Anaesthesia, 2002, 57, pages 348±356

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REVIEW
Acid)base physiology: the ÔtraditionalÕ and the ÔmodernÕ
approaches
A. A. Sirker, A. Rhodes, R. M. Grounds and E. D. Bennett
Department of Intensive Care, St. Georges Hospital, London SW17 OQT, UK

Summary
The interpretation and understanding of acid±base dysfunction has recently been revisited. The
ÔtraditionalÕ approach developed from the pioneering work of Henderson and Hasselbalch and is
still the most widely used in clinical practice. There are a number of problems identi®ed with this
approach, however. The ÔmodernÕ approach derives from Stewart's work in physical chemistry. In
this review we describe the origins of the traditional approach and discusses related concepts. We
then describe Stewart's approach, including how it is derived and how it may be used to classify
acid±base derangements. The applications of Stewart's approach to clinical scenarios in intensive
care is then discussed brie¯y before we examine some published clinical studies based on his work.

Keywords Acid base balance: Stewart; Henderson and Hasselbalch.

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Correspondence to: Dr A. Rhodes
E-mail: arhodes@ sghms.ac.uk
Accepted: 15 October 2001

The concentration of hydrogen ions within plasma and The ÔmodernÕ approach to acid±base disorders was
other aqueous solutions of the human body is maintained initially proposed by Stewart in the early 1980s [2, 3].
within very narrow limits. This control is needed because Stewart used the fundamental principles of physical
of the powerful effects these ions have on cellular chemistry to elucidate factors that must determine [H+]
function, particularly through alterations in hydrogen in biological solutions. Using this mechanistic approach,
bonding and protein structure [1]. Enzymatically driven he derived three independent variables that ought to be
biological reactions and other intracellular processes are the sole ®nal determinants of pH and explained how
signi®cantly affected by local hydrogen ion concentration other factors, including the bicarbonate concentration
[H+]. Understanding how derangements of [H+] arise is [HCO3± ], would be dependent on these three indepen-
therefore clinically important both for diagnosis and for dent variables.
guiding appropriate treatment. This review describes the origins of the traditional
The ÔtraditionalÕ approach to interpreting acid±base approach and related concepts. We then describe
disorders developed from the pioneering work of Stewart's approach, including its deviation and use for
Henderson and Hasselbalch and is still the most widely classifying acid±base derangements. The application of
used in clinical practice. One advantage of this approach is Stewart's approach to clinical scenarios in intensive care is
that it is relatively easy to understand and to apply in discussed brie¯y before we examine some published
common clinical situations. However, problems have clinical studies based on his work.
been identi®ed with its interpretation. The use of HCO3±
and PaCO2 to describe different types of acid±base
The traditional approach
disturbance has sometimes led to the supposition that
these two variables are independently adjusted factors that The Law of Mass Action states that the velocity of a
ultimately determine pH. This implies that the dissoci- chemical reaction is proportional to the active concentra-
ation equilibrium for carbonic acid is used as the control tions of the reactants. Many reactions in biological systems
system for setting pH (thereby determining the position are reversible and so reach equilibrium. The equilibrium
of the equilibrium for other buffer pairs in the body). constant indicates to which side of the reaction the

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equilibrium point lies. The value of the equilibrium and K1, K2, K3 and K4 are numerically different
constant depends on a number of factors including the constants.
temperature. In a reversible chemical reaction, In that same year, Sorensen introduced the pH scale
[5]. Plasma pH measurement became available over the
A‡B,C‡D
next few years [6]. It was already known that changes
in plasma [HCO3± ] re¯ected the accumulation of non-
‰C Š  ‰DŠ
Kˆ volatile acids such as lactic and keto-acids. With the
‰ A Š  ‰ BŠ availability of pH measurement (involving glass electrodes
where K denotes the equilibrium constant. The Ô[ ]Õ terms or indicator dyes), it became clear that changes in PaCO2
here should strictly represent activities (i.e. effective also directly affected pH. This led to the concepts of
concentrations), rather than concentrations. However, for metabolic vs. respiratory causes of acid±base derange-
ease of discussion, concentrations are used in this review. ments. Hasselbalch re-arranged the Henderson's equation
Hence for an acid HE, in logarithmic form in 1916 [7].
 
HE , H ‡ ‡ Eÿ HCO3ÿ
pH ˆ pK ‡ log
‰CO2 Š
‰H ‡ Š  ‰Eÿ Š
KE ˆ
‰HE Š and introduced pCO2 into the equation in place of
[CO2].
The KE will be large for a strong acid (i.e. one which  
almost fully dissociates) and smaller for a weak acid HCO3ÿ
pH ˆ pK ‡ log
(which dissociates to a lesser extent). SCO2  pCO2
In 1909, Henderson applied the Law of Mass Action to
the equilibrium reaction for carbonic acid. He then where SCO2 is the solubility coef®cient for carbon dioxide
substituted a function of the derivable carbon dioxide and pK is the negative logarithm of the equilibrium
concentration [CO2] in place of the unmeasurable constant K4 above.
carbonic acid concentration [H2CO3] and then rear- From this followed the concept of carbon dioxide and
ranged the equation to allow calculation of the pH [4]. HCO3± as variables that are adjusted as a control system to
His equation expressed in algebraic form is: correct derangements of [H+] and which, in doing so, set
the position of other buffer-pair equilibria. The organs
CO2 ‡ H2 O , H2 CO3 , H ‡ ‡ HCO3ÿ systems involved in this putative control system were as
  follows.
‰H ‡ Š  HCO3ÿ
K1 ˆ
‰H2 CO3 Š The respiratory system
therefore The principal acidic product of cellular metabolism is
carbon dioxide [8]. This travels down a concentration
K1  ‰H2 CO3 Š gradient from cells into the interstitial ¯uid and blood to
‰H ‡ Š ˆ
‰HCO3ÿ Š be expired via the lungs. Chemoreceptors in the medulla
‰CO2 Š  ‰H2 OŠ of the brainstem and the carotid and aortic bodies respond
K2 ˆ to alteration in the [CO2] of cerebrospinal ¯uid and the
‰H2 CO3 Š
[H+] and pCO2 of arterial plasma, respectively [9].
therefore Minute ventilation is thereby increased when plasma
[CO2] or [H+] increase.
‰CO2 Š  ‰H2 OŠ
‰H2 CO3 Š ˆ
K2 The kidneys
and if [H2O] is large enough to be considered a constant Non-volatile acids are produced to a far lesser extent than
volatile (carbonic) acid. Sources of non-volatile acids
‰H2 CO3 Š ˆ K3  ‰CO2 Š include metabolism of methionine and cystine in dietary
Substituting for H2CO3 proteins and the incomplete metabolism of carbohydrates
and fats. The free protons (H+) are removed very rapidly
K4  ‰CO2 Š from body ¯uid by reaction with buffers. The pK of the
‰H ‡ Š ˆ
‰HCO3ÿ Š bicarbonate system is 6.1, whereas the normal pH of
where [CO2] ˆ dissolved molecular carbon dioxide extracellular ¯uid is  7.4 and that of mean intracellular
which can be calculated from PaCO2 using Henry's law ¯uid  6.9 [8]. A buffer system functions most effectively

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when its pK lies close to the pH of the compartment in then diffuses back into plasma. The H+ generated in the
which it is present. However, the bicarbonate system is same process is buffered by combination with haemoglo-
viewed as the most important buffer system in the body bin. In order to maintain electrical neutrality within all
because it is so plentiful [10]. compartments, movement of a bicarbonate ion out of the
The amount of available buffer would be depleted by cell is balanced by movement into the cell of a Cl± ion
the continual production of acid were it not for the ability from plasma (the chloride shift) [9].
of the kidney to reclaim and regenerate bicarbonate.
Bicarbonate ®ltered by glomeruli, combines with a free Assessing the metabolic component
proton secreted by the renal tubular cell to produce It is clear from the carbonic acid equilibrium reaction
H2CO3. This is then converted by carbonic anhydrase to that a change in PaCO2 will cause a change in [HCO3± ].
carbon dioxide which diffuses into the renal cell (along its Thus value of [HCO3± ] per se cannot be used as an
concentration gradient because of increasing luminal indicator of the metabolic contribution to any disorder
pCO2). Inside the cell the pathway is reversed, with unless this is taken into account. A number of methods
HCO3± passing back into the blood and H+ being secreted of assessing the metabolic component have been
into the lumen to retrieve more bicarbonate. However, in devised. In 1948, Singer & Hastings [12] suggested the
addition, bicarbonate regeneration occurs because of concept of Ôbuffer baseÕ as the sum of all the plasma
carbon dioxide production within the tubular cell by buffer anions, i.e. bicarbonate plus the nonvolatile weak
cellular metabolism. The carbon dioxide is converted to acid buffers. In 1960, Astrup et al. [13] devised the
H+ and HCO3±. This HCO3± then diffuses into the blood, Ôstandard bicarbonateÕ, which was the value of [HCO3± ]
and the H+ is passed into the tubular lumen where it once pCO2 was standardised to 40 mmHg. Also in
combines with an anion B± and is excreted in the urine. 1960, Siggaard-Andersen & Engel [14] proposed the
(B± represents a nonbicarbonate anion; the two important term Ôbase excessÕ. This was de®ned as the concentration
examples in this context are phosphate and ammonia). of titratable H+ required to return the pH to 7.4, while
This process produces new bicarbonate for buffering in the pCO2 was maintained at 40 mmHg by equilibra-
the blood. tion. Data collection studies in Danish volunteers in the
The role of ammonia in the kidney in the conventional 1950s allowed the empirical development of nomograms
approach is worth further comment [10]. Ammonia is for the value of in vitro base excess once the temperature,
produced by hepatic deamination of amino acids and pH, pCO2 and haemoglobin concentration (Hb) of a
then incorporated into urea and glutamine. Glutamine is blood sample were known. These nomograms were used
taken up by renal tubular cells and hydrolysis releases in computerised blood gas analysers in the 1960s. In 1977,
NH4+, which is in equilibrium with NH3. NH3 diffuses Siggaard-Andersen published the ÔVan SlykeÕ equation,
into the tubular lumen where it combines with H+ to which was derived from known physicochemical rela-
produce NH4+ which then combines with Cl± to be tionships and enabled calculation of the base excess from
excreted in the urine. This allows excretion of H+ in the the variables pH, [HCO3± ] and the Hb [15]. This has
urine but this process has required the production of subsequently been validated by others as showing good
another H+ within the renal cell hence the overall bene®t agreement with nomogram results when applied in vitro
is unclear. over a wide spectrum of pCO2 values [16]. This equation
is now widely used in blood gas analysers.
The gastrointestinal tract
The stomach's parietal cells secrete Cl± and H+ into the The anion gap
gastric lumen. This H+ is derived, via carbonic anhydrase, Another recognised limitation of the traditional approach
from carbon dioxide produced within the cell. HCO3±, is its inability to separate the various possible causes of
which is also produced in the process, passes into blood, metabolic acidoses. There is practical bene®t in being able
supposedly the mechanism causing the recognised post- to divide these conditions into smaller groups in order to
prandial Ôalkaline tideÕ [11]. The pancreas' secretion of facilitate diagnosis and treatment. The Ôanion gapÕ concept
bicarbonate-rich ¯uid, with net movement of HCO3± was developed for this purpose. It is derived from the
from plasma into pancreatic cells and thereafter into the principle of electroneutrality and is calculated by
duodenal lumen, corrects this alkaline tide. ([Na+] + [K+]) ) ([Cl± ] + [HCO3± ]) where [ ] represents
the millimolar concentration. Its value is usually positive
Red blood cells and re¯ects anions which are not accounted for in the
Carbon dioxide in plasma diffuses into red blood cells above expression, such as proteins (the most quantita-
along a concentration gradient and, in a reaction catalysed tively important in healthy subjects), phosphate, sulphate
by carbonic anhydrase, is converted to bicarbonate which [17], as well as other unidenti®ed anions [18]. More

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Anaesthesia, 2002, 57, pages 348±356 A. A. Sirker et al. á
Acid)base physiology
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recent reviews of the Ôanion gapÕ have cited many ionic strength of the solution. However, it is termed a
potential confounding factors that may limit its usefulness constant as its value is not affected by any of the other
[19]. Particularly relevant to critically ill patients is the terms in the equation.
concentration of plasma protein, as reduced plasma
albumin concentrations result in a reduction in the Strong ion solutions in water
expected or ÔnormalÕ anion gap. These are solutions that contain ions that are effectively
fully dissociated in biological solutions, because their
dissociation equilibria have pK values far removed from
Stewart's physicochemical approach
the local pH. They are always present at the concentration
Stewart's approach employs fundamental principles of at which they were added and do not participate in any
physical chemistry on increasingly complex solutions in reactions within the solution. In mammalian extracellular
order to derive variables that actually determine [H+]. solutions, the most abundant strong ions are Na+ and Cl±.
The principles involved are: Other strong ions include K+, Mg2+, Ca2+ and SO42±.
1 Electroneutrality. In aqueous solutions in any com- In a solution which contains Na+, Cl± and K+ ions in
partment, the sum of all the positively charged ions must water, the principle of electroneutrality dictates that:
equal the sum of all the negatively charged ions.
‰Na ‡ Š ‡ ‰K ‡ Š ‡ ‰H ‡ Š ÿ ‰Clÿ Š ÿ ‰OH ÿ Š ˆ 0
2 The dissociation equilibria of all incompletely dissoci-
ated substances, as derived from the law of mass action, Using the water dissociation equilibrium, which must still
must be satis®ed at all times. be satis®ed,
3 Conservation of mass. The amount of a substance
remains constant unless it is added, removed, generated ‰OH ÿ Š ˆ KW
0
=‰H ‡ Š
or destroyed. The relevance is that the total concentration which can then be substituted into the last equation. Hence
of an incompletely dissociated substance is the sum of
concentrations of its dissociated and undissociated forms. ‰Na ‡ Š ‡ ‰K ‡ Š ÿ ‰Cl ÿ Š ‡ ‰H ‡ Š ÿ …KW
0
=‰H ‡ Š† ˆ 0:
Stewart's analysis involves examining the various
This equation can be solved for [H+] to give the quadratic
components which constitute human ¯uids and applying
equation:
the above principles. The relevant components are: s
1 water, …‰Na‡ Š ‡ ‰K ‡ Š ÿ ‰Clÿ Š†2 …‰Na‡ Š ‡ ‰K ‡ Š ÿ ‰Cl ÿ Š†
‡ 0
2 strong ion solutions in water, ‰H Š ˆ KW ‡ ÿ
4 2
3 weak acid (or ÔbufferÕ) solutions in water,
4 solutions containing carbon dioxide. The term strong ion difference (SID) can be used to
Stewart creates a model of human solutions by adding conveniently denote ([Na+] + [K+] ) [Cl± ]). It can be
each of these constituents in turn. seen that [H+] is a function of SID in the above
expression. For a solution containing additional strong
Pure water ions, the term SID could then be more generally de®ned
Water has a high dielectric constant, so causing substances as the sum of all the strong cation concentrations in the
which contain electrostatic bonds (including water itself) solution minus the sum of the strong anion concentra-
to dissociate into component ions. The degree of tions in the solution. The ionic concentrations need to be
dissociation of water itself is slight but is of great expressed in milliequivalents per litre to account for the
importance in Stewart's analysis. different ionic charges.
The equilibrium can be written as: The important conceptual point is that [H+] and hence
pH are dependent variables in this system and their values
‰H ‡ Š ‰OHÿ Š ˆ KW ‰H2 OŠ depend on the SID. The SID is an independent variable
where KW is the dissociation constant. because it is imposed externally on the system and can be
And because [H2O] is so much larger than [H+] and primarily altered by other factors.
[OH±], it too can be considered constant. Hence
Weak acid together with strong ions in solution
‰H ‡ Š ‰OHÿ Š ˆ KW
0
with water
0 A weak acid HA will, by de®nition, dissociate only partially
where K W is a dissociation constant (different value to
into its constituent ions, and will satisfy the equilibrium:
KW).
The value of K W 0
depends on temperature and, in ‰H ‡ Š ‰Aÿ Š ˆ KA ‰HAŠ
solutions other than pure water, also on osmolarity and
where KA is the dissociation constant for this acid.

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Following the principle of conservation of mass, if HA Because carbonic acid dissociates to H+ and HCO3± ,
and A± take part in no other reactions in the solution, the this dissociation can be combined with the previous
sum of [HA] and [A±] will remain constant: equation to give:
‰HAŠ ‡ ‰Aÿ Š ˆ ‰ATOT Š ‰H ‡ Š ‰HCOÿ
3 Š ˆ M  pCO2 ;

where ATOT is the total weak acid. where M is a constant.

The system must still satisfy the water dissociation The ®nal equilibrium to be considered is the relation-
equilibrium [H+][OH ± ] ˆ K W 0
and the principle of ship between [HCO3± ], [H+] and [CO32± ].
electroneutrality SID + [H+] ± [OH± ] ± [A± ] ˆ 0. This is de®ned by
The formula to calculate [H+] involves solving a third
order (cubic) polynomial equation (shown below) that ‰H ‡ Š ‰CO23 ÿ Š ˆ N  ‰HCOÿ
3 Š;
conforms to the simultaneous requirements to satisfy the where N is a constant.
four algebraic statements immediately above. It can be In a solution containing carbon dioxide, weak acids and
shown that the formula for [H+] is a function of SID, strong ions in water, the formula to calculate [H+] relies
0
[ATOT], KA and K W only [3]. on solving the following simultaneous equations:
‰H ‡ Š3 ‡ …KA ‡ SID†  ‰H ‡ Š2 ‡ …KA  …SID ÿ ATOT † (1) Water dissociation equilibrium [H+] [OH± ] ˆ K W 0
+ ±
0
(2) Weak acid dissociation equilibrium [H ] [A ] ˆ
ÿ KW †  ‰H ‡ Š ÿ KA  KW
0
ˆ 0: KA [HA]
The important point is that in this solution SID and (3) Conservation of mass for weak acid A
[ATOT] are independent variables whilst [H+], [OH± ], [HA] + [A± ] ˆ [ATOT]
[A± ] and [HA] are dependent variables. The only way that (4) Bicarbonate)carbon dioxide equilibrium [H+]
[H+] or any of the other dependent variables can change [HCO3± ] ˆ M ´ pCO2
is because of a change in either SID or [ATOT] or both. (5) Bicarbonate-carbonate equilibrium [H+] [CO32± ] ˆ
N ´ [HCO3± ]
Solutions containing carbon dioxide, in addition (6) Electroneutrality SID + [H+] ) [HCO3± ] ) [A± ]
2± ±
to weak acids and strong ions in water ) [CO3 ] ) [OH ] ˆ 0
In bodily solutions, carbon dioxide is present at an The expression describing these simultaneous require-
externally regulated partial pressure. ments involves fourth-order polynomials and its solution
Four molecular species are added whenever carbon reveals that [H+] is a function of SID, [ATOT], pCO2 and
dioxide is added to an aqueous solution, namely dissolved the constants K 0 W, KA, M and N.
molecular carbon dioxide [denoted CO2(d)], carbonic ‰H ‡ Š4 ‡ …SID ‡ KA †  ‰H ‡ Š3
acid (H2CO3), bicarbonate ions (HCO3± ) and carbonate 0
‡ …KA  …SID ÿ ATOT † ÿ KW ÿ M  pCO2 †
ions (CO32± ).
Henry's Law for gases allows dissolved molecular  ‰H ‡ Š2 ÿ …KA  …KW
0
‡ M  pCO2 †
carbon dioxide to be related to pCO2 via the formula: ÿ N  M  pCO2 †  ‰H ‡ Š
‰CO2 …d†Š ˆ SCO2  pCO2 ÿ KA  N  M  pCO2 ˆ 0:
where SCO2 is the solubility coef®cient for carbon dioxide. In other words, in this solution which approaches human
The value of SCO2 varies with temperature, other solute arterial plasma in its constitution, the only independent
concentrations and ionic strength of the solution. variables which determine pH are SID, [ATOT] and
Because carbonic acid is in equilibrium with CO2(d) pCO2. Any change in pH must be because of a change in
and H2O, the dissociation equilibrium for carbonic acid one or more of these.
can be written, with the CO2(d) term substituted, as: Consequently, [HA], [A± ], [HCO3± ], [CO32± ], [OH± ]
and [H+] are the dependent variables. If one of the
‰H2 CO3 Š ˆ L  …SCO2  pCO2 †  ‰H2 OŠ;
independent variables changes in value, all of these
where L is another equilibrium constant. dependent variables in that body compartment will con-
As [H2O] is so large as to be virtually constant, this sequently change. The fact that HCO3± and H+ are both
expression can be rewritten, with the constants combined dependent variables emphasises the differences between
into one: the traditional and Stewart's approaches. If the Stewart
approach is valid, it is misleading to think of bicarbonate as
‰H2 CO3 Š ˆ L 0  pCO2 ;
being speci®cally regulated to manipulate pH as bicarbon-
where L 0 is another constant (numerically different to L). ate cannot be individually or primarily altered.

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Applying the model the three independent variables which determine [H+].
There are certain points to note when applying this model Carbon dioxide diffuses freely across all membranes in the
to human plasma. First, PaCO2 is an independent variable body, hence carbon dioxide cannot ordinarily be used to
in an ÔopenÕ system, i.e. where the total carbon dioxide is regulate pH. Proteins do not cross intact biological
not ®xed because it is in equilibrium with alveolar gas. membranes. Phosphate is regulated by mechanisms in the
However, this does not strictly apply to venous blood and gut and kidneys to maintain calcium homeostasis rather
¯uid within the tissues, where the system is closed and the primarily than for acid±base regulation. Consequently,
total carbon dioxide content rather than PaCO2 is the SID is considered the mechanism for generating pH
independent variable. Second, the independent variable differences in adjacent compartments.
[ATOT] is composed in plasma mainly of serum proteins The speci®c mechanisms that regulate the SID between
and inorganic phosphate. Figge et al. [20, 21] have shown compartments include the following.
that albumin normally accounts for almost all the acid±
base effects of plasma proteins, with globulins playing a The kidneys
negligible role. They calculate that in normal human The kidneys are the most important regulators of SID for
serum at pH 7.4, with [total protein] ˆ 70 g.l)1 and acid±base purposes. The concentration of strong ions in
[albumin] ˆ 43 g.l)1, the charge attributable to proteins plasma can be altered by adjusting absorption from
is  12 mEq.l)1 [20]. Figge's group developed a mathe- glomerular ®ltrate or secretion into the tubular lumen
matical model of the contribution of albumin to [ATOT] from plasma. However, plasma [Na+] is used in the
by ®rstly assigning dissociation constants to all the control of intravascular volume and plasma [K+] needs to
ionisable groups on the albumin molecule (derived from be closely controlled to ensure appropriate cardiac and
the amino acid sequence of albumin). A computer neuromuscular function. Hence, Cl± appears to be the
program was then used to adjust the value of the strong ion that the kidney uses to regulate acid±base status
dissociation constants so as to produce the best ®t for without interfering with other important homeostatic
the model to measured data from solutions containing processes. For example, in the compensation for a
albumin as the only protein. This optimised model was respiratory acidosis, the excretion of H+ in the urine is
then compared with measured data using human serum in itself not important. Instead, the removal of Cl± in the
and in fact matched well, suggesting that other serum urine (as opposed to its resorption back into plasma) will
proteins such as globulins usually make little contribution increase the value of the SID in plasma and thus help
to the total anionic charge. However, the caveat remains return plasma pH towards normal. The importance of
that only serum with normal albumin ¤ globulin ratios ammonia when using Stewart's approach is that the weak
(1.3±2.0) was examined and hence the above conclusions ammonium cation allows the urinary excretion of the
may be incorrect in some situations, e.g. severe hypo- chloride anion without loss of any strong cations. In the
albuminaemia and hyperglobulinaemias. correction of an alkalosis, resorption of additional Cl± by
renal tubular cells will reduce the plasma SID and
Implications of Stewart's theory therefore lower plasma pH.
One implication which is stressed in Stewart's original
study is that the movement of hydrogen ions between The gastrointestinal tract
solutions (by ion channels or pumps) will not actually In the stomach, there is net movement of Cl± ions from
affect local hydrogen ion concentration. If one considers a plasma into gastric parietal cells and then into the lumen
membrane separating two body ¯uid compartments, for of the stomach. This is increased after meals and the
each compartment the value of [H+] depends solely on resulting reduction in the plasma SID (because no strong
the value of the independent variables in that compart- cations are involved in this process) can account for the
ment. Directly adding or removing H+ to or from one of postprandial Ôalkaline tideÕ. Normally this is corrected by
the compartments will not alter the value of any of the movement of chloride in the opposite direction in the
independent variables present and hence [H+] will be duodenum. If there is loss of gastric ¯uid from the body,
maintained at the same value as previously by a change in alkalosis develops because Cl± is removed from plasma in
the dissociation of water to reverse any [H+] ¯uctuations. far greater amounts than it is returned, thereby increasing
The water dissociation equilibrium is able to provide an plasma SID.
essentially inexhaustible source or sink for H+ ions. The pancreas secretes ¯uid which is low in Cl± and has
A related question then is how the body normally a high (very positive) SID. In order to generate this, the
maintains different pH values in adjacent ¯uid compart- plasma returning from the pancreas has a lower SID than
ments separated by a membrane. Clearly, if Stewart's that arriving and this assists in the correction of the
approach is correct, this must involve manipulating one of postprandial Ôalkaline tideÕ.

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Red blood cells The strong ion difference gap (SIG) as an indicator
The previously described Ôchloride shiftÕ defends plasma of unmeasured strong ions
pH against a decrease caused by increasing plasma carbon The term SID has been used thus far to describe the
dioxide. This Cl± movement between compartments difference between the concentrations of the strong cations
raises plasma SID and hence will help return plasma pH and strong anions in a ¯uid compartment. In health, the
towards normal. strong ions present in plasma are Na+, K+, Mg2+, Ca2+
(cations) and Cl± (anion). Because these anions are all easily
Classi®cation of acid±base disorders using measured, the term Ôapparent SIDÕ (SIDapp) is used:
Stewart theory
A natural division of acid±base disorders when using SIDapp ˆ ‰Na ‡ Š ‡ ‰K ‡ Š ‡ ‰Mg2‡ Š ‡ ‰Ca2‡ Š ÿ ‰Cl ÿ Š
Stewart's approach is based on derangements of the Using the law of electroneutrality as applied to a solution
independent variable(s). As with the conventional whose constitution mimics that of plasma,
approach, respiratory acidoses or alkaloses are those in
which the ®rst independent variable affected is the pCO2. SID ‡ ‰H ‡ Š ÿ ‰OH ÿ Š ÿ ‰HCO3ÿ Š
A change in the plasma SID may then occur as a ÿ ‰CO23 ÿ Š ÿ ‰A ÿ Š ˆ 0 …as stated earlier†
compensatory response.
ÔMetabolicÕ acidoses might be considered to arise from The major weak anions (A± ) in plasma are provided by
conditions that cause either a reduction in the plasma albumin and inorganic phosphate. The [H+], [OH± ] and
SID or increase in [ATOT]. Conversely, ÔmetabolicÕ [CO32± ] in the above expression are present in nmol.l)1
alkaloses could be de®ned as those which produce either and lmol.l)1 concentrations rather than the mmol.l)1
a primary increase in the plasma SID or a decrease in concentrations of SID and A±. Hence an approximation
[ATOT]. However, whereas there appears to be complex for the electroneutrality equation can be produced by
regulation of SID for acid±base purposes, no such disregarding the charge contributions of the [H+], [OH± ]
mechanisms are known to control [ATOT] for this and [CO32± ] ions. Hence
purpose. For this reason, changes in [ATOT] are not SID ÿ ‰HCO3ÿ Š ÿ ‰Albx ÿ Š ÿ ‰Piy ÿ Š  0
classi®ed as Ôacid±baseÕ disorders by some authors [22]
despite their effect on pH. where the last two terms refer to the milliequivalent
Stewart's approach allows an understanding of the concentration of the anionic contribution from serum
commonly seen metabolic acidosis following the admin- albumin and inorganic phosphate, respectively. So,
istration of large volumes of normal saline. The another expression for the SID in plasma, which does
concentration of chloride in plasma increases to a not make any assumption about which strong cations or
greater extent than that of sodium when normal saline anions constitute the SID, may be written
is given because normal saline (unlike plasma) contains SID  ‰HCO3ÿ Š ‡ ‰Albx ÿ Š ‡ ‰Piy ÿ Š:
sodium and chloride in equal amounts. This leads to a
reduction in the value of plasma SID and a consequent This version of the SID is termed the Ôeffective SIDÕ
decrease in pH. (SIDeff) and may encompass strong ions other than those
Two terms that have been used previously in the covered in the term SIDapp. The calculation of SIDeff
classi®cation of acid±base derangements are Ôcontractional involves
alkalosisÕ and Ôdilutional acidosisÕ. These terms may lead to 1 the measured concentration of HCO3±,
the erroneous idea that change in extracellular ¯uid 2 the calculated concentration of [Piy± ], obtained from
volume alone might cause acid±base disturbances. an empirically derived formula involving the measurable
Stewart's approach implies that changes in plasma or independent variable [PiTOT] and the known pH [20],
extracellular ¯uid volume alone will not change the value 3 the calculated [Albx±]. This is obtained from Figge's
of any of the three independent variables and hence (revised) model which indicates the charge contribution
cannot affect pH. However, if the change in volume is from albumin at a given pH. Their experimental data (to
accompanied by a change in the proportional water which they ®t their model) demonstrate that there
content of plasma, the SID will change. For example, if appears to be a linear relation between pH and the
water is removed from plasma, the concentration of anionic charge contribution of protein in serum (see,
strong cations and strong anions is increased in equal Fig. 2, Ref. 21).
proportion. This increases the SID by the same propor- The quantitative difference between SIDeff and SIDapp
tion and so causes an increase in pH. However, this effect is termed the strong ion gap or SIG:
may be complicated by compensatory mechanisms that SIG ˆ SIDapp ÿ SIDeff :
regulate plasma volume.

354 Ó 2002 Blackwell Science Ltd

Anaesthesia, 2002, 57, pages 348±356 A. A. Sirker et al. á Acid)base physiology
. ....................................................................................................................................................................................................................

The SIG indicates the presence of unmeasured strong base excess or de®cit. Relatively simple formulae quantify
anions (if its value is positive) or strong cations (if its value the base excess ¤ de®cit produced by these factors and
is negative). The ÔnormalÕ value of the SIG is zero [23], necessarily involve setting some arbitrary limits on
implying that there are very few strong ions other than reference values.
Na+, K+, Ca2+, Mg2+ and Cl± in the plasma of healthy The difference between the base excess attributable to
subjects (though lactic acid levels are elevated in vigor- the above factors and the actual measured base excess is
ously exercising subjects [24]). The anions which may termed the Ôbase excess gapÕ and will re¯ect the contri-
result in an elevated SIG are those which will also cause bution to base excess from Ôother charged speciesÕ present.
an Ôelevated anion gapÕ or ÔnormochloraemicÕ metabolic This study indicated that there is a tight correlation
acidosis, e.g. lactic acid, keto-acids, sulfates, which between the detection of unmeasured anions or cations
accumulate in renal impairment and various exogenous using the SIG and the base excess gap approaches. The
acids, e.g. formic acid following methanol ingestion. The authors suggest that the base excess gap may therefore
SIG is similar in concept to the anion gap, once the latter provide a good estimation of the SIG and that its
has been corrected for anionic contributions of albumin calculation can be performed relatively easily at the
and phosphate. In critically ill patients, a number of other bedside rather than requiring a computer.
Ôunidenti®edÕ strong anions can also often be detected by The relationship between SIG and the traditional anion
calculation of the SIG. gap is less strong in the study by Gil®x et al. Kellum and
colleagues examined data on ICU patients with sepsis and
Clinical studies using the Stewart approach also those with severe liver disease [29]. They showed that
McAuliffe and colleagues studied hypoproteinaemic the relationship between the SIG and the anion gap
patients on an American surgical intensive care unit becomes much stronger if one corrects the anion gap for
[25]. They did not study patients with conditions asso- the charge contribution from protein and phosphate in
ciated with a high anion gap (e.g. renal failure, cardio- the spec®c patient. This is not altogether surprising, as the
vascular instability and hyperglycaemia). Nor did they formulae for calculating SIG and corrected anion gap
study patients with deranged serum [Na+] in order to encompass the same molecular species although the
remove any possible effects of osmolarity on acid±base. numerical values are derived in different ways. Regardless
All other measured strong cation and anion concentra- of which method is used, it is clear that unknown and
tions were within normal limits, i.e. these patients had a unidenti®ed anions are frequently present in the plasma of
normal SIDapp. Over the course of 6 months they critically ill patients and contribute signi®cantly to the
identi®ed eight patients who satis®ed all their criteria. metabolic acidoses often seen in these patients.
In each of these patients a signi®cant ÔmetabolicÕ alkalosis
was identi®ed (by a positive base excess and an elevated
Conclusion
standard bicarbonate). The calculated levels of Ôanion gapÕ
were normal after correction for hypoproteinaemia. The This review describes the important features of both the
authors concluded that these patients had a primary conventional and more modern approaches to the analysis
hypoproteinaemic alkalosis, in keeping with the predicted and interpretation of acid±base disturbances. The tradi-
results of Stewart's work. Kellum has pointed out that tional approach evolved from the work of nineteenth and
critically ill patients with hypoalbuminaemia often have a early twentieth century researchers and thus led to a
normal pH, reduced SID and a normal base excess [26]. pragmatic classi®cation system based on those variables
In this situation, the reduced SID can be considered a which were, at the time, easily measured. This approach
physiological response to hypoalbuminaemia (in order to remains by far the most widely used in everyday clinical
keep pH normal) rather than constituting part of a practice and, as discussed above, with only minor
complex mixed metabolic disorder [27]. This point is also adjustments can provide the same practical information
emphasised by proponents of the Ôbase excessÕ concept as that obtained using Stewart's approach. The impor-
such as Siggard-Andersen & Fogh-Andersen [22]. tance of Stewart's work is the insight it provides by
Gil®x and colleagues examined 21 patients with a identifying the factors that actually determine pH. It
mixture of medical and surgical problems in an intensive promotes review of the mechanisms by which organ
care unit. They examined the use of three different systems such as the kidney might act to regulate the
measures in the assessment of unidenti®ed ions in these body's acid±base status and how, in illness, derangements
patients [28]. They looked at the SIG, the anion gap and of pH may arise. Stewart's work has its critics [22], who
also what they de®ne as a Ôbase excess gapÕ. The last of particularly dislike the way in which quantitative
these takes into account the fact that any deviation in derangements in any strong ion or weak acid (including
[Na+], [Cl±] or [Albx±] from normal values will produce a proteins) are potentially regarded as metabolic acidoses or

Ó 2002 Blackwell Science Ltd 355

A. A. Sirker et al. á Acid)base physiology
. ....................................................................................................................................................................................................................
alkaloses. In addition, the cumbersome nature of some of
the calculations needed in Stewart's work has limited its
use in clinical settings. Nevertheless, Stewart's work has
highlighted the importance of rigorously distinguishing
between independent and dependent variables in pH
setting in order to understand the primary derangement,
its secondary consequences and thus allow appropriate
direction of therapy.
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