DESCRIPTION

Metformin and biguanide hypoglycemic agents are used to treat non-insulin-dependent diabetes mellitus and to reduce insulin requirements in patients with insulin-dependent diabetes.

FORMS AND USES

• Substances include metformin (Glucophage) and phenformin.
• Metformin is available in 500- and 850-mg tablets; adult dosage is 500 mg twice daily, up to 2,500 mg/day divided three times a day.

TOXIC DOSE

The toxic dose is unknown; metformin is thought to be less likely than sulfonylurea agents to produce hypoglycemia in nondiabetic patients who ingest a single pill.

PATHOPHYSIOLOGY

• The mechanism of the action is unclear; biguanides may increase glucose reuptake by cells, decrease gluconeogenesis, and increase glucose turnover.
• Lactic acidosis may be secondary to impaired adenosine triphosphate production due to actions on mitochondrial membranes.

EPIDEMIOLOGY

• Poisoning is uncommon, but increasing in incidence.
• Toxic effects are typically mild.
• Death occurs rarely, primarily in patients with underlying renal or hepatic disease who develop lactic acidosis.

CAUSES

• Acute overdose is usually caused by intentional ingestion.
• Child neglect should be considered in patients under 1 year of age; suicide attempt in patients over 6 years of age.

DRUG AND DISEASE INTERACTIONS

• Patients with underlying hepatic or renal dysfunction are at risk for metformin-induced lactic acidosis.
• Enhanced hypoglycemic effects occur with other oral hypoglycemics or insulin.

PREGNANCY AND LACTATION

US FDA Pregnancy Category B. Animal studies indicate no fetal risk, and there are no controlled human studies, or animal studies show an adverse fetal effect but well-controlled studies in pregnant women do not.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• TOXIC DOSE
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• CAUSES
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

DIFFERENTIAL DIAGNOSIS

• Toxic causes of metabolic acidosis include isoniazid, iron, methanol, ethylene glycol, and salicylates, among others.
• Nontoxic causes include diabetic ketoacidosis, sepsis, renal failure, seizure, and renal tubular acidosis.

SIGNS AND SYMPTOMS

• Severe lactic acidosis may develop after either an overdose or chronic excessive dosing of any biguanide.
• Metabolic acidosis or hypoglycemia suggest a serious overdose and a need for immediate therapy.

Vital Signs

• Hypothermia may develop in patients with coma and acidosis.
• Tachycardia may develop from volume depletion.

Cardiovascular

• Hypotension, bradycardia, and dysrhythmia may appear in patients with severe acidosis.
• Myocardial infarction may be either the precipitating factor or the result of severe acidosis during chronic therapy.

Pulmonary

• Kussmaul respirations may occur with lactic acidosis.
• Pulmonary edema may occur after severe overdose.

Gastrointestinal

• Nausea, vomiting, and abdominal pain develop as side effects with an acute overdose or with lactic acidosis.
• Gastrointestinal bleeding is a rare effect.

Renal

Acute renal failure may develop in patients with acidosis and hypotension.

Fluids and Electrolytes

• Lactic acidosis may develop after an acute overdose or chronic excessive dosing of any biguanide hypoglycemic agent.
• Lactic acidosis from chronic therapeutic use of metformin has been reported in patients with underlying renal or hepatic insufficiency.

Neurologic

• CNS depression, coma, and abnormal reflexes are seen in patients with hypoglycemia or severe acidosis.
• Seizures rarely occur.

Endocrine

Hypoglycemia may develop after an overdose or with acidosis.

PROCEDURES AND LABORATORY TESTS

Essential Tests

Serum electrolytes, glucose, BUN, creatinine, and arterial blood gas may be monitored to assess the presence and severity of acidosis.

Recommended Tests

• Liver function tests are recommended for patients with acidosis; patients with hepatic insufficiency are susceptible to metformin-induced acidosis.
• Serum iron, methanol, ethylene glycol, salicylate, and lactate levels may be needed to evaluate other causes of acidosis.
• Blood cultures, a lumbar puncture, and a head CT may be needed to rule out other causes of altered mental status.
• An ECG may be useful for patients with acidosis; severe acidosis may precipitate myocardial infarction.
• Serum acetaminophen and aspirin levels in overdose setting to detect occult ingestion.

Not Recommended Tests

Serum levels of biguanides are not readily available or useful.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Vital Signs
  • Cardiovascular
  • Pulmonary
  • Gastrointestinal
  • Renal
  • Fluids and Electrolytes
  • Neurologic
  • Endocrine
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests
  • Not Recommended Tests

• Treatment should focus on managing the airway, supporting cardiovascular function, correcting hypoglycemia, and reversing acidosis as clinically indicated.
• The dose and time of exposure should be determined for all substances involved.

DIRECTING PATIENT COURSE

The health-care professional should call the poison control center when:

• Metabolic acidosis, hypotension, dysrhythmia, or other severe effects are present.
• Toxic effects are not consistent with metformin toxicity.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

The patient should be referred to a health-care facility when:

• Attempted suicide or homicide is possible.
• Patients or caregivers seem unreliable.
• Toxic effects develop.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

Admission Considerations

Inpatient treatment is warranted when the patient has altered mental status, hypoglycemia, acidosis, hypotension, or dysrhythmia.

DECONTAMINATION

Out of Hospital

Emesis should be induced with ipecac within 1 hour of ingestion for alert pediatric or adult patients if health-care evaluation will be delayed.

In Hospital

• Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult (tube size 36-42 French) patients presenting within 1 hour of a large ingestion or if serious effects are present.
• A dose of activated charcoal (1-2 g/kg) should be administered if a substantial ingestion has occurred within the previous few hours.

ANTIDOTES

There are no specific antidotes available for metformin poisoning.

ADJUNCTIVE TREATMENT

• Hemodialysis using a sodium bicarbonate buffer has been used for biguanide-induced metabolic acidosis.
• Dextrose is indicated for symptoms of hypoglycemia or a serum glucose less than 60 mg/dl.
  • Adults should receive 50 ml of D50W by bolus intravenous infusion.
  • Children should receive 2 to 4 ml/kg D25W (1-2 ml/kg D10W for neonates).
  • The dextrose dose should be repeated until the blood glucose is more than 100 mg/dl.
  • The patient's blood glucose level should be followed hourly to guide further therapy.
  • An infusion of 5%, 10%, or 20% dextrose should be initiated as needed if recurrent hypoglycemia develops.
  • Dextrose infusions of D20W or more require a central venous line to reduce venous injury.
• Insulin and dextrose infusion is indicated for severe biguanide-induced lactic acidosis; retrospective data suggest that the survival rate is better with insulin and dextrose infusion than with bicarbonate or hemodialysis; however, no well-controlled studies have been published.
  • Dose for adults. Insulin should be administered 2 to 5 U/h, dextrose 1 to 3 g/h intravenously; titration is indicated to maintain euglycemia and improve acidosis.
  • Adverse effects include hypoglycemia and hyperglycemia.
• Sodium bicarbonate may be indicated for severe metabolic acidosis (pH less than 7.1).
  • Dose. 1 to 2 mEq/kg intravenous push is a reasonable starting dose in adults or children, repeated as needed to correct pH; arterial blood gases and electrolytes should be monitored frequently.
  • Adverse effects include hypernatremia, volume overload, hyperosmolality, and alkalosis.
• Hypotension should be treated with isotonic fluid infusion (10-20 mg/kg), Trendelenburg positioning, and a vasopressor if needed (preferably dopamine). Norepinephrine may be added for refractory hypotension.

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
  • Out of Hospital
  • In Hospital
• ANTIDOTES
• ADJUNCTIVE TREATMENT

PATIENT MONITORING

Any patient with acidosis, hypotension, altered mental status, hypoglycemia, or dysrhythmias should be monitored in an intensive care setting.

EXPECTED COURSE AND PROGNOSIS

• Hypoglycemia or mild acidosis usually resolves over 1 to 2 days.
• Sequelae of severe prolonged acidosis or hypoglycemia may develop.
• Severe acidosis is often associated with underlying illness (myocardial infarction, sepsis, renal failure), and mortality has approached 50% in some series.

DISCHARGE CRITERIA/INSTRUCTIONS

• From the emergency department. Discharge is recommended for asymptomatic patients who do not develop hypoglycemia, acidosis, hypotension, dysrhythmias, mental status changes during 6 hours of observation, decontamination, and psychiatric evaluation if needed.
• From the hospital. Patients may be discharged after resolution of hypoglycemia and metabolic acidosis, dysrhythmia, and hypotension, and after stabilization of any precipitating factors (e.g., sepsis, myocardial infarction, and renal failure).

Section Outline:

• PATIENT MONITORING
• EXPECTED COURSE AND PROGNOSIS
• DISCHARGE CRITERIA/INSTRUCTIONS

Acidosis may develop without a change in the dose in patients with underlying disease states.

Poisoning by hormones and synthetic substitutes: insulins and antidiabetic agents.

See Also: SECTION II, Hypotension chapter; SECTION III, Dextrose chapter.

RECOMMENDED READING

Luft D, Schmulling RM, Eggstein M. Lactic acidosis in biguanide-treated diabetics. Diabetologia 1978;14:75-87.

Misbin RI. Phenformin-associated lactic acidosis: pathogenesis and treatment. Ann Intern Med 1977;87:591-595.

Wilholm PE, Myrhed M. Metformin-associated lactic acidosis in Sweden 1977-1991. Eur J Clin Pharmacol 1993;44:589-591.

Author: Katherine M. Hurlbut

Reviewer: Richard C. Dart