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Acid-base balance: Strong ion difference

The “Strong Ion Difference” (SID) is defined as the difference between the completely dissociated cations (e.g. Na+, K+, Ca2+, and Mg2+) and anions (Cl, lactate) in plasma. As not all strong ions can be measured, the apparent SID (SIDa) is defined as the difference between the sum of the measured strong cations and the sum of the net charge of the measured major strong anions. This usually takes the form of one of two formulas:

  1. SIDa = [Na+] + [K+] + [Ca2+] + [Mg2+] – [Cl] – [lactate]

Or, simplified:

  1. SIDa = [Na+] + [K+] – [Cl]

Under normal physiologic conditions, the SIDa is approximately 40 mEq/L. Derangements that increase the strong ion difference increase the pH (i.e. increased SID = alkalosis), whereas derangements that decrease the strong ion difference decrease the pH (i.e. decreased SID = acidosis). Some causes of increased SIDa include chloride loss (e.g. from gastric losses due to vomiting), or increased sodium (e.g. dehydration, contraction alkalosis). Some causes of decreased SIDa include lactic acidosis, unmeasured anions such as ketoacids, and aggressive administration of normal saline (hyperchloremic acidosis).

Another important calculation when considering strong ion difference in acid-base balance is the “effective” SID, which includes the bicarbonate concentration, the anion equivalency of albumin, and the anionic equivalency of inorganic phosphate. The “SIDe” can be used (along with the SIDa), to determine the strong ion gap (SIG), a surrogate version of the anion gap which also accounts for disturbances in albumin and phosphate, and thus may be more accurate than the standard anion gap in certain clinical settings (e.g. hypoalbuminemia).

SIDe = [HCO3] + [Alb] + [Pi]

Where [Alb] (the anion equivalency of albumin) is estimated by the formula:

[Alb] = [Alb] x [(0.123 x pH) – 0.631]

And [Pi] (the anion equivalency of phosphate) is estimated by the formula:

[Pi] = [Pi] x [(0.309 x pH) – 0.469]

As cations and anions must be equal in concentration, under normal conditions, the SIDa = SIDe. However, if there is an accumulation of unmeasured anions (due to intake of exogenous acids or endogenous acids), SIDa will not equal SIDe, and the difference between the two is called the strong ion gap (SIG):

SIG = SIDa – SIDe.

As mentioned above, under normal conditions, SIG should be 0. A positive value suggests an organic acidosis. (If lactate is not included in the calculation of SIDa, then a lactic acidosis can increase SIG as well.)

All of these calculations are part of the Stewart approach to acid-base disturbances, as opposed to the more traditional approach popularized by Relman and Schwartz in the 1960s. The Stewart approach minimizes bicarbonate’s effect on pH, instead supporting that the strong ion difference (along with the arterial carbon dioxide tension) play a much larger role. Some evidence suggests that the Stewart method may provide more accurate analysis of blood gasses than the traditional method; however, this benefit largely vanishes when the effects of albumin are considered in the traditional calculation of anion gap.


  1. Rastegar, A. Clinical Utility of Stewart’s Method in Diagnosis and Management of Acid-Base Disorders. CJASN. July 2009, 4 (7) 1267-1274 PubMed Link
  2. Kurtz I, Kraut J, Ornekian V, Nguyen MK: Acid-base analysis: A critique of the Stewart and bicarbonate-centered approaches. Am J Physiol Renal Physiol. 294 :F1009– F1031,2008 PubMed Link

Other References

  1. Sterns, Richard H. Strong ions and the analysis of acid-base disturbances (Stewart approach). In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2020 Link