Reviewed and updated by Jennifer Collins, MSN, CRNP, ACACNP-BC: March 20, 2024
 

The anion gap (AG) can be used as an indicator of the type and severity of an acid-base imbalance. Your body maintains its acid-base balance by holding on to or releasing carbon dioxide (a relative acid) through the lungs or bicarbonate (a base) through the kidneys. Cations are positively charged molecules and anions are negatively charged. The anion gap is the difference between the number of cations versus anions. An anion gap can be high, normal, or low (rare). A high anion gap indicates the presence of more anions than cations, which results in an acidosis. With most causes of metabolic acidosis, the anion gap widens as bicarbonate (an anion base) is used up in an attempt to correct an acid-base imbalance (Kraut & Madias, 2007). A patient with metabolic acidosis who has a normal anion gap has what is called a hyperchloremic acidosis. This type of acidosis is a result of a renal, GI, or exogenous loss of bicarbonate, resulting in a relative hyperchloremia.

How to Calculate Anion Gap

The normal value for the serum anion gap is approximately 3 to 10 mEq/L (averaging 6 mEq/L) but may vary according to your lab (Kraut & Madias, 2007). When calculating the anion gap, the CO₂ value from a patient’s basic metabolic panel (BMP) is often used as an equivalent value for the HCO₃^- from an arterial blood gas. This is acceptable because the total CO₂ content includes the serum bicarbonate in addition to available forms of carbon dioxide. The serum HCO₃^- accounts for about 95% of the BMP’s total CO₂.  Since a BMP is easier to obtain in most cases than an ABG, it is common to use this measurement to estimate the serum HCO₃^- level.

Causes of Anion Gap Acidosis

High anion gap acidosis may be caused by:

• ketoacidosis
• lactic acidosis
• renal failure
• toxic ingestions

Normal anion gap acidosis may be caused by:

• gastrointestinal or renal bicarbonate losses
• impaired renal excretion

Anion Gap Acidosis Signs and Symptoms

A mild acidemia is typically asymptomatic, but symptoms and signs indicative of a high anion gap acidosis may include:

• nausea
• vomiting
• malaise
• hyperpnea (long, deep breaths at a normal rate)
• fatigue
• cardiac dysfunction with hypotension, shock, ventricular arrhythmias 

Diagnosing the Cause of High Anion Gap Acidosis

The cause of high anion gap acidosis may be obvious as in diabetic ketoacidosis, hypovolemic shock, or missed hemodialysis. Other data that is helpful in determining the cause include arterial blood gas (ABG), serum electrolytes, lactate and possible toxins. A normal anion gap with a low HCO₃^- (< 24 mEq/L) and high serum chloride indicates a non-anion gap (hyperchloremic) metabolic acidosis.
 
If a high anion gap acidosis is present, a delta ratio is calculated to help determine its cause. This ratio compares the change (or delta) in the anion gap to the change in bicarbonate levels. Winters’ formula can also be applied to determine whether respiratory compensation is present or whether there is a second acid-based disorder. This formula calculates the predicted CO₂ level based on the bicarbonate level.

• Delta ratio = Delta anion gap/Delta HCO₃^- = [AG -12] ÷ [24 - HCO₃^-]
• Winter's formula: PCO₂ = (1.5 x HCO₃^-) + 8 ± 2

High Anion Gap Acidosis Treatment

Treatment is directed at reversing the underlying cause. Hemodialysis is required for renal failure and sometimes for ethylene glycol, methanol, or salicylate poisoning. When metabolic acidosis results from loss of bicarbonate (as seen in normal anion gap acidosis), bicarbonate therapy is usually safe and effective. However, treatment with sodium bicarbonate for high anion gap acidosis is controversial and is typically used only in cases of severe metabolic acidosis when the bicarbonate is very low and the pH is below 7.1 (Emmett & Szerlip, 2023).

Anion Gap Acidosis Mnemonics

Here are some helpful ways to remember the causes of high anion gap acidosis.
The most common mnemonics are:

• KUSMALE
  • Ketoacidosis
  • Uremia
  • Salicylate poisoning
  • Methanol
  • Aldehyde
  • Lactate
  • Ethylene glycol
• MUD PILES
  • Methanol
  • Uremia
  • Diabetes
  • Paraldehyde
  • Iron/Isoniazid
  • Lactate
  • Ethylene glycol
  • Salicylate

A newer mnemonic takes into account new organic anion gap generating acids and precursors that have been recognized in recent years.  It also replaces paraldehyde which has become exceedingly rare (Mehta, Emmett, & Emmett, 2008).

• GOLD MARK
  • Glycols
  • Oxoproline
  • L-lactate
  • D-lactate
  • Methanol
  • Aspirin
  • Renal failure
  • Ketoacidosis

Many times, when an obvious cause of high anion-gap acidosis cannot be identified, having an expanded differential diagnosis can be helpful. Therefore, a modified mnemonic CUTE DIMPLES can be used (Azim et al., 2023).

• CUTE DIMPLES
  • Cyanide
  • Uremia
  • Toluene
  • Ethylene glycol
  • Diabetic ketoacidosis
  • Isoniazid
  • Methanol
  • Propylene glycol
  • Lactic acidosis
  • Ethanol
  • Salicylates

How do you apply anion gap knowledge in clinical practice?  

In the hospital setting, you may hear the phrase “the anion gap is closed.” This often refers to the patient who is admitted to the hospital with ketoacidosis from uncontrolled diabetes. Typically, IV fluids and an insulin drip are administered until the gap is closed, and then a maintenance regimen may begin. In what other instances have you heard discussion about a patient’s anion gap? Have you ever had to use the calculation?
 

Anion Gap Acidosis References

Albert, M. S., Dell, R. B., & Winters, R. W. (1967). Quantitative displacement of acid-base equilibrium in metabolic acidosis. Annals of internal medicine, 66(2), 312–322. https://doi.org/10.7326/0003-4819-66-2-312 

Azim, A., Hu, B., Gilligan, S., Sarwal, A., Hartsell, S., Pandya, V., & Raphael, K. L. (2024). How I Evaluate a High Anion Gap Metabolic Acidosis. Clinical journal of the American Society of Nephrology: CJASN, 19(4), 525–527. https://doi.org/10.2215/CJN.0000000000000381

Emmett, M. & Szerlip, H. (2023, September 8). Approach to the adult with metabolic acidosis. UptoDate. https://www.uptodate.com/contents/approach-to-the-adult-with-metabolic-acidosis

Gabow P. A. (1985). Disorders associated with an altered anion gap. Kidney international, 27(2), 472–483. https://doi.org/10.1038/ki.1985.34

Kraut, J. A., & Madias, N. E. (2007). Serum anion gap: its uses and limitations in clinical medicine. Clinical journal of the American Society of Nephrology: CJASN, 2(1), 162–174. https://doi.org/10.2215/CJN.03020906

Mehta, A. N., Emmett, J. B., & Emmett, M. (2008). GOLD MARK: an anion gap mnemonic for the 21st century. Lancet (London, England), 372(9642), 892. https://doi.org/10.1016/S0140-6736(08)61398-7

Rastegar A. (2007). Use of the DeltaAG/DeltaHCO3- ratio in the diagnosis of mixed acid-base disorders. Journal of the American Society of Nephrology: JASN, 18(9), 2429–2431. https://doi.org/10.1681/ASN.2006121408