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Moderm quantitative acid- base chemistry

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

Can. J. Physiol. Pharmacol. Downloaded from by UNIV CHICAGO on 11/13/14
For personal use only.

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]

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.

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

Dependent variables are internal to a system: their values are determined by the systcm equations and by the values of the lndependent variables. is of the order of 10 ''M (Harned and Owen l958). The analysis to follow will establish what does determine changes in [ H t ] . Quantitative analysis also requires us to recognize the n t . and do not determine each other. The question is. activities or effective concentrations should always be used when dealing with reaction ratcs or equilibrium constants.Ol tern1 may therefore be considered constant." While this analysis and its computer implementation are simple and straightforward. and mechanistic explanations. so that this dissociation ~ ~process t has a completely negligible effect On the Water concentration The il1. the first question we normally want to ask is "what is the (implying just one) mechanism which produces a change in [H']'?" In fact. most complex. but the dependent variables are not causally related to each other. understanding of hydrogen ion behavior. also depends on whether the [] symbols denote concentrations or activities. . and on the presence of specific ions.for H7&rtc. Although often overlooked. but they do not determine the value of [H']. the dissociation constant for water. (4). That final C02 containing solution.nrcresearchpress. It should also be recognized that activity corrections apply to chemical concentrations. as in the dependent variables are ~~ecessarily they all depend on changes in the independent ones. In solutions other than pure water. because the [H20]term does. and quantitative understanding requires that we take them all into account. we must always have K. 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. Water is therefore a strongly ionizing solvent. Strictly speaking. 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. and by themselves can not explain changes in it. to reap its full benefits requires an attitude towards solutions as systems which is quite different from the conventional one. Downloaded from www. Fortunately. and extraordfnarily high molar concentration (about 55. very slight dissociation into H i and OH ions.r.It is very sensitive to temperature. but not to charges per ~ e . Physiol. but the analysis applies regardless of complexity. While the extent of water dissociation is minute..5 M). and the identification of these two kinds of variables will be an essential part of that analysis. 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. nor by changes in the system. and on ionic strength. Dependent variable values can not be set arbitrarily. and are not affected by the q u a tions which govern the system. nor even correct qualitative. the large molar concentration of liquid water is also iinportant for the analysis of hydrogen ion bchavior. will provide a good approximation to mammalian body fluids. The numerical value of K k . and must be replaced by the one posed above which implies more than one factor interacting to determine [H ' ]. Pharmacol. 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. 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. therefore.Can. There must always be as many equations as there are dependent variables. Changes orre related. the difference between activities and concentrations is usually not large. inappropriately wortled. several interacting mechanisms are always involved. linear. That it has this effect on itself partly explains its own slight dissociation. HS naovemei~tsinto or out of a solution do not provide quantitative explanations for changes in [H ' I . Since the water dissociation reaction equilibrates rapidly. and the dependent variables must satisfy all those equations simultaneously. and [ I ] rewritten as: KL is called the ion product. J. because Kw is. enormous biological importance is attributed to it. stepwise. Because we are conditioned to simple. as well as of all the other constants we shall introduce later. but must always adapt to the independent variable valuec. it may then become important to use activities to ensure numerical agreement with real system behavior. nor by each other. Only changes in the independent variables in a system can cause changes in the dependent ones. and our analysis s f it will dispel much of the mystery surrounding physiological "acid-base balance. Three of them are iinportant for this analysis: high dielectric constant. They may contribute part of the mechanism for changing [Hi ] in some situations. No single mechanism in these complex systems can ever by itself provide quantitative. its value also depends on osmolarity. For by UNIV CHICAGO on 11/13/14 For personal use only. since [Hf] is a dependent variable. ~ ~ dvariable ~ values ~ are ~ imposed ~ don a ~ system from outside.

PHYSIOL. 61.[Cl 1) in [ 5 ] .i. this means that: [ 2 ]and ( 31 are simultaneoe~s. or determined by. electrical neutrality muqt always be preserbetl (Gusgenheirra 1957). ""K:". [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). 'l'he rule\ of algebra. [2j and [ 51.nrcresearchpress. [SID] slmcbuld be thoe~gtntof as a . This gives us [ H ' l ' = K : or [ I f ] = To solve for IOH 1. ranti represent it by the symbol (SIIIj. expressing the rule\ of the game for [ I I ' J aend [Oil ion\ arc Na and Cl . we write the equaticsnu for clcctrical neutrality and for wrater dissc~clationequilibriun-8. Pharmacol. their known concenta-ationswould also appear within the ( ). We call it the S ~ T O B PCIM d[flirefzc-~. J. Electrical neutrality nlcans that the sum of all the charges in the solution must be p. ' h i s gives us 1011 I' = Kk. as in all solutions.ifiotz. then [SID] will be ncgativc..1446 CAN. 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.[CI 1112 - - These expressionc answer the question '\+hat c1etermines the [I1' 1 of pure water?" The aalswca. in turn. They constitute the urabreakakk "rules of the game" which control how thoss two concentrrations must behave. We can not. write a diysociation uquiilibriium for theral. Water dis\c~ciationequilibrium is still constrained by equation 121. Physiol. In pure water. and very convenient. but they are a l w a y ~present in n~a~ch lower concentrations than Na or CI . and OI 1 ions. 'H'hcy also tell that K: dctcrn-aints the [OII ] of pure water. Consider wow a simple strong ion soluticr1-8nnadc up by mixing appropriate volumeh of specified %QCl and NaOH scslutions.. but they also occur at low concea~traaionsin coanparison with N a ' and CI .com by UNIV CHICAGO on 11/13/14 For personal use only. but these are outside the It is therefore pernnissikle. are simply always present in the solution at whatever cc~ilcentration they were originally added. VOL..[CI 1). Strong electrolytes dissociate completely for all practical purposes. simultaneouq equations. It Inlay be quantitatively signlficatat under some circumstances. What we want to krlerw is "R hat deteraa~ine\the [ H ' ] of this sole~tion'?l" To answci. ttaat requires As cmly strong ioras have been added. the nlo\t iaamportant + 171 loll-]= \/K: + ([Na'] - -k [CI ]1'/4 ( [ N a ' ] . That solution will contain Na' . The final results for pure water therefore are: k'z. expressed only in tenns of the parameter K. equations which [ I l t ] and [OH-] must always satisfy in 1m-e water. strong ion is K ' . or [ O H p ] = \/=. For this solution.and [71.atl . Ac the] remain completely iiissociated. are also strong ionc. K ' and SO. so that we usually neglect them. to represent this ( ) quantity by a sl~ortsymbol instead of having to write ~ . then ([Nat1 . we call use 131 to ~ub~titinte fi~r [OIl ] in ['I. Intracellularly. 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. [(>I. Lactic acid ha$ a dissociation constant tsn the order of I 0 ' eyuiv . Strong ion.(Cl j)/2 These equations dell us that ( H ' ] ant1 (OH -1 arc functions of. no ncw equilibria are involved. 1983 Can. Bcforc exploring in detail what these cquatio~lssay.that question. In this sisripls cane.: and ([N. the concentration of strong cation positive charge in the solutioa~ which is Paot electrically balanced by strong anion negative charge. to make a final volume of 1 E. ~ it out in detail each time.just as wc iiid fk~rwader.[Cl-1) B3 clear11 the quantity u hich determines the values of both [ H ) and (OH ] in thin system. so we know the vale~eof this ( ) term. PHARM. Downloaded from www. but this tianc the results are the follow ing qttacfratic exprcsxions: [6] (H-1 = t'K\l + ( [ N a '] [Cl ] ~ ' / 4 ( [ N a b] . Node that if strong anions exceed strong cations. therefore.4COL. and we are concerned fc~rhe tnornellt only with strictly isolated solution. both in thc electrical neutrality equation. the values of both K. ]ti ' . it fi~llowsthat they do not participate in any reactions \albthin thc~soh. the whole process is rather trivial. C1 .'. (Balce again we have two independent. It is the rzcf strong icva positive charge. [ 5 ] . To scll~efor [H' 1. such as K I or lactate . If we consider K: to be a known constant parameter. We can combine and rearrange tl~eanby the rules of algebra just as before. J. we uhe 131 to substitute for [ H ' ] in 121. 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./I. consider the quantity ( [ S a t ] .'They t-aaay react with other entities such as ceI1 anennbranes.inc1cpenden1. so that lactate behaercs as an organic strong ion when present in plahnasa or cxtracelltalar fleaids. and only there.the most concen!rated inorganic \tn. Hecauhe I I ' anc1 O H are the only ions present in pure water. If trther strong ions were present. Ca" and ~ g may " function as strong ions.and in [6] and 171. In ma~nrnalianextracellular solutia~nc. but exactly the same proced~arcc apply in the hame way in all the following nnore conlplicated cascs. Sormaetirncs.

Hydrogen ion ([H+]f and hydroxyl ion ([OH I) conccntratisns. 1. Note the smooth gentle curves of transition from linear to nonlinear behavior on going through [SID] = 0./l. over the [SIDI range from . but difkrently.)'.4 STRONG I 8 N DIFFERENCE. symbol for the net unbalanced positive charge on the strong ions present in the solution. When [SIII] = 0. and pH versus [SID] for any strong ion solution. 1 CSIDS FIG.OG15 fl STRONG ION DIFFERENCE. indicates.1.ION SOLUTIONS STRONG Can. CSIDl FIG. for any strong ion solution. I . As the solution must be electrically neutral.4 -0.10 to + 1 0 mequiv.2 9. the value for blood plasma at 37"C. J. over the [SID] range from . by UNIV CHICAGO on 11/13/14 For personal use only. ( 5 ) . Figures 1 ./l. So is [OH-]. Pharmacol. 6 -0. 2. as the electrical neutrality equation. pH AND [OH-I VERSUS CSIDl -0.6 0. CH+S AND C8H-1 O i " ' i " " ' " ' " " -1 -0. Downloaded from www. for this and all the following figures. Equations 6 ancf 7 for [ H ' ] and [OH 1 can now be written more neatly in terms of [S119]: - 181 IH'] 191 [OH ] \ / K .4 x HO '"(equiv.10 "to + 1 0 ' equiv. and 3 display the behavior of these .nrcresearchpress.2 " " 0 VERSUS CSIBI t 0. &l@5 0. Compare the very steep change in pH around [SID] = 0 with the gradual [Hf ] transition over this range displayed in Fig. as indicated by the arrow. [OH.2. /k. K k = 4.8 0. IH+]. STRONG ION SOLUTIONS CH+3. + ( [ 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]. [SIDI tm~ustalways be balanced by the net charge on all the other weak ions in the solution.8 .8 . [H'] = [OH 1 = VIE. plotted against strong ion difference ([SIDJ).

is therefore negligible compared with ( [ S I D ] / ~ )in~ [8] and [9]./L. while [H"] is large and equal to the magnitude of [SID]. 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 . even though it is rzot one. 1983 STRONG CH+3 AND COH-3 LOG-LOG 7 \ Can. Adding x moles of H' per litre to such an acid solution (as HCI [13] [PI'] = KL/[SID] Now./~)'. In the rest of the equation. First. however. [OH-] is greater than [H'] . [H'] is larger than [OH-]. In this case. and [H'] must be kept equal to -[SID].com by UNIV CHICAGO on 11/13/14 For personal use only. It is important to understand that this happens because the added Cl-. and plots Hog([H+j)and log ([OH-]) versus log([SIB]).ions increase the magnitude of . 61. and result in [H' j decreasing by x. The addition of x moles of H' per Iitre to this alkaline solution (as HCI) will not change [H"] by x this time. when strong base cations exceed strong acid anions. and the solution is acidic. 11. 2.still changes [SIDI by x. and reinforces their significance. and varies inversely with [SID]. the solution is alkaline. on the other hand. 1131 and (9) become [ l o ] [H '1 = . Log-log plots of [H+3 and [OH-] versus [SIB] for any strong ion solution. while [OH-] seems to behave like a strong ion. J./L. PHAWMACBL. regardless of the sign of [SIDJ. This simple linear behavior of [PIil with . which can now be rewritten by substituting -[SID] for [H'] from [lo]: Here again. The left side of this graph has the horizontal scale direction reversed. have been taken out of the solution.B to + 1 equiv. since it changes directly with [SID]. i t only occurs whe~z[SiD] is negative and the solution is acidic. [ H t ] seems to behave like a strong ion in such acid solutions.[SID] by x. for example. so that the value of the whole square root term will be +[SID]/2. VOL.CAN. not simply because of the added hydrogen ions. PHYSIOL. and clearly depends not only on how much [SID] . Physiol. In blood plasma. Similarly. +18-3 CSIDI RG. CDH-1 +18-5 STRONG I O N DIFFERENCE.nrcresearchpress. ION SOLUTIONS VERSUS PLOTS la-3 CSIDI r CH+I . The slopes of the linear portions of the curves must be interpreted accordingly. As a result. over the [SIB] range from .[SID] can be seen clearly on the left side of the graphs in each of Figs. [2]. adding x moles per litre of Na' (as NaOH) will make -[SIID] more positive by x. KL is of the order of 18-l4 (equiv. then (SID] is negative. [H'] is very small. The algebra behind some of those surprises is illuminating. [OH-] is very small in a strong acid solution. and varies inversely with the value of (SID]. its more exact value can be found from [2] rewritten in this form: ~ 1 1 3 [OH-] = -K:/[SIDI In words. [ H t ] is not exactly zero. K:. even though the C1. while [SID] is usually on the order of lo-' equiv. Whenever strong acid anions exceed strong base cations. Its more exact value has to be found from the water dissociation equation. the sign of [SID] makes a profound difference to the way in which the values of [H'] and [OH-I depend on it. even though no H t per . and 3. Pharmacol. of course. This time. How much [H'] will change can be calculated from [8\ or 1131. [SID] is positive./l. [SID] is normally close to 40 rnequiv. and provide a number of surprises. Downloaded from www.[SID] and [OH-] = 0 [I21 [OH-] = [SID] and [H'] = 0 [OH-] isn't quite zero. I . and to the same excellent approximation as before. equations graphically.

8 and 9. that measured increases in [H'] can sometimes be interpreted to indicate how much H + has been added to a solution. The pH curve also displays a highly misleading symmetry on the two sides of the origin. or to show how some specific process "depends on pH. Pharmacol. In both Fig. its disadvantage is its nonlinearity. 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. by itself. In alkaline (biological) solutions. is not generally recognized. can be seen clearly. value of (H ' 1 (and pH) at this acid-base neutral point. The sample calculations for a very simple experiment. but over a much larger range of ISID] magnitudes. That is not true for the inverse semilog or pH plot included in Fig. Nothing corresponding to it happens to the chemically significant quantity [ H ' ] . That means we can not arrange a series of experiments in which only [ H t ] is varied. The added Cl. on Fig. The simple linear behavior of [H'] when (SID] is negative.necessarily decreases the + . and from these by UNIV CHICAGO on 11/13/14 For personal use only. all that such experiments can demonstrate is the dependence of enzyme activity on [SID]. 2. and can not. Because of the necessary reciprocal relationship between [OH-] and ( H i ] imposed by the requirement of water dissociation equilibrium. I what happens to [H '1 around [SID] = 0. and all quantities other than [H ] are kept constant. measured changes in [H'] (pH) can never tell us how much Hi has moved into or out of the solution." Measurements of enzyme activity in solutions of different pH. the acid-base neutrality point is easy to see as the point at which [H') = [OH-). that any change in [SID] must change hotlz [OH-] and [H']. The curves in the accompanying figures clearly show these aspects of [H'] and [OH-] behavior2. The obvious advantage of such a plot is the wide range of magnitudes it can display. It also includes the pH curve. 1 and Fig. 3. In Fig. Because they are. 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. [Ht 1. In fadct. we can recognize the very steep pH change around this point for the mathematical artefact that it is. 2. depending on whether [SID] is negative or positive. 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. and therefore very different [HS] values. J. where [SID] is negative and [ H i ] is large. 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. and vice versa. and [H'] all change. such an interpretation can never be made. 1 at the horizontal arrow. [H ' I and [OH'-] are plotted against [SlD] over a small range of [SID) values on either side of neutrality ([SID] = 0). Figure 2 shows a similar plot. for example. Downloaded from www. it almost never behaves like a strong ion because biological solutions are almost never acidic. In most physiological situations the magnitudes of [OH-) and its changes are at least ten times larger than the corresponding values for [H']. despite its familiarity. As we shall see. The activity may actually depend on [H']. The amount of H ' added is essentially irrelevant to either the amount by which [H ' 1 changes or the final [H'] value achieved. so that it is not possible to change onby the [H'] (or pH) of a solution. which it clearly does not. demonstrate these properties of strong ion solutions numerically rather than graphically. and suggests that [H'] behaves in much the same way in either acidic or alkaline solutions. which is consequently much more difficult to interpret. but correlation is not the same as physical dependence. 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. while enzyme activity. presented in Table 1.Can. It is only in acidic solutions. Two milliequivalents per litre of H' and C1. but such experiments can not demonstrate that it does." Now that we know from Fig. only that it changes when [SID]. 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. In strong ion solutions. and the smooth gradual transition to the nonlinear inverse behavior when [SID] is posltive. which is the classical strong acid-strong base "pH titration curve. but at least that nonlinearity is the same on both axes. The precisely complementary behavior of [OH-] is equally obvious. It follows from Eqs. [OH-] must always go up when [H '1 goes down. as HC1. and [OH-] are all dependent variables. Since the value of K : is specific for each solution. 1 . We begin with three solutions which have very different initial [SID] values. their behaviors must be correlated. [SID] is the independent variable in these solutions. Physiol. this must always be the point at as indicated which both these quantities equal <. Because of Eq. but also on what the initial [SID) value of the solution was. H is usually treated as if it always behaved like a strong ion. [OH-]. These conclusions work in the opposite direction as well. This dramatic difference in the behavior of [H'] and of [OH 1. establish causal mechanisms. changes because of the added C1-.nrcresearchpress.are added to each s f these solutions.

We may then measure. 0 BBB ~ ' 1. It has prevented the quantitative analysis of even simple ionic solutions like these fror~ibeing carried forward io useful rcsults.00 1. and ( H '1.l 4 ( e q t a i v . Just as bcfore.001 -0.99 1 . must a l w a y ~adI~ They just their values so as to satisfy asbar ~ C P L ecjjkliations. 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. new [W'] values shown in the table for each of the three solutions.ions. as before: [f] [HI] x [OH-] = Change Ii~itial + 5 . Kk and Kqrwe treat as constant parameters for the system. but this time the algebra results in cubic polynomial expressions. The reader is urged to carry out the calculations required for this table. KAB . + [SID]) x [IJ + I " + (K. VOIL.39 -0. or use Eq. 4 lo-" ~ 3. which we call [ATOT]: We must still have water dissociatioin equilibrium. ISID] and [A. 61. the rcadcr may verify that the sol~~tion for [W * ] is [ I 71 [H+]' + ( K .)I [A I = FA([SIDI. and thorough1y understand.411 concentrations in eqrlivatents per litre.CrlN. [s~rq Solution Initial Final Initial Final No. 0 lo-' ~ 4. PHYSIOL.041 1../Lof HCI to three strong ion solutions Can. Instead. Each of then1 contains just one of the dependent variables.OX 10 ' 10.$ x dlSIDl X [H'] - [AloTl).' and electrical neutrality.1 X 10 NOTE: . however. We assume that HA and A take part in no other reactions in the solution. the results show enormous differences in the [H '1 changes between the three solutions. Physiol. Downloaded from www. and 6. and are not affected In any way by the pi-cpcesscs these equations represent. is the lack of correlation between these [H '1 changes and the associated pH changes which are supposed to represent them. ' [STD] value of each solution by the same amount.36 t 2 . First. we can examine. and [HA] must therefore satisfy this dissociation equilibrium: + [A-j = K A x [HA] KA is the weak acid dissociation constant. to that simple strong ion solutiomn. This new fact makes modern quantitative acid.07X10" 4 . / ~ ) . Pharmacol. to appreciate the validity and i~nportanceof these aspects of strong ion solution behavior.]. HA dissociates only partially into H and A. [ A 1. &'. 5 . 1141 [H'] pH [M'J A:. this probleila of calculating nura~crical values from such nasty expressions has always been an absolute csbstacle to qbarantitativc understanding.. I ? K : . 3 0. and are presented in Figs.039 -0. With that cornputcr assistance. by UNIV CHICAGO on 11/13/14 For personal use only.9X 10 ' B. which this time requires that: [I61 [SID] + [H'] . their values are assumed not to change significantly even when [SID] or do. are the dcpendctzt variables in the syster~iwhich are determined by the values of [SIID] and IA-r. 2 No.however.] . [A 1. HA. . and confusing. J. made up by adding a specified amount of a weak acid.~1 . NOW. Even more striking. a variety of sirnplificaticans has had t o be used.30 -0. Even though identical amounts of H' were added in each case. The co~nputercalculated behaviors of the dependent variables iin this system are best exarnincd graphically. For cxarnple.13xlO'' 1 . the values of the dependent variables can be found by "solving" the four equations by ahe rules of algebra.nrcresearchpress. are determined when we make up the solution.base analysis pmsible. 8 to calculate. the precise qa~antltativeprcpperties of these solutions just as easily as we were able to do with strong ion colutions in the previous section.41 + Final Change 11.02 4.039 0. Two of the quantities involved. K4 and K:. .4 z. K: = Weak acid "'bufler" so&utio~ts Consider next a slightly snore complex solution.041 0. 5 ~ 1 0 .95 3. but both of the independermt variables. I No. The three quantities. Wc may therefore exprc\s them symbolically in this way: - [MA1 F./L. or for other similar examples.[OH-] = 0 Now we have four independent equatic~nswhich this systcm rrl~~st always satisfy. [SID] and [ATol]. 1983 1450 T/znr. The other four cjlmantities. 'Twc~others.h([SIDl. ( A .[AToIB..001 -0.02 -7. [ O H . J. The addition of 2 rneq~iiv. 4..' ~ 11. and they have done much to ccpnfusc the subject. [H'l.[A^] . and both of the parameters. They are thc independent variables for this system.KGB Kh x K: = ( I Calculating numerical values from such an expression is clearly not something to do by hand very often! Historically. 2 rnequiv. PHARMACOL. so that the total amount of substance "A" per Bitre must remain equal to the amouilt initially present. [HA!. By definition. it is impcsi-tant to understand what those cumbersome cubic polynomials Iikc ( 171 mean.l via these four ccjuations.

between the concentration of species i and the independent variables [SID] and [A1. or is determined by./L and K A = 3 x 10 ' equiv. [Alcyl]./l. be used to ca/rulate any one of the quantities in it if all tlne others except that one are known. It can.In words.i. J. [HA]. and must not. Pharmacol. or why. It alone.nrcresearchpress.cPTj.All the equations must be taken into account. physics is more than just algebra! Unfortunately.].. be interpreted to indicate how [H 'J depends on./k. then we can not explain that changc its it result of a change in [A 1. H + l = KA can not. Any change in [ W t 1 implies that the iizdependc~atvariables rnust have changed to cause that [ H t ] change.. [M ' 1 . There must also be accompanying changes in [HA] and [OH 1.0095 equiv. no single one of them can teil us how. 'Third.4. H VERSUS STRONG ION DIFFERENCE. ~ . and the quantitative relationships they symbolize. have several powerful consequences. and [ A p ] are ail dc>pencknt variables. because a change in either independent variable causes a / / the dependent variables to change at the same tirne. 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. and by itself it docs not determine the value of any oine of these variables. [MA]. thcrefore. In particular. because we must satisfy all of them before we can solve thc system and find out how the dependent variables behave. of course. Downloaded from www. The change in the independent variables must also cause a change in [A-] .019 equiv. the dcpendent quantitics [HA]. for example.WEAK ACID SOLUTIONS Can. [ A L o ~KL. Kd K A ) [ H t l = Flr([SID]. or both. as indicated on the right hand graph. and K k ./L. K A . the so-called "buffer equation": [ 141 . or [I71 which it represents. All four equations are equally important. Physiol. or their ratio. 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. is measured. Equation 14 is just onc of the four equations they must all satisfy at the same time. there are no useful algebraic approxinaations for this system like thc ones we were able to . [OH-] F O ~ I( [SID1 [ATOI 1. CSID3 &SID3 Fmc. [A 1. Thc vertical dashed lines are at [SID] = [ATOT]= 0. First. so [A 1 changes when [ H L 1does.(. can not explain [H'] behavior. any of thc dependent variables behaves as it does in response to changes in [SIDJ or [AlOT].Y)stands for the unique functional relationship which each appropriate cubic polynomial expresses. it merely accompanies it. If a change in any one. 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. KA) F. [A 1. they indicate that we can never change only one of thc dependent variables in this system. These f m a l representations. but that is true of any equation! Calculation is not cause and effect. Second. also provides the answer to our standard question: the value of [MS] in weak acid solutions is determined by the values of [SIB]. 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. say [H ' 1.. these statements tell us that nonc of those four dependent variables is determined by any of the other dependent variables. [OH 1. but the change in [A-] does not cause the change in [H '1.019 cquiv. so that each of them is separately determined by [SID] and [ATur\.com by UNIV CHICAGO on 11/13/14 For personal use only. and [SID] = [ATOT]/2= 0.

In the next section. PHAWMACOL. KA and [ATOT] values used were those for standard blood plasma. These cun7es clearly show more complex behavior than is conventionally attributed to "buffers. Outside those limits.. after we have added C 0 2 we shall look again at the effects of changes in [A. It also brings some surprises. lowers pH. solutions like this of weak acids without 602are of alnnost no biological interest because they so seldom occur. in most biological solutions which do contain weak acids. 0% 0 CSIDI 0. to compare with Fig. 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. 3 as well as with the [ H t ] and pH curves in Fig. Figure 5 shows plots of [HA] and [Ap] versus [SID]. and weak acid anion concentration. [A -1./t> RG. The effects on (OH-] are just the opposite. CSIDI (egu i by UNIV CHICAGO on 11/13/14 For personal use only. 02 ION DIFFERENCE. 61. Fortunately. A thorough analysis of that sort would require a very large number of graphs. use in analyzing strong ion solutions. J. where the pH curve shows what is usually called "buffering. At this point therefore we shall only look at variations with changes in [SIDJ. PHYSIOL. 602is everywhere! Furthermore. symbol . Physiol. 4. the [HA] and [A-] curves are not linear." As we should expect from the fact that it is an acid. for the same solution as Fig. [ATOT]tends to be relatively constant. The change in [ H t ] is much steeper over the "buffering" range near [ATOT1/2than in strong ion solutions.nrcresearchpress. The distortions of the inverted semilog or pH plot in Fig.. Figure 6 shows a log-log plot of [H'] versus [SID]. and demonstrates the surprisingly linear behavior of [HA] and [A-] with changing [SID].]. addition of the weak acid at any given [SID] value results in larger [H '1. Undissociated weak acid concentration. Pharmacol. which show that [H'] does change rapidly over this region. Figure 4 presents linear plots of [H'] and [OH-] and a parallel plot of pH. Comparison of the pH and [H'] curves shows that [ H t ] is changing rapidly over the [SID] range centered around the [SID] = [ATOT]/2point.CAN. 5. J. plotted against [SIDI. all versus [SIB]. 4. but not [H'] or pH. the dashed vertical lines have the same meaning as in Fig. 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. Tn other words. [HAS AND -0. keeping [ATOT]constant. [HA) = [Au]. Downloaded from www. as we might have expected from the term "buffer. From 1141 it also follows that at this point [H ] = KA.mT]. and do not intersect at the [SIE)] = [ATm1//2point. [HA]. 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. From these results we may conclude that when [SID] is positive.or pH = pKA. but is consistent with the [PI'] cunre in Fig. and smaller [OH-]. the addition of a weak acid "buffer?' to a strong ion solution raises jH '1.01 STRONG CA-I VERSUS 0. More detailed analysis shows that these conclusions are only valid so long as KA is within about three orders of magnitude of Kk." This is not merely a distortion produced by the double log plot." 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. 4. than are seen in a strong ion solution without weak acid. a weak acid solution "buffers" [OH-]. As indicated. 4. 1983 ACID SOLUTIONS WEAK Can. rather than shallower. VOL. Note that at the [SID] = [AToT]/2 point.

322 Pa). For convenience. The quantitative relationship is called Henry's Law: [181 [CO%W)I= Sco2 x pco2 Sco. to compare with Fig. therefore.I = Kc PCO~ We can arrive at this same result by substituting for [H2C03]from [19] into [21] and again combining constants. ~ 0 : ~ . partial pressure in the gas with which the solution is in equilibrium. The vertical dashed line is at [ A T ~ T ] / as ~ . Dissolved CO. [2]. HCO. because H2CO3is not a gas: water dissociation equilibrium. dissociates to form CO:. The quantitative expressions for the 2 equilibria are: [2] [Ht] x [OH-] = Kk Weak acid dissociation equilibrium: [I4] iHt] = K . Its value depends on temperature. [l8].nrcresearchpress. and then combine constants. but isn't.] [21] [H 7 [HCO. C02(d).carbonic acid. The quantitative constraints of equilibria. and carbonate] = K2 x [H2C03] If we combine [20] with Henry's Law. 4 and 5.6. can be written which looks Just like Henry's Law. so that [H2C03]is generally less than 0. H2C03.ions to form HCO..%b> FIG. and substituting for [C02]from [ 181.bicarbonate ion. L-' mrnHg-I. J. EH+I -10 -2 -10 AND -4 STRDNG -IB -8 [OH-1 -10 -8 SOLUTIONS CSIDI VERSUS 18 -a H ON DIFFERENCE. mass conservation. Downloaded from www. 18 -8 18 KS I87 -4 10 -2 (esuiv. the result is the more familiar farm: [22] [Hi] [HCo.WEAK A C I D Can.. pC02. iHA] Conservation of mass for "A": [20] [C02(d)] x [OH-] = K.. Log-Iog plots of [#'I and [OH-] versus [SID] for the same solution as in Figs. and ionic strength. The concentration of C02(R) is determined by the CO. a single weak acid HA. x [HCO. and largely ignore both [C02(d)] and [H2CO3]from here on. Physiol. Equilibrium for this reaction requires that: Consider now a solution containing strong ions. At 37°C in mammalian blood plasma. H2CO3.' (1 mmHg = about 3 x 133.Remembering that [H. and electrical neutrality on all the components require us to write the following six equations: Water dissociation equilibrium: [H2C031 = Sg12co. it is mol * L-I m m ~ g . indicated.The concentration sf H2CO3is therefore proportional to [CO2(d3]and [H20].5% of [C02(d)]. other solute concentrations. we shall let [22] replace both 1201 and [&I].and Ht . and C02 at an externally regulated partial pressure pC02. a quantitative relationship between [H2C03Jand pCO.O) is large and effectively constant. HCO. and with Bicarbonate ion formatioia equilibrium: [22] [Ht] X [HCO. about 1.X the C02 solubility coefficient. and Ht .com by UNIV CHICAGO on 11/13/14 For personal use only. 3. Dissolved C 0 2also combines with OH.5 x - equiv.] = Kc x pC02 . and H2C03dissociates to form HCO. combines with water to form carbonic acid.

[OH -1 lHSI = = (Am17 pCO2) FOFI ([SIDl .([SIDl.nrcresearchpress. (HCO.K3 X K. Nothing less thain the whole set of six equations is sufficient. (asstanaing constant parameter values). weak acids (proteins).com by UNIV CHICAGO on 11/13/14 For personal use only. ancl C02. a weak acid. we can easily find out what these otherwise intractable polynonnials tell us about the behavior of this kind of solution. we find [H' I = 40 nequiv. PHAKMACOL. for example. C 0 2 is constantly produced in the tissues. contains negligible weak acid concentrations. and removed in the lungs. 61.pCOa) The exact solution for [ H A ]is [25] [H']' + (K4 + ([SID] + KA) X [H']~ ./L or pH 7. Nothing else is needed. and @02 pC02 determined by the balance between tissue metabolism and respiration. and nothing else will do! The same is true independently for each of the other five dependent variables. formation equilibrium.K. C1-). by their having to obey nlE six of 121. dependent variables determined by them. pCO2) BHCQ_II = ~ ~ ~ c o . [Cl-1.^ . To understand a change in [H'].[OW 1 = 0 We have six simultaneous. and pCO?. [K']. In fact. (A I . this equatio~n is called the Henderson -Hasselbalch equation. only with changes in the independent variables.Kc X pCO2) X [H']' (KL + Kc x pCOz) . [l5l7[22]. ISF. We shall therefore adopt this idealized solution as a simplified nmodel for body fluids. By itself. VOI. Physiol. K'. and co~npletelyexplained. and . Dl. + [H'j . P C O ~ 1co:-1= Fc. [A. To get 1251. Fortunately. inilependt~nt variables are ISID].. Equation 22 for HCB. If we set [AToa)= O in the equations for [H ' 1 etc. [AIoTI. 25 for [H'j. we should be conapletely stopped at this point without computer assistance.and PCB. Just as in the previous case. AT. and can never tell change in respiration immediately causes significant us how [H ' 1 depends on [HCO.] Electrical neutrality: Can. [SID]. arnd is often nnisrepresented as the clue to understanding [H '1 (pH) behavior. We have now answered our standard question for this system. X pCO2) x [H'j . the number of possibly interesting graphs is unmanageably large. we must look for a change in one or more of the three independent variables which caused it./ld. [Aroa]. 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. and 1241. x Kc X p C Q z = O X ([SID] - In logarithmic form. changes in the pC02 of plasma. If we use Eq.[CO: ] . total protein. [ C O ~I.pCO2) F. simply by calculating the dependent variable values for any given set of values of the independent variables and parameters. we had to have all six equations.C.p C 0 d FII([SIDI. and is uniquely determined by. Interstitial fluid. In particular. and use it to examine their quantitative properties for selected ranges of physiologically and cli~lically interesting values of the independent variables. Now that we have it. 1983 1454 Carbonate ion formation equilibriuna: 1231 [H'] x [co:-] = K3 x [HCO. the properJust as before. independent equations and just six unknown. x K. [ATOT]and pC02 The algebra to solve these equations is routine.[HCOI] . 1.4. and do provide a basis for selection. The three known. J. the value of [H'] is determined by.(ISIDI. 1.[A ] . [HA].1. and thus of other body .. these dependent variables all change ties of this system. 1141. Blood plasnna contains strong ions at a (Na ' . Downloaded from www. expanded to take care of the larger numbers of independent anel dependent variables. It should be clear from the arguments in the preceding sectionh that all the same conclusions apply in this case as well. Equation 25 tells us that 111 any solution containing strong ions. all three independent variables. Equation 22 then produces (HCOS] = 24 mequiv. ~ n ' t . Blood plasma model behavior Now that we have three independent variables. plus our conventional focus on [H'].. ( l s I[ATu~Y. for example. does not. Pharmacol. and [Hi].%N.. wlaich does explain [H ] behavior. the behavior of [H ' ] and all klne other dependent variables is determined. These are close to the "normal9' values for standard arterial plasma at this pC02. and only by. It depends partly on the not determine each other. and use appropriate values for [SID] and lA~o1. each of the dependent variables in this system is its own specific function of. so that any dependent variables. J. [231.(KA X six dependent ones. PHYSIOL. as expressed by the following symbolic representations of those fourth-order pslynomials: [241 [SID] [HA1 BA-1 = = FHA(BSID1. but this time we get fourth-order polyno~nialsin the 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.we get results which also match closely the accepted values for this fluid. because it d ( ~ e .Kk . and substitute known arterial plasma values for (Na' 1. [OH 1.

and therefore requires us to stay on one of the constant [SID] curves. AS might be expected frsrn the nonlinear nature of the [ H ' ] to pH transformation. Physiol. fluids.9./I. since it refers to [H ' ] changes not due to pCOz changes. and 1 I ./L. One striking feature of these curves is that their cur- EFFECTS O F LSIDI Frci. are much more highly curved. [H+] plotted against pCOz for the Standard Plasma model.19 mequiv. is less specific. are detemined by absorption frorra the gut and reinoval by the kidneys.. and other paranaeter valiaes as in previous figures. = 6 X 10 I equiv.nrcresearchpress. Qualitatively. here and in Figs. What is most important about these curves is that they ~natchvery closely the corresponding "titration curves" for isolated bIood plasma. on the order of hours. The terns acidosis and alkalosis in this context mean "relative to normal[". and their total concentration is determined priinarily by the Iiver. Pharmacol. 8. - FIG. Changes usually occur only over pcriods of by UNIV CHICAGO on 11/13/14 For personal use only. 8. 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]. and [SID] values indicated on the curve. This means that all those proteins in the plasma. It is therefore physiologically reasonable to examine the dependent variable behaviors in this system by plotting against pC02. 7. so that changes in [SID] only occur slowly.46 X 10-' ' ( e q u i v . the corresponding pH curves. these curves tell ais that [H ] increases as pCOz increases. so that C 0 2acts as an acid. shown in Fig. which is what we shoulel expect frotrl the definition of [SID]. Figalres 7 and 8 make clear the meaning of "respiratory" acidosis and alkalosis. plasnaa is still alkaline.. 10. Downloaded from www. on the other hand. 8. vature is so slight. so that even at pH 6.] values as used in Flgs. pCOz therefore changes rapidly and often. since neutral pH for plasma is 6./L and 40 nlmHg represents the "normal" operating point for arterial blood. J. with [SID] = 42 l~equiv. [H'] varies almost linearly with pCO. in a way which makes no particular sense in terans of what is happening to [Hf 1./L and [ATOT] -. "rnetabolic" acidosis and alkalosis. a solution with the same KA and [AT. with [AToTl fixed.. with Kc. '6Respiratory" means "due only to it change in pC02". 5 . For large values of ISID].7. 9. 25. despite their chemical csrnpliexity in detail.STANDARD PLASMA STANDARD P L A S M A IN+! VERSUS p C 0 2 p H VERSUS p C 0 2 Can. and therefore due to SID] or . 4. [H'] also increases as [SID] decreases. These curves are solutions of Eq. Proteins are the only significant weak acids m i plasilsa. / ~ ) L / r n n a ~ KT g . Figure 7 shows ~ u c ha set of curves for m'1... The same values as ill Fig. The other term often used. and 6. plotted as pH instead of [ U ' ] . = 2. and [SIT>] set to a series of values. Concentrations of strong ions in body fluids. The broken cross centered at 40 nequiv. 7.

or both.base data. 7: or Fig. In a case of diabetic acidosis.CAN. Fig. Physiol. and Na' between erythrocyte intracellulu fluid and plasma. combined with Eq. and therefore [ATOT]. point on Fig. 7. and must be taken into account in interpreting clinical acid. in which [ATOT] was held constant and [SIDJ was varied. owing to movement of C1-. and the curvature of these curves. or the pH-pC02 point on Fig. ([Na'] + [ K f ] . I i - R G . [W+]plotted against pCOz for the standard plasma model.[Cl-]). 7 or 8. 9.) It follows that if acid-base data alee available . as Figs. usually called the "chloride shift. 8. 9. the only significant change in plasma as it goes through the lungs and is transformed from venous to arterial. Compare with Fig.nrcresearchpress. They do not normally alter the strong ion composition or the protein concentration of the plasma circulating through them. this difference should agree closely with the measured value for the total keto acids present. plasma protein concennsay change significantly. 8. J. so that the inorganic component of [SIB]. plotted as pH. PHYSIQL. 24. Thus. is known. The result is a different [PI'] (or pH) versus pCOz curve. 7. Pharmacol. J. therefore. and if the subject's plasma protein concentration is known to is. PHARMACOE. 9 and 10 show. the slope. and [ATOTJ set to the values indicated beside the curves. The same values as in Fig. K'. FIG. This quantitative analysis permits us to separate and understand these two kinds of changes in new and very useful ways. [AgOg]changes./ L. If pH and pC02 values are available for a plasma sample. These curves demonstrate the iinpartance for blood plasma [H'] sf changes in plasma protein concentration (LATOTI). 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 by UNIV CHICAGO on 11/13/14 For personal use only. so that [ATOT] [H'] -pCO. So far as electrolyte chemistry is concerned. tells us immediately the effective value for [SID] in that plasma. If plasma electrolyte values are also available. In pathological conditions. The primary function of the lungs is to exchange C 0 2 and O2 between plasma and alveolar gas. Campare with Fig. provides the means to monitor a particular subject's acid-base status quantitatively and precisely. with \SID] fixed at 42 mequiv. Venous plasma is merely arterial plasma with respiratory acidosis! In Figs. for example. 10. the venous to arterial transition can be simply represented by movement along whatever [SID] line the plasma [M'] or pH currently falls on. In "pure" lactic acidosis. 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 Can. this difference should be just equal to the lactate concentration in the plasma. (There is known to be a very small change in plasma [SID] during this transition. is in pC02." but it is only I or 2 mequiv. Changes in plasma protein change the position. 8. tration./L. therefore. then the position of the be near normal. VOL. Downloaded from www. and is quantitatively negligible far acid-base purposes.

is [c@-1. 7. As we should expect from Eq. 2. Compare with Fig. On the other hand. 7 or 8. We can then solve Eq. on log-log scales to permit the very wide range of values involved all to be shown on a single graph. K values and [AFOT]the same as in Fig. for constant normal [ATOT]. 12 and 13 for plasma. Log-log plots of all six dependent variables versus pCB2 for the Standard Plasma model. and counterintuitive. with [SID] held constant at 42 mequiv. 50 E F F E C T S OF I I STANDARD PLASMA VERSUS pC02 I I CSIDI . This is clinically important. whereas peripheral venous samples may not be. 12.] plotted against pCOz for the Standard Plasma model. The ticks on the horizontal axes between 1 and 2 indicate the normal operating pC02 of 40 mmHg. Additional information about the properties of this solution is presented in Figs. The FIG.] is of much less acid-base interest once it is realized that the value of [H'] is not determined by it. then the corresponding values for the other kind of plasma can be calculated easily by changing the pC02 appropriately. Like Fig. for either a venous or an arterial plasma sample. 11. which can usually be obtained only at much greater hazard to the patient. and then decreases with increasing pCO. arterial samples are automatically well mixed. either on Figs. Pharmacol. / l . and [Cl-] values in ISF.] changes with [SIT)] and pC02. [HCO. Model for interstitial fluid (ISF) Plasma and ISF differ primarily in their [ATor] v d ues. Figure 1l shows how [HCO. or by using Eq. [K']. 7: with which it should be compared. I EFFECTS OF pCO2 0 I I l I I ' I LOG pC02 FIG. and for the slightly different [Na']. These curves emphasize the extreme minority position occupied by [H '1. Note the decrease in [c@-] with increasing g o 2 . to compare with Figs. Downloaded from www. Figures 12 and 13 summarize how all six dependent variables in plasma depend on pCOz ancl on ISID]. 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. Physiol. it can also be used as a kind of graphical calculator if desired. although the behavior of [HCO. 14 and 15. ./L. with the results for [H'] and pH shown in Figs. over the physiological range. since it means that mixed venous samples may be just as informative as arterial ones.nrcresearchpress. so that for modelling purposes we may take it to be effectively by UNIV CHICAGO on 11/13/14 For personal use only.S T A N D A R D PLASMA CHC03-3 Can. 25. and 13. 12. 7. [HS] and [OH-] always show mutually complementary behavior. 11./l at most. 25 for this condition. most surprising. J. It shows a maximum at very low pC02 values. Compared with the plasma value of 19 mequiv. the value for ISF is only 1 or 2 rnequiv. as well as the variety of different behaviors displayed by the six dependent variables. 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.

100 VERSUS p C 0 2 EFFECTS OF STRONG I O N ~IFFERENCE -21 . 1 through 17 will appear in different positions when different temperatures.1 LOG 0 6SIE3 FIG.5 -5 . and in Butler 19823. Temperature e&cts Temperature elfects on dependent ion concentrations in isolated sc~lutionscan be calculated easily by this quantitative approach. 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. 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. Log. and why'?" During the hypothermia accompanying open heart surgery. 1 2. [H'] plotted against pCO.CAN. interpretation of temperature effects is made more ccsmplicated by changes in inetabolic and cardiovascular f~incticanwhich alter independent variables. Physiologically. such regulation of protein dissociation could have important implications for physiological responses to temperature changes. Downloaded from www. PFIARMAC">L.. all four Ks must be changed when tennperature changes. We nced only to know how the various Ks change with te~nperature. with [SID] values indicated on the curves. All the curves presented in Figs. In strong ion solutions. 13. K values at different temperatures are available in Robinson and Stokes (19591. and therefore Ks./L. but their effects are only significant over the [SID] range from 0 to [AT. 7 . J . or even whether [H ' 1 is important. . 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. 14. will change with temperature...nrcresearchpress. for the Standard Interstitial Fluid (ISF) mc)del. are used in the calculatic~nswhich produce them. and sets important constraints on possible answers. 1983 INTERSTITIAL FLUID STANDARD P L A S M A EFFECTS OF fSIDl CH+I Can. tickc on the [SID] axes between . but the quantitative approach now available provides new avenues for exploration. PIIYSBOI. what is the optimal plasma [Wt].4 -3 . FIG. Pharmacol. If it were a general phenomenon.In solutions with C 0 2 by UNIV CHICAGO on 11/13/14 For personal use only. As [ 11] and 1131 show. J. versus [SID]. VOL. Same K ' s as in Fig.1 and -2 are at the nonnal plasma operating [SID] of 42 mequiv. with pC02 held constant at 41 m ~ n H g The . Reeves (1972) has suggested that the answer to such questions may depend on [A the degree of dissociation of the proteins involved. In weak acid solutions with no C 0 2 .lT]. but [AT(n] set to 0 throughout. by surprisingly large amounts. is needed before these physiological questions can be answered. Physiol. only KI.log plots of the salnc six dependent variables as in Fig. for example. is involved. h i . Equation 25 still applies and still enables us to calculate the resulting [H' ] changes.2 . Kk will affect only [Ht] in alkaline solutions and only [OW-] in acid solutions. notably pC02 and ISID]. both KL and K.

The most coanplicatcd case is probably the kidney. and all the other dependent variables.The same is true of [HCO. and protein movements betwien body fluids are not used as a-means of ionic interaction. 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'. most nlembrancs arc highly inapermcable to proteins niost of the time./l. tl-arough the membranes which separate thenm. Same values as in Fig. On the other hand. Physiol. and can not explain. &'O2is very sol~lble.. 'I'o change [ H ' j in any body fluicl. has a profound%yitnportant implication for understanding the possible ionic interactions betwcen body fluids. At the other extreme. or [ A r c . we have to change pCO?. K ' and C1 from plasma to urine.. 14. a change in [ l i ' ] (or pH) in either sola~tion. we only have to loc~kat three iradepcnticnf variables. the fact that [ H ' 1 is a dependent variable means that anovial3 H ' from one solution to another. but it is rera~arkablysanall. Pharmacol.nrcresearchpress. 15. and its eralpl-nasis on dependent versus independent ariablcs. so that it diffuses rapidly between body fluids on the basis of pC02 cfifkrences between them. which are well known to be moved between body fluids by a variety of special naechanisms ("pulnps") in many nneralbranes. There is an overall pC02 gradient from tissues to alveolar gas.the independent variables irl f87hitf/1iid. [SID] held constant at 3 I rnequiv. We can therefor6 [lot look to manipulation of pCO. J. r ] . This mean\ that these acid. That leaeies only strong ions. 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. Most of the ionic interactions which occur betwcen body fluids occur through these strong ion movements. The same argiarncnts apply nonetheless.As already pointcd oinf. It tells us that they can on1y interact through their intfq)entipilt variables.ba5e or ionic interactions are xnukh simpler to understand than might f i r ~ tappear. body fluids to interact with each other itrnically. where the tubule tnernbrane has many different specific properties at different pocitions along its length. the pervasiveness of CO. ancl [SILII changes are the nlajor vihicle for body fluid inferactions. As plasraaa and urine are separate solutions. 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. [SID]. the [ H '1 of urine is not relevant to . 16. the tissuc-alveolar difference is only on the ordcr of a k w mmHg in most situations. 1. Downloaded from www. as a convenient way for FIG.INTERSTITIAL FLUID pH VERSUS p C 0 2 Can. bjr itself will not produce.c~g-log plots of the fo~ardependent variables in the Standard ISF model versus pCO7. 1.and almost all biological mcmbranes are highly permeable t o by UNIV CHICAGO on 11/13/14 For personal use only. plotted as pH. Body fluid interactions The preceding quantitative analysis.

and it is not significantly affected by Acid -base balance Whole body "acid. the [H'] of plasma. may prevent equilibration with pCOf in one of the fluids. It should be clear that so long as they do not their identity is not important to the final alter [A~r(. the pC02 of the tissues and tissue fluids. PHAWMACOL. and therefore [H']. into or out of the plasma at the kidney tubules can not alter plasma [Hi]. J. movements across membranes between body fluids can not alter the equilibrium [H' ] or [HCO. HCO. and then more complicated calculations are called for. (i) The [Ht fluid is determined by the pC02.base balance" presumably means "how is the [H'] (pH) of body fluids regulated?" The answer which this quantitative analysis provides is remarkably simple. When Cl. ( i v ) Strong ions are moved between body fluids through membranes. Normally. The final result will be a change in [SID] owing tca the C1.ions.]. but they can still be carried out (Bidani et al. indirectly.nrcresearchpress. J.14641. In general. or both. of each body ments. changes in tissue C 0 2 production are matched by changes in circulation and respiration so that pCO. for reasons of electrical neutrality. to change [H']. CAN. the dynamics of the situation. in all body fluids.T]. 17. they must excrete more C1. [HCO. and that can only be achieved by moving strong ions. and excreting it as NH: can have no effect on plasma [H']. If the kidneys are to lower the [Ht] of plasma. so as to raise plasma [SID].base interactions between body fluids. Changes in plasma strong ion concentrations produced by kidney and gut activity are communicated to other body fluids. PHYSIOL. They may excrete C1. and it is the final [SID] value which determines the final [Hi].') is a dependent variable.. so [Ht ] can not be. [HCO. so long as carbonic anhydrase is effective. etc. c(Z LOG CSIDl FIG. and [HCO. since capillary membranes a-e generally permeable to strong ions but not proteins. and therefore decreased [SID] value in the urine./L. In most cases. so that [ATOT]interactions are not normally significant. the independent variable is pC02. or the absence of carbonic anhydrase activity. I . or an O H or HCO. Downloaded from www. VOL. or in the opposite direction. What determines the VH'] of plasma isthe pCOz. 1983 INTERSTITIAL FLUID Can..] changes in body fluids. however. with appropriate modifications by Donnan effects. however. it is [SID] and pCOz changes which determine [H']. of arterial blood. and may be summarized in four state] (pH). 1978).] of those by UNIV CHICAGO on 11/13/14 For personal use only. etc. etc. and the resulting changes in [SID] values provide the major mechanism for acid.than Na' from it. carbonic anhydrase is present and active. Synthesizing NH. they have consequences for [H '1 in the fluids between which they occur. In some cases. and those accompanying ions must not be strong ions. Movement of HCO.].. is well controlled. not by moving H '. [ATOT]changes may occur in pathological situations. the [SIDJ and the [ATJT]epf plasnm. and when they do.movement. and [ATOT] values in that %fluid. and the conventlonal treatment of the urine as a vehicle for removing HS from the body is incorrect. [OM 1. Physiol. but it may be changed rapidly when needed. Normally. Log-log plots of the 4 dependent variables in the Standard ISF model versus [SID]. [SID]. some other ions must accompany the strong ions being moved. Pharmacol. not the amounts of these ions which may have been moved. The kidneys and gut thereby . 61. This quantitative analysis makes clear that the oxyntic cells can only make that acid by adjusting [SID]. (pH). In all these "pumped.(ii) Most membranes separating body fluids are not normally permeable to protein. pCOz held constant at 47 mmHg. not by pumping H'. Exactly similar arguments apply to HCO. values achieved. since [HCO. although it may be very important in keeping the urine [H'] from rising too far due to the excess C1-. of the order of -100 mequiv. it does not matter which. or absorb Ma' and K ' . [HCOI] and [co:-] values. but so long as carbonic anhydrase is present. Stomach acid formation is another clear example. but the end result must be a high negative [SID] value in the luminal fluid. [SID]. EFFECTS OF CSIDI HCO. [HCO. (iii) Circulating plasma carries C 0 2to the lungs. which set the pCO. and thereby. movements." either an H' must must move accompany it.

How to understand acid-base: a quantitative acid.236. only changes in independent variables can.1972. This control is much slower than that for pC02. Co. A.]. Co. Schematic diagram which summarizes the major physiological organs and processes involved in dependent variable regulation in circulating plasma. 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. Van Nostrand-Reinhold. and their physiological regulation by the lungs. net strong ion charge ([SID]). Butterworths Scientific Publications. J. STEWART. kidneys. Physiol .A . VENTILATION CA . 1141. Thermodynamics. Figure 18 sum~glarizes these relationships schematically. D.[co:-1. BIDAKI. . The physical chemistry of electrolytic solutions. and can be calculated from 121. (2) Quantitative understanding emphasizes dis- tinctions between independent and dependent variables in ionic solution systems. Chap.. 44(5): 770-781. HARNED. and P41.usually protein. Amsterdam. A. J.JAMESN. and is therefore generally involved in chronic acid-base alterations. and [Ht ] (or pH) are dependent variables. 3rd ed. An imidazole alphastat hypothesis for vertebrate acid-base regulation: tissue carbon dioxide content and body temperature in bullfrogs. Carbon dioxide equilibria and their applications. Appl. IHA]. [HCO. GUGGENHEIM. and total protein. but not the calculations. E. Physiol. 198 1 . OWEX. PI. gut.8959. Body fluids interact through the membranes separating them primarily by movements of strong ions. which alter [SII)] by UNIV CHICAGO on 11/13/14 For personal use only. Physiological changes in independent variables complicate the situation. Physiol. Mass. [OH J. [SIR]. (5) Temperature effects on dependent ion concentrations can be calculated from known changes in the equilibrium parameters. an advanced treatment for chemists and physicists. and total weak acid ([ATOT]). independent variables are pC02. Exercise Physiol. 9. Downloaded from www. London. Elsevier North Holland. Respir. W 1 . New York. R. and BENTONB.l [HA3 CC03=3 CQH-I LH+1 CpH> FIG. Respir. Analysis of postcapillary pH changes in blood in vivo after gas exchange. 1982.HERBERTS. ROBINSON. REEVES. Environ. BUTLER. and should be more thoroughly explored. North-Holland Pub.. Addison-Wesley Pub. and R. STOKES. In body fluids.ACID-EASE BALANCE Can. and presents qualitatively the results of the quantitative analysis. are the primary controllers of body fluid [SID] values.nrcresearchpress. FORSTER. New York..ROBERTBLAKE. and liver. The implications for the analysis and understanding of ionic behavior in body fluids are profound. [ K ] . Reading. Electrolytic solutions. pC02. 1151. 1958. (4) Movements of 14' between solutio~mscan not affect [PI '1 of either solution. [221. . CRANUALL. Pharmacol. Their values in any solution are determined by the values of the independent variables and the four parameters.base primer for biology and medicine. 1957. 14: 2 19. 2nd ed. (6) Whole body acid-base balance can be understood quantitatively in terms of just three independent variables. 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. 18. Many current models for ion movement through biological membranes appear to require modification on the basis of this quantitative analysis. 3rd ed. 1978. E.PETERA. and KOBEK~E. (3) Those six equations.