What is the step‑by‑step evaluation and management of an elevated anion‑gap metabolic acidosis?

Evaluation and Management of Elevated Anion-Gap Metabolic Acidosis

When you encounter an elevated anion gap (>12 mEq/L), immediately obtain venous or arterial blood gas, calculate the anion gap, identify the source using the GOLD MARK mnemonic, and initiate aggressive fluid resuscitation with isotonic saline while treating the underlying cause—never give bicarbonate unless pH falls below 6.9–7.0. 1

Step 1: Confirm the Diagnosis

• Calculate the anion gap using the formula: Na⁺ − (HCO₃⁻ + Cl⁻); normal range is 10–12 mEq/L, and values >12 mEq/L indicate high-anion-gap metabolic acidosis. 1, 2
• Obtain blood gas analysis (arterial or venous) to measure pH and PaCO₂; venous pH is acceptable and typically ≈0.03 units lower than arterial pH. 1
• Assess expected bicarbonate decline: for each 1 mEq/L increase in anion gap above 12, bicarbonate should fall by ≈1 mEq/L in a pure high-anion-gap acidosis. 1
• Perform delta-gap analysis (Δ anion gap : Δ HCO₃⁻) to detect mixed disorders: a ratio <1:1 suggests combined high and normal anion-gap acidosis, while >2:1 indicates concurrent metabolic alkalosis. 3

Step 2: Identify the Underlying Cause

Use the GOLD MARK mnemonic systematically: 2

Diabetic Ketoacidosis (DKA)

• Measure serum and urine ketones, especially β-hydroxybutyrate; DKA diagnostic thresholds are glucose >250 mg/dL (or lower with SGLT2-inhibitors), pH <7.3, bicarbonate <18 mEq/L, positive ketones, anion gap >10 mEq/L. 1
• Remain vigilant for euglycemic DKA in patients on SGLT2-inhibitors; glucose may be <200 mg/dL despite significant ketoacidosis. 1

Lactic Acidosis

• Obtain serum lactate; elevated levels indicate tissue hypoperfusion, sepsis, or drug-induced lactate production. 1
• Use standardized collection: prechilled fluoride-oxalate tubes, immediate transport on ice, processing within 4 hours, no tourniquet or fist-clenching. 2
• Interpret lactate: 2–5 mmol/L is elevated, >5 mmol/L is abnormal, >10 mmol/L indicates life-threatening situation. 2

Uremic Acidosis

• Assess renal function (BUN, creatinine, estimated GFR); chronic kidney disease with GFR <30 mL/min can generate high-anion-gap acidosis. 1

Toxic Ingestion

• Calculate osmolar gap (>10) and measure serum osmolality if history suggests toxic alcohol ingestion. 1, 4
• For anion gap >27 mmol/L with suspected ethylene glycol exposure, immediately initiate hemodialysis (strong recommendation); mortality in patients with anion gap >28 mmol/L is significantly higher (20.4%). 2
• For anion gap 23–27 mmol/L with suspected ethylene glycol exposure, consider hemodialysis (weak recommendation). 2
• Administer fomepizole to block metabolism of toxic alcohols to toxic metabolites. 2
• Check urinalysis for calcium oxalate crystals in suspected ethylene glycol poisoning. 2

Other Causes

• Consider salicylate levels, alcoholic ketoacidosis, starvation ketosis, and rare causes like benzoic acid toxicity or NRTI-associated lactic acidosis. 2, 5

Step 3: Initial Fluid Resuscitation

• Give isotonic saline 0.9% NaCl at 15–20 mL/kg/h during the first hour to restore intravascular volume and renal perfusion. 1
• After the initial bolus, switch to balanced crystalloids (e.g., Lactated Ringer's or Plasma-Lyte) to avoid iatrogenic hyperchloremic acidosis. 1
• Once urine output is adequate, add potassium chloride 20–30 mEq/L to the IV fluids if serum potassium >3.3 mEq/L. 1

Step 4: Treat the Underlying Cause

For Diabetic Ketoacidosis

• Initiate continuous IV regular insulin at 0.1 U/kg/h after confirming serum potassium >3.3 mEq/L. 1
• Bicarbonate therapy is NOT indicated unless pH <6.9–7.0; the concurrent metabolic alkalosis makes bicarbonate even less appropriate. 1
• When glucose falls to ≈250 mg/dL, reduce insulin infusion rate and add dextrose to the IV fluids. 1
• DKA resolution criteria: glucose <200 mg/dL, bicarbonate ≥18 mEq/L, and pH ≥7.3. 1

For Lactic Acidosis

• Prioritize restoration of tissue perfusion with fluids and, if needed, vasopressors; sodium bicarbonate is NOT recommended for sepsis-related lactic acidosis. 1, 2

For Uremic Acidosis

• Adequate volume resuscitation often improves prerenal AKI; persistent creatinine elevation after hydration warrants nephrology consultation. 1

For Toxic Ingestion

• Immediate hemodialysis for anion gap >27 mmol/L with suspected ethylene glycol poisoning; high-efficiency hemodialysis typically corrects acidemia within four hours. 2
• Administer fomepizole and consider thiamine/riboflavin supplementation. 2

Step 5: Ongoing Monitoring

• Check venous pH and anion gap every 2–4 hours until the anion gap normalizes to ≤12 mEq/L. 1
• Measure serum electrolytes (Na⁺, K⁺, Cl⁻, HCO₃⁻) every 2–4 hours during acute management. 1
• In DKA, monitor blood glucose hourly; when glucose falls to ≈250 mg/dL, reduce insulin infusion rate and add dextrose. 1
• Serum potassium should be re-checked every 2–4 hours, as insulin-mediated intracellular shift can precipitate life-threatening hypokalemia. 1

Critical Pitfalls to Avoid

• Do NOT attribute the entire clinical picture to vomiting when an elevated anion gap is present; a mixed disorder mandates urgent investigation. 1
• Avoid bicarbonate administration for high-anion-gap acidosis when metabolic alkalosis coexists; treat the underlying cause instead. 1
• Discontinue large-volume normal saline after the initial resuscitation phase to prevent hyperchloremic acidosis and further renal impairment. 1
• Do not rely solely on anion gap without clinical context; it has poor predictive value if used indiscriminately and may overestimate (with AKI or ketoacidosis) or underestimate (with hypoalbuminemia) severity. 2
• Be aware that certain medications and conditions can falsely alter the anion gap (e.g., lithium, barium, hyperphosphatemia) and that elevated glycolate can falsely elevate plasma lactate on some analyzers. 2