Water, strong ions, and weak ions
Gunjan Chawla MBBS DA
Key points
The law of electrical
neutrality states that, in any
aqueous solution in
equilibrium, the sum of the
positive charges always
equals the sum of the
negative charges.
An acid or base is defined
as strong if it is fully
dissociated at the pH of
interest.
Strong ion difference (SID)
is the amount by which the
strong positive ions
(cations) are in excess of
the strong negative ions
(anions).
Weak acids and bases are
only partially dissociated in
the range of body pH.
Acid – base balance can be
characterized quantitatively
in terms of three
independent variables: PCO2,
[SID], and total weak acid.
The dependent variables:
[HCO2 2
3 ], [HA], [A ],
[CO3 ], [OH ] and [Hþ]
22 2 this had limitations. For pH to be determined
or pH can be calculated
from these.
Gunjan Chawla MBBS DA
Senior House Officer
University Department of Anaesthetics
Critical Care and Pain Medicine
Royal Infirmary of Edinburgh
Edinburgh EH16 4SA
UK
Gordon Drummond FRCA
Senior Lecturer
University Department of Anaesthetics
Critical Care and Pain Medicine
Royal Infirmary of Edinburgh
Edinburgh EH16 4SA
UK
Tel: þ44 131 242 3134
Fax: þ44 131 242 3138
E-mail: g.b.drummond@ed.ac.uk
(for correspondence)
108
Gordon Drummond FRCA
The term ‘acid– base balance’ was coined by
Henderson in the early 20th century. In his
work, CO2 was the centre of attention as it was
for a long time the only measurable quantity
relevant to acid –base status. Henderson applied
the law of mass action to the carbonic acid
equilibrium and we got the Henderson
equation:
 
½CO2 
½Hþ  ¼ K0
½HCO3
The role of respiratory control of PCO2 was
recognized and Hasselbach introduced this into
the equation and gave it a logarithmic form, the
Henderson–Hasselbach equation:
 
½HCO3
pH ¼ pK þ log
SCO2  PCO2
The constant SCO2 (solubility factor ¼
0.03 mm litre21 mm Hg21 or 0.23 mm litre21
kPa21) allows conversion of PCO2 into [CO2].
Acid –base disturbances could now be
classified as respiratory or non-respiratory but
by CO2 and bicarbonate, these two had to be
independent of each other, which is not poss-
ible. In addition, the equation did not take
into account non-volatile weak acids present in
the body. To overcome these limitations,
Siggard-Anderson proposed PCO2-independent
indicators of acid –base disturbances. These
include standard bicarbonate, buffer base and
base excess/deficit. However, these approaches
do not take into account PCO2 and do not
differentiate between different causes of non-
respiratory acid –base disturbances.
In the 1980s, Stewart proposed a physico-
chemical approach to acid– base physiology.
The complex calculations involved in this
approach were not possible in the precomputer
era but are easily done today. He wrote of this
approach having ‘revolutionized our ability to
understand, predict and control what happens to
hydrogen ions in living systems’.
doi:10.1093/bjaceaccp/mkn017
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& The Board of Management and Trustees of the British Journal of Anaesthesia [2008].
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Definitions
‘Acid’ and ‘alkali’ are derived from Latin
(acidus ¼ sour) and Arabic (al qaliy ¼ ashes of
plant). Acids possess a sour taste in solution
and alkalis reverse their action in solution.
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Using the simplest terminology, acidosis
denotes an excess addition of Hþ and alkalosis
an excess removal of Hþ.
The Arrhenius theory of acids and bases
was based on their dissociation into ions. Thus,
acids are defined as producers of hydrogen ions
and all bases produce hydroxyl ions. Lowry
and Bronsted gave this theory a more general
basis. They defined an acid as a molecule or
ion that can lose or donate a proton (a hydro-
gen ion is a single free proton released from a
hydrogen atom) and a base as a molecule or
ion that can accept a proton. Lewis further
extended this concept. He defined an acid as
any substance that accepts electrons and a base
as any substance able to donate electrons. Since
a Lowry–Bronsted base donates electrons to a
hydrogen ion, a Lowry–Bronsted base is also a
Lewis base. This concept usefully extends the
definitions of acid and base to include reactions
that do not involve hydrogen ions.
Stewart defined a solution as neutral if the
concentration of hydrogen ions was equal to
the concentration of hydroxyl ions, acidic if the
concentration of hydrogen ions was greater
than the concentration of hydroxyl ions and
basic if the concentration of hydroxyl ions was
greater than hydrogen ions. According to his
approach, an acid is a substance that increases
the [Hþ] of a solution and a base is a substance
that decreases it, relative to the hydroxyl ion
concentration. Electrolytes are substances that
dissociate into ions when dissolved in water.
Stewart classified these into strong and weak.
Strong electrolytes are always completely dis-
sociated in solution and the resulting ions are
called strong ions. Weak electrolytes are sub-
stances that only partly dissociate into ions
when dissolved in water and yield weak ions.
The effects of strong and weak electrolytes on
acid –base balance are very different.
Electrolytes may yield (based on degree of

dissociation in solution): strong ions (complete dissociation),
e.g. Naþ, Kþ, Mg2þ, Ca2þ , SO22 2
4 , Cl , and weak ions (incomplete
dissociation), e.g. protein, phosphate, HCO2
3.
Stewart’s concept of acid– base: the
‘modern’ approach
According to this view, the acid– base state in different parts of the
body depends on: (i) water; (ii) strong ions; (iii) weak ions; and
(iv) solutions containing CO2 as indicated by the PCO2 of the sol-
ution. To understand this concept we have to keep the following
principles in mind:
1. The law of electroneutrality: this states that in aqueous solutions
in any compartment the sum of all the positive ions must equal
the sum of all the negatively charged ions.
2. The law of mass action: this law dictates the dissociation equili-
bria of incompletely dissociated substances.
3. The law of conservation of mass: the amount of a substance
remains constant unless it is added, removed, generated or
destroyed. The total concentration is the sum of the concen-
tration of dissociated and undissociated forms.
Law of electrical neutrality
In any aqueous solution in equilibrium, the sum of the positive
charges always equals that of the negative charges. For instance, in
a solution of NaCl
½Naþ  þ ½Hþ  ¼ ½Cl  þ ½OH 
This concept can be expressed graphically, using two columns:
one each for positive and negative charges, keeping them equal in
height. Gamble developed figures now called ‘Gamblegrams’ to
help express the composition of complex solutions such as plasma
(Fig. 1).
Fig. 1 Gamblegrams for NaCl solution, and after an increase in Naþ or
Cl2 ions in the solution.
Continuing Education in Anaesthesia, Critical Care & Pain j Volume 8 Number 3 2008
Water, strong ions, and weak ions
Dissociation of water
Let us consider the water molecule. Water is formed by strong
covalent bonding between H and O and dissociates only very
slightly. The reaction: H2O $ Hþ þ OH2 is therefore far
to the left. At equilibrium, if we apply the law of mass action:
K  [H2O] ¼ [Hþ]  [OH2], the concentration of water [H2O] is
altered very minutely by dissociation; therefore, K  [H2O] can be
taken as a constant known as K0 w (the ion product of water).
Therefore, [Hþ]  [OH2] ¼ K0 w.
þ 2
pffiffiffiffiffiffiffiffi neutrality, [H ] ¼ [OH ] and 0 both
To ensure electrical
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þ 2 0
[H ] and [OH ] ¼ K w. At 258C pure water has a K w of
1.008  10214 mol2 l23 and thus we can approximately state:
[Hþ] ¼ [OH2] ¼ 1027 Eq litre21. As activity increases with temp-
erature, at 378C in solutions in the body, K0 w ¼ 4.4 
10214 mol2 l23. Thus both [Hþ] and [OH2] are increased.
Pure water is always acid– base neutral, i.e. [Hþ] ¼ [OH2] but,
as described above, its hydrogen ion concentration varies consider-
ably with temperature from pH 7.5 at 08C to pH 6.1 at 1008C. The
neutral pH (i.e. 7) occurs at 258C and at body temperature the
neutral pH is 6.8.
Water has a large dielectric constant. This means that molecules
containing strong ionic bonds dissociate to some extent in water.
Its own dissociation constant is small (10216 mEq litre21), i.e.
it dissociates to a very small extent. Thus the concentration of
hydrogen ions in body fluids is much lower than in water. The
extent of dissociation of water depends on temperature, concen-
tration, ionic strength, and the presence of specific substances.
Water has a concentration of 55.3 M at 378C, which is around 400
times the concentration of any other substance in the body fluids
(Fig. 2). However, it is vital to realize that because water dis-
sociates so little, the concentrations of hydrogen ions in body
fluids are very small. Hydrogen ion concentrations are measured in
NANO moles (nmol, 1029 mol) whereas important ions such as
sodium are present in concentrations nearly a million times greater
(mmol, 1023 mol) (Fig. 2). Figure 3 shows Gamblegrams for some
important body fluids.
Fig. 2 Relative concentrations of water and NaCl in the extracellular
fluids, and sodium and hydrogen ions in plasma.
109
Water, strong ions, and weak ions

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Fig. 3 Gamblegrams of ionic composition of body fluids.

Strong ions
Let us now explore the concept of strong ions. An acid or base is
defined as strong if it exists in a fully dissociated state at the pH of
interest. Consider the strong acid HX: the reaction HX ! Hþ þ
X2 is always far to the right. Similar conditions would apply for
the strong base BOH and the reaction BOH ! Bþ þ OH2. When
a known amount of HX or BOH is added to a solution, the
increase in X2 and Bþ is equal to the amounts added.
Strong ions are derived from compounds that dissociate com-
pletely in water. A strong ion is one that is always present in a
fully dissociated state. The predominant strong cations in blood are
Naþ, Kþ, Ca2þ, and Mg2þ, and Cl2 and SO22 4 . These relate to the Fig 4. Strong ion differences.
substances we think of as powerful acids and bases, such as sul-
phuric acid or sodium hydroxide. In a pure salt solution, NaCl
exists as equal amounts of Naþ and Cl2. Thus, the [Hþ] and pH of
Strong ion difference
the solution will remain unchanged upon addition of sodium chlor-
ide. Following the law of electrical neutrality: [Naþ] 2 [Cl2] þ SID (Fig. 4) indicates the amount by which the strong positive
[Hþ] 2 [OH2] ¼ 0. ions (cations) are in excess of the strong negative ions (anions). It
Addition of the strong acid HCl increases [Cl2] more than is an indication of ‘unmeasured’ ions in the solution: SID þ
[Naþ], thus [Hþ] increases to make up the difference and the sol- [Hþ] þ [OH2] ¼ 0 (law of electrical neutrality). SID . 0 implies
ution becomes acidic. [OH2] must decrease because the dis- the presence of unmeasured anions, i.e. alkalosis. If the SID , 0,
sociation equilibrium of water is constant and electrical neutrality this indicates the presence of unmeasured cations, i.e. acidosis. In
has to be maintained. On the other hand, addition of a strong all biological fluids, SID is almost always positive. In mammalian
alkali NaOH increases [Naþ] more than [Cl2] and [OH2] body fluids, it is approximately þ40 mEq litre21.
increases. By the law of mass action, and according to the dis- For plasma: SID ¼ [Naþ] þ [Kþ] þ [Mg2þ] þ [Ca2þ] 2
sociation constant of water, [Hþ] decreases so that [Hþ]  [OH2] f[SO4 ] þ [Cl ]g but the simplification: SID ¼ [Naþ] þ [Kþ] 2
22 2

is constant. [Cl2] is generally sufficient, as these are the dominant ions.

110 Continuing Education in Anaesthesia, Critical Care & Pain j Volume 8 Number 3 2008
 Water, strong ions, and weak ions

Within the cells: SID ¼ [Kþ] þ [Mg2þ] as the concentration of Table 1 Clinical situations illustrating the interaction of SIG with weak acids
other anions is very low and [Naþ]  [Cl2]. Metabolic change SIG Condition Clinical scenario
SID as calculated above may be termed ‘inorganic’. However,
in diseases, organic strong ions such as lactate may make an Hyperalbuminaemia # Acidosis ECF loss, cholera
Hypoalbuminaemia " Alkalosis Critically ill patients
additional contribution to the SID. The SID for human fluids Hyperphosphataemia Acidosis Renal failure
can then be calculated as: SID ¼ [Naþ] þ [Kþ] þ [Mg2þ] þ
[Ca2þ] 2 f[lactate2] þ [Cl2]g. This is known as the apparent SID
or SIDa, as it does not take into account the role of weak acids (ii) Plasma protein, mainly albumin [Alb2] ¼ [Alb]  (0.123 
(buffers). pH 2 0.631)
Figge et al. developed a formula for effective SID (SIDe), (iii) Phosphate [HPO22
4 ] ¼ [Phos]  (0.309  pH 2 0.469)
which allowed the contribution of weak acids to be taken into (iv) SIDeff ¼ [HCO2 22
3 ] þ [Alb 2 ] þ [HPO4 ]

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account. The strong ion gap (SIG) is the difference between appar-
ent and effective SID and measures the contribution to SID of Weak acids cause a slight increase in the hydrogen ion concen-
unmeasured anions such as sulphate, ketoacids, pyruvate, acetate, tration of the plasma. Therefore, a decrease in weak acids will
and gluconate. This is sometimes termed the ‘anion gap’. cause alkalosis, and an increase produces acidosis. Also note that
an increase in SID produces an increase in dissociated proteins and
an increase in PCO2 reduces dissociated protein.
Weak ions Clinical situations illustrating the interaction of SIG with weak
acids are listed in Table 1.
Weak acids and bases are only partially dissociated in the range of
body pH. For a weak acid: HA $ Hþ þ A2. At equilibrium, the
flux in one direction is equal to that in the other, and the balance Solutions containing carbon dioxide
may be affected by the other ions present. For a strong ion in sol-
We are already familiar with the CO2 –bicarbonate system. This is
ution, the ionized form X2 is unchanged whatever happens, but
an ‘open’ system capable of varying the total CO2 content within
for weak ions, only the total amount of A (Atot or HA þ A2) is
wide limits. CO2 is present in the body in metabolic substrates, in
constant. The ratio [A2]/[HA] depends on the equilibrium constant
bone and as HCO2 3 in tissues. The ‘fixed’ stores cannot be
Ka. As [Hþ] increases, [A2] decreases and [HA] increases in
accessed but about 500 mmol is readily available. In the basal
equal amounts. Following the law of mass action: [Hþ] ¼ Ka[HA]/
state, a healthy adult produces at least 10 000 mmol of CO2 in
[A2] or pH ¼ pKa þ logf[A2]/[HA]g (Henderson–Hasselbach
24 h. It is highly diffusible and completely equilibrates across
equation). pKa can be defined as the pH at which the concentration
membranes. PCO2 is controlled by rapid changes in ventilation.
of a conjugate base equals that of the acid, the ‘midpoint’ of the
Thus, CO2 is the most mobile component and the CO2 –bicarbon-
dissociation of the substance. pKa allows calculation of the degree
ate system a very powerful plasma buffer system.
of dissociation at any pH.
The reaction involved is: H2CO3 $ Hþ þ HCO2 3 . Most buffers
The constraints of electrical neutrality imply that in a solution
are not free to leave the tissues and [Atot] is almost constant in any
containing both strong ions and weak ions, if something happens
particular compartment. However, CO2 is freely diffusible and
to change the [H þ ], then the extent of the change will be less
[CO2tot] (i.e. [H2CO3] þ [HCO2 3 ]) can vary considerably. CO2 dis-
than it would have been if strong ions alone had been present. This
solves in water producing H2CO3, HCO2 22
3 and CO3 . The concen-
brings us to the phenomenon of buffering. A buffer is a substance
trations of the dissolved CO2 and H2CO3 are directly proportional
which can bind or release Hþ in solution, and can maintain an þ
to the PCO2, but the concentrations of HCO2 22
3 and CO3 , H , OH
2
almost constant pH, despite addition of considerable amounts of
are also affected by changes in SID.
acid or base. The Henderson– Hasselbach equation is used to
describe the pH changes due to the addition of Hþ or OH2 to any
buffer system. Summary
Principal buffers in body fluids are as follows:
Stewart’s work has simplified our understanding of the mechan-
(i) Blood: H2CO3 $ Hþ þ HCO2 3; HProt $ Hþ þ Prot2; isms of conditions such as dilutional acidosis, concentrational alka-
þ 2
HHb $ H þ Hb losis, hyperchloraemic acidosis, hypochloraemic alkalosis, and
(ii) Interstitial fluid: H2CO3 $ Hþ þ HCO2 3 hypoalbuminaemic alkalosis (Fig. 5). Using basic physicochemical
(iii) Intracellular fluid: HProt $ Hþ þ Prot2 laws, such as the law of mass action, law of conservation of mass,
(iv) Kidneys: H2CO3 $ Hþ þ HCO2 3; NH3 þ Hþ $ NH4; and the law of electrical neutrality, we can explain the acid– base
2 þ 2
HPO4 þ H $ H2PO4 systems of the body. Acid– base balance can be understood quanti-
tatively in terms of three independent variables:
Figge quantified the contribution of weak acids to SID as:
PCO2, [SID] and total weak acid, i.e. [Atot] (usually protein and
(i) Bicarbonate [HCO2
3 ] ¼ 1000  2.46  10
211
 PCO2/102pH phosphates) and their regulation by the lungs, kidneys, gut, and

Continuing Education in Anaesthesia, Critical Care & Pain j Volume 8 Number 3 2008 111
Water, strong ions, and weak ions

strong ions. Body fluids interact through membranes. Most mem-

branes are impermeable to proteins under normal physiologic con-
ditions so [Atot] interactions are significant only when disease
damages membranes.
Changes in respiration and circulation match the tissue pro-
duction of carbon dioxide and control PCO2. These are responsible
for the acute alterations in acid– base disorders. Movement of Hþ
between solutions cannot affect the Hþ, only changes in the strong
ions can. Strong ions move freely in body fluids, across mem-
branes. The kidneys and gut regulate their levels and thus are the
major determinants of SID in chronic acid –base disorders.

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Fig 5. Regulation of plasma composition according to Stewart’s concept.
liver. The dependent variables: [HCO2 2 22
3 ], [HA], [A ], [CO3 ],
2 þ
[OH ], and [H ] or pH can be calculated from these.
The pH and other dependent variables for any body fluid are
determined by the independent variables in that particular fluid
since hydrogen ions are affected by the other, more abundant,
Further reading
Stewart PA. Modern quantitative acid-base chemistry. Canadian J Physiol
Pharmacol 1983; 61: 1444– 62
Rinaldi S, DeGaudio AR. Strong ion difference and strong anion gap: the
Stewart approach to acid base disturbances. Curr Anaesth Crit Care 2005;
16: 395–402
Gluck SL. Acid-base. Lancet 1998; 352: 474–79
Please see multiple choice questions 25 –29

112 Continuing Education in Anaesthesia, Critical Care & Pain j Volume 8 Number 3 2008