Strong Ion Difference

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

OVERVIEW

• 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 AND INDEPENDENT VARIABLES

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^–
• CO₃^2-
• HA (weak acid)
• A^– (weak anions)

Independent variables:

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

PHYSICAL LAWS UNDERPINNING THE PHYSICOCHEMICAL METHOD

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 ION DIFFERENCE

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 SO₄^2-

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

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

pCO₂

• 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

CLASSIFICATION OF ACID-BASE DISORDERS

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^–]
• A_TOT abnormalities (non-volatile weak acids)
  • excess or deficit of inorganic phosphate
  • excess or deficit of albumin

PROS AND CONS OF THE PHYSICOCHEMICAL METHOD

Advantages

• 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

Criticisms

• 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

References and links

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

• Acid Base Physiology by Kerry Brandis
• EMCrit — Acid Base in the Critically Ill – Part I and Acid Base in the Critically Ill – Part II (2016)
• EMCrit — Acid Base Ep. 7 – Bicarb Updates, Quantitative Approach, and Prof. David Story (2018)
• How to interpret acid-base by Peter Stewart
• The Physicochemical approach to Acid-Base
• Acid Base Tutorial — Stewart’s Strong Ion Difference
• PulmCrit — The Great Lactate Debate Part 1: should we be counting protons or strong ions? by John Emille Kenny (2018)
• PulmCrit — The Great Lactate Debate Part 2: can we ‘myth-bust’ the strong ion approach? by John Emille Kenny (2018)
• PulmCrit — The Acidity of Normal Saline and the Stewart Approach by John Emille Kenny (2016)

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