What is the approach to diagnosing and managing an elevated anion gap?

Approach to Elevated Anion Gap

Immediate Calculation and Confirmation

Calculate the anion gap using Na+ + K+ - Cl- - HCO3- and immediately obtain arterial blood gases to confirm metabolic acidosis, as this combination drives all subsequent management decisions. 1

Critical Initial Assessment

Life-Threatening Scenarios Requiring Immediate Action

• If anion gap >27 mmol/L with suspected ethylene glycol or methanol poisoning, immediately initiate hemodialysis (strong recommendation) while simultaneously starting fomepizole. 1
• For anion gaps 23-27 mmol/L with suspected toxic alcohol exposure, consider hemodialysis (weak recommendation). 1
• Begin fomepizole treatment immediately upon suspicion of ethylene glycol or methanol ingestion based on clinical presentation (anion gap metabolic acidosis, increased osmolar gap, visual disturbances, or oxalate crystals in urine) or documented serum concentration >20 mg/dL. 2

Essential Laboratory Workup

Obtain the following immediately to identify the underlying cause 1:

• Plasma glucose and serum ketones (beta-hydroxybutyrate preferred)
• Blood urea nitrogen, creatinine, and electrolytes
• Serum osmolality and calculate osmolar gap
• Arterial blood gases
• Complete blood count
• Urinalysis with urine ketones
• Electrocardiogram
• HbA1c (distinguishes acute decompensation from chronic poor control)
• Bacterial cultures (blood, urine, throat) if infection suspected 1

Algorithmic Approach by Cause

Diabetic Ketoacidosis (Glucose typically >250 mg/dL, pH <7.3, bicarbonate <15 mEq/L)

Fluid resuscitation takes priority: 1

• Administer isotonic saline (0.9% NaCl) at 15-20 mL/kg/hour for the first hour (1-1.5 liters in average adults)
• After initial resuscitation, switch to 0.45% NaCl at 4-14 mL/kg/hour if corrected sodium is normal or elevated; continue 0.9% NaCl if corrected sodium is low
• Add 20-30 mEq/L potassium (2/3 KCl and 1/3 KPO4) to IV fluids once renal function is confirmed

Insulin therapy: 1

• Initiate insulin to suppress ketogenesis
• Monitor electrolytes frequently, particularly potassium, and replace as needed
• Insulin requirements typically decrease around 18 hours after treatment initiation

Toxic Alcohol Ingestion (Ethylene Glycol or Methanol)

Fomepizole dosing protocol: 2

• Loading dose: 15 mg/kg IV over 30 minutes
• Maintenance: 10 mg/kg every 12 hours for 4 doses
• Then 15 mg/kg every 12 hours until toxic alcohol concentration <20 mg/dL and patient is asymptomatic with normal pH
• During hemodialysis: increase frequency to every 4 hours

Hemodialysis indications: 2

• Measured ethylene glycol or methanol concentration ≥50 mg/dL
• Renal failure
• Significant or worsening metabolic acidosis despite fomepizole

Treatment discontinuation: 2

• When toxic alcohol concentrations are undetectable or <20 mg/dL AND patient is asymptomatic with normal pH

Lactic Acidosis

• Address the underlying cause (shock, sepsis, tissue hypoxia) to improve tissue perfusion and oxygen delivery. 1
• Bicarbonate administration is controversial and may worsen outcomes by generating PCO2. 3

Uremic Acidosis

• Manage underlying renal failure and consider renal replacement therapy. 1

Alcoholic Ketoacidosis and Starvation Ketosis

• Distinguished by clinical history and plasma glucose typically <250 mg/dL (often hypoglycemic in alcoholic ketoacidosis). 1
• These patients have ketoacidosis but are not diabetic ketoacidosis.

Critical Pitfalls to Avoid

• Do not rely solely on anion gap without clinical context—it has poor predictive value if used indiscriminately. 1
• The anion gap may overestimate severity with concomitant acute kidney injury or ketoacidosis, or underestimate severity with hypoalbuminemia. 1
• Certain medications (lithium, barium) and conditions (hyperphosphatemia) can falsely alter the anion gap. 1
• Elevated glycolate concentration can falsely elevate plasma lactate on some analyzers. 1
• Patients with diabetic ketoacidosis can be normothermic or hypothermic despite infection as a precipitating factor due to peripheral vasodilation. 1
• Do not administer fomepizole undiluted or by bolus injection—causes venous irritation and phlebosclerosis. 2
• Never use polycarbonate syringes or needles with fomepizole—it compromises syringe/needle integrity. 2

Special Populations

• In pregnancy, use lower thresholds for extracorporeal treatment in toxic alcohol ingestions. 1

Monitoring During Treatment

• Reassess electrolytes frequently, particularly potassium in diabetic ketoacidosis patients. 1
• Monitor arterial blood gases to track pH normalization. 1
• For toxic alcohol poisoning, monitor serum concentrations of ethylene glycol/methanol and acid-base status frequently throughout treatment. 2