 98.9 degrees Fahrenheit, HR initially 140 bpm which improved to 110 bpm soon after arrival, BP 100/50, RR 22, O2 sat 98% on room air. On examination she was agitated and restless, with noted tachycardia and lungs were clear to auscultation with slightly rapid respirations. She is alert and oriented to person, place and time without rigidity or clonus. She had some self-inflicted, superficial, linear lacerations. Cardiac telemetry monitoring showed a narrow complex sinus tachycardia. Laboratory analysis of blood collected soon after arrival showed the following blood gas: pH 7.16, pCO2 30 mmHg and bicarbonate of 15. Comprehensive metabolic panel was significant for a sodium of 144 mEq/L, chloride of 105 mEq/L, bicarbonate 15 mEq/L and creatinine of 1.2 mg/dL. Anion Gap was calculated to be 24. Other labs include: ethanol 105 mg/dL, lactate of 8.7 mmol/L (normal range 1-1.8 mmol/L), acetaminophen and salicylate concentrations were not measureable.
1) Under which clinical scenarios should metformin poisoning be suspected?
2) Which laboratory tests may be helpful in the management of metformin poisoning?
3) When should dialysis be used in the management of metformin-associated lactic acidosis (MALA)?
MALA is a rare but potentially lethal complication associated with the use of metformin. The incidence is thought to be 2-9 cases per 100,000 patients per year. Lactic acidosis is about 20 times less frequent with metformin than phenformin.
The exact mechanism and role of metformin in the setting of MALA is a controversial subject. The mechanism for the reduction of hepatic gluconeogenesis is due to inhibition of mitochondrial respiratory chain complex I causing a decline in cellular ATP production. Gluconeogenesis, an energetically costly process, is reduced as the result of an impaired energy state. It is this mitochondrial impairment that leads to a buildup of lactic acid, a substrate of stalled gluconeogenesis. It is a very commonly used drug, but MALA is a rather rare clinical entity. The role of metformin in the development of lactic acidosis had not been completely elucidated and is further complicated in the literature by many reported cases of MALA without elevated metformin concentrations.
Metformin does not undergo hepatic metabolism and is primarily excreted through the renal system unchanged. Predisposing conditions leading to renal failure are typically associated with MALA. MALA should likely be categorized into separate entities: 1) acute overdoses associated with lactic acidosis 2) those with underlying causes for metformin and lactate accumulation and 3) those with coincidental lactic acidosis from other etiology rather than causal from metformin. MALA is extremely rare when prescribed to a low-risk groups less inclined to develop lactic acidosis and avoided in those with alcoholism, heart failure and significant respiratory disease. A Cochrane review concluded therapeutic use of metformin is not associated with an increased risk of lactic acidosis if no contraindications are present. Unlike the sulfonylureas, it is not typically associated with hypoglycemia in the setting of overdose or poisoning, with the exception of rare critically ill cases with systemic cellular dysfunction.
MALA is potentially lethal and identification is crucial. It can be a difficult diagnosis in the setting of limited history. Typical symptoms can be fairly nebulous and include abdominal pain, nausea, vomiting, malaise, myalgia and dizziness. Tachypnea in physiological response to metabolic acidosis can be an early sign. Gastrointestinal side effects are a common side effect with therapeutic metformin use in the absence of lactic acidosis. In more severe cases it can present with altered mental status, coma, hypotension, hypothermia and respiratory insufficiency.
MALA is often associated with new onset renal insufficiency, so concurrent conditions such as sepsis, cardiac insufficiency, and hypovolemia from fluid losses often precipitate the onset of MALA. These concurrent comorbidities and illness can provide a diagnostic challenge in the ability to ascertain whether metformin is the culprit or just a bystander in the development severe lactic acidosis.
The classic triad of MALA is renal failure, severe lactic acidosis and elevated metformin concentrations. However, metformin concentration is not often a readily obtainable laboratory test at most hospitals. Metformin overdose can also occur in the absence of renal failure, particularly with acute overdoses. Therefore, timely diagnosis is often based on clinical manifestations and reliance on surrogate markers in the context of clinical history to make the diagnosis. Lactic acidosis is typically defined as a pH less than 7.35 and blood lactate = 5 mmol/L. Severe lactic acidosis is certainly not specific to MALA and is associated with many other life-threatening conditions such as ischemic gut and sepsis as well as other toxic exposures such as cyanide, carbon monoxide, hydrogen sulfide, etc. These other alternative diagnoses should all be considered in the setting of severe lactic acidosis. Creatinine will often be elevated as a marker of renal insufficiency, but may be normal, especially in the setting of acute overdoses. Metformin concentration measurement should be obtained when available, however, results are rarely available in a timely manner to be useful in initial treatment and clinical management.
Initial management of MALA is largely supportive and includes supplemental oxygen as well as airway and ventilator support. Activated charcoal may be considered in conscious patients who present soon after ingestion. Intravenous crystalloid should be administered initially to resuscitate hypotensive patients. Patients who are unresponsive to fluid administration should be given vasopressors. Sodium bicarbonate may be considered in severely acidemic patients that are refractory to other supportive measures, but its use and efficacy is controversial. Identification and treatment of underlying conditions that may have contributed the development of MALA is of paramount importance. Obviously, cessation of metformin in the setting of renal insufficiency is a key factor in both prevention and management of MALA.
Metformin is dialyzable. Extra-corporeal removal is recommended in severe metformin poisoning. Some general recommendations for initiating dialysis are as follows: 1) lactate concentration greater than 20 mmol/L 2) pH less than or equal to 7.0 3) shock 4) decreased level of consciousness and 5) failure of other standard supportive care. Intermittent hemodialysis is the initial treatment option of choice. Hypotension may make hemodialysis a challenging endeavor.
Discussion of case questions
1) Under which clinical scenarios should metformin poisoning be suspected?
Answer: Metformin poisoning and MALA can present with a rather nebulous clinical presentation. Identification of acidosis and obtaining a clinical history of metformin exposure are essential components of the diagnosis.
2) Which laboratory tests maybe helpful in the management of metformin poisoning?
Answer: Metformin poisoning and MALA can present clinically in a nonspecific manner. Altered mental status, abdominal pain, nausea, vomiting, tachypnea, hypotension in a person taking metformin therapeutically or in overdose should raise suspicion for MALA. Identification of an unexplained lactic acidosis is often a first clue. Patients on metformin with a recent decline in renal function is often the precipitant to the development of MALA. Serum chemistry panel, lactic acid and blood gas may be helpful in establishing a presumptive diagnosis of metformin poisoning when correlated with clinical history and manifestations. These tests may also be helpful in monitoring response to therapy. Metformin concentrations may be useful in confirming the diagnosis, but this test is typically not available in a timely manner to guide clinical decisions at the bedside.
3) When should dialysis be used in the management of MALA?
Answer: Metformin is primarily cleared by the kidneys and MALA often presents in the setting of renal failure. General guidelines for initiating dialysis include the presence of severe lactic acidosis with ph < 7.0 or lactate greater than 20 mmol/L, shock, altered mental status and failure of other supportive care.
The patient was admitted to the intensive care unit and given vigorously hydrated with normal saline to treat hypotension with systolic blood pressures in the 80-90’s mmHg overnight. Acidosis and lactic acid levels cleared over the next 24 hours and creatinine levels remained normal. She was discharged on hospital day 2 after being cleared by psychiatry.
Consultation with a specialist in poison information or with a medical toxicologist can be obtained free of charge by calling the California Poison Control System at 1-800-222-1222.
This issue of CALL US... was written by Charles W. O’Connell, MD
Published on October 30, 2015
CALL US... is published by the California Poison Control System. Editorial Board: Executive Director, Stuart E. Heard, PharmD; CPCS Medical Directors: Timothy E. Albertson, MD, Richard F. Clark, MD, Richard Geller, MD, Kent R. Olson, MD; CPCS Managing Directors: Justin Lewis, PharmD, Thomas E. Kearney, PharmD, Lee Cantrell, PharmD; Editor:Binh T. Ly, MD; Assistant Editor: Alicia Minns, MD.
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