Moderm quantitative acid- base chemistry

PETERA. STEWART"
Department of Physiology and Biophysics, Brown U n S v e ~ s i f Provtsl'ence,
~),
RI, U.S.A. 02912

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Received April 26, 1983

STEWART,P. A. 1983. Modern quantitative acid-bass chemistry. Can. J. Physiol. Pharmacol. 6%: 1444- 1461.
Quantitative analysis of ionic solutions in terms of physical and chemical principles has been effectively prohibited in the
past by the overwhelming amount of calculation it required, but computers have suddenly eliminated that prohibition. 'Fhe
result is an approach to acid-base which revolutionizes our ability to understand, predict. and control what tnappens to
hydrogen ions in living systems. Thls review outlines that approach and suggests some of its most useful implications.
Quantitative understanding requires distinctions between indcpe~ldenfvariables (in body fluids: pCOz, net strong ion charge,
and total weak acid. usually protein), and dependent variables ([HCO, 1, [HA], [A 1 , [co:-], [OH-], and [M'] (or pH)).
Dependent variables are determined by independent variables, and can be calculated from the defining equations for the specific
system. Hydrogen ion movements bctween solutions can not affect hydrogen ion conceintration; onlj) changes in independent
variables can. Many current n~odelsfor ion movements through membranes will require modification on the basis of this
quantitative analysis. Whole body acid-base balance can be understood quantitatively in terms of the three independent
variables and their physiological regulation by the lungs, kidneys, gut, and liver. Quantitative analysis also stnows that body
fluids interact mainly by strong ion movements through the membranes separating them.
STEWART,P. A. 1983. hqodern quantitative acid-base chemistry. Can. J. Physiol. Pharmacol. 61: 8444- 1461.
Bar le pass6. le nombre exorbitant des calculs necessaires pour effectuer I'analyse quantitative de solutions ioniques en
termes des principcs playsiques et chjmiques nous obligeait a rcnoncer a cette mCthode; toutefois, le dCve1oppement dcs
ordinateurs permet dorknavant dq61iminer cet obstacle. Le resultat est une approche i une condition acido-basiquc qui
revolutionsme notre abilitk 2 csmprendre, 5 pr6voir et 2 contr6ler ce qui survient aux ions hydrogene dans les systennes vivants.
Cette rkvision decrit cette approche et suggkre certaines de ses implications les plus utiles. La comprChension quantitative exigc
que I'on distinguc variables ind6penciantes (dans Ies liquides corporels: pC02, charge ionique nette forte, el acide total faible,
gCnCralement une p r o t h e ) , de variables dkpendantes ([HCO, 1, [MA], [A-I, [ c o : ~ , [OH I et [Hi] iou pH)). Les variables
dkpcndantes sont d6tcrmninCes par les variables indkpendantes, et eIles peuvent Ctre calcuI6es ii partir des kquations definics
pour Ie systkme spkcifique. Les mouvements des ions hydroghe entre les solutions ne peuvcnt influer sur la concentration en
ions hydrogkne; seules les variations des varicables kndkpendclntes ont ce pouvoir. Cette analyse induira inkvitablernent la
rnsdification des plusieurs modkles cokarants sur les inouvernents ioniques ii travers Ies membranes. Tout l'kquilibrc
acido-basique coporel peut etre compris quantitativcment en termes des trois variables independantes et dc leur rkgulation
physiolsgique par les poumons, les reins, les intestins et le foie. L'analyse quantitative motltrc aussi que les liquides coqorels
interagissent priincipalement par des inouvements ioniques forts a travers Ies membranes qui Ics skparcnt.
[Traduit par Ie journal]

Introduction
Quantitative analysis of ionic solutions by direct
application of fundamental physical and chemical
principles has always been possible in principle, but
has been effectively prohibited until recently by the
overwhelming amounts of calculation required. Now,
however, computers can do at1 those calculations easily
and quickly, so that direct quantitative analysis is
simple and extremely useful. The approx irnations , simplifications, and "tricks" which the precomputer situation required are no longer needed, and the confusion
which they have generated is no longer necessary. The
result is a new quantitative approach to acid-base
which has revolutionized our ability to understand, predict, and control what happens to hydrogen ions in
living systems (Stewart 1981).
'Present address: P.O. Box 24, Beer Harbor, WA, U.S .A.
98243.

The physicochernical analysis required is at a remarkably elementary level, is easy to understand, and
can be readily applied to biological sca8utions. The
mathematics required is only high school algebra.
While this is a simple and practical approach to ionic
solutioms, it requires significant changes in many gemerally accepted concepts of hydrogen ion behavior. The
purpose s f this review is to outline the analysis and to
suggest a few of its most useful implications. More
complete details are spelled out Ira the above reference.
The analysis will be developed by progressive application to four isolated solutions: ( I ) pure water, (2)
strong ion solutions, (3) weak acid "buffer'9 solutions,
and finally, (4) solutions also containing C 0 2 . At
each stage, we shall ask, and answer quantitatively, the
fundamental question: "what factors determine the hydrogen ion concentration ([H' 1) in this solution?"
so soluBiological solutions always contain @02,
tions with C 0 2 are most interesting. They are also the

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most complex, but the analysis applies regardless of

complexity. That final C02 containing solution, (4),
will provide a good approximation to mammalian
body fluids, and our analysis s f it will dispel much
of the mystery surrounding physiological "acid-base
balance."
While this analysis and its computer implementation
are simple and straightforward, to reap its full benefits
requires an attitude towards solutions as systems which
is quite different from the conventional one. It is a
general property of systems that the quantitative results
of several interacting but independent mechanisms can
not be explained or understood solely in terms of the
action of any single one of those mechanisms. Because
we are conditioned to simple, linear, stepwise, and
mechanistic explanations, the first question we normally want to ask is "what is the (implying just one)
mechanism which produces a change in [H']'?" In fact,
several interacting mechanisms are always involved,
and quantitative understanding requires that we take
them all into account. The question is, therefore, inappropriately wortled, and must be replaced by the one
posed above which implies more than one factor interacting to determine [H ' ]. No single mechanism in these
complex systems can ever by itself provide quantitative, nor even correct qualitative, understanding of
hydrogen ion behavior.
Quantitative analysis also requires us to recognize the
n t , than an indepenstatus of [H t ] as a d e ~ p ~ r r d ~rather
~h~ distinction is essential because it is
dent
basic to the whole idea of cause and effect in such
systems. ~
~
dvariable
~ values
~
are
~ imposed
~
don a ~
system from outside, and are not affected by the q u a tions which govern the system, nor by changes in the
system, nor by each other. Dependent variables are
internal to a system: their values are determined by the
systcm equations and by the values of the lndependent
variables. There must always be as many equations as
there are dependent variables, and the dependent variables must satisfy all those equations simultaneously.
Only changes in the independent variables in a system
can cause changes in the dependent ones. Dependent
variable values can not be set arbitrarily, but must always adapt to the independent variable valuec. Changes
orre related, as
in the dependent variables are ~~ecessarily
they all depend on changes in the independent ones, but
the dependent variables are not causally related to each
other, and do not determine each other.
For example, since [Hf] is a dependent variable, HS
naovemei~tsinto or out of a solution do not provide
quantitative explanations for changes in [H ' I . They
may contribute part of the mechanism for changing
[Hi ] in some situations, but they do not determine the
value of [H'], and by themselves can not explain
changes in it.

The analysis to follow will establish what does determine changes in [ H t ] , and the identification of these
two kinds of variables will be an essential part of that
analysis.

Theoretical development
Pure lvutPr
Liquid water is so much a part trf all living systems
that it is easy to overlook its very peculiar properties.
Three of them are iinportant for this analysis: high dielectric constant, very slight dissociation into H i and
OH ions, and extraordfnarily high molar concentration
(about 55.5 M).
The high dielectric constant of water causes substances whose atoms are held together primarily by
electrostatic bonds to dissociate into their component
ions when they dissolve in it. Water is therefore a
strongly ionizing solvent. That it has this effect on itself
partly explains its own slight dissociation. While the
extent of water dissociation is minute, enormous biological importance is attributed to it. Although often
overlooked, the large molar concentration of liquid water is also iinportant for the analysis of hydrogen ion
bchavior.
Since the water dissociation reaction equilibrates rapidly, we must always have

K,. the dissociation constant for water. is of the order

of 10 ''M (Harned and Owen l958), so that this dissociation
~
~process
t has a completely negligible effect On
the Water concentration The
il1,Ol tern1 may
therefore be considered constant, and [ I ] rewritten as:

KL is called the ion product,for H7&rtc.r.It is very sensitive to temperature, because Kw is. In solutions other
than pure water, its value also depends on osmolarity,
because the [H20]term does, and on ionic strength, and
on the presence of specific ions.
The numerical value of K k , as well as of all the other
constants we shall introduce later. also depends on
whether the [] symbols denote concentrations or activities. Strictly speaking. activities or effective concentrations should always be used when dealing with reaction ratcs or equilibrium constants. Fortunately, the difference between activities and concentrations is usually
not large, and concentrations are so much simpler to
think about that it is preferable to use them at first.
When the resulting theory is applied in practice, it may
then become important to use activities to ensure numerical agreement with real system behavior. It should
also be recognized that activity corrections apply to
chemical concentrations, but not to charges per ~ e .

1446

CAN. J. PHYSIOL. PHARM.4COL. VOL. 61. 1983

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In pure water, as in all solutions, electrical neutrality

muqt always be preserbetl (Gusgenheirra 1957). Hecauhe I I ' anc1 O H are the only ions present in pure
water, this means that:

[ 2 ]and ( 31 are simultaneoe~s,inc1cpenden1, equations

which [ I l t ] and [OH-] must always satisfy in 1m-e
water, They constitute the urabreakakk "rules of the
game" which control how thoss two concentrrations
must behave. 'l'he rule\ of algebra, in turn. tell aab how
to solve these equations hy combining and rearranging
them to a forrn irr which therc is a separate equation for
each of the tanknown5 by itwlf, expressed only in tenns
of the parameter K,',. In this sisripls cane. the whole
process is rather trivial, but exactly the same proced~arcc
apply in the hame way in all the following nnore conlplicated cascs.
To scll~efor [H' 1, we call use 131 to ~ub~titinte
fi~r
[OIl ] in ['I. This gives us [ H ' l ' = K : or [ I f ] =
To solve for IOH 1, we uhe 131 to substitute for
[ H ' ] in 121. ' h i s gives us 1011 I' = Kk, or [ O H p ] =
\/=.
The final results for pure water therefore are:

k'z.

strong ion is K ' .

Consider wow a simple strong ion soluticr1-8nnadc up
by mixing appropriate volumeh of specified %QCl
and
NaOH scslutions, to make a final volume of 1 E. That
solution will contain Na' , C1 , ]ti ' , and OI 1 ions.
What we want to krlerw is "R hat deteraa~ine\the [ H ' ] of
this sole~tion'?l"
To answci- that question, we write the equaticsnu for
clcctrical neutrality and for wrater dissc~clationequilibriun-8,just as wc iiid fk~rwader. Electrical neutrality
nlcans that the sum of all the charges in the solution
must be p.er-o. For this solution, ttaat requires

As cmly strong ioras have been added, no ncw equilibria are involved. Water dis\c~ciationequilibrium is
still constrained by equation 121. (Balce again we have
two independent, simultaneouq equations, [2j and [ 51,
expressing the rule\ of the game for [ I I ' J aend [Oil I.
We can combine and rearrange tl~eanby the rules of
algebra just as before, but this tianc the results are the
follow ing qttacfratic exprcsxions:

[6]

(H-1

t'K\l

+ ( [ N a ']

[Cl ] ~ ' / 4
( [ N a b] - [CI 1112

These expressionc answer the question '\+hat c1etermines the [I1' 1 of pure water?" The aalswca- i, ""K:".
'H'hcy also tell
that K: dctcrn-aints the [OII ] of pure
water.

S t r o ~ gi o ~ ls o k ~ f f o ? ~ ~
Electrolytes are substances whose rnolectales itr
solution dissociate to sorrle degree into ions. Strong
electrolytes dissociate completely for all practical purposes. We can not. therefore, write a diysociation uquiilibriium for theral. Strong ion, are simply always present
in the solution at whatever cc~ilcentration they were
originally added. Ac the] remain completely iiissociated, it fi~llowsthat they do not participate in any
reactions \albthin thc~soh.ifiotz.'They t-aaay react with other
entities such as ceI1 anennbranes, but these are outside
the solution. and we are concerned fc~rhe tnornellt only
with strictly isolated solution,.
In ma~nrnalianextracellular solutia~nc,the most concen!rated inorganic \tn,ng ion\ arc Na and Cl . K ' and
SO, are also strong ionc. but they are a l w a y ~present
in n~a~ch
lower concentrations than Na or CI . Sormaetirncs. Ca" and ~ g may
"
function as strong ions. but
they also occur at low concea~traaionsin coanparison
with N a ' and CI , so that we usually neglect them.
Lactic acid ha$ a dissociation constant tsn the order of
I 0 ' eyuiv ./I,, so that lactate behaercs as an organic
strong ion when present in plahnasa or cxtracelltalar fleaids. It Inlay be quantitatively signlficatat under some
circumstances. Intracellularly, the nlo\t iaamportant
+

171

loll-]= \/K:

+ ([Na']

-k

[CI ]1'/4
( [ N a ' ] - (Cl j)/2

These equations dell us that ( H ' ] ant1 (OH -1 arc functions of, or determined by, the values of both K,: and
([N,atl - [CI 1). If we consider K: to be a known
constant parameter, then ([Nat1 - [Cl-1) B3 clear11 the
quantity u hich determines the values of both [ H ) and
(OH ] in thin system.
Bcforc exploring in detail what these cquatio~lssay,
consider the quantity ( [ S a t ] - [Cl 1) in [ 5 ] , [(>I,and
[71. It is the rzcf strong icva positive charge, the concentration of strong cation positive charge in the solutioa~
which is Paot electrically balanced by strong anion negative charge. We know the vtllues of [ N a ' ] and [CI I
because we know how match of each wc atfded to make
up the litre of solution, so we know the vale~eof this ( )
term. If trther strong ions were present, such as K I or
lactate . their known concenta-ationswould also appear
within the ( ). and only there. both in thc electrical
neutrality equation, [ 5 ] .and in [6] and 171. It is therefore pernnissikle, and very convenient, to represent this
( ) quantity by a sl~ortsymbol instead of having to write
~ , ~
it out in detail each time. We call it the S ~ T O B PCIM
d[flirefzc-~.
ranti represent it by the symbol (SIIIj.
[SIfIJ is formally defiraetf as (the suan of all the strong
cation concentrations in the scplutiol~)nainxi (the surn of
all the strong araicpn co~lcentrationsin the bc~lutic~n).
Node that if strong anions exceed strong cations, then
[SID] will be ncgativc. [SID] slmcbuld be thoe~gtntof as a

ION SOLUTIONS

STRONG

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CH+S

AND

C8H-1

O i " ' i " " ' " ' " "

-1 -0.8 - 8 . 6 -0.4 -0.2

"

"
0

VERSUS

CSIBI

0.2

9.8

0.6

0.4

STRONG I 8 N DIFFERENCE,

CSIDS

FIG. 1. Hydrogen ion ([H+]f and hydroxyl ion ([OH I) conccntratisns, for any strong ion solution, plotted against strong
ion difference ([SIDJ), over the [SID] range from - 10 "to + 1 0 ' equiv./l. When [SIII] = 0, [H'] = [OH 1 = VIE,
as
indicated by the arrow. Note the smooth gentle curves of transition from linear to nonlinear behavior on going through [SID]
= 0. K k = 4.4 x HO '"(equiv./l,)'. the value for blood plasma at 37"C, for this and all the following figures.

STRONG ION SOLUTIONS

CH+3, pH AND [OH-I VERSUS CSIDl

-0. &l@5

0.OG15

fl

STRONG ION DIFFERENCE, CSIDl

FIG.2. IH+], [OH- 1, and pH versus [SID] for any strong ion solution, over the [SIDI range from - 10 to + 1 0 mequiv. /k.
Compare the very steep change in pH around [SID] = 0 with the gradual [Hf ] transition over this range displayed in Fig. I .

symbol for the net unbalanced positive charge on the

strong ions present in the solution. As the solution must
be electrically neutral, [SIDI tm~ustalways be balanced
by the net charge on all the other weak ions in the
solution, as the electrical neutrality equation, ( 5 ) ,
indicates.
Equations 6 ancf 7 for [ H ' ] and [OH 1 can now be
written more neatly in terms of [S119]:

181

IH']

191

[OH ]

\ / K ; + ( [ S I D J ~ Z )-: [SIDJ/Z
=

\/K:

+ ((SIDjjZ)' + [SID]/2

These two equations provide the general answer to

our question: ( H S ] in strong lon solutions is determined
by the value of ISID]. So is [OH-], but difkrently.
Figures 1 , 2, and 3 display the behavior of these

CAN. I . PHYSIOL. PHAWMACBL. VOL. 61, 1983

STRONG
CH+3

AND COH-3
LOG-LOG
7

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ION SOLUTIONS
VERSUS
PLOTS

la-3

CSIDI

r CH+I , CDH-1

+18-5

STRONG I O N DIFFERENCE,

+18-3

CSIDI

RG. 3. Log-log plots of [H+3 and [OH-] versus [SIB] for any strong ion solution, over the [SIB] range from - B to

+ 1 equiv./l. The left side of this graph has the horizontal scale direction reversed, and plots Hog([H+j)and log ([OH-]) versus
log([SIB]). The slopes of the linear portions of the curves must be interpreted accordingly.

equations graphically, and provide a number of surprises. The algebra behind some of those surprises is
illuminating, and reinforces their significance.
First, KL is of the order of 18-l4 (equiv./~)', while
[SID] is usually on the order of lo-' equiv./L. In blood
plasma, for example, [SID] is normally close to 40
rnequiv./L. K:, is therefore negligible compared with
( [ S I D ] / ~ )in~ [8] and [9], so that the value of the whole
square root term will be +[SID]/2, regardless of the
sign of [SIDJ. In the rest of the equation, however, the
sign of [SID] makes a profound difference to the way in
which the values of [H'] and [OH-I depend on it.
Whenever strong acid anions exceed strong base cations, then (SID] is negative, [H'] is larger than [OH-],
and the solution is acidic. Equations 8 and 9 can then be
rewritten to a very good approximation (at least 1 : 10')
as:

for example) results in [ H ' ] increasing by x . It is important to understand that this happens because the
added Cl-- ions increase the magnitude of - [SID] by x,
and [H'] must be kept equal to -[SID], not simply
because of the added hydrogen ions. Similarly, adding
x moles per litre of Na' (as NaOH) will make -[SIID]
more positive by x, and result in [H' j decreasing by x,
even though no H t per .ye have been taken out of the
solution. This simple linear behavior of [PIil with
- [SID] can be seen clearly on the left side of the graphs
in each of Figs. 11, 2, and 3. i t only occurs whe~z[SiD]
is negative and the solution is acidic.
[SID] is positive, on the other hand, when strong
base cations exceed strong acid anions. In this case,
[OH-] is greater than [H'] , the solution is alkaline, and
to the same excellent approximation as before, 1131 and
(9) become

[ l o ] [H '1 = - [SID] and [OH-] = 0

[I21 [OH-] = [SID] and [H'] = 0

[OH-] isn't quite zero, of course. Its more exact

value has to be found from the water dissociation equation, [2], which can now be rewritten by substituting
-[SID] for [H'] from [lo]:

Here again, [ H t ] is not exactly zero. This time, its more

exact value can be found from [2] rewritten in this form:

~ 1 1 3 [OH-]

-K:/[SIDI

In words, [OH-] is very small in a strong acid solution, and varies inversely with the value of (SID], while
[H"] is large and equal to the magnitude of [SID]. As
a result, [ H t ] seems to behave like a strong ion in such
acid solutions, even though it is rzot one. Adding x
moles of H' per litre to such an acid solution (as HCI

[13] [PI']

KL/[SID]

Now, [H'] is very small, and varies inversely with

[SID], while [OH-] seems to behave like a strong ion,
since it changes directly with [SID].
The addition of x moles of H' per Iitre to this alkaline
solution (as HCI) will not change [H"] by x this time,
even though the C1- still changes [SIDI by x. How
much [H'] will change can be calculated from [8\ or
1131, and clearly depends not only on how much [SID]

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changes because of the added C1-, but also on what the

initial [SID) value of the solution was. The amount of
H ' added is essentially irrelevant to either the amount
by which [H ' 1 changes or the final [H'] value achieved.
This dramatic difference in the behavior of [H'] and
of [OH 1, depending on whether [SID] is negative or
positive. is not generally recognized. H is usually
treated as if it always behaved like a strong ion. In fadct,
it almost never behaves like a strong ion because biological solutions are almost never acidic.
The curves in the accompanying figures clearly show
these aspects of [H'] and [OH-] behavior2. In Fig. 1 ,
[H ' I and [OH'-] are plotted against [SlD] over a small
range of [SID) values on either side of neutrality
([SID] = 0). The simple linear behavior of [H'] when
(SID] is negative, and the smooth gradual transition to
the nonlinear inverse behavior when [SID] is posltive,
can be seen clearly. The precisely complementary behavior of [OH-] is equally obvious.
Figure 2 shows a similar plot, but over a much larger
range of ISID] magnitudes. It also includes the pH
curve, which is the classical strong acid-strong base
"pH titration curve." Now that we know from Fig. I
what happens to [H '1 around [SID] = 0, we can recognize the very steep pH change around this point for the
mathematical artefact that it is. Nothing corresponding
to it happens to the chemically significant quantity
[ H ' ] . The pH curve also displays a highly misleading
symmetry on the two sides of the origin, and suggests
that [H'] behaves in much the same way in either acidic
or alkaline solutions, which it clearly does not. This
misleading symmetry of the pH titration curve is probably the major reason why the very different behavior of
[ H + jin acid and in alkaline solutions is not more generally recognized.
Figure 3 presents a log-log plot of [H'] and [OH-]
versus [SlD] which demonstrates these properties over
a much wider range of values of all the quantities of
interest. The obvious advantage of such a plot is the
wide range of magnitudes it can display; its disadvantage is its nonlinearity, but at least that nonlinearity is
the same on both axes. That is not true for the inverse
semilog or pH plot included in Fig. 2, which is consequently much more difficult to interpret, despite its
familiarity.
In both Fig. 1 and Fig. 3, the acid-base neutrality
point is easy to see as the point at which [H') = [OH-).
Because of Eq. 2, this must always be the point at
as indicated
which both these quantities equal <,
on Fig. 1 at the horizontal arrow. Since the value of K :
is specific for each solution, it is important to use the
appropriate value for this parameter in calculating the
+

y o p i e s of the (HP85 Basic) computer programs used to

generate all the figures are available from the author.

value of (H ' 1 (and pH) at this acid-base neutral point.

It follows from Eqs. 8 and 9, and from these curves,
that any change in [SID] must change hotlz [OH-] and
[H'], so that it is not possible to change onby the [H']
(or pH) of a solution. That means we can not arrange a
series of experiments in which only [ H t ] is varied, and
all quantities other than [H ] are kept constant. Because
of the necessary reciprocal relationship between [OH-]
and ( H i ] imposed by the requirement of water dissociation equilibrium, [OH-] must always go up when
[H '1 goes down, and vice versa. In most physiological
situations the magnitudes of [OH-) and its changes are
at least ten times larger than the corresponding values
for [H']. As we shall see, the magnitudes of the
concentrations and their changes for the other ions in
physiological solutlons are generally several orders of
magnitude larger than that! This fact has startling consequences for the interpretation of experiments which
are claimed either to "calibrate" a pH meter, or to show
how some specific process "depends on pH."
Measurements of enzyme activity in solutions of different pH, for example, can only be interpreted as
showing the dependence of that activity on [H'] if the
basic facts of ionic solution behavior just outlined are
deliberately ignored. The activity may actually depend
on [H'], but such experiments can not demonstrate that
it does, only that it changes when [SID], [OH-], and
[H'] all change. [SID] is the independent variable in
these solutions, while enzyme activity, [Ht 1, and
[OH-] are all dependent variables. Because they are,
their behaviors must be correlated, but correlation is not
the same as physical dependence, and can not, by itself,
establish causal mechanisms. In strong ion solutions,
all that such experiments can demonstrate is the dependence of enzyme activity on [SID].
These conclusions work in the opposite direction as
well. It is only in acidic solutions, where [SID] is negative and [ H i ] is large, that measured increases in [H']
can sometimes be interpreted to indicate how much H +
has been added to a solution. In alkaline (biological)
solutions, such an interpretation can never be made;
measured changes in [H'] (pH) can never tell us how
much Hi has moved into or out of the solution. A large
part of current biological literature dealing with supposed H+ transport through membranes needs to be
reevaluated on the basis of this simple property of alkaline solutions.
The sample calculations for a very simple experiment, presented in Table 1, demonstrate these properties of strong ion solutions numerically rather than
graphically. We begin with three solutions which have
very different initial [SID] values, and therefore very
different [HS] values. Two milliequivalents per litre
of H' and C1- are added to each s f these solutions,
as HC1. The added Cl- necessarily decreases the
+

CrlN. J. PHYSIOL. PHARMACOL. VOIL. 61, 1983

1450

T/znr,~1 . The addition of 2 rneq~iiv./Lof HCI to three strong ion solutions

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[s~rq
Solution

Initial

Final

Initial

Final

No. I
No. 2
No. 3

0.041
0.001
-0.039

0.039
-0.001
-0.041

1.07X10"
4 . 4 lo-"
~
3.9X 10 '

B.13xlO''
1 . 0 lo-'
~
4.1 X 10

NOTE: ,411 concentrations in eqrlivatents per litre. K:

Weak acid "'bufler" so&utio~ts

Consider next a slightly snore complex solution,
made up by adding a specified amount of a weak acid,
HA, to that simple strong ion solutiomn. By definition,
HA dissociates only partially into H and A- ions. The
three quantities, [H'l, [A 1, and [HA] must therefore
satisfy this dissociation equilibrium:
+

[A-j

K A x [HA]

KA is the weak acid dissociation constant.

We assume that HA and A take part in no other
reactions in the solution, so that the total amount of
substance "A" per Bitre must remain equal to the amouilt
initially present, which we call [ATOT]:

We must still have water dissociatioin equilibrium, as

before:
[f]

[HI] x [OH-]

Change

Ii~itial

+ 5 . 5 ~ 1 0 - ' ~ 11.99
1 .OX 10 '
10.36
t 2 . 0 BBB
~ '
1.41

Final

Change

11.95
3.00
1.39

-0.02
-7.30
-0.02

4.4 z; 10- l 4 ( e q t a i v . / ~ ) . '

[STD] value of each solution by the same amount,

2 rnequiv./L. We may then measure. or use Eq. 8 to
calculate, new [W'] values shown in the table for each
of the three solutions. Even though identical amounts of
H' were added in each case, the results show enormous
differences in the [H '1 changes between the three solutions. Even more striking. and confusing, is the lack of
correlation between these [H '1 changes and the associated pH changes which are supposed to represent them.
The reader is urged to carry out the calculations required for this table, or for other similar examples, to
appreciate the validity and i~nportanceof these aspects
of strong ion solution behavior.

1141 [H']

pH

[M'J

A:,'

and electrical neutrality, which this time requires that:

[I61 [SID] + [H'] - [A^] - [OH-] = 0
Now we have four independent equatic~nswhich this
systcm rrl~~st
always satisfy. Two of the quantities involved, [SID] and [ATol], are determined when we
make up the solution, and are not affected In any way
by the pi-cpcesscs these equations represent. They are thc
independent variables for this system. 'Twc~others, Kk
and Kqrwe treat as constant parameters for the system;
their values are assumed not to change significantly

even when [SID] or

do. The other four cjlmantities, [HA!. [ A 1, [ O H - ] , and ( H '1, must a l w a y ~adI~
They
just their values so as to satisfy asbar ~ C P L ecjjkliations.
are the dcpendctzt variables in the syster~iwhich are
determined by the values of [SIID] and IA-r,,l via these
four ccjuations.
Just as bcfore, the values of the dependent variables
can be found by "solving" the four equations by ahe
rules of algebra, but this time the algebra results in
cubic polynomial expressions. For cxarnple, the rcadcr
may verify that the sol~~tion
for [W * ] is
[ I 71

[H+]'

+ ( K , + [SID]) x

[IJ

+ I "

+ (K,$ x dlSIDl
X

[H']

[AloTl)- KGB
Kh x K: = ( I

Calculating numerical values from such an expression

is clearly not something to do by hand very often!
Historically, this probleila of calculating nura~crical
values from such nasty expressions has always been an
absolute csbstacle to qbarantitativc understanding. It has
prevented the quantitative analysis of even simple ionic
solutions like these fror~ibeing carried forward io useful
rcsults. Instead, a variety of sirnplificaticans has had t o
be used. and they have done much to ccpnfusc the subject. NOW,however, we can easily get a conlputer to do
all those calculations for US very quickly (Stewart B 98 I )
so that this potential problem is no longer of any practical significance. With that cornputcr assistance. we
can examine, and thorough1y understand, the precise
qa~antltativeprcpperties of these solutions just as easily
as we were able to do with strong ion colutions in the
previous section. This new fact makes modern quantitative acid- base analysis pmsible.
The co~nputercalculated behaviors of the dependent
variables iin this system are best exarnincd graphically,
and are presented in Figs. 4. 5 , and 6. First, however,
it is impcsi-tant to understand what those cumbersome
cubic polynomials Iikc ( 171 mean. Each of then1 contains just one of the dependent variables, but both of the
independermt variables, ISID] and [A,,,], and both of
the parameters, K4 and K:. Wc may therefore exprc\s
them symbolically in this way:

[MA1 F,,h([SIDl, ( A , , , I ? K : , &',)I

[A I = FA([SIDI,[AToIB,
KAB

WEAK

ACID SOLUTIONS

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H VERSUS

STRONG

ION DIFFERENCE,

CSID3

&SID3

Fmc;.4. Combined plots of [H+] and [OW-] versus [SIDI (Icft side) and pH versus ISID] (right side) for a weak acid solution
with [ATC)T]= 0.019 cquiv./L and K A = 3 x 10 ' equiv./k. Thc vertical dashed lines are at [SID] = [ATOT]= 0.019 equiv./L,
and [SID] = [ATOT]/2= 0.0095 equiv./l. as indicated on the right hand graph.
[OH-] F O ~ I( [SID1 [ATOI 1, Kd K A )
[ H t l = Flr([SID], [ A L o ~KL,
~ , KA)

F,(.Y)stands for the unique functional relationship

which each appropriate cubic polynomial expresses,
between the concentration of species i and the independent variables [SID] and [A1.cPTj.In words. the dcpendent quantitics [HA], [A 1, [OH 1, and [H '1 in this
wreak acid solution are each uniquely determined by the
independent quantities [SID] and [A
The last one of
these formal statements, or [I71 which it represents.
also provides the answer to our standard question: the
value of [MS] in weak acid solutions is determined by
the values of [SIB], [Alcyl], K A , and K k .
These f m a l representations, and the quantitative
relationships they symbolize, have several powerful
consequences. First, they say that thc trtat'y way any of
the four dependent variables in the systcn~can change
is as a result of a change in either [SID] or [A.i,,,]. or
both. Second, they indicate that we can never change
only one of thc dependent variables in this system,
because a change in either independent variable causes
a / / the dependent variables to change at the same tirne.
'Third, these statements tell us that nonc of those four
dependent variables is determined by any of the other
dependent variables. If a change in any one, say [H ' 1,
is measured, then we can not explain that changc its it
result of a change in [A 1, for example. Any change in
[ W t 1 implies that the iizdependc~atvariables rnust have
changed to cause that [ H t ] change. The change in the
independent variables must also cause a change in [A-] ,

so [A 1 changes when [ H L 1does, but the change in

[A-] does not cause the change in [H '1, it merely accompanies it. There must also be accompanying
changes in [HA] and [OH 1.
Another pl-(>foundgeneral property of these solution
systems is that we can not understand the behavior of
any of the dependent variables by looking at only one
of the four original equations. All four equations are
equally important; no single one of them can teil us
how, or why, any of thc dependent variables behaves as
it does in response to changes in [SIDJ or [AlOT].All the
equations must be taken into account, because we must
satisfy all of them before we can solve thc system and
find out how the dependent variables behave.
In particular, the so-called "buffer equation":
[ 141 , H + l
= KA
can not, and must not, be interpreted to indicate how
[H 'J depends on, or is determined by, [MA], [A 1, or
their ratio. [M ' 1 , [HA], and [ A p ] are ail dc>pencknt
variables, so that each of them is separately determined
by [SID] and [ATur\. Equation 14 is just onc of the four
equations they must all satisfy at the same time, and by
itself it docs not determine the value of any oine of these
variables. It alone, thcrefore, can not explain [H'] behavior. It can, of course, be used to ca/rulate any one
of the quantities in it if all tlne others except that one are
known, but that is true of any equation! Calculation is
not cause and effect; physics is more than just algebra!
Unfortunately, there are no useful algebraic approxinaations for this system like thc ones we were able to

CAN. J. PHYSIOL. PHAWMACOL. VOL. 61. 1983

ACID SOLUTIONS

WEAK

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[HAS

AND

-0.01

STRONG

CA-I

VERSUS

0. 0%

CSIDI

0. 02

ION DIFFERENCE, CSIDI

(egu i v./t>

RG. 5. Undissociated weak acid concentration, [HA], and weak acid anion concentration, [A -1. plotted against [SIDI, for
the same solution as Fig. 4. As indicated, the dashed vertical lines have the same meaning as in Fig. 4.

use in analyzing strong ion solutions, so we can only

examine the specific behaviors of the dependent variables in this system by looking at computer generated
plots of their values against [SIB] and [A,,,]. A thorough analysis of that sort would require a very large
number of graphs. Fortunately, solutions like this of
weak acids without 602are of alnnost no biological
interest because they so seldom occur. 602is everywhere! Furthermore, in most biological solutions which
do contain weak acids, [ATOT]tends to be relatively
constant. At this point therefore we shall only look at
variations with changes in [SIDJ, keeping [ATOT]constant. In the next section, after we have added C 0 2 we
shall look again at the effects of changes in [A.mT].
Figure 4 presents linear plots of [H'] and [OH-] and
a parallel plot of pH, all versus [SIB]. KA and [ATOT]
values used were those for standard blood plasma.
These cun7es clearly show more complex behavior
than is conventionally attributed to "buffers." As we
should expect from the fact that it is an acid. addition
of the weak acid at any given [SID] value results in
larger [H '1, and smaller [OH-], than are seen in a
strong ion solution without weak acid. Comparison of
the pH and [H'] curves shows that [ H t ] is changing
rapidly over the [SID] range centered around the [SID]
= [ATOT]/2point, where the pH curve shows what is
usually called "buffering." It can also be shown easily
that the slopes of both the pH and the [H'] curves over
this [SIB] range are considerably steeper than those of
the corresponding curves for a strong ion solution without weak acid. Tn other words, the addition of a weak
acid "buffer?' to a strong ion solution raises jH '1, lowers

pH, and causes both the pH and the [H ' ] of the solution
to change more rapidly with [SID] than they did before
the weak acid was added. The effects on (OH-] are just
the opposite. From these results we may conclude that
when [SID] is positive, a weak acid solution "buffers"
[OH-], but not [H'] or pH.
Figure 5 shows plots of [HA] and [Ap] versus [SID],
and demonstrates the surprisingly linear behavior of
[HA] and [A-] with changing [SID]. Note that at the
[SID] = [AToT]/2 point, [HA) = [Au]. From 1141 it
also follows that at this point [H ] = KA,or pH = pKA.
More detailed analysis shows that these conclusions are
only valid so long as KA is within about three orders of
magnitude of Kk. Outside those limits, the [HA] and
[A-] curves are not linear, and do not intersect at the
[SIE)] = [ATm1//2point.
Figure 6 shows a log-log plot of [H'] versus [SID],
to compare with Fig. 3 as well as with the [ H t ] and pH
curves in Fig. 4. It also brings some surprises. The
change in [ H t ] is much steeper over the "buffering"
range near [ATOT1/2than in strong ion solutions, rather
than shallower, as we might have expected from the
term "buffer." This is not merely a distortion produced
by the double log plot, but is consistent with the [PI']
cunre in Fig. 4, which show that [H'] does change
rapidly over this region. The distortions of the inverted
semilog or pH plot in Fig. 4 are the more difficult ones
to understand!
+

Solutions wifh carbon dioxide

Adding carbon dioxide tcp any aqueous solution
adds four molecular species: dissolved COz, symbol

WEAK A C I D

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EH+I

-10

-2

-10

AND

-4

STRDNG

-IB

-8

[OH-1

-10

-8

SOLUTIONS
CSIDI

VERSUS

18

-a

H ON DIFFERENCE,

18

-8

18

KS I87

-4

10

-2

(esuiv.%b>

FIG.6. Log-Iog plots of [#'I and [OH-] versus [SID] for the same solution as in Figs. 4 and 5, to compare with Fig. 3.
The vertical dashed line is at [ A T ~ T ] / as
~ . indicated.

C02(d);carbonic acid, H2C03;bicarbonate ion, HCO,;

and carbonate ion, ~ 0 : ~ .
The concentration of C02(R) is determined by the
CO, partial pressure in the gas with which the solution
is in equilibrium, pC02. The quantitative relationship is
called Henry's Law:
[181 [CO%W)I= Sco2 x pco2

Sco,is the C02 solubility coefficient. Its value depends

on temperature, other solute concentrations, and ionic
strength. At 37C in mammalian blood plasma, it is
mol * L-I m m ~ g - - ' (1 mmHg =
about 3 x
133.322 Pa).
Dissolved CO, combines with water to form carbonic
acid, H2CO3.The concentration sf H2CO3is therefore
proportional to [CO2(d3]and [H20].Remembering that
[H,O) is large and effectively constant, and substituting
for [C02]from [ 181, a quantitative relationship between
[H2C03Jand pCO, can be written which looks Just like
Henry's Law, but isn't, because H2CO3is not a gas:

water dissociation equilibrium, [2], and then combine

constants, the result is the more familiar farm:
[22] [Hi]
[HCo;I = Kc
PCO~
We can arrive at this same result by substituting for
[H2C03]from [19] into [21] and again combining constants. For convenience, therefore, we shall let [22]
replace both 1201 and [&I], and largely ignore both
[C02(d)] and [H2CO3]from here on.
HCO; dissociates to form CO:- and Ht . Equilibrium
for this reaction requires that:

Consider now a solution containing strong ions, a

single weak acid HA, and C02 at an externally regulated partial pressure pC02. The quantitative constraints
of equilibria, mass conservation, and electrical neutrality on all the components require us to write the following six equations:
Water dissociation equilibrium:

[H2C031 = Sg12co,X
SH,co,is about 1.5 x

equiv. L-' mrnHg-I, so that

[H2C03]is generally less than 0.5% of [C02(d)].
Dissolved C 0 2also combines with OH- ions to form
HCO;, and H2C03dissociates to form HCO; and Ht .
The quantitative expressions for the 2 equilibria are:

[2]

[Ht] x [OH-] = Kk
Weak acid dissociation equilibrium:

[I4]

iHt]
= K , iHA]
Conservation of mass for "A":

[20] [C02(d)] x [OH-] = K, x [HCO,]

[21] [H 7

[HCO,] = K2 x [H2C03]

If we combine [20] with Henry's Law, [l8], and with

Bicarbonate ion formatioia equilibrium:

[22] [Ht]

[HCO,] = Kc x pC02

C.%N. J. PHYSIOL. PHAKMACOL. VOI,. 61, 1983

1454

Carbonate ion formation equilibriuna:

1231 [H'] x [co:-]

K3 x [HCO;]

Electrical neutrality:

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[H'j - [HCOI] - [A ] - [CO: ]

- [OW 1 = 0
We have six simultaneous, independent equations
and just six unknown, dependent variables determined
by them, [HA], (A I , (HCO, 1, [ C O ~I. [OH 1, and
[Hi]. The three known, inilependt~nt variables are
ISID], [ATOT]and pC02
The algebra to solve these equations is routine, but
this time we get fourth-order polyno~nialsin the dependent variables. Just as in the previous case, we
should be conapletely stopped at this point without computer assistance. Now that we have it, we can easily
find out what these otherwise intractable polynonnials
tell us about the behavior of this kind of solution, simply by calculating the dependent variable values for any
given set of values of the independent variables and
parameters.
It should be clear from the arguments in the preceding sectionh that all the same conclusions apply in
this case as well, expanded to take care of the larger
numbers of independent anel dependent variables. In
particular, each of the dependent variables in this system is its own specific function of, and is uniquely
determined by, all three independent variables, as expressed by the following symbolic representations of
those fourth-order pslynomials:
[241 [SID]

[HA1
BA-1

=
=

FHA(BSID1, AT,,^ - pCO2)

F,(ISIDI, [A.ro-rl, pCO2)

BHCQ_II = ~ ~ ~ c o , ( l s I[ATu~Y,
Dl, P C O ~

1co:-1= Fc,,([SIDl,
[OH -1

lHSI

(Am17 pCO2)

FOFI
([SIDl , [AIoTI.p C 0 d

FII([SIDI, lA~o1.1,pCOa)

The exact solution for [ H A ]is

[25] [H']'
+ (K4

+ ([SID] + KA) X

[H']~
- Kk - Kc X pCO2)
X [H']'
(KL + Kc x pCOz) - K3 X K, X pCO2)
x [H'j - K, x K, x Kc X p C Q z = O

([SID] -

In logarithmic form, this equatio~n is called the

Henderson -Hasselbalch equation, arnd is often nnisrepresented as the clue to understanding [H '1 (pH) behavior. In fact, the behavior of [H ' ] and all klne other
dependent variables is determined, and co~npletelyexplained, by their having to obey nlE six of 121, 1141,
[l5l7[22]. [231, and 1241. Nothing less thain the whole
set of six equations is sufficient. To get 1251, for example. wlaich does explain [H ] behavior, we had to have
all six equations.
We have now answered our standard question for this
system. Equation 25 tells us that 111 any solution containing strong ions, a weak acid, ancl C02. the value of
[H'] is determined by, and only by, [SID], [Aroa],and
PCB, (asstanaing constant parameter values). To understand a change in [H'], we must look for a change in
one or more of the three independent variables which
caused it. Nothing else is needed, and nothing else will
do! The same is true independently for each of the other
five dependent variables.
+

Model systems for body fluids

What makes this solution and these equations interesting biologically is that they provide useful models
for body fluids. Blood plasnna contains strong ions
at a
(Na ' , K', C1-), weak acids (proteins), and @02
pC02 determined by the balance between tissue metabolism and respiration. If we use Eq. 25 for [H'j, and
substitute known arterial plasma values for (Na' 1,
[K'], [Cl-1, total protein, and pCO?, we find [H' I =
40 nequiv./L or pH 7.4. Equation 22 then produces
(HCOS] = 24 mequiv./ld. These are close to the
"normal9' values for standard arterial plasma at this
pC02. Interstitial fluid, ISF, contains negligible weak
acid concentrations. If we set [AToa)= O in the equations for [H ' 1 etc.. and use appropriate values for [SID]
and p@02,we get results which also match closely the
accepted values for this fluid. We shall therefore adopt
this idealized solution as a simplified nmodel for body
fluids, and use it to examine their quantitative properties for selected ranges of physiologically and cli~lically
interesting values of the independent variables.

Blood plasma model behavior

Now that we have three independent variables, and
- (KA X
six dependent ones, the number of possibly interesting
graphs is unmanageably large. Fortunately, the properJust as before, these dependent variables all change ties of this system, plus our conventional focus on [H'],
only with changes in the independent variables, and do provide a basis for selection. It depends partly on the
not determine each other. By itself, none of the original very different dynamics of the three independent varisix equations can explain the behavior of any s f the ables in body fluid systems. C 0 2 is constantly produced
in the tissues, and removed in the lungs, so that any
dependent variables. Equation 22 for HCB, formation
equilibrium, for example, does not, and can never tell change in respiration immediately causes significant
us how [H ' 1 depends on [HCO, 1. because it d ( ~ e , ~ n ' t . changes in the pC02 of plasma, and thus of other body

STANDARD PLASMA

STANDARD P L A S M A
IN+! VERSUS p C 0 2

p H VERSUS p C 0 2

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FIG. 7. [H+] plotted against pCOz for the Standard Plasma

model, a solution with the same KA and [AT,,,] values as used
in Flgs. 4, 5 , and 6, and [SID] values indicated on the curve,.
These curves are solutions of Eq. 25, with Kc. = 2.46 X 10-' '
( e q u i v . / ~ ) L / r n n a ~ KT
g , = 6 X 10 I equiv./I,, and other
paranaeter valiaes as in previous figures. The broken cross
centered at 40 nequiv./L and 40 nlmHg represents the
"normal" operating point for arterial blood, with [SID] =
42 l~equiv./L and [ATOT] -- 19 mequiv./L, here and in
Figs. 8, 9, 10, and 1 I .

fluids. pCOz therefore changes rapidly and often. Concentrations of strong ions in body fluids, on the other
hand, are detemined by absorption frorra the gut and
reinoval by the kidneys, so that changes in [SID] only
occur slowly, on the order of hours. Proteins are the
only significant weak acids m
i plasilsa, and their total
concentration is determined priinarily by the Iiver.
Changes usually occur only over pcriods of days. It is
therefore physiologically reasonable to examine the dependent variable behaviors in this system by plotting
against pC02, with [AToTl fixed, and [SIT>] set to a
series of values. Figure 7 shows ~ u c ha set of curves for

m'1.
Qualitatively, these curves tell ais that [H ] increases
as pCOz increases, so that C 0 2acts as an acid. [H'] also
increases as [SID] decreases, which is what we shoulel
expect frotrl the definition of [SID].
One striking feature of these curves is that their cur-

EFFECTS O F

LSIDI

Frci. 8. The same values as ill Fig. 7, plotted as pH instead

of [ U ' ] .

vature is so slight. For large values of ISID], [H']

varies almost linearly with pCO,. AS might be expected
frsrn the nonlinear nature of the [ H ' ] to pH transformation, the corresponding pH curves, shown in
Fig. 8, are much more highly curved, in a way which
makes no particular sense in terans of what is happening
to [Hf 1.
What is most important about these curves is that
they ~natchvery closely the corresponding "titration
curves" for isolated bIood plasma. This means that all
those proteins in the plasma, despite their chemical
csrnpliexity in detail, act as weak acids with sufficiently
restricted ranges of Ka values and effective csncentrations that they can be usefully approximated by a
single weak acid with a single Ka and [AT(PT].
Figalres 7 and 8 make clear the meaning of
"respiratory" acidosis and alkalosis. '6Respiratory"
means "due only to it change in pC02". and therefore
requires us to stay on one of the constant [SID] curves.
The terns acidosis and alkalosis in this context mean
"relative to normal[", since neutral pH for plasma is 6.7,
so that even at pH 6.9, plasnaa is still alkaline.
The other term often used, "rnetabolic" acidosis and
alkalosis, is less specific. since it refers to [H ' ] changes
not due to pCOz changes, and therefore due to SID] or

CAN. J. PHYSIQL. PHARMACOE. VOL. 61, 1983

STANDARD P L A S M A
CH+3

VERSUS p C 0 2

STANDARD PLASMA
p H VERSUS p C 0 2

EFFECTS OF PROTEIN CQIVCENTRAT I ON

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i
-

R G . 9. [W+]plotted against pCOz for the standard plasma

model, with \SID] fixed at 42 mequiv./L, and [ATOTJ set to
the values indicated beside the curves. These curves demonstrate the iinpartance for blood plasma [H'] sf changes in
plasma protein concentration (LATOTI). Campare with Fig. 7.
in which [ATOT] was held constant and [SIDJ was varied.

[AgOg]changes, or both. This quantitative analysis permits us to separate and understand these two kinds of
changes in new and very useful ways.
Thus, Fig. 7: or Fig. 8, combined with Eq. 24, provides the means to monitor a particular subject's
acid-base status quantitatively and precisely. If pH and
pC02 values are available for a plasma sample, and if
the subject's plasma protein concentration is known to
is, then the position of the
be near normal, so that [ATOT]
[H'] -pCO, point on Fig. 7, or the pH-pC02 point on
Fig. 8, tells us immediately the effective value for [SID]
in that plasma. If plasma electrolyte values are also
available, so that the inorganic component of [SIB],
([Na'] + [ K f ] - [Cl-]), is known, then the difference
between that measured inorganic component and the
effective [SID] value from the graph is a measure of the
unidentified strong ions which must be present in that
plasma. In "pure" lactic acidosis, for example, this
difference should be just equal to the lactate concentration in the plasma. In a case of diabetic acidosis, this
difference should agree closely with the measured value
for the total keto acids present.

FIG. 10. The same values as in Fig. 9. plotted as pH.

Compare with Fig. 8.

In pathological conditions, plasma protein concennsay change significantly.

tration, and therefore [ATOT],
The result is a different [PI'] (or pH) versus pCOz
curve, as Figs. 9 and 10 show. Changes in plasma
protein change the position, the slope, and the curvature
of these curves, and must be taken into account in
interpreting clinical acid- base data.
The primary function of the lungs is to exchange C 0 2
and O2 between plasma and alveolar gas. They do not
normally alter the strong ion composition or the protein
concentration of the plasma circulating through them.
So far as electrolyte chemistry is concerned, therefore,
the only significant change in plasma as it goes through
the lungs and is transformed from venous to arterial, is
in pC02. Venous plasma is merely arterial plasma with
respiratory acidosis! In Figs. 7 or 8, therefore, the venous to arterial transition can be simply represented by
movement along whatever [SID] line the plasma [M']
or pH currently falls on. (There is known to be a very
small change in plasma [SID] during this transition,
owing to movement of C1-, K', and Na' between
erythrocyte intracellulu fluid and plasma, usually
called the "chloride shift," but it is only I or 2 mequiv./
L, and is quantitatively negligible far acid-base purposes.) It follows that if acid-base data alee available

S T A N D A R D PLASMA
CHC03-3

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50

E F F E C T S OF
I

STANDARD PLASMA

VERSUS pC02
I

CSIDI

EFFECTS OF pCO2
0

'

LOG pC02
FIG. 11. [HCO,] plotted against pCOz for the Standard
Plasma model. Compare with Fig. 7.

for either a venous or an arterial plasma sample, then

the corresponding values for the other kind of plasma
can be calculated easily by changing the pC02 appropriately, either on Figs. 7 or 8, or by using Eq. 25. This
is clinically important, since it means that mixed venous samples may be just as informative as arterial
ones, which can usually be obtained only at much greater hazard to the patient. On the other hand, arterial
samples are automatically well mixed, whereas peripheral venous samples may not be.
Additional information about the properties of this
solution is presented in Figs. 11, 12, and 13. Figure 1l
shows how [HCO,] changes with [SIT)] and pC02, for
constant normal [ATOT]. Like Fig. 7: with which it
should be compared, it can also be used as a kind of
graphical calculator if desired, although the behavior of
[HCO,] is of much less acid-base interest once it is
realized that the value of [H'] is not determined by it.
Figures 12 and 13 summarize how all six dependent
variables in plasma depend on pCOz ancl on ISID], on
log-log scales to permit the very wide range of values
involved all to be shown on a single graph. These
curves emphasize the extreme minority position occupied by [H '1, as well as the variety of different
behaviors displayed by the six dependent variables. The

FIG. 12. Log-log plots of all six dependent variables versus pCB2 for the Standard Plasma model, with [SID] held
constant at 42 mequiv./L. K values and [AFOT]the same as in
Fig. 7. Note the decrease in [c@-]
with increasing g o 2 .
The ticks on the horizontal axes between 1 and 2 indicate the
normal operating pC02 of 40 mmHg.

most surprising, and counterintuitive, is [c@-1. It

shows a maximum at very low pC02 values, and then
decreases with increasing pCO, over the physiological
range. It is also the variable which changes most rapidly
with changes in [SID]; the [co:-] versus [SID] curve is
steeper than any of the others. As we should expect
from Eq. 2, [HS] and [OH-] always show mutually
complementary behavior.

Model for interstitial fluid (ISF)

Plasma and ISF differ primarily in their [ATor] v d ues. Compared with the plasma value of 19 mequiv. / l ,
the
value for ISF is only 1 or 2 rnequiv./l at
most, so that for modelling purposes we may take it to
be effectively zero. We can then solve Eq. 25 for this
condition, and for the slightly different [Na'], [K'],
and [Cl-] values in ISF, with the results for [H'] and
pH shown in Figs. 14 and 15. Figures 16 and 17 show
log-log plots of all the dependent variables (only four
in this solution) as functions of [SID] and of pC02, to
compare with Figs. 12 and 13 for plasma.

CAN. J . PIIYSBOI... PFIARMAC">L. VOL. h i . 1983

INTERSTITIAL FLUID

STANDARD P L A S M A
EFFECTS OF fSIDl

CH+I

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100

VERSUS p C 0 2

EFFECTS OF STRONG I O N ~IFFERENCE

-21
- 5 -5 - 4 -3 - 2 - 1

LOG

6SIE3

FIG. 13. Log- log plots of the salnc six dependent variables as in Fig. 1 2, versus [SID], with pC02 held constant at
41 m ~ n H g The
.
tickc on the [SID] axes between - 1 and -2
are at the nonnal plasma operating [SID] of 42 mequiv./L.

FIG. 14. [H'] plotted against pCO,, for the Standard Interstitial Fluid (ISF) mc)del, with [SID] values indicated on the
curves. Same K ' s as in Fig. 7 , but [AT(n] set to 0 throughout.

Temperature e&cts
Temperature elfects on dependent ion concentrations
in isolated sc~lutionscan be calculated easily by this
quantitative approach. We nced only to know how the
various Ks change with te~nperature. All the curves
presented in Figs. 1 through 17 will appear in different
positions when different temperatures, and therefore
Ks, are used in the calculatic~nswhich produce them.
In strong ion solutions, only KI, is involved. As [ 11]
and 1131 show, Kk will affect only [Ht] in alkaline
solutions and only [OW-] in acid solutions. In weak
acid solutions with no C 0 2 , both KL and K,, will change
with temperature, but their effects are only significant
over the [SID] range from 0 to [AT,lT].In solutions with
C 0 2 , all four Ks must be changed when tennperature
changes. K values at different temperatures are available in Robinson and Stokes (19591, and in Butler
19823.
Physiologically, interpretation of temperature effects
is made more ccsmplicated by changes in inetabolic and
cardiovascular f~incticanwhich alter independent variables, notably pC02 and ISID], by surprisingly large
amounts. Equation 25 still applies and still enables us to
calculate the resulting [H' ] changes, but it can not

answer the physiological cijuestic~n"what is the nac~st

appropriate [Ht] for this organism's body fluid at this
ternperature, and why'?" During the hypothermia accompanying open heart surgery, for example, what is
the optimal plasma [Wt], and how should plasma p C Q
be regulated by the anesthetist to prc~ducethat [H' j at
any given body temperature'? Much more information
about how, or even whether [H ' 1 is important, is
needed before these physiological questions can be
answered, but the quantitative approach now available
provides new avenues for exploration, and sets important constraints on possible answers.
Reeves (1972) has suggested that the answer to such
questions may depend on [A
the degree of
dissociation of the proteins involved. He and others
have shown that several organisms adjust their independent variable values with changes in temperature so that
the calculated degree of dissociation of the irn-aidazole
groups in plasma proteins mnnains essentially unchanged. If it were a general phenomenon, such regulation of protein dissociation could have important
implications for physiological responses to temperature
changes.

INTERSTITIAL FLUID
pH VERSUS p C 0 2

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E F F E C T S 8F

E F F E C T S QF p C 0 2

CSIDl

L O G pCOZ
Frc;. 15. Same values as in Fig. 14, plotted as pH.

Body fluid interactions

The preceding quantitative analysis, and its eralpl-nasis
on dependent versus independent ariablcs, has a profound%yitnportant implication for understanding the
possible ionic interactions betwcen body fluids,
tl-arough the membranes which separate thenm. It tells us
that they can on1y interact through their intfq)entipilt
variables. 'I'o change [ H ' j in any body fluicl, we have
to change pCO?, [SID], or [ A r c , r ] ,the independent variables irl f87hitf/1iid.As already pointcd oinf, the fact that
[ H ' 1 is a dependent variable means that anovial3 H '
from one solution to another, bjr itself will not produce,
and can not explain, a change in [ l i ' ] (or pH) in either
sola~tion.The same is true of [HCO, 1, and all the other
dependent variables. This mean\ that these acid- ba5e
or ionic interactions are xnukh simpler to understand
than might f i r ~ tappear; we only have to loc~kat three
iradepcnticnf variables.
&'O2is very sol~lble,and almost all biological mcmbranes are highly permeable t o it. so that it diffuses
rapidly between body fluids on the basis of pC02 cfifkrences between them. There is an overall pC02 gradient
from tissues to alveolar gas. but it is rera~arkablysanall;
the tissuc-alveolar difference is only on the ordcr of a
k w mmHg in most situations. We can therefor6 [lot
look to manipulation of pCO, as a convenient way for

FIG. 16. 1,c~g-log plots of the fo~ardependent variables in

the Standard ISF model versus pCO7. [SID] held constant at
3 I rnequiv./l,.

body fluids to interact with each other itrnically. On the

other hand, the pervasiveness of CO, cc~upledwith the
lability of pCO? via respiration makes pCO? thc control
variable of choice to bring about sirnultaneous short
term changes in all body fluid [ H 1 values.
At the other extreme, most nlembrancs arc highly
inapermcable to proteins niost of the time, and protein
movements betwien body fluids are not used as a-means
of ionic interaction.
That leaeies only strong ions, which are well known
to be moved between body fluids by a variety of special
naechanisms ("pulnps") in many nneralbranes. Most of
the ionic interactions which occur betwcen body fluids
occur through these strong ion movements, ancl [SILII
changes are the nlajor vihicle for body fluid inferactions.
The most coanplicatcd case is probably the kidney,
where the tubule tnernbrane has many different specific
properties at different pocitions along its length. The
same argiarncnts apply nonetheless, and thi\ analysis
rnakes clear that the major nlecbanism by whiclm the
kidney can affect plasma [ H ' j is the adjust~nentof
plasma [SIlIJ by differential rernoval of Na', K ' and
C1 from plasma to urine. As plasraaa and urine are
separate solutions, the [ H '1 of urine is not relevant to

14641,

CAN. J. PHYSIOL. PHAWMACOL. VOL. 61, 1983

INTERSTITIAL FLUID

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EFFECTS OF CSIDI

HCO, movements, so [Ht ] can not be.

Stomach acid formation is another clear example.
This quantitative analysis makes clear that the oxyntic
cells can only make that acid by adjusting [SID], not by
pumping H'. They may excrete C1- ions, or absorb Ma'
and K ' , or both, but the end result must be a high
negative [SID] value in the luminal fluid, of the order
of -100 mequiv./L, and that can only be achieved by
moving strong ions, not by moving H '.
In all these cases. some other ions must accompany
the strong ions being moved, for reasons of electrical
neutrality, and those accompanying ions must not be
strong ions. It should be clear that so long as they do not
their identity is not important to the final
alter [A~r(,T],
[SID], and therefore [H'], [HCO, I , etc. values
achieved. When Cl- is "pumped," either an H' must
must move
accompany it, or an O H or HCO, or
in the opposite direction, but so long as carbonic anhydrase is present, it does not matter which. The final
result will be a change in [SID] owing tca the C1- movement, and it is the final [SID] value which determines
the final [Hi], [OM 1, [HCOI] and [co:-] values. not
the amounts of these ions which may have been moved.

c(Z

LOG CSIDl
FIG. 17. Log-log plots of the 4 dependent variables in the
Standard ISF model versus [SID]. pCOz held constant at 47

mmHg.

the [H'] of plasma, and the conventlonal treatment of

the urine as a vehicle for removing HS from the body is
incorrect. What determines the VH'] of plasma isthe
pCOz, the [SIDJ and the [ATJT]epf plasnm. If the kidneys are to lower the [Ht] of plasma, they must excrete
more C1- than Na' from it, so as to raise plasma [SID].
Synthesizing NH, and excreting it as NH: can have no
effect on plasma [H'], although it may be very important in keeping the urine [H'] from rising too far due
to the excess C1-, and therefore decreased [SID] value
in the urine.
Exactly similar arguments apply to HCO,, since
[HCO,') is a dependent variable. Movement of HCO,
into or out of the plasma at the kidney tubules can not
alter plasma [Hi], so long as carbonic anhydrase is
effective. In general, HCO, movements across membranes between body fluids can not alter the equilibrium
[H' ] or [HCO,] of those fluids. In some cases, the
dynamics of the situation, or the absence of carbonic
anhydrase activity, may prevent equilibration with
pCOf in one of the fluids, and then more complicated
calculations are called for, but they can still be carried
out (Bidani et al. 1978). In most cases, however, carbonic anhydrase is present and active, the independent
variable is pC02, and it is not significantly affected by

Acid -base balance

Whole body "acid- base balance" presumably means
"how is the [H'] (pH) of body fluids regulated?" The
answer which this quantitative analysis provides is remarkably simple, and may be summarized in four state] (pH), [HCO,], etc., of each body
ments. (i) The [Ht
fluid is determined by the pC02, [SID]. and [ATOT]
values in that %fluid.(ii) Most membranes separating
body fluids are not normally permeable to protein, so
that [ATOT]interactions are not normally significant.
[ATOT]changes may occur in pathological situations,
and when they do, they have consequences for [H '1
in the fluids between which they occur. Normally,
however, it is [SID] and pCOz changes which determine [H'], (pH), and [HCO,] changes in body fluids.
(iii) Circulating plasma carries C 0 2to the lungs, which
set the pCO, of arterial blood, and thereby, indirectly,
the pC02 of the tissues and tissue fluids. Normally,
changes in tissue C 0 2 production are matched by
changes in circulation and respiration so that pCO, is
well controlled. but it may be changed rapidly when
needed, to change [H'], [HCO;], etc., in all body
fluids. ( i v ) Strong ions are moved between body fluids
through membranes, and the resulting changes in [SID]
values provide the major mechanism for acid- base interactions between body fluids. Changes in plasma
strong ion concentrations produced by kidney and gut
activity are communicated to other body fluids, with
appropriate modifications by Donnan effects, since
capillary membranes a-e generally permeable to strong
ions but not proteins. The kidneys and gut thereby

ACID-EASE

BALANCE

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VENTILATION

CA - l

[HA3
CC03=3

CQH-I
LH+1 CpH>

FIG. 18. Schematic diagram which summarizes the major

physiological organs and processes involved in dependent
variable regulation in circulating plasma.

are the primary controllers of body fluid [SID] values.

This control is much slower than that for pC02, and is
therefore generally involved in chronic acid-base
alterations.
Figure 18 sum~glarizes these relationships schematically, and presents qualitatively the results of the
quantitative analysis.

Summary and conclusions

( I ) Quantitative understanding of ionic solutio~ashas
become practical now that computers provide easy
access to numerical solutions for hitherto intrdctable
equations. The implications for the analysis and understanding of ionic behavior in body fluids are profound,
and should be more thoroughly explored. Many current
models for ion movement through biological membranes appear to require modification on the basis of
this quantitative analysis.
(2) Quantitative understanding emphasizes dis-

tinctions between independent and dependent variables

in ionic solution systems. In body fluids, independent
variables are pC02, net strong ion charge ([SID]), and
total weak acid ([ATOT]),usually protein. [HCO,],
IHA], [ K ] ,[co:-1. [OH J. and [Ht ] (or pH) are
dependent variables. Their values in any solution are
determined by the values of the independent variables
and the four parameters, and can be calculated from 121,
1141, 1151, [221, W 1 , and P41.
(3) Those six equations, or their algebraic solutions
(such as [25) for [H ' I ) provide the means for explaining
quantitatively the behavior of all six dependent ion concentrations in all body fluids.
(4) Movements of 14' between solutio~mscan not
affect [PI '1 of either solution; only changes in independent variables can. Body fluids interact through the
membranes separating them primarily by movements of
strong ions, which alter [SII)] values.
(5) Temperature effects on dependent ion concentrations can be calculated from known changes in the
equilibrium parameters. Physiological changes in independent variables complicate the situation, but not the
calculations.
(6) Whole body acid-base balance can be understood quantitatively in terms of just three independent
variables, pC02, [SIR], and total protein, and their
physiological regulation by the lungs, kidneys. gut, and
liver.
BIDAKI,A . , E. D. CRANUALL,
and KOBEK~E. FORSTER.
1978. Analysis of postcapillary pH changes in blood in
vivo after gas exchange. J. Appl. Physiol. Respir. Environ.
Exercise Physiol. 44(5): 770-781.
BUTLER,JAMESN. 1982. Carbon dioxide equilibria and their
applications. Addison-Wesley Pub. Co. Reading, Mass.
GUGGENHEIM,
E. A. 1957. Thermodynamics, an advanced
treatment for chemists and physicists. 3rd ed. Chap. 9.
North-Holland Pub. Co., Amsterdam.
HARNED,HERBERTS., and BENTONB. OWEX. 1958. The
physical chemistry of electrolytic solutions. 3rd ed. Van
Nostrand-Reinhold, New York.
REEVES,ROBERTBLAKE.1972. An imidazole alphastat hypothesis for vertebrate acid-base regulation: tissue carbon
dioxide content and body temperature in bullfrogs. Respir.
Physiol . 14: 2 19- 236.
ROBINSON,
R. A., and R. PI. STOKES.8959. Electrolytic
solutions. 2nd ed. Butterworths Scientific Publications,
London.
STEWART,PETERA. 198 1 . How to understand acid-base: a
quantitative acid- base primer for biology and medicine.
Elsevier North Holland, New York.