What are the causes of high anion gap (anion gap, a measure of the difference between major cations and anions in the blood) metabolic acidosis (a condition characterized by an excess of acid in the blood)?

From the Guidelines

High anion gap metabolic acidosis should be treated by identifying and addressing the underlying cause, with initial management involving stabilization with intravenous fluids and specific treatments based on the cause, such as insulin for diabetic ketoacidosis or fomepizole for methanol or ethylene glycol poisoning, as recommended by the most recent guidelines 1.

Causes and Diagnosis

High anion gap metabolic acidosis occurs when there is an excess of acid in the bloodstream, characterized by a low blood pH, low bicarbonate levels, and an elevated anion gap (typically >12 mEq/L) 1. The underlying causes can include diabetic ketoacidosis, lactic acidosis, kidney failure, or toxin ingestion (such as methanol, ethylene glycol, or salicylates). Diagnosis involves measuring blood lactate, serum salicylate, and blood methanol levels, as well as assessing for clinical signs of toxin exposure, such as the presence of calcium oxalate and hippurate crystals in the urine for ethylene glycol poisoning.

Treatment

Initial management involves stabilizing the patient with intravenous fluids, typically normal saline at 10-20 mL/kg in the first hour, followed by maintenance rates based on clinical status. For diabetic ketoacidosis, insulin therapy is essential, starting with an IV bolus of regular insulin at 0.1 units/kg followed by a continuous infusion at 0.1 units/kg/hour until the anion gap normalizes. In severe acidosis (pH <7.1) with hemodynamic compromise, sodium bicarbonate may be administered at 1-2 mEq/kg IV over 1-2 hours, though this remains controversial. For toxin-related acidosis, specific antidotes are required: fomepizole (15 mg/kg loading dose) for methanol or ethylene glycol poisoning, or hemodialysis for severe cases of toxin ingestion or renal failure, with recommendations for extracorporeal treatment (ECTR) based on ethylene glycol concentration, osmol gap, and clinical indications 1.

Key Recommendations

• For ethylene glycol poisoning, ECTR is recommended if the EG concentration is > 50 mmol/L (> 310 mg/dL), or if the osmol gap is > 50, with consideration of individualized decisions based on clinical context and availability of antidotes 1.
• Continuous monitoring of electrolytes, glucose, and acid-base status is crucial during treatment.
• The acidosis typically resolves as the underlying condition improves, with the body's natural buffering systems gradually restoring normal pH.

Clinical Considerations

The decision to initiate ECTR should be based on the severity of the poisoning, the availability of antidotes, and the clinical status of the patient, with consideration of the potential risks and benefits of treatment, as well as the cost-effectiveness of ECTR in the specific scenario 1.

From the FDA Drug Label

Sodium Bicarbonate Injection, USP is indicated in the treatment of metabolic acidosis which may occur in severe renal disease, uncontrolled diabetes, circulatory insufficiency due to shock or severe dehydration, extracorporeal circulation of blood, cardiac arrest and severe primary lactic acidosis

• High anion gap metabolic acidosis is not explicitly mentioned in the label, but metabolic acidosis is indicated as a treatment option.
• The label does mention severe primary lactic acidosis, which is a type of high anion gap metabolic acidosis.
• Sodium bicarbonate is indicated for treatment of metabolic acidosis, but the label does not provide specific guidance on high anion gap metabolic acidosis. 2

From the Research

Definition and Causes of High Anion Gap Metabolic Acidosis

• High anion gap metabolic acidosis (HAGMA) is a condition characterized by an increased anion gap, which is a mathematical construct that compares the blood sodium concentration with the sum of the chloride and bicarbonate concentrations 3.
• The causes of HAGMA include lactic acidosis, ketoacidosis, renal failure, and intoxication with ethylene glycol, methanol, salicylate, and less commonly with pyroglutamic acid (5-oxoproline), propylene glycol, or djenkol bean (gjenkolism) 4.
• Other causes of HAGMA include sepsis, hyperglycemia, prior gastric bypass surgery, decreased renal perfusion, and paracetamol intake 5.

Diagnosis and Calculation of High Anion Gap Metabolic Acidosis

• The anion gap is calculated by comparing the blood sodium concentration with the sum of the chloride and bicarbonate concentrations 3.
• The anion gap can be used to divide metabolic acidoses into two categories: high anion gap metabolic acidosis and hyperchloremic metabolic acidosis 3.
• The calculation of the anion gap should be corrected for hypoalbuminemia and severe hyperglycemia 3.
• Plasma osmolality and osmolal gap calculations can be used to guide appropriate clinical decision making 3.

Treatment and Management of High Anion Gap Metabolic Acidosis

• The treatment of HAGMA should be aimed at correcting the underlying cause of the condition, such as lactic acidosis, ketoacidosis, or renal failure 6.
• The administration of alkalizing agents, such as sodium bicarbonate, should be carefully evaluated, taking into account the risk of side effects and the potential need for renal replacement therapy 6.
• In cases of severe acidosis, the therapeutic approach should be first aimed at early correction of concurrent clinical problems, such as fluids and hemodynamic optimization in case of shock, mechanical ventilation in case of concomitant respiratory failure, and hemodialysis for acute intoxications 6.
• The recognition of 5-oxoproline acidosis, a rare etiology of HAGMA, is crucial, as it indicates underlying metabolic derangements and necessitates prompt therapeutic intervention, such as the discontinuation of acetaminophen and the initiation of N-acetylcysteine therapy 7.