OSMOLARITY DISORDERS OF THEBODY FLUIDS

VICTOR X\VYNN, M.D.Silugical Unit, St. Vlar's Hospital, Lontdont, 1fI.2.

'The development of rapid and precise methodsfor the measurement of the concentration ofseveral important electrolytes has done much toelucidate the nature of body fluid disorders and toimprove their treatment. Much of this work, asfar as clinical problems is concerned, stems fromthe development about i5 years ago of the flamephotometer as an instrument suitable for routineuse.2, 8, 19There is, at the present time, an impressive list

of newv biochemical techniques which promise toextend even further the potential usefulness of theclinical laboratory in water and electrolyteproblems. I need mention only a few of these,for example, apparatus designed to be automaticor semi-automatic, new electrode systems tomeasure sodium, pH and respiratory blood gastensions with an ease and precision better thanbefore, and atomic absorption spectroscopy wvithits promise of greatly extending the range ofelements of clinical importance which can bereadily measured by spectral analysis. Togetherwith this flowering of biochemical techniquesthere are also impressive recent advances of aphvsiological, biochemical, pharmacological andclinical nature which concern the general subjectof water and electrolyte balance. The discoveryby Simpson and Tait"' of aldosterone, the workdesigned to elucidate this hormone's control,6, 20, 3the discovery of new diuretics and a whole host ofuseful synthetic steroids, the development of newmethods for treating renal failure, hepatic failure,and the metabolic problems in surgery, are a fewexamples.

This rapid progress of clinical science poses thequestion of howv to ensure the widest possibledissemination of new knowledge. Doctors canloften expect to be confronted with a problem inwater and electrolyte balance, albeit as a segmentof a wider clinical entity, for example, heartfailure, renal disease, or an endocrine disorder.

It is by familiarity with general principles, ratherthan by preoccupation with minutiae or the use ofrule-of-thumb methods, that the general physiciancan best be expected to keep abreast of moderIn

de-velopments and to obtain most benefit from ththerapeutic advances derived from laboratowork.A problem which often confronts the clinician i

the correct interpretation of laboratory reportsIn the case of the electrolytes, plasma estimationare mostly concerned with sodium, potassiumchloride, and bicarbonate levels, although calciumand now magnesium, are achieving increasinprominence. A great deal can now be said abouthe significance of changes of the level of each othese clectrolytes, but I shall confine my attentionin this paper, exclusively to the significance of thplasma sodium level.

The 'Normal' Plasma SodiumIn the sense that ' normal' implies ' healthy,

it cannot be said that there is such a thing asnormal' plasma sodium for a hospital popula

tion, however, much care is taken to excludpatients suffering from diseases with known effectupon electrolytes. The failure to appreciate thipoint reduces the value of several reports uponormal values. Fawcett and 71 analysed thplasma of 25 healthy young men and 25 healthyoung women. We used a laboratory builflame photometer, burning coal-gas and air, anemploying light filters and an external standardWith this instrument the coefficient of variatio(due to analytical error) was 0.5 per cent., and,for duplicate analyses which were employed ill thistudy, o.4 per cent. We obtained the followinresults for the ' nlormal' plasma sodium.

r.ABLE 1.-PLASI.-SIA SODItUM CONCENTRATIONS (MEQ L.IN 25 HI:.lu.,!HY YOUNG MIEN ANI) 25 HEALTHY YOUN

WOMEN

Ien Women

Mlean.. .. ! I41.7 I40.5Standard deviation (C) 1.o 1.7(5°o range (m11 26) . 1I39.7-143.7 137.1-x43.9Value of t for sex

difference .... .. 3. IProbability level for

sex differences .. 0o.ooI P- o.oI

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F,uar3 1960 -\NV NN: Osmolaritv Disorders of thle Bodiy Fluids -7

We concluded that, in healthv young peopletl medical students and laboratory staff),normal range for plasma sodium wXas nlarrow--Ut I37 to I44 mnEq 1. and that there was atistically significant sex difference, womenng, on the average, 1.2 mEq I. less sodiummen. This normal range is considerably lessthat reported by other Xworkers.13. 12. 9.

nton and Danowski w-ere unable to show anyficant difference in plasma sodiumn w-ith age

cluding the new-born). \W\e found a tendencyplasma sodium to be lower (by about 2 mEq 1.)ng the w-eek before menstrluation comparedtwo weeks after the onset of the flo-.7

In individuals, repeated estimations of thema sodium level during the course of the daywed remarkably little variation (less than'een individuals) and meals, Inoderate exertion,posture seemed to be without noticeable effect

this (Table 2). On the other hand, repeatedmations in individuals over a period of sixnths gave a slightly greater scatter of resultsich we interpreted as most likely due totematic analytical errors (Table 3).

LE 2.-PLAS.MA SODIVt_l CONCENTRATIO.XNS (iEQ) 1..)FivE Yo.NGc; \IEN DRING.(;'rHE C()tISE: o'()OFONE DA

Subject J F. V.W. B.H. F.(). T.I.

. of samples 6 10 7 10 Ion -alue .. I2.5 139.9 142.2 139.8 139.9

... o.S. 0.7 0.7 o.9

.F., VA.\., and B.H. were ambulator-..0. and T.I. were confined to bhed.ormal meals were consumned.

he conclusions are that the plasma sodiunmcentration in healthy individuals falls w-ithin a

wow range, that variations within the day in anvidual are even less than the Xvariations betweenviduals, but day to day variations may be some-t greater than the diurnal variations, mostbably due to the effect of analytical error. They consistent influence on the normal plasmaum we could detect was a small change whichrred during the menstrual cycle. These con-ions are based upon duplicate analysis andcise work. In routine clinical chemical labora-es duplicates are rarely practical, while theure of work may easily impair precision.

der the best conditions, however, repeated

plasma sodium estimliatioIns performed routinelyon hospital patients should not differ by morethan 3 to 4 mEq I. in an indiv-idual, due toanalytical error and ' randoml -ariations alonle.

The Plasma Sodium in Hospital PatientsApart from the effect of analytical error upon

the results it is general experience that the ' usual 'plasma sodium lev-el in patients is, on the average,loNwer than in health, and nearer 135 thain 140mEq I. The reason for this is not knoNwn.'Variations of the plasma sodium level about theindividual patient's mean value, how-ever, are notnoticeably greater than in healthy people, unlessthe patieInt is suffering from a disorder involvingwater and electrolyte balance. In many illnessesthere is a tendency for the plasma sodium level tobe distinctly low and levels below 130 mEq l.occur commlonly. If such vXalues persist it isnearli always a mark of serious illness, and thelower the plasma sodiunm level, generally the wvorseis the outlook for the patient.

Misleading Plasma Sodium ValuesBefore discussing the interpretation of the

plasma sodium level it is necessary to discussbriefly four possible sources of confusion. Thefirst is frank analytical error. This is difficult toguard against but if the four electrolytes, sodium,potassium, chloride and bicarbonate are deter-mined, it may be pcssilble to detect a gross error inthe sodium value by finding an obvious imbalancebetween the milli-equivalents of cations and anions.The second is contamination of the blood sample.If the sodium salt of heparin is used as an anti-coagulant excess of this elevates the plasma sodiumlevel. The third possibility for confusion ariseswhen the plasma solids form a much greater pro-portion of the whole plasma than is usual (thesodium of course is confined to the water of theplasma). This arises in hyperlipaemic plasmaand when plasma protein values are greatlyincreased. Fig. I is an informative demonstra-tion of this problem and shows how much lowerthe plasma sodium level is in whole, lipaemic,plasma compared w-ith the normal values obtainedfrom the analysis of the plasma water of thecorresponding sample.1 Finally, hyperglycaemiacauses the plasma sodium to be lower than it

I.-E3.PLASMAI SODIUMI CON('cI)N-rR-XIoI()NS (mIEQ L.) IN 10 S F.PIIHlRDEMRO EACH o)1: EI(;FHI HE.ALTHY SIBJECIS OVERPERIODS OF 2 To()6 LIONITHS

Subject K. K. G. . J.F. V.. P.B. IE.L. IE.V. M.M.

142.7 14.41.6 142.7 . 41.9 140.5 140.5 I 41.32.6 11.7 1.7 o.X8 I.6 I.O I.7 1.3

LK., G.H., J.<F., and V.W. were men, and the remainder of the subjects wnomen.

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72 POS'I'GRADUA'TIE MIEDICAL JOURNAL February I9x

w 160

3 ·

· ·

z Xcr- 140

X X

I 0.LJ

(1) 120 X

200 400 600FATTY ACIDS, rEq/L

FIG. I.-Relationship between concentration of sodiuimin serum and in serum water and concentration oftotal serum fatty acids.

would otherwise be because glucose, being con-fined to the extra-cellular fluid, draws water fromthe cells, by its osmotic effect, thus diluting theE.C.F. solutes, including the plasma sodium.l4The Significance of the Plasma Sodium

If we exclude the four possible sources of con-fusion just mentioned, the plasma sodium con-centration indicates the effective osmotic pressureof the body fluids,* which may be normal, low orhigh. A low plasma sodium level is called hypo-natraemia and defines hypo-osmolarity or thehypotonic syndrome. A high plasma sodiumlevel is referred to as hypernatraemia, and defineshyper-osmolarity, or the hypertonic syndrome.Since the plasma sodium level reflects changes inthe osmotic pressure or chemical potential of thebody water it is appropriate to discuss the wayin which osmotic adjustments are made in thebody, and the nature of the osmotic stresses whichmay arise in clinical fluid balance problems.The Osmotic Behaviour of the Body CellsThe usual division of body water into two main

compartments, intra-cellular (I.C.F.) and extra-cellular (E.C.F.), serves well for our presentpurpose. The composition of these two fluids isquite different. The bulk of the solutes in theE.C.F. comprise sodium salts, the chief anionsbeing chloride and bicarbonate ions. i\lost of theintra-cellular solutes consist of the cations potas-sium and magnesium, the anions in this case beingchiefly organic phosphates, protein and sulphate.

Some solutes are shared equally between the twifluids for example, urea and creatinine. Thesjtherefore exert no influence upon the distributiolof body water between compartments and ther6fore, in this sense, are said to be not osmoticalliactive. The osmotically-active solutes in bodcwater are the electrolytes named above.The exact reason why the composition of cel

fluid and the E.C.F. are so strikingly differentnot known. It seems to be a function of tmetabolic processes within the cells. Thability to maintain a characteristic fluid pattecan easily be impaired, for example by anoxihypothermia, and enzyme poisons. Undoubtemany disease processes have the same effeHowever, so long as the cells function normathe cell niembrane can be regarded as beieffectively impermeable to electrolytes. MIoreovexperiments, which I shall discuss later, show thcells are freely and rapidly permeable to watIt follows therefore that the cell membrane mabe regarded as being semi-permeable, and thatosmotic pressure (or chemical potential) ofbody fluids will be determined by the total cocentration of impermeable solutes, both undsociated molecules and ions. The total electrolconcentration must therefore be an importfactor in determining the distribution of wabetween cells and E.C.F., and the extent to whithe cells behave as ' ideal ' osmotic systems (insense of obeying the Boyle-van't Hoff Law) wdetermine the extent to which other factors neto be considered in this context.

*When a solution is separated from a quantity ofpure solvent by a membrane which is permeable tosolvent and not to the solute, then the solvent tendsbe drawn through the membrane into the solution soto dilute it. Movement of solvent can be preventedapplying a certain hydrostatic pressure to the solutiThis pressure is called the osmotic pressure. Tosmotic pressure is thus defined in terms of ceexperimental conditions. It is an expression of a specphysical property of the solution but it comesexistence only wlhen the defined conditions are fulfillThe osmotic pressure of a solution is proportionalthe sum of the individual concentrations of undissociamolecules and ions to which the membrane is impmoeable. In the case of the body fluids these osmoticactive particles are mostly electrolytes. The unitosmotic pressure is the milliosmol. Chemical analof the solution will giv-e the millimolar value for esolute and this is converted to milliosmols by mplying by a factor called the osmotic coefficient.corrects for incomplete dissociation of the salts andany other factor causing the solution to depart frombehaviour of an ideal solution. It will be shown lathat in the case of the E.C.F., since the plasma toelectrol-yte le-els mirror closely changes in E.Cosmolarity, and since the sodium salts form about 9of the osmotically-active solutes of the plasma, it isplasma sodium which reflects changes in the effeosmolarity of the E.C.F.

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uary i1960 WYNN: Osmolarity Disorders of the Body Fluids 73

Potential ofWater in Mammalian Tissuesor more than half a century there has beenest in the problem of whether the osmotic

ivity of water inside and outside the livingmalian cell is the same, or whether osmotic

dients are maintained, and what influencease plays in these processes. The problem isextremely complex one to solve by experiment,cially because of the unstable nature of some

the intra-cellular solutes, and because pressure-ume changes cannot be directly measured inue cells unless these are separable, as, forple, is the case with red blood cells, sea

hin eggs and similar material. The main linesinvestigation have been by direct chemicalysis of the tissues, especially after bathing inds of varying osmolaritv, by using melting pointfreezing point depression as an index of theer potential of the tissues, compared w-ithma, and by in-vivo methods which may best beribed as measuring the osmotic volume ofribution of either Mwater or solutes or both.e results of all these investigations tend toort the idea that the osmotic pressure of cellsextra-cellular fluid is the same. I will describee of these latter experiments since they havelose bearing upon clinical problems and therpretation of electrolyte results.

otic Volume of Distribution of Waterhe effective osmotic pressure of the E.C.F.

y be calculated by measuring the concentra-of the individual ions and applying the

ropriate correction (osmotic co-efficient) tow for incomplete dissociation of the salts.ally, in the case of the E.C.F., since mostly

valent ions are involved, a close approximationthe effective osmolarity can be achieved byuring only the cations, and multiplying the

lt by two. If water alone is added to the bodyds and there is no change in electrolyte balancee amount of other osmotically-active material,assuming free distribution of the added waterughout the already existing body water, thecation concentration of the E.C.F. should fallly by the amount predicted by simpleion. This experiment has been carried outogs°0 and in dogs and man.15 The results2) confirm that added water is distributedly over total body water, even when theee of dilution is extreme and much below thath would normally be fatal without cardio-ratory supportive measures. These experi-ts show that cell membranes are freelynable to water, and support the idea oftic equality throughout the body fluid.have helped to clarifyr the nature of certain

40

357/ *

E30 /

m 7

25 . .

20 25 30 35 40Observed a (x) mM/I.

Fic;. 2.--Correlation of predicted and observedchange of E.C.F. total cation level (IB) inexperiments involving water loading in anuricdogs. The continuous line represents theregression of Y upon X (y -o.82x - 4.6). Theouter dotted lines represent the 9500 confidencelimits. The line Y - X is shown by the inter-rupted line.

hyponatraemic states in man, especially thesyndrome of acute water intoxication.18

Observations upon Acute Osmolarity Changesin DiseaseThe same principle 'which underlies the experi-

ment just described can be applied to the moreusual clinical situation in which there is a changenot only in water balance, but in electrolytebalance as well.The following argument will show how to

predict the changes in the plasma sodium con-centration .which would follow any given change inwater and electrolyte balance.

Let A represent the total number of osmotically-active solutes in body water (milli-osmoles).

Let W represent the total body water (litres).The symbol [ ] denotes osmolar concentration

per litre.The subscripts I and 2 refer to the values

before and after a change in the quantity beingconsidered.

Suppose the effective osmotic pressure of cellsand E.C.F. is the same, and is represented by[B] which denotes the total concentration ofosmotically-active solute particles in milli-osmolesper litre of fluid.Then at equilibrium

Al[B1] - .'. [B1]Wl- Al

W,

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74 POSTGRADUATE MEDICAL JOURNAL February i94

+20-

0 0EA 0

2 AEI o

a Aw0-AU AL

o Awa:

AA

---I,0x

0

-20- 0

AOBSERVED AB mM r litre.

-20 -l o +10 +20

Fi(;. 3.-Each point in the graph in fig. 3 represents the observed change in total cationlevel of the E.C.F. plotted as abscissa compared with the value predicted by meansof the osmotic equation (ordinate). Each point represents an observation made in apatient at the end of 24 hours, during which time there has been a large change in thewater and electrolyte balance, often involving extreme variations in plasma osmolarity.It can be seen that the correlation between the observed change in the E.C.F. totalcation level and the predicted change is very close and indistinguishable from unity.The metabolic data of these patients are recorded elsewhere.'- l

after any change in A or WVA2

[B2 --- [B2]W2 - A2W2

Now suppose that the change in A is representedby X milli-osmoles

. A - A1 + X- [B2]W',Substituting [B,]W1 for Al

we have finally[B,l\lW + X = [B21W2

It has already been said that the effectiveosmolarity of the E.C.F. may be taken as twice theplasma sodium concentration, as a close approxi-mation, and therefore for [B1] and [B2] we maywrite 2[Nal] and 2[Na2]. The osmotically-activesolutes which may alter rapidly in the body (ex-cluding glucose from this argument) are nearly allsalts of sodium and potassium with mostlyunivalent anions. So as an approximate value forX we may take the algebraic sum of twice the

external sodium and potassium balance2(Na + K). Our osmotic formula may nowwritten as

2[Nal]. W, + 2(Na + K)- 2[Na2]. W2and finally

[Na,]. W,1 + (Na + K)= [Na2]. W2.All the measurements necessary to apply thi

osmotic formula can be made in man. Thisbeen done in a wide variety of clinical situatioinvolving large acute changes of water anelectrolyte balance'6. 17 and the results are shoin Fig. 3. It can be seen that the observed changin extra-cellular osmolarity (here measuredtotal cations) agree well with those predictedsimple osmotic theory.

These observations support the idea that tosmolarity inside the cells is the same as that in tE.C.F. Further studies, the data of which cannbe given here16 show also that acute changesE.C.F. osmolarity are followed by movements

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emuary 1960 WYNN: Osmolarity Disorders of the Body Fluids 75r to equalize the changes and that shifts ofrolytes play little part in acute osmotic ad-ments. Movement of electrolytes, however,play a part in stabilizing the osmolarity of

body fluids in chronic disorders.ese observations have practical application.

is not necessary to measure total body watertly because knowledge of normal physiologyclinical judgement will usually suffice to give aestimate. Acute changes in total body waterbe assessed from weight changes or from thed balance record if this is accurately known.rnal electrolyte balance is readily determinede difference between input and output. Frome data one can proceed to elucidate disorders ofosmolarity of the body fluids and prescribentitatively for their correction.16t is worth stressing at this point that the osmoticula gives the same osmotic value to potassium

to sodium. The loss of large amounts ofium from cells causes their osmolarity to

ine. This may be countered by inwardvement of sodium from the E.C.F., or by anard movement of water. In either case the

sodium would fall, but the distribution ofy water would be different in the two eventu-es described. The osmotic formula indicateshyponatraemia may be the result of excessiver retention, loss of sodium, loss of potassium,

any combination of these disorders. Hyper-aemia, on the other hand, results from theerse changes, namely, water depletion, sodiumpotassium gain, or any combination of thesenes.he normal stability of the plasma sodium levelalready been discussed. When acute changesobserved they have as their explanation somege in the three parameters which control theolarity and distribution of the body fluids,ely, the water balance and the sodium andium balance (but see paragraph on mislead-

plasma sodium values).rvations upon Chronic Osmolarityges in Diseaseile acute changes in water and electrolytece are quite common, the more usual clinicaltion is a chronic change occurring in a long--out illness. The interpretation of these

lished osmolarity disorders, and the quanti-relationships between body composition and

concentration of plasma sodium has beenlished recently.4elman and co-workers4 measured effectivea osmolarity, plasma sodium concentration,body water, and total exchangeable sodiumpotassium in a heterogeneous group ofically ill patients. Ninety-eight patients

whose illnesses varied widely, were studied.Their ages ranged from 27 years to go years.The plasma sodium level was between io8 and I93mEq/l. These workers' results are very in-formative. They found a close relationshipbetween the plasma sodium level and the effectiveosmolarity of the plasma, as has been alreadywidely accepted. The correlation coefficient, r,of this relationship was o.97.They found a high degree of correlation between

plasma sodium and the fractiontotal body sodium + potassium

Total body waterThe correlation coefficient of this relationship,

corrected for attenuation,* was o.92.These results suggest that total body sodium and

potassium, and total body water are the primarydeterminants of the plasma sodium concentration.This relation seems to hold for the full range ofclinical osmnolarity disorders and without regard tothe seriousness of illness. The results support theidea of a uniform osmolarity throughout bodywvater and provide no evidence for the occurrenceof ' shifts 't of electrolytes, ion-binding, osmoticinactivation or activation and similar deviceswhich have often been invoked to explain thechanges seen in the plasma sodium concentrationin disease.

ConclusionObservations in animals and in patients now

make it possible to give an integrated account ofconcomitant alterations in plasma sodium con-centration and body composition. There is aquantitative relationship between the plasmasodium level and the total amount of water,sodium, and potassium in the body. Variations inplasma sodium can be explained in terms of thealteration of these three parameters of the bodyfluids, taking into consideration a few exceptionalsituations which would be misleading if over-looked. These results, if applied to clinicalproblems, can do much not only to elucidate thenature of disturbances in the osmolarity of thebody fluids, but also to suggest ways of preventingthese or treating them if they occur.

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*That is, corrected for errors of measurement.tThat is, in the sense of shifting into an osmotically-

inactive area. Movements of ions between cells andE.C.F. are not precluded.

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