• Anion gap (AG) = [(Na⁺ + K⁺) – (Cl^- + HCO₃^-)]; normal 7–14 mEq/L
• In metabolic acidosis, the concept of the AG is utilized to assist with the differential diagnosis. It functions to distinguish acidosis as either an:
  • Increase in total body acids (HCO₃^- anion is titrated by H⁺); or a
  • Decrease in total body HCO₃^- (abnormal loss from the body).
  • In both scenarios, HCO₃^- is reduced; a calculation of the AG aids in determining which of these 2 mechanisms is responsible.
• The term "gap" does not imply that anions are missing, but only that they are not directly measured. By applying the concept that the serum is electrically neutral, measurable values for major cations and anions allow for unmeasured anions to be calculated.
• Unmeasured anions include phosphates (PO₄^-) and sulfates (SO₄^-) as well as lactates, ketoacids, and toxins. Their corresponding cation (H⁺) dissociates and is titrated by HCO₃^- or other buffering systems, or it increases the acid:base ratio (causing a metabolic acidosis).

• The anions of organic and inorganic acids are not easily or routinely measured. However, it is possible to measure serum Na⁺ and K⁺ (cations) and Cl^- and HCO₃^- (anions) and "calculate" the AG: [(Na⁺ + K⁺) – (Cl^- + HCO₃^-)]. Or, AG = measured cations – measured anions; potassium may be excluded.
• Normally, the serum AG is determined by negative charges on serum proteins, particularly albumin.
• Metabolism results in the production of volatile, organic, and inorganic acids.
  • Volatile acids: Carbon dioxide (CO₂) is a byproduct of sugar, fat, and amino acid metabolism. Basal CO₂ production is approximately 12,000 mmols/d and is exhaled/excreted by the lungs, as well as buffered by the bicarbonate system.
  • Inorganic acids: Sulfate and phosphates are byproducts of amino acid metabolism; basal production is approximately 50–100 mEq/d. Excretion occurs renally.
  • Organic acids: Lactate and ketones. Lactate is produced via anaerobic metabolism. Ketones result from fatty acid breakdown when insulin is not present via a beta-oxidizing process. Both are excreted by the liver and kidneys.
• HCO₃^- is ubiquitous in the body and exists in equilibrium between the intravascular and extracellular compartments. It is present in the stool and carefully regulated by the renal tubules.

• High AG metabolic acidosis:
  • Results from an increase in an acid molecule's corresponding anion; thus represents increased total body acid.
  • Acids are composed of a cation (H⁺) and an anion (A^-).
  • In solution, the acid compound (HA) dissociates into a H⁺ and its corresponding anion (HA H⁺ + A^-).
  • The H⁺ is buffered by one of the body's buffering systems, including bicarbonate (H⁺ + HCO₃^- H₂CO₃ H₂O + CO₂) in order to "cushion" or decrease adverse effects of the acid load.
  • However, this "titration" results in a reduction in HCO₃^- values; when the acid load exceeds the buffering capacity, acidosis manifests.
  • Electroneutrality is maintained during this titration process (H⁺ cation plus a HCO₃^- anion). There is no increase or decrease in positive- or negative-charged molecules.
  • Increased acid production can result from anaerobic metabolism (lactic acidosis), ketone production (diabetic ketoacidosis), toxins (methylene, ethanol, salicylates), and hyperosmolar hyperglycemia.
  • Reduced acid excretion can result from impaired renal function (uremia).
• Normal AG metabolic acidosis:
  • Loss of HCO₃^- (or bicarbonate precursors) from the body results in an increase in the acid:base ratio.
  • There is no increase in total body acid, and hence no increase in anions.
  • In order to maintain electroneutrality, a loss in HCO₃^- is balanced by a "gain" in Cl^-; this results in a hyperchloremic state.
  • HCO₃^- can be lost by diarrhea, renal tubular acidosis, carbonic anhydrase inhibitors, ureteral diversion, and intestinal losses; additionally, hyperchloremic crystalloid solutions (normal saline, [Cl^-] 154 mEq/L) serve to dilute the bicarbonate concentration as well as increase the chloride concentration (resulting in renal excretion of bicarbonate).
• Low AG is a less commonly utilized term that describes low albumin states. Albumin is a negatively charged protein and its loss from the serum results in the retention of other negatively charged ions such as chloride and bicarbonate. Because they are utilized in the calculations, there is a decrease in the gap. AG falls by 2.3–2.5 mEq/L for every 1 g/dL reduction in serum albumin concentration.

• Base excess is more frequently utilized than the AG in the perioperative period. This is because metabolic acidosis is often the result of lactic acidosis secondary to anaerobic metabolism.
  • Lactic acidosis indicates that there is tissue hypoxia either from hypovolemia, hypoperfusion, hypovolemia, or hypotension.
  • Perioperatively, this can result from surgical blood loss; evaporative/insensible losses; episodes of hypoxia at induction, intraoperatively, or at emergence; anemia; or hypotension.
  • Base excess is useful in determining the extent of the increased acid load, as opposed to aiding in the differential diagnosis.
• The AG can be implemented perioperatively to determine if the metabolic acidosis is secondary to a hyperchloremic non-AG acidosis. This can manifest from as little as 2 L of normal saline solution. Na⁺ 154 mEq/L is balanced by Cl^- 154 mEq/L. The chloride concentration is not physiologic and initially results in the dilution of HCO₃^-. Ultimately, however, HCO₃^- anion is eliminated by the kidneys in order to maintain electroneutrality (increased chloride anion load). Clinical consequences of the metabolic acidosis are unclear. However, attempts at correcting the abnormality may actually cause more issues (iatrogenic causes such as administering additional hyperchloremic crystalloids).
• In the ICU and at the bedside, the AG can provide a clinically useful tool to identify one of the many causes of metabolic acidosis in the critically ill, especially when hypoalbuminemia and lactate are considered. Additionally, it can be utilized to monitor, assess, and guide therapy during sepsis.
• Ketoacidosis: The measured AG disturbance is often less than expected from the fall in serum bicarbonate. This results from the renal loss of ketoacid anions (beta hydroxyl butyrate) that accompany sodium and potassium salt excretion.
• Multiple myeloma results in a pathologic increase in cations that are not measured; IgG paraproteinemia causes a reduced AG.
• Postcardiac surgery metabolic acidosis is typically the result of an increase in unmeasured acids, and less commonly from lactic acidosis.
  • Cardiopulmonary bypass (CPB) circuits are usually primed with 1.4–2 L of hyperchloremic crystalloid.
  • ABG taken immediately after "going on pump" demonstrates a non-AG metabolic acidosis.
  • More frequent in children due to the ratio of CPB priming fluid to smaller blood volumes (even with low-volume priming)
  • This acidosis is transient and lasts <24 hours.

• AG = [(Na⁺ + K⁺) – (Cl^- + HCO3^-)]
• AG corrected (for albumin) = calculated AG + 2.5 (normal albumin g/dL – observed albumin g/dL)

• Metabolic Acidosis
• Diabetic Ketoacidosis
• Carbon Dioxide Transport
• Lactic Acidosis

J. andrew Dziewit , MD

Nina Singh-Radcliff , MD