Strong Ion Difference

Strong Ion Difference and Stewart’s physicochemical approach to acid-base chemistry


  • The quantitative approach to acid-base chemistry is also known as the physicochemical method or the Stewart approach
  • Proposed by Canadian physiologist Peter Stewart in 1981
  • It provides a mathematical explanation of the relevant variables that control H+ in body fluids and their interactions
  • The approach treats body fluids as a system that contains multiple interacting constituents and is based on the physical laws of aqueous solutions to write equations that describe how the variables interact.
  • The Stewart approach shows that pH is not simply determined by the [H+] and [HCO3] (as in the Henderson-Hasselbach approach) but involves interactions of other variables, three of which are independent variables that control acidity.


Dependent variables are thought of as internal to the system; their values depend on the values of the independent variables and reflect the behaviour of the equilibrium reactions in the system. The independent parameters control acidity ([H+]) in arterial or venous plasma.

Dependent variables:

  • H+
  • OH
  • HCO3
  • CO32-
  • HA (weak acid)
  • A (weak anions)

Independent variables:

  • pCO₂
  • ATOT (total weak non-volatile acids)
  • SID (net Strong Ion Difference)


The interactions among the variables in the system that determine pH obey the physical laws of aqueous solutions –

  • maintenance of electrical neutrality
  • dissociation equilibria for weak electrolytes (partially dissociated when dissolved in water)
  • conservation of mass

Thus the influence of the independent variables can be predicted through 6 simultaneous equations:

  1. [H+] x [OH] = K ‘w (water dissociation equilibrium)
  2. [H+] x [A-] = KA x [HA] (weak acid equilibrium)
  3. [HA] + [A-] = [ATOT] (conservation of mass for “A”)
  4. [H+] x [HCO3] = KC x pCO₂ (bicarbonate ion formation equilibrium)
  5. [H+] x [CO32-] = K3 x [HCO3] (carbonate ion formation equilibrium)
  6. [SID] + [H+] – HCO3-] – [A-] -[CO32-] – [OH] = 0 (maintenance of electrical neutrality)


Strong ions are those ion that dissociate completely at the pH of interest in a particular solution. In blood at pH 7.4:

  • strong cations are: Na+, K+, Ca2+, Mg2+
  • strong anions are: Cl- and SO42-

Strong Ion Difference (SID) is the difference between the concentrations of strong cations and strong anions.

  • SID = [strong cations] – [strong anions]
  • apparent SID = SIDa = (Na+ + K+ + Ca2+ + Mg2+) – (Cl + L-lactate + urate)
  • Abbreviated SID = (Na+) – (Cl)

In normal human plasma the SID is 42 mEq/L (which suits fans of the Hitchhiker’s Guide to the Galaxy)

  • the number of positive and negative ions in a solution must be equal (SID = 0), so there are unmeasured anions
  • increased SID (>0) leads to alkalosis (increase in unmeasured anions)
  • decreased SID (<0) acidosis
  • given that SID is about 40mEq/L, plasma is normally slightly alkaline (any departure is roughly equivalent to the standard base-excess, although because SID doesn’t allow for Hb there is often a discrepancy)

The SID can be changed by two methods:

(1) Concentration change

  • dehydration: concentrates the alkalinity and increases SID
  • overhydration: dilutes the alkaline state (dilutional acidosis) and decreases SID

(2) Strong Ion changes

  • Decreased Na+: decreased SID and acidosis
  • Increased Na+: increased SID and alkalosis
  • Increased Cl-: decreased SID and acidosis (NAGMA; occurs with normal saline as the relative increase in Cl- exceeds that of Na+)
  • increased in organic acids with pKa < 4 (lactate, formate, ketoacids): decreased SID and acidosis (HAGMA))

Strong Ion Gap (SIG)

  • SIG = SIDa – SIDe
  • SIDa = apparent SID = calculation of {strong cations] – [strong anions] shown above
  • SIDe = [A-] + [HCO3]
  • Thus unmeasured anions will increase SIDa, but not SIDe, thus increasing SIG
  • SIG is analogous to AGc (anion gap corrected for albumin) but has the advantage of less unmeasured components
  • SIG is still suspectable to unmeasured cations (e.g. Li) and anions (e.g. myeloma)
  • SIG suffers from imprecision due the acculumation of measurement errors in multiple individual components
  • normal SIG may not be zero if calculated from the mid-range of individual hospital normal ranges for each component (likely due to systematic bias in measurement methods)
  • changes in SIG
    • high: increased unmeasured anions
    • low: increased unmeasured cations
    • independent of pH, albumin, PO4, Ca, Mg


  • ATOT = total plasma concentration of inorganic phosphate, serum proteins and albumin (weak non-volatile acids)
  • ATOT = [PiTOT] + [PrTOT] + [albumin]
  • hypoproteinaemia = base excess


  • at a molecular level, it is the concentration of CO₂, not the partial pressure which governs its effect on other molecules and ions
  • However, in practice, our warm blood means that CO₂ is scarcely soluble and measured pCO₂ can be used to measure effect


Respiratory causes

  • increased or decreased PaCO2

Non-respiratory causes

  • Abnormal SID (due to excess or deficit of water)
    • Water excess: ↓ SID, ↓ [Na+]
    • Water deficit:↑ SID, ↑ [Na+]
  • Imbalance of strong ions (due to excess or deficit of strong ions)
    • Chloride excess/ deficit
      • ↓ SID, ↑ [Cl]
      • ↑ SID, ↓ [Cl]
    • Unidentified anion excess
      • ↓ SID, ↑ [XA]
  • ATOT abnormalities (non-volatile weak acids)
    • excess or deficit of inorganic phosphate
    • excess or deficit of albumin



  • acknowledgement of the importance of other factors controlling pH
  • diminishes the importance of the HCO3 ion which is just a dependent variable
  • based on physicochemical principles
  • provides elegant explanations for phenomena such as the acidosis induced by normal saline administration


  • complex!
  • SID only reflects plasma (whereas SBE reflects the whole body and the influence of Hb)
  • SID is calculated from multiple measurements, leading to accumulation of measurement error
  • lack of clinical correlation to validate the benefit
  • standard base excess accuracy has been well validated and accepted in clinical correlation
  • emerging chemistry research suggests that the Stewart approach may not be mechanistically correct in describing acid-base chemistry

Journal articles and textbooks

  • Doberer D, Funk GC, Kirchner K, Schneeweiss B. A critique of Stewart’s approach: the chemical mechanism of dilutional acidosis. Intensive Care Med. 2009;35(12):2173-80. [pubmed]
  • Gunjan Chawla, Gordon Drummond; Water, strong ions, and weak ions, Continuing Education in Anaesthesia Critical Care & Pain, 2008; 8(3):108–112, https://doi.org/10.1093/bjaceaccp/mkn017
  • Knight C, Voth GA. The curious case of the hydrated proton. Acc Chem Res. 2012;45(1):101-9. [pubmed]
  • Morgan TJ. The meaning of acid-base abnormalities in the intensive care unit: part III — effects of fluid administration. Crit Care. 2005;9(2):204-11. [pubmed] [article]
  • Morgan TJ. The Stewart approach–one clinician’s perspective. Clin Biochem Rev. 2009;30(2):41-54. [pubmed] [article]
  • Morgan TJ. What exactly is the strong ion gap, and does anybody care?. Crit Care Resusc. 2004;6(3):155-9. [pubmed] [article]
  • Sirker AA, Rhodes A, Grounds RM, Bennett ED. Acid−base physiology: the ‘traditional’ and the ‘modern’ approaches. Anaesthesia. 2002;57(4):348-356. [article]
  • Stewart PA. How to Understand Acid-Base. New York: Elsevier, 1981 (available at: http://www.acidbase.org/)
  • Stewart PA. Independent and dependent variables of acid-base control. Respir Physiol. 1978;33(1):9-26. [pubmed]
  • Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol. 1983;61(12):1444-61. [pubmed]
  • Story DA, Poustie S, Bellomo R. Quantitative physical chemistry analysis of acid-base disorders in critically ill patients. Anaesthesia. 2001;56(6):530-3. [pubmed] [article]
  • 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. 2008;294(5):F1009-31. [pubmed] [article]

FOAM and web resources


CCC 700 6

Critical Care


Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also a Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of three amazing children.

On Twitter, he is @precordialthump.

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