Question 3.1

A 24-year-old female with a history of depression presents with seizures and decreased consciousness. 

The following are her arterial blood gas analysis, taken on FiO2 0.3:.


Patient Value

Normal Adult Range

Barometric pressure

760 mmHg (100 kPa)



7.35 – 7.45


40 mmHg (5.3 kPa)

35 – 45


110 mmHg (14.6 kPa)


24 mmol/L

22 – 27

Base Excess

-0.4 mmol/L

-2 – +2


136 mmol/L

135 – 145


4 mmol/L

3.5 – 4.5


118 mmol/L*

110 – 110


4.2 mmol/L

3.0 – 7.8


0.8 mmol/L

0.5 – 2.2

a) What is the likely cause of her presentation? 

b) Give your reasoning.

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College Answer

a) Lithium toxicity. 

b) Negative anion gap and history of depression.


Let us dissect these results systematically.

  1. The A-a gradient is slightly raised:
    PAO2 = (0.3 × 713) - (40 × 1.25) = 163.9
    Thus, A-a = ( 163.9 - 110) = 53.9mmHg.
  2. There is no acidaemia
  3. The PaCO2 is normal
  4. The SBE is -0.4, suggesting a normal acid-base balance
  5. The respiratory compensation is irrelevant (bicarbonate is ideal)
  6. The anion gap is negative:
    (136) - (118 + 24) = -6, or -2 when calculated with potassium

There are few causes of negative anion gap.

The usual reason for such a result is an abundance of a cation which does not get measured in the normal biochemistry panels. Of these cations, lithium is the most commonly encountered in the clinical setting, followed by Polymyxin B. Halides such as bromide and iodide can cause a negative anion gap in spite of actually being anions themselves; however, by being chemically similar to chloride these ions tend to confuse the chloride-measuring electrode, "posing" as chloride in the laboratory and generating a spuriously elevated chloride value. Magnesium and calcium elevation can also result in a negative anion gap, but this is because they are not routinely included in the calculation of the gap.

Artifactual causes of a low or negative anion gap may include hyperlipidaemia and hypoalbuminaemia (although the "normal" anion gap value will merely trend towards zero with decreasing albumin levels- even without any albumin, the expected "normal" AG is 2.)

In short, the causes of a negative anion gap are as follows:

  • Increase in unmeasured cations
    • Lithium
    • Polymyxin B
    • Magnesium
    • Calcium
  • Interference with the measurement of chloride
    • iodide
    • bromide



Vasuvattakul, S. O. M. K. I. A. T., et al. "A negative anion gap as a clue to diagnose bromide intoxication." Nephron 69.3 (1995): 311-313.

Fischman, Ronald A., Gordon F. Fairclough, and Jhoong S. Cheigh. "Iodide and negative anion gap." The New England journal of medicine 298.18 (1978): 1035. - This one is not even available as an abstract! Atrocious, NEJM. Somebody want to send me a copy?..

O'Connor, Daniel T., and Richard A. Stone. "Hyperchloremia and negative anion gap associated with polymyxin B administration." Archives of internal medicine138.3 (1978): 478-480.

GRABER, MARK L., et al. "Spurious hyperchloremia and decreased anion gap in hyperlipidemia." Annals of internal medicine 98.5_Part_1 (1983): 607-609.

Kraut, Jeffrey A., and Nicolaos E. Madias. "Serum anion gap: its uses and limitations in clinical medicine." Clinical Journal of the American Society of Nephrology 2.1 (2007): 162-174.

Silverstein, Freya J., et al. "The effects of administration of lithium salts and magnesium sulfate on the serum anion gap." American Journal of Kidney Diseases 13.5 (1989): 377-381.