Metformin poisoning and toxicity

INTRODUCTION — 

Metformin is the principal biguanide in clinical use. Biguanides are antihyperglycemic agents, not hypoglycemic agents; they promote euglycemia but alone are unlikely to cause hypoglycemia. Biguanides are used both as monotherapy and in combination with other oral hypoglycemic agents. The major toxicity from acute poisoning or chronic biguanide use is lactic acidosis; biguanides can also exacerbate hypoglycemia caused by other types of antidiabetic medicines and contribute to vitamin B12 deficiency [1,2].

Galega officinalis (goat's rue or French lilac) was used to treat diabetes in medieval Europe. The active ingredient, guanidine, was used to synthesize other antidiabetic agents in the 1920s [3], and the biguanide agents phenformin and metformin became available for clinical use in the 1950s. The high rate of severe lactic acidosis from phenformin led to the withdrawal of this drug from the United States market in 1976, although it remains available in several countries.

The evaluation and management of metformin poisoning/toxicity and metformin-associated lactic acidosis are reviewed here. A summary table to facilitate emergency management is provided (table 1). The therapeutic use of biguanides, evaluation, and management of lactic acidosis, and the general clinical management of drug intoxication are presented separately.

●(See "Metformin in the treatment of adults with type 2 diabetes mellitus".)

●(See "Causes of lactic acidosis" and "Bicarbonate therapy in lactic acidosis".)

●(See "General approach to drug poisoning in adults" and "Initial management of the critically ill adult with an unknown overdose" and "Enhanced elimination of poisons" and "Approach to the child with occult toxic exposure".)

PHARMACOLOGY AND CELLULAR TOXICOLOGY — 

Metformin decreases insulin resistance, decreases hepatic glucose output, and enhances peripheral glucose uptake [4]. Proposed mechanisms of action include enhanced suppression of gluconeogenesis by insulin, reduced glucagon-stimulated gluconeogenesis, and increased uptake of glucose by muscle and adipose cells [4]. The net effects of these changes in patients with diabetes are to decrease fasting and post-prandial blood glucose, decrease hemoglobin A1C, decrease body weight slightly, decrease low density lipoprotein (LDL), and increase high density lipoprotein (HDL) [5]. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Mechanism of action'.)

The mechanism of metformin-associated lactic acidosis (MALA) is complex and not fully understood. MALA should not be confused with an elevated lactate seen in therapeutic dosing, which is not associated with acidosis or symptoms. Metformin promotes the conversion of glucose to lactate in the splanchnic bed of the small intestine [6]. Metformin also inhibits mitochondrial respiratory chain complex 1 and glycerol 3-phosphate dehydrogenase, leading to decreased hepatic gluconeogenesis from lactate, pyruvate, and alanine [7]. This results in a type B lactic acidosis (independent of tissue hypoxia) from lactate accumulation and increased substrates for lactate production [8]. Metformin also stimulates adenosine monophosphate-activated protein kinase phosphorylation, which activates endothelial nitric oxide synthase, increasing nitric oxide production and vascular smooth muscle relaxation [9]. Subsequent hypotension can cause tissue ischemia and a concomitant type A lactic acidosis. 

PHARMACOKINETICS — 

Metformin is absorbed primarily in the upper part of the intestine [10]. It has negligible plasma protein binding and a volume of distribution ranging from 63 to 276 L (1 to 5 L/kg) [5,10,11]. The elimination half-life of metformin in patients who take multiple doses and have good kidney function is approximately five hours [10]. Metformin is excreted, unmetabolized, via transporters in the proximal tubules of the kidneys, and may accumulate in acute and chronic kidney disease [12].

CLINICAL PRESENTATION

History to obtain — Metformin toxicity, specifically metformin-associated lactic acidosis (MALA), may occur following acute overdose (intentional ingestion or supratherapeutic dosing) [13-18] or from impaired metformin elimination and accumulation in patients with comorbidities (eg, chronic kidney disease, liver disease, heart failure) and/or a precipitating disease (eg, infection, decompensated heart failure, acute kidney injury). In all patients who present with concern for metformin poisoning and/or MALA, it is important to inquire about comorbidities, which are discussed in detail separately. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Contraindications'.)

●Acute overdose — Following an intentional ingestion or accidental supratherapeutic dosing, clinicians should seek information about dose and coingestants. It is unclear what minimum dose of metformin can cause toxicity (ie, MALA) following overdose because patient reports are often unreliable. A United Kingdom poison center study that included 117 patients with single-substance metformin overdose found that 28 percent developed lactic acidosis [19]. The clinician should have a high index of suspicion that toxicity will develop in a child who ingests more than one or two tablets, any patient who presents with a report of intentional ingestion, and a patient with comorbidities.

●Suspected metformin accumulation — If there is no history of acute metformin overdose, inquire about conditions that could predispose to hypoperfusion or hypoxemia (eg, infection, dehydration, decompensated heart failure, acute or progressive reduction in kidney function, bowel ischemia). Chronically impaired kidney function is a common risk factor for MALA [20], but patients who develop a severe lactic acidosis typically have additional risk factors or a predisposing illness. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Lactic acidosis'.)

Clinical features of toxicity

Signs and symptoms — Patients with metformin toxicity may complain of nausea, vomiting, diarrhea, abdominal pain, and/or shortness of breath [7,14,18,21,22]. Physical examination findings may include tachycardia, hypotension, and tachypnea in patients with lactic acidosis. Alterations in mental status can include agitation, confusion, lethargy, or coma and may be due to acidosis or hypoglycemia [14,18,21]. Life-threatening toxicity, often in the setting of severe lactic acidosis, can include respiratory failure, multiple organ dysfunction, profound vasoplegic shock, and ventricular dysrhythmias.

Following acute ingestion, symptom onset generally occurs within four to eight hours, but lactic acidosis may not develop for up to 12 hours or longer [23].

Metformin-associated lactic acidosis — An extremely elevated lactate concentration (ie, >8 mmol/L) suggests that metformin is contributing to the clinical presentation. For example, a retrospective study of emergency department patients with suspected sepsis-induced lactic acidosis found that patients with metformin-associated lactic acidosis (MALA) had much higher lactate concentrations (14.7 versus 5.9 mmol/L) [24]. Patients with MALA also had lower arterial pH (7.04 versus 7.38) and higher serum creatinine (7.3 versus 2.0 mg/dL).

Distinguishing whether metformin is causing or contributing to the acidosis and clinical picture does not alter management. Therefore, while some authors use the term "metformin-induced" lactic acidosis (rather than "metformin-associated") to distinguish the condition where metformin is clearly responsible, making this distinction may require obtaining a metformin concentration, which is not readily available [25]. (See 'Role of metformin concentration' below.)

Mortality is high in patients with MALA. Several meta-analyses have found mortality rates of 20 to 36 percent [22,26]. Similarly high mortality has been reported in multiple case series [7,25,27,28].

●In patients with MALA from confirmed acute metformin overdose, a systematic review found that lower serum pH and higher serum lactate concentrations correlated with increased mortality [29]. All 16 survivors had a serum pH above 6.9 and a serum lactate below 25 mmol/L, while 5 of the 6 patients with a pH less than 6.9 or a lactate greater than 25 mmol/L died. The United Kingdom poison center study found that the degree of toxicity correlated with the serum lactate concentration and inversely correlated with the arterial pH. These laboratory values did not correlate with each other, and either could be an independent marker of poisoning severity [19].

●In patients with MALA from a precipitating disease, neither arterial lactate levels nor plasma metformin concentrations predict mortality. Death more closely correlates with underlying acute or comorbid conditions. In a case series of 66 patients with MALA, the absolute metformin and lactate concentrations were not different in survivors and non-survivors [7]. Multiple organ dysfunction, such as liver dysfunction as demonstrated by an elevated prothrombin time, has been found to predict mortality in patients with MALA [28].

The incidence and predisposing factors for MALA are discussed separately. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Lactic acidosis'.)

Hypoglycemia (uncommon) — Metformin can contribute to hypoglycemia when combined with other hypoglycemic agents but is alone unlikely to cause hypoglycemia [1,2].

LABORATORY TESTING

Studies to obtain — For a patient with concern for metformin poisoning and/or metformin-associated lactic acidosis (MALA), we obtain the following studies:

●Fingerstick blood glucose measurement in any patient with altered mental status to rule out hypoglycemia

●Arterial or venous blood gas for accurate determination of the patient's acid-base status

●Serum lactate concentration, to confirm that a metabolic acidosis, if present, is in fact a lactic acidosis

●Complete blood count to rule out anemia as a contributing factor

●Basic chemistries, blood urea nitrogen, and creatinine to determine the bicarbonate concentration and to assess kidney function

●Liver biochemical tests and coagulation studies to evaluate for a possible comorbid condition and multiple organ dysfunction

●Pregnancy test in females of childbearing age

In a patient with concern for an intentional ingestion, we also obtain the following:

●Acetaminophen, salicylate, and ethanol concentrations, to rule out these common coingestions

●Electrocardiogram to rule out conduction system poisoning by coingestants that affect the QRS or QTc intervals

Further testing is guided by the history and examination and could include tests for comorbidities or for precipitating illnesses (eg, cultures, urinalysis, chest radiograph, abdominal imaging).

Role of metformin concentration — Obtaining a serum metformin concentration is unhelpful in most cases because few hospitals perform the test and thus timely results are rarely available, and because the serum concentration often does not correlate with the severity of the poisoning or patient outcome [7,27,29,30]. An undetectable concentration excludes metformin as the cause of lactic acidosis in most cases.

DIAGNOSIS — 

Metformin poisoning (ie, intentional overdose or accidental supratherapeutic dosing) is a clinical diagnosis and usually suspected on the basis of corroborating history in a patient with consistent signs and symptoms (eg, vomiting, abdominal pain, hypotension, altered mental status, lactic acidosis). (See 'Signs and symptoms' above.)

Metformin-associated lactic acidosis (MALA) is diagnosed by an elevated serum lactate concentration (generally >4 to 5 mmol/L), the presence of metabolic acidosis (ie, acidemia with arterial serum pH <7.35), and metformin exposure. The presence of metabolic acidosis is required for the diagnosis of MALA; the diagnosis of metabolic acidosis is discussed separately. (See "Approach to the adult with metabolic acidosis", section on 'Diagnosis'.)

MALA is not present in an asymptomatic patient who takes metformin, does not have a history of ingestion, and has an isolated hyperlactatemia without a metabolic acidosis.

DIFFERENTIAL DIAGNOSIS — 

Once a metformin-associated lactic acidosis (MALA) is identified, unless there is a clear history of metformin overdose, the differential diagnosis includes other causes of lactic acidosis (see "Causes of lactic acidosis"). If the diagnosis of MALA is established, the clinician should identify precipitating causes including illness (eg, sepsis, bowel ischemia, heart failure, volume depletion), which are typically necessary for MALA to develop and may independently cause or contribute to the acidosis. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Lactic acidosis'.)

MALA typically causes an extremely elevated lactate (>8 mmol/L), which may help to distinguish it from other causes of lactic acidosis (table 2). The serum salicylate and acetaminophen concentrations, osmolal gap (for ethylene glycol or methanol), and glucose (for diabetic ketoacidosis) may help exclude other causes. The history and examination may suggest causes such as sepsis, seizures, bowel or other tissue ischemia, or other forms of shock. Alcohol or starvation ketoacidosis often cause a lesser degree of acidosis. The causes of lactic acidosis are discussed separately. (See "Causes of lactic acidosis".)

MANAGEMENT — 

The following treatment recommendations are based upon our clinical experience and the limited available evidence. A summary table to facilitate emergency management is provided (table 1).

All patients: supportive care — Patients with metformin toxicity rarely require tracheal intubation. Hyperpnea and tachypnea may reflect respiratory compensation for a metabolic acidosis and may not represent impending respiratory failure. If tracheal intubation is required and the patient has severe metabolic acidosis, the patient should be managed as having a "physiologically difficult airway" because administration of induction medications and neuromuscular blocking agents may make the apneic phase of rapid sequence intubation intolerable and create a risk for circulatory collapse. Ventilator settings require a minute ventilation sufficient to compensate for any underlying acidosis and arterial blood gas results should be checked frequently until the patient is stabilized. (See "The physiologically difficult airway: Optimization of airway management in adults at risk of decompensation for emergency medicine and critical care", section on 'Severe metabolic acidosis'.)

If a patient deteriorates despite appropriate supportive care, the clinician should promptly consult nephrology regarding the possibility of hemodialysis. During this consultation, the clinician should convey to the nephrologist both the patient's clinical condition and, if available, serial acid-base determinations to help document the patient's deterioration. (See 'Role of kidney replacement therapy (hemodialysis)' below.)

Hypotension should initially be treated with intravenous (IV) fluids followed by vasopressors if needed. (See "Use of vasopressors and inotropes".)

Dysrhythmias should be treated with standard protocols. (See "Advanced cardiac life support (ACLS) in adults", section on 'Management of specific arrhythmias'.)

Acute ingestion: gastrointestinal decontamination — We suggest gastrointestinal (GI) decontamination with activated charcoal (AC) in a patient with acute metformin ingestion, unless specific contraindications (such as an unprotected airway, bowel obstruction, or GI perforation) exist. Patients with toxicity from chronic use are unlikely to benefit from GI decontamination. The clinician must assess aspiration risk, including mental status and ability to protect the airway, in all patients before any attempts to administer AC. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Activated charcoal'.)

Hypoglycemia — If hypoglycemia is present, it should be treated with IV dextrose 10 to 25 g (20 to 50 mL of 50% solution) in adults, 0.5 to 1 g/kg (2 to 4 mL/kg of 25% solution) in children, followed by a meal if food is not contraindicated. (See "Hypoglycemia in adults with diabetes mellitus", section on 'Reversing hypoglycemia' and "Approach to hypoglycemia in infants and children", section on 'Treatment'.)

Metformin alone should not cause hypoglycemia and other causes should be sought.

Recalcitrant vasoplegic shock — In a patient with recalcitrant vasoplegic shock (ie, persistent hypotension despite adequate IV fluids and vasopressor therapy), it is reasonable to administer methylene blue. Evidence is based on case reports [31-36]. Methylene blue reduces nitric oxide-mediated vasodilation by inhibiting guanylate cyclase and nitric oxide synthase, which may reverse metformin-induced nitric oxide release. Methylene blue has been used to treat refractory hypotension due to vasoplegia caused by sepsis or other etiologies (eg, anaphylaxis, cardiopulmonary bypass); the dose is 1 to 2 mg/kg IV with repeated doses up to a total of 6 mg/kg. (See "Methemoglobinemia", section on 'Methylene blue (MB)'.)

Persistent hypotension suggests profound toxicity, and in such cases, hemodialysis is often necessary. (See 'Role of kidney replacement therapy (hemodialysis)' below.)

Lactic acidosis

Treat precipitating cause — Unless the metformin-associated lactic acidosis (MALA) was caused by an acute ingestion, a precipitating illness or exacerbation of a comorbid condition likely exists and should be treated appropriately (eg, antibiotics for sepsis, IV fluids for volume depletion). (See 'History to obtain' above.)

Severe acidosis: sodium bicarbonate — We suggest limiting the use of sodium bicarbonate to patients with severe metabolic acidosis (arterial pH below 7.1, or below 7.2 in patients with severe acute kidney injury), with the aim being to maintain the pH above 7.1 (or above 7.3 in patients with severe acute kidney injury) until the acute toxicity resolves. The use of sodium bicarbonate in MALA is controversial and is evidence is extrapolated from other clinical scenarios. Theoretical disadvantages to sodium bicarbonate include leftward shift of the hemoglobin dissociation curve, excess sodium load, rebound metabolic alkalosis, disturbances in serum potassium and calcium, decreased myocardial contractility, increased carbon dioxide production, and reflex vasodilation after bolus injection [18,21]. (See "Bicarbonate therapy in lactic acidosis".)

Role of kidney replacement therapy (hemodialysis) — Hemodialysis has been used successfully in patients with MALA that developed from accumulation or acute overdose [11,21,37-39]. We agree with the Extracorporeal Treatments in Poisoning Workgroup and recommend hemodialysis for patients with any of the following findings associated with severe metformin poisoning [11]:

●Severely elevated serum lactate concentration (>20 mmol/L)

●Severe metabolic acidosis (pH ≤7.0)

●Failure to improve (as determined by pH, lactate concentration, or clinical status) with supportive care and bicarbonate therapy within two to four hours

Although evidence is limited, we suggest hemodialysis for patients with any of the following findings:

●Elevated serum lactate concentration between 15 to 20 mmol/L

●Metabolic acidosis (pH >7.0 and ≤7.1)

●Comorbidities:

•Shock or persistent hemodynamic instability requiring vasopressor therapy despite acute administration of IV boluses of isotonic crystalloid totaling 30 mL/kg

•Kidney injury – Creatinine >2 mg/dL (adults), or >1.5 mg/dL (older adult), or 2 times upper limit of normal (children), or chronic kidney disease (stage 3b or higher with eGFR <45 mL/min/1.73 m², oliguria, or anuria)

•Liver failure – Liver injury with coagulopathy (INR >1.5) and any degree of encephalopathy

•Decreased level of consciousness

For critically ill patients who do not meet any of the above criteria, (eg, those with lactate concentrations >15 mmol/L, or pH 7.0 to 7.1), or who have important comorbid conditions (eg, kidney insufficiency, liver failure, decreased level of consciousness), it is important to obtain early consultation with a medical toxicologist and a nephrologist and to coordinate care with these specialists, as such patients may progress quickly to needing hemodialysis [11].

Hemodialysis should be performed using a bicarbonate buffer, as the benefits are from correcting the metabolic acidosis more so than increasing metformin elimination. Treatment may need to be repeated should metabolic derangements recur. Hemodialysis may be discontinued when the lactate concentration is <3 mmol/L and the pH is >7.35 [11]. (See "Acute hemodialysis prescription", section on 'Patients with metabolic acidosis'.)

For patients with severe metformin poisoning requiring kidney replacement therapy, hemodialysis is the preferred approach if the hemodynamics are adequate. Continuous hemodialysis (>15 hours) has been used successfully in extremely ill patients. If the patient is hemodynamically unstable, continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodiafiltration (CVVHD) should be considered. Continuous venovenous hemofiltration has been performed in patients with metformin overdose [21,40]. According to case reports, the clearance of drug by CVVH was less than that generally reported to occur with conventional hemodialysis [37,40]. Therefore, CVVH should only be considered in patients who are too hemodynamically unstable to tolerate hemodialysis.

Although there are no randomized trials of prolonged kidney replacement therapy in severe metformin poisoning, retrospective series and case reports support this approach when necessary [28,40-42].

DISPOSITION — 

The onset of lactic acidosis may take several hours, so patients reporting an acute metformin ingestion should be observed for at least six to eight hours [1,23]. Patients who are asymptomatic, have a normal acid-base status, and a stable (ie, non-increasing) lactate after six to eight hours may be discharged or referred for mental health evaluation.

Patients may present with a mild lactate elevation or mildly increased anion gap but have normal vital signs and an unremarkable physical examination. Such patients may be discharged home with instructions to stop taking metformin and to see their primary clinician within the next several days if the laboratory abnormalities are minor and resolve on repeat evaluation after a brief period (approximately six hours) of uneventful observation. Asymptomatic patients with persistent abnormalities (metabolic acidosis; elevated lactate) and symptomatic patients should be observed using the same guidelines described for acute ingestions, or they should be admitted to the hospital for observation.

PEDIATRIC CONSIDERATIONS — 

Clinicians should have a high index of suspicion that toxicity will develop in children who ingest more than one or two tablets. We treat pediatric metformin toxicity similarly to adults, which is supported by anecdotal reports [43,44].

ADDITIONAL RESOURCES

Regional poison centers — Regional poison centers in the United States are available at all times for consultation on patients who are critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have clinical and/or medical toxicologists available for bedside consultation and/or inpatient care. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment" and "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse".)

SUMMARY AND RECOMMENDATIONS

●Pharmacology, toxicology, and pharmacokinetics – Biguanides are antihyperglycemic agents (not hypoglycemic agents) since they promote euglycemia. The mechanism of metformin-associated lactic acidosis (MALA), the major toxicity of metformin, is complex and includes inhibition of mitochondrial respiration, decreased hepatic gluconeogenesis, and increased nitric oxide production. Metformin absorption occurs primarily in the intestine, and the drug is excreted unmetabolized from the kidneys. (See 'Pharmacology and cellular toxicology' above and 'Pharmacokinetics' above.)

●Clinical presentation – Metformin toxicity, specifically MALA, may occur following acute overdose (intentional ingestion or supratherapeutic dosing) or from impaired metformin elimination and accumulation in patients with comorbidities (eg, chronic kidney disease, liver disease, heart failure) and/or a precipitating disease (eg, infection, decompensated heart failure, acute kidney injury). (See 'Clinical presentation' above.)

Signs and symptoms can include nausea, vomiting, abdominal pain, and shortness of breath. Life-threatening toxicity, often in the setting of severe lactic acidosis, can include respiratory failure, multiple organ dysfunction, profound vasoplegic shock, and ventricular dysrhythmias. Alterations in mental status may be due to acidosis or hypoglycemia, but the latter is uncommon unless combined with other hypoglycemic agents. (See 'Signs and symptoms' above.)

An extremely elevated lactate concentration (ie, >8 mmol/L) suggests that metformin is contributing to the clinical presentation and that the patient has MALA. Mortality is high in patients with MALA and has been estimated at 20 to 36 percent. In patients who develop MALA from a precipitating illness, mortality correlates with the severity of the underlying medical conditions. In patients with MALA from acute metformin overdose, death correlates with high plasma lactate and low serum pH.

●Laboratory testing – For a patient with concern for metformin poisoning/MALA, we obtain serum chemistries, arterial or venous blood gas, serum lactate concentration, liver biochemical tests, coagulation studies, complete blood count, and pregnancy test in females of childbearing age. If there is concern for intentional ingestion, we also obtain acetaminophen, salicylate, and ethanol concentrations and an electrocardiogram. A fingerstick blood glucose measurement should be obtained immediately in any patient with altered mental status. (See 'Laboratory testing' above.)

Obtaining a serum metformin concentration is unhelpful in most cases because few hospitals perform the test, and the concentration often does not correlate with the severity of the poisoning or patient outcome. If the test is available, an undetectable concentration excludes metformin as the cause of lactic acidosis in most cases. (See 'Role of metformin concentration' above.)

●Diagnosis – Metformin poisoning (ie, intentional overdose or accidental supratherapeutic dosing) is a clinical diagnosis and is usually suspected on the basis of corroborating history in a patient with consistent signs and symptoms (eg, vomiting, abdominal pain, hypotension, altered mental status, lactic acidosis). Metformin-associated lactic acidosis (MALA) is diagnosed by an elevated serum lactate concentration (generally >4 to 5 mmol/L), the presence of metabolic acidosis (ie, acidemia with arterial serum pH <7.35), and metformin exposure. (See 'Diagnosis' above.)

●Differential diagnosis – Once MALA is identified, unless there is a clear history of metformin overdose, the differential diagnosis includes other causes of lactic acidosis (table 2). It also includes precipitating illness (eg, sepsis, bowel ischemia, heart failure, volume depletion), which are typically necessary for MALA to develop and may independently cause or contribute to the acidosis. (See 'Differential diagnosis' above.)

●Management – A summary table to facilitate emergency management of metformin intoxication is provided (table 1). Care is mainly supportive, and hemodialysis may be used to treat MALA. (See 'Management' above.)

•Supportive care – Patients with metformin toxicity rarely require tracheal intubation. If tracheal intubation is needed in a patient with severe metabolic acidosis, approach the procedure as a "physiologically difficult airway" because administration of induction medications and neuromuscular blocking agents may make the apneic phase of rapid sequence intubation intolerable and create a risk for circulatory collapse. (See 'All patients: supportive care' above.)

Treat hypotension with intravenous (IV) fluids, followed by vasopressors if needed. Methylene blue is an option in a patient with recalcitrant vasoplegic shock (ie, persistent hypotension despite adequate IV fluids and vasopressor therapy). (See 'Recalcitrant vasoplegic shock' above.)

•Gastrointestinal decontamination – In patients with acute metformin ingestion, we suggest gastrointestinal (GI) decontamination with activated charcoal (AC) (Grade 2C). Activated charcoal should not be given to patients with toxicity from chronic use. The clinician must assess aspiration risk before any attempts to administer AC. (See 'Acute ingestion: gastrointestinal decontamination' above.)

•Hypoglycemia – Treat hypoglycemia with IV dextrose 10 to 25 g (20 to 50 mL of 50% solution) in adults, 0.5 to 1 g/kg (2 to 4 mL/kg of 25% solution) in children, followed by a meal if food is not contraindicated. (See 'Hypoglycemia' above.)

•Metformin-associated lactic acidosis (MALA) – We limit the use of sodium bicarbonate to patients with severe metabolic acidosis (arterial pH below 7.1 or below 7.2 in patients with severe acute kidney injury) until the acute toxicity resolves. (See 'Severe acidosis: sodium bicarbonate' above and "Bicarbonate therapy in lactic acidosis".)

In patients with MALA and any of the following, we recommend hemodialysis (Grade 1C):

-Lactate concentrations >20 mmol/L

-Severe metabolic acidosis (pH ≤7.0)

-Failure to improve within two to four hours despite appropriate supportive care and bicarbonate therapy

In patients with MALA and any of the following, we suggest hemodialysis (Grade 2C):

-Lactate concentrations between 15 to 20 mmol/L

-Metabolic acidosis with pH >7.0 and ≤7.1

-Presence of comorbid conditions (shock, kidney impairment, liver failure, or decreased level of consciousness)

Hemodialysis has been used successfully in patients with MALA due to acute overdose and metformin accumulation. (See 'Role of kidney replacement therapy (hemodialysis)' above.)

●Disposition – Patients reporting an acute ingestion should be observed for at least six to eight hours. Patients who are asymptomatic, have a normal acid-base status, and a stable (ie, non-increasing) lactate after six to eight hours may be discharged or referred for mental health evaluation. (See 'Disposition' above.)