Metabolic acidosis

• Calculation of the anion gap is the first step in the evaluation of metabolic acidosis.

  • Maintenance of electrical neutrality requires that the total concentration of cations approximate that of anions.

  • Anion gap: the difference between the concentration of measured cations and measured anions

  • High anion gap: increased concentration of organic acids such as lactate, ketones (e.g., beta-hydroxybutyrate, acetoacetate), oxalic acid, formic acid, or glycolic acid, with no compensatory increase in Cl-.

  • Normal anion gap: primary loss of HCO3- compensated with ↑ Cl-

• Depending on the results, further evaluation and calculations may be needed

Review clinical features and initial studies and follow a stepwise approach to identify the underlying cause of high anion gap metabolic acidosis.

1. Exclude accumulation of endogenous organic acids.

   • Exclude ketoacidosis : Consider measuring ketone levels in urine or serum (e.g., beta-hydroxybutyrate).

   • Exclude lactic acidosis: Measure or review lactate levels.

   • Exclude uremia: Measure or review BUN and creatinine levels.

2. Consider accumulation of exogenous organic acids (ingestion) as the cause: e.g., if the cause remains unclear, or initially if the patient is comatose

   • Consider obtaining serum or urine toxicology screen.

   • Calculate serum osmolal gap: If elevated (≥ 10 mOsm/kg), consider propylene glycol, ethylene glycol, diethylene glycol, methanol, and isopropanol as potential causes.

3. Calculate the delta gap: to exclude concomitant acid-base disturbances

Concomitant acid-base disturbances

Calculation of the delta gap can help determine if another acid-base disturbance is present in addition to a high anion gap metabolic acidosis. Cut-off values may vary depending on the source.

• Delta gap < 1 : Hyperchloremic or normal anion gap metabolic acidosis is present in addition to high anion gap metabolic acidosis.

• Delta gap 1–2 : Only high anion gap metabolic acidosis is present.

• Delta gap > 2 : A metabolic alkalosis is present in addition to high anion gap metabolic acidosis

Review clinical features and initial studies and consider further diagnostic workup to determine the underlying cause of normal anion gap metabolic acidosis.

• Calculate the urine anion gap

  • Negative urine anion gap: Acidosis is likely due to loss of bicarbonate.

  • Positive urine anion gap: Acidosis is likely due to decreased renal acid excretion.

• Consider calculating the urine osmolal gap

  • Preferred over urine anion gap if the urine pH is > 6.5 or urine Na+ is < 20 mEq/L

  • ↓ Urine osmolal gap (< 80–100 mOsm/kg) suggests impairment in the excretion of urinary ammonium.

• Etiology of low anion gap

  • Hypoalbuminemia → ↓ unmeasured anions → ↓ anion gap

  • Paraproteinemia (e.g., in multiple myeloma), severe hypercalcemia, severe hypermagnesemia, and/or lithium toxicity → ↑ unmeasured cations → ↓ anion gap

• Etiology of high anion gap

  • Severe hyperphosphatemia → ↑ unmeasured anions → ↑ anion gap

  • Severe hypocalcemia and/or hypomagnesemia → ↓ unmeasured cations → ↑ anion gap