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The Distribution of Body Fluids In

Congestive Heart Failure

I. Theoretic ConsiderationsBy J. R. ELKINTON, M.D., AND R. D. SQUIRES, M.D.

The pathogenesis of congestive heart failure is discussed. Experimental evidence is cited to supportthe thesis that abnormalities in the distribution of body fluids may affect circulatory and renalfunction, and hence may be a cause as well as an effect in the complex sequence of events leadingto the congestive state. Emphasis is placed upon alterations in cellular metabolism which may leadto such disturbances in body fluids and so through various mechanisms, cellular, humoral, andcirculatory, may modify the volume regulation of the body.

D URING the past few years the clinicalentity, congestive heart failure, hasbeen subjected to a great deal of physi-

ologic reinterpretation. This reinterpretationhas been due for the most part to the develop-ment of new technics for the study of circula-tory dynamics, of renal dynamics, and oftransfers of body water and electrolytes. It isnow appreciated that this syndrome is oneinvolving a complex series of events often oc-curring over a considerable period of time be-tween the initiating factors and the finalcondition of venous congestion and edema ofmany tissues. Indeed, the lack of correlationbetween immediate and measurable abnormali-ties of cardiac function and the congestive statehave led some writers to challenge the im-portance of the factor of "cardiac damage" andto speak of the state as "congestive circulatoryfailure" or simple "congestive failure." Never-theless, as Starr1 points out, "congestive failureoccurs with great frequency in persons withdamaged hearts," and this fact strongly sup-ports the conclusion that disease of the heart iseither an initiating factor, or at least an im-portant contributory factor, in the etiology of

From the Chemical Section of the Department ofMedicine and the Hospital of the University of Penn-.sylvania, Philadelphia, Pa.

During this work, J. R. E. was Established Inves-tigator of the American Heart Association; R. D. S.was Research Fellow of the Department of Medicine-supported by a grant from the National Heart Insti-tute of the U. S. Public Health Service.

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this syndrome. Our problem, therefore, is theelucidation of the events which lead fromcardiovascular dysfunction on one hand to theedematous state on the other.From new data many investigators have

emphasized especially the role of the kidney inthe development of congestive failure, and im-paired glomerular filtration has been consideredby some to be the principal renal abnormality.Yet much evidence points as well to abnormalfunction of the kidney tubules, and this in turnsuggests the possible involvement of the severalendocrine glands which normally share in theregulation of renal tubular transfers of salt andwater. The problem, therefore, devolves in parton ascertaining how the kidney operates in theregulation of the fluid balance of the body andhow this regulation is disturbed in the conditionof congestive failure.Evidence is accumulating from the study of

normal organisms that variations in the volumeand composition of fluids in tissues other thanthe heart or kidney affect the fluid balance ofthe body. Intake (thirst and appetite) and renaloutput of water and electrolytes are so adjustedto each other that the volume of body fluids ismaintained in a steady state. The means bywhich changes in the water and solute contentof various tissues help to effect this homeostaticcontrol of total body fluid volume are essen-tially unknown. Yet such knowledge wouldappear to be of paramount importance to thestudy of congestive failure. Furthermore, it isnow recognized that the differential distribution

Circulation, Volume I V, November, 1951

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BODY FLUIDS IN CO.NGESTIVE HEART FAILURE. I

of solutes, and therefore of water, between cellsand their surrounding mediums, are maintainedby energy derived from metabolic processeswithin the cells.2 Any role which may be playedby the state of fluid distribution in particulartissues, or in tissues ill general, in the fluidbalance of the body, is inevitably linked to re-actions which take place in the intracellularphase.

For these reasons it seemed advisable, ill unI-dertaking an investigation of the distributionof body fluids in congestive failure, to considerin the light of present experimental evidence thevarious relationships which may obtain be-twveen the circulation, the kidney, and the fluidcontent of other tissues, especially as related to

Extrocellulor (E) Intracellular (I)A Isotonic

edema

c0

+*.- volume-

B Hypertonic r

edema

Total electrolyte conc., IB tIntracellular fluid vol., I tExtrocellulor fluid vol., E +

[B] +I -E +

C Hypotonic [B] -

edema I +

E +

Fic;. 1. Diagram of theoretic types of abnorniali-ties ill volume and total electrolyte concentration ofthe several phases of body fluids, in edema. Brokenlines represent the tiormnal pattern.

cellular metabolism. Such theoretic considera-tiois is undertakess ill the hope that it mightplace in proper perspective the role of abnormalfluid distribution as a cause as well as ans effectin the chain of evenits leading to the accumula-tion of edema.The discussion of this complex problem is

perhaps best accomplished by considering theevidence bearing on the following four ques-

tions: (1) What are the abnormalities of bodyfluid distributiots in congestive failure whichare due to (a) the disease itself, or (b) at-tempted therapy (for example, mercurials)? (2)To what extent are these abnormalities ill conl-gestive failure due (a) to changes in circulatorydynamics directly, (b) to changes inl renal fune-

tioll, (c) to modifications of cellular metab-olism? (3) Do these abnormalities in body fluiddistribution in turn affect (a) circulatory func-tion, (b) renal function? (4) If so, in what ways?Although the experimental evidence bearing onthese questions is fragmentary, it is extensiveenough to justify the opinion that, in additionto circulatory and renal dynamics, factors ofcellular metabolism and tissue fluid distributionmust be considered in the pathogenesis of con-gestive heart failure.

In view of these questions certain observa-tions were made on patients with heart diseaseand edema. These observations are reported inthe succeeding papers.'-' The data which arepresented by no means provide the answers,but they do again emphasize that the questionsoutlined above are pertinent to the problem of(conigestive failure.

DISTRIBUTION OF BODY FLUIDS IN CONGESTIVEFAILURE

Expansion of the extracellidar fluid is the pre-dominant abnormality. The edema of cardiacfailure has usually been considered to be anisotonic expansion of extracellular fluid (fig.1.4). Evidence for this rested upon the observa-tion that the products of diuresis are mostlywater, sodium, and chloride in the same relativeproportions as in extracellular fluid.' Variousdeviations from this simple pattern have beenreported. It has been reported7 that in conges-tive failure sodium is retained by the kidneys toa greater degree than is chloride; if the dis-parity in clearances of these two ions is not dueto the simultaneous administration of am-monium chloride, an increase in the extracellu-lar (olncentration of bicarboi ate should ensue.Indeed, many patients with congestive failurehave been found to have an elevated concentra-tion of serum bicarbonate,8-10 a finding whichindicates that some type of disturbance in acid-base equilibrium occurs in relation to thedisease or to its treatment. If more sodium werereabsorbed in order to retain water as part ofthe dehydration reaction,1' as suggested byPeters,'2 the concentration of sodium in serumand extracellular water should tend toward orbeyond the upper limits of normal, dependingon the relative rates of water ingestion and

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sodium reabsorption. Conversely, if water isretained in excess of sodium, the serum andextracellular sodium concentration should bedepressed. Hyponatremia has been reported or

implied from the existence of hypochloremiain congestive failure, but such hyponatremia(and hypochloremia) are almost always ob-served to follow prolonged courses of treatmentwith mercurial diuretics.'3' 14 Since water shiftsacross cell membrane when the sodium concen-

tration is changed in extracellular fluid inl nor-mal subjects," such a phenomenon immediatelyimplicates the intracellular phase in the fluidabnormality of edema at least under certaincircumstances of therapy (figs. lB and 1C).

Intracellular content of water and of certainelectrolytes may also be abnormal. Disturbancesin intracellular fluid have been found in manydisease states, including water deprivation anddehydration, starvation, gastrointestinal fluidloss, metabolic alkalosis, acidosis due to diabeticcoma and renal insufficiency, and in diseasesinvolving hypo- and hyperfunction of the ad-renal cortex. In most of these states the fluidabnormalities described have been depletionor excess of intracellular sodium and intracellu-lar potassium. In considering intracellular fluiddisturbances, other components in addition tothese must be taken into account. With presentmethods of study it should be possible to de-scribe changes in the following: (1) transfers ofwater across the cell boundary according to thedictates of variations in the effective osmo-

lar concentrations in the two phases, (2) trans-fers of potassium into and out of cells, (3) trans-fers of sodium into and out of cells, (4) transfersinto and out of cells of other anions, particu-larly phosphate and possibly chloride, and(5) changes in osmotic activity of solutes withinthe cells (fig. 2). Abnormal transfers of some

of these constituents have been described incongestive failure. Newman and co-w orkers'6found that potassium was retained in excess ofnitrogen in a number of cardiac patients duringdiuresis of edema fluid. Fox and co-workers'7have reported the occurrence of diuresis follow-ing the administration of hypertonic solutionsof sodium and potassium and have postulatedthat in congestive failure there is a hypotonicoverhydration of the intracellular phases. Other

workers'5-'0 have also described the uptake ofpotassium in cardiacs, but more complete in-formation has yet to be obtained concerning ab-normalities in the major fluid constituents ofthe intracellular phase in patients with conges-

tivre heart failure.There are regional differences in fluid distribu-

tion in congestive failure. This statement needsno further support than the common observa-tion that the edema is usually greater in thedependent portions of the body. This disparityof distribution presumably is due to the effectof gravity on the hydrostatic pressure in veinsand capillaries in these regions, although otherfactors such as local anoxia may play a role.

Extracelluic

_

ar (E) Intracellular ( I )g.1

To0

5

>1

To

volume

Fic;. 2. Diagram of transfers of certain constitu-ents of the body fluids between cells, extracellularfluid and environment. Arrows bet weeii the severalphases indicate only the directions of movement ofthe individual constituent; no quantitation of rate or

magnitude of transfer, or of concentration, is implied.The cross-hatched area on the right represents frac-tions of intracellular solute that are osmotically in-active and as such may be considered to be trans-ferred out of the aqueous phase of cellular fluid.

Iii summary, from this brief review it appearsthat the evidence in regard to the first questionmay be stated as follows. The common fluidabnormality in congestive failure is retention ofextracellular electrolytes and water. Intracellu-lar disturbances in respect to volume of waterare suggested by the occurrence of an abnor-mally low electrolyte concentration (hypo-natremia) but this phenomenon is probably theresult of therapy rather than of the congestivefailure per se. Intracellular disturbances in con-

tent of electrolytes, especially potassium, havebeen documented, but the relationship of theseabnormalities to the disease or to the state ofnutrition has not been established. Finally, ab-normalities in the regional distribution of bodyfluids are present in this condition.

Nov _ NO+

K + K +

H.O H.O

HPO. _ _ HPO.-

Cl- --cGlmt

1

1

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BODY FLUIDS IN CONGESTIVE HEART FAILURE,1s. I

Given these disturbances of body fluid dis-tribution in congestive heart failure, we turnto the second question, namely, how are theyinitiated by cardiovascular and renal dys-function.

CIRCULATORY AND RENAL FACTORS IN EDEMA

This discussion deals with the type of conges-tive failure which develops over a prolonged periodof time in patients with heart disease. It isrecognized that congestive failure may developacutely: (1) in cardiac patients as a result of asudden redistribution of fluids without an in-crease in total body weight, for example, acutepulmonary edema; and (2) in patients withoutheart disease who in various ways acquireabruptly a large increment of total body waterand salt. However, we are concerned with thepatient with a damaged heart who accumulatesedema more slowly, that is, who over a pro-tracted period has a total output that fails toequal the total intake of fluids. In some mannerthis must result from a functional impairmentof the damaged heart.

"Backward failure" and "forward failuue"have both been proposed to account for congestiveheart failure. For many years the sequence ofevents as deduced from Starling's2' originalhypothesis was held to describe adequatelythe development of edema. Essentially, thissequence was as follows: cardiac failure withdiminished output, elevation of venous andcapillary hydrostatic pressure, transudation offluid from plasma to interstitial spaces causingedema, diminution of plasma volume, and re-duction of sodium and water excretion by thekidney. In 1943 Starr and co-workers22 andsubsequently Warren and Stead23 proposedanother sequence of events: cardiac failure withdiminished output, decreased renal blood flowand rate of glomerular filtration, decreased ex-cretion of sodium and water, increased plasmavolume, increased venous and capillary pres-sure, transudation and edema. This hypothe-sis" 22 23 rests in part on evidence that fall incardiac output, expansion of blood volume, andthe development of edema may precede the risein venous pressure in congestive failure, and inpart on the demonstration of changes in renalhemodynamics. However, Peters12 has ques-

tioned the validity of the evidence for highblood volumes in this condition. He points outthat in any case Starling's theory in regard tothe distribution of fluid across the capillarymembrane must obtain and challenges the pri-mary place of the renal dysfunction in thesequence of events. Thus, the role of the changesin renal hemodynamics is still the subject ofconsiderable controversy.

Neither "backward failiure" nor ".forwad.fail-ure" accounts for the lack of correlation betweenthe output of the heart and the development ofcongestive failure. These two theories have beenbased on the assumption that an absolute dim-inution in cardiac output to below the averagenormal range is the critical impairment of func-tion in the diseased heart. Yet signs and symp-toms resembling congestive failure are knowntto occur in the presence of abnormally highlevels of cardiac output, as in beriberi andthyrotoxicosis.24 21 Decompensation and recom-pensation may occur in a patient with verylittle change in the level of cardiac output.26For these reasons other factors would appearto be involved which relate the output of theheart to (lemands which the body placesupon it.

Disparity between the ouitput (of the heart andthe metabolic demands of the body may be thebasic cause of the signs and symptoms of conges-tive heart failure, including edema. This concept,stated by Altschule,27 is suggested to explainthe lack of correlatioii between the absolutelevel of cardiac output and the degree of con-gestive failure. Such a concept receives furthersupport from the observation that recompensa-tion of the failing heart can occur when anunchanged or falling cardiac output is associ-ated with a lowering of the basal metabolicrate.26 This demand on the heart by the bodycan be stated in terms of oxygen requirement,although other metabolic factors conceivablymay be involved. Evidence has been presentedby Little29 of inverse correlations betweenthe degree of congestive failure and the ratioof oxygen supply to oxygen consumption, andalso between central venous pressure and mixedvenous oxygen tension. Briggs and associates26ifound that oxygen A-V differences decreasedwith recompensation. These observations sug-

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J. R. ELKINTON AND R. D. SQUIRES

gest that lack of oxygen (hypoxia) in one ormore areas of the body is a next step in thesequence leading to congestive failure. Whetheror not hypoxia may influence directly at thecellular level the retention of fluid in tissues(see below), it at least has an effect on thegeneral and regional dynamics of the circula-tion. Regional changes in circulation are knownto result when the blood volume and oxygensupplY are inadequate for the entire body.30' 1

These regional dlifferelnces in circulation mayinifluieni(ce the accumulationi of edema in avariety of ways, as set forth ill the last sectionof this paper. But diminished blood flow to thekidiiey- with consequent impairment of glomer-ular filtration has been considered by theproponents of "forward failure" to be the majorfactor in the development of congestive failure.

Dimiinished glomerular filtration and a fixedrate of tubular reabsorption of sodium do notalone e.rplain the retention of salt and water.The studies of Merrill,32 Mokotoff, Ross andLeiterY and others, have shown conclusivelythat renal blood flow and glomerular filtrationare markedly reduced in many patients withcongestive failure. Leiter34 and Wessoni, Anslowandl Smith3. have used these findings to supportthe hypothesis that a constant maximal rate ofreabsorption of sodium obtains in the distalrenal ttubtule anl1 hence, when filtration ofso(ium (liminishes, the excretion rate of the ionfalls. This hypothesis is difficult to substantiateor refute since the amount of sodium rejectedlbv the tubule and excreted is such a minutefraction of the amount filtered and reabsorbedthat it falls well within the error of measure-ment of the latter. However, considerable evi-den(ce has accumulated that tubular transfersare likewise important in determining the ab-normally low rate of sodium excretion in heartfailure. In the patients studied by Merrill andl\Iokotoff and associates the correlation wasvery poor b-etw\eeni excretion rate and filtrationrate, and other workers'6' 26, 36-8 have foundthat the excretion rate may vary considerablywith the loss or gain of edema without muchchange in the rate of glomerular filtration. Innormal subjects, when renal plasma flow hasbeen varied independently of filtration, theexcretion rate of sodium has been found to

correlate more closely with the former thanwith the latter.A9 It would appear, therefore,that abnormalities of renal tubular transfersare integral to the pathologic function of thekidney in edema.

Tubular transfers are abnormal in congestivefailure and may be influenced by circulatory,humoral and cellular factors. The relationshipof circulatory insufficiency to glomerular func-tion in the kidney is much more easily under-stood than its relationship to that of thetubules. To what extent is there a direct effectof circulatory factors on the renal tubules andto what extent is there an indirect effect medi-ated through one or more endocrine glands?Hormonal regulation of such transfers in thenormal kidney is well established. The anti-diuretic hormone (ADH) of the posterior pitu-itary gland regulates water reabsorption, andat least one of the adrenal cortical steroids,closely resembling, if not identical with, desoxy-corticosterone acetate (DCA), affects the reab-sorption of sodium and potassium. Abnormalamounts of antidiuretic substance and of ad-renal cortical steroids have been found in theurine of patients with congestive heart fail-ure40 42 but it has not yet been shown conclu-sively that the failure of the kidney to excretewater or salt is mediated primarily througheither of these hormones. A variety of circula-tory factors have been investigated for theireffects, direct or indirect, on renal tubular func-tion in this condition. Renal venous hyperten-sion has been shown experimentally by Blakeand co-workers43 to result acutely in increasedrenal tubular reabsorption of sodium. The im-portance of the time factor in this phenomenonws as emphasized by Hwang and associates44who demonstrated that with prolongation ofthe renal venous hypertension over a period ofa week or more, the rate of sodium excretionreturned to control levels. Wilkins and col-leagues45 have found a decreased excretion ofsodium following venous congestion of thelimbs. The observations of Blake and co-workers suggest a direct effect of renal circula-tion on the tubule, those of Wilkins and hisassociates suggest a humoral as well as a directcirculatory effect. Anoxia might logically bethought to be a factor but the experiments of

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BODY FLUIDS IN CONGESTIVE HEART FAILURE. I

Berger and colleagues46 indicate that in thenormal subject systemic anoxia acceleratesrather than retards the excretion of sodiumand water. However, these also were acutestudies; protracted anoxia in certain cases hasbeen associated with the accumulation ofedema, which in turn was relieved by the ad-ministration of oxygen.1' 47 In fact, both thedegree and the duration of anoxia must beconsidered before a clear cut idea can be enter-tained as to its effect on sodium metabolism.Again, the immediate receptor of this stimulusmay be in the kidney or elsewhere. Perhapsalterations in the fluids of various tissues areshared by the tubular cells of the kidney andso directly effect tubular transfers of electro-lytes and water. Thus, despite the many possi-bilities which have been considered, one of thekey questions remaining unanswered is how thekidney tubular cells know how to regulate theirtransfers of electrolytes and water in terms ofthe distribution of fluids in tissues at a dis-tance, and how this process functions abnor-mally in the patient with congestive heartfailure.In summary, it is apparent that much re-

mains to be learned concerning the relativeroles of cardiac and renal dysfunction in con-gestive heart failure. The absolute level of car-diac output does not correlate with the degreeof edema, and cannot explain it on either a"backward" or a "forward failure" theory. Anoutput of the heart which is inadequate in rela-tion to metabolic demands would appear to bea primary factor leading to secondary changesin circulatory dynamics in several regions ofthe body. Renal retention of salt and waterresults from more than a circulatory distur-bance causing a diminished glomerular filtra-tion; tubular transfers are involved and theseare conditioned by humoral and cellular, aswell as by circulatory, factors.

EFFECTS OF ABNORMALITIES OF BODY FLUIDSON CIRCULATORY AND RENAL FUNCTIONWhat are the properties of the body fluids and

their component parts which effect their regulationby the kidney? It is perhaps stating the obviousto say that changes in the volume and composi-tion of body fluids produce effects on renal

function. Yet, as indicated above, little isknown as to just how renal regulation of bodyfluid volume takes place. Wolf48 has recentlyreviewed this problem and points out that mostof the emphasis in the past in investigation ofrenal function has been placed upon the regu-lation of concentration of solute rather than ofvolume of solvent. Clearly the regulation ofbody content of electrolytes is intimately tiedup with that of water, but there is some evi-dence that such renal regulation is more thana function of concentration, ionic or total os-molar, in circulating plasma. Warren andStead,23 Borst49 and Dock50 have related therenal regulation of body fluid volume to main-tenance of an adequate cardiac output. Asidefrom the problem of how these two factors actupon one another, there are other difficultiesinvolved in this concept which have been re-viewed by Lewis and co-workers.5' These in-clude the observation referred to above, thatthere may be no correlation between the levelof cardiac output and the degree of edema incongestive failure, and that alterations of car-diac output in other conditions are not asso-ciated with corresponding changes in the renalexcretion of water and electrolytes. Therefore,in addition to cardiac output, it is necessary tolook for certain characteristics of the bodyfluids, such as regional composition and volume,which may influence their regulation by thekidney.

Cellular hydration, interstitial volume, and in-tracranial volume appear to condition the renalexcretion of water and electrolytes. Uinder condi-tions of water deprivation and dehydration,sodium and chloride are increasingly reabsorbedby the renal tubule despite rising concentra-tions of these ions in the plasma."1 Peters'2 hastermed this the "dehydration reaction" andsuggests that in congestive failure a similarstimulus mistakenly occurs. The precise natureof the stimulus is not apparent, although itmay he related to a contraction of the effectivecirculatory volume; in any case it is certainlynot the concentration of electrolytes in theextracellular fluid and plasma. Seldin andTarail'2 hare shown in normal subjects thatthe increased excretion of sodium which occursduring certain types of osmotic diuresis occurs

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only following the injection of solutes whichare essentially excluded from cells, such as freeglucose and mannitol, and not following theinjection of urea which is freely diffusible anddoes not cause cellular dehydration. These au-thors interpret these data to indicate that theexcretion of sodium under these circumstancesis conditioned not merely by the total osmolarconcentration of solute in the tubular urinebut also by the effects of the specific soluteinjected on cellular hydration of tissues else-where in the body. It should be pointed outthat in these experiments expansion of extra-cellular fluid volume was an invariable accom-paniment of the contraction of the intriacellularfluid and hence may be a significant variable.Green and Farah,53 in experiments oni the renaleffects of sodium loading in dogs, have pre-sented evidence that the rate of tubular rejec-tion of this ion is more closely related to therate of cellular dehydration produced by theload imposed, than to the concentration orabsolute amount of sodium in the extracellularfluid. Welt and ()rloff54 studied the effect onwater and sodium excretion of variations inplasma volume, plasma colloid osmotic pres-sure, and interstitial fluid volume, as producedby injectioti of human albumin in X arious oll-centrations. They found that ele\-ation ofplasma volume without elevation of the colloidosmotic pressure led to an increased rate ofexcretion of wsater and possibly sodium, whereasa decrease ill sodium excretioun resulted fromraising the colloid osmotic pressure as well.The data were interpreted to indicate that therenal excretion of water and sodium is influ-enced by not only plasma volume awd colloidosmotic pressure but possibly also by inter-stitial fluid volume. Harrison and co-workers51have found evidence that compression of theneck veins is associated with increased exc-retioliof sodium by the kidney, indicating that someattribute, possibly volume, of the intracranialfluids may condition the renal excretion ofelectrolytes. The experimental manipulationsin normal subjects, cited above, of Seldin andTarail and of Welt and Orloff lead to differentresults in edematous patients. 55 56 This sug-gests that ill the edematous state additionalfactors influence renal function. But, neverthe-

less, experimental evidence of this kind in-dicates that in some way, directly or indirectly,changes in the distribution of fluids in the body,including expansion of plasma and interstitialvolumes and contraction of intracellular vol-ume, effect changes in renal function.Body fluid distribution and circulatory system

arc closely interrelated because of the role of thelatter as the "mixing apparatus." There is aninterrelationship between body fluid distribu-tion and circulatory dynamics as well as be-tween the former and renal function. Primarychanges in the circulation may induce second-ary changes in the distribution of body fluids,and vice versa. This is best understood if oneconsiders the multicompartmental character ofthe body fluids. It is an error to conceive of theextra- and intracellular fluids as single homo-geneous solutions contained, so to speak, in abeaker (fig. IA). The extra- and intracellularfluids are parts of many different tissues widelyseparated throughout the body, and are con-nected by extended lines of communication,the ciiculation (fig. 3). The circulation is the"mixing apparatus" and its efficiency deter-mines the constancy of composition, or homo-geneity, of the fluid phases (the extracellulardirectly and the intracellular indirectly). It isnot surprising, therefore, that disturbances incirculatory function may lead to differences incomposition and distribution of fluid in variousparts of the body. It is, perhaps, less obvious,but nevertheless true, that disturbances in thecomposition and distribution of body fluidsmay affect the function of the circulation.Primary changes in the circulation may cause

secondary disturbances in the fluid content oftissues, for example, "prerenal deviation."Changes in the circulation which affect fluiddistribution are many and some may be enu-merated. Increased venous pressure due to ob-struction or gravity leads to local transudationof fluid from plasma to interstitial spaces.57Diminished cardiac output, arterial occlusion,or peripheral vascular collapse may producetissue anoxia and so disturb electrolyte equi-libria which are maintained by oxidative reac-tions; for instance, potassium may leave andsodium enter cells.58"61 Under such circum-stances cellular water may or may not be re-

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leased, according to the dictates of the changesin the effective osmolar concentration of solutesin the two phases. Collapse of the circulationmay result in the retention of water and solutesin the body because of the simple failure oftransport of such substances to the organ ofexcretion.62 Borst49 and Wolf' have inveighedagainst the validity of this concept of "pre-renal deviation." Wolf states that there is little

ney is greatly increased. Such a concept is easilyunderstood by the clinician who observes, forinstance, certain effects of transfusion on apatient in shock, such as absorption of sub-cutaneous pools of fluid (hypodermoclyses, forexample), reestablishment of urinary flow, cor-rection of acid-base disturbances (for instance,chloride acidosis) and excretion of accumulatedmetabolites.

receptor for osmoreceptor forthirst 9 1 9 || post pituitary

f c

EXTRACELLULARFLUID

INTRACEFL

11lungs

hearta

i i

.

1 peripheral tissues, ( muscle)

g

ELLULAR G tUID

periph. vascular /| rcpo osystem- ~~~~~receptor for

b ---V oadrenal cortex11- S 22ZI- d

FIG. 3. Diagram of the intracellular and extracellular fluids of the body, including pathways ofcirculation in the latter, and sites of transfers with the external environment.

The multicompartmental character of the body fluids is emphasized, as well as the role of thecirculation as the "mixing apparatus" for the extracellular fluid. Transfers of the various constit-uents between the two fluid phases, diagrammatically shown in figure 2, take place in each of themany units of the body fluids. Loci of some of the intracellular fluids in which changes in composi-tion may affect, directly or indirectly, the distribution of fluids in the body as a whole, are indi-cated by letters a to g, inclusive.

evidence that all parts of the body fluids arenot readily accessible to renal regulation. Yetin the instances just set forth it appears to theauthors that the integrity of the circulationstands between the fluids of peripheral tissuesand the action of the kidney upon them. Hencecirculatory dysfunction may lead to "prerenaldeviation," at least in the sense that the timethat is required for their regulation by the kid-

Primary changes in the body fluids may affectthe circulation; for example, sodium depletioncauses diminution of cardiac output and renalblood flow. Changes in the body fluids whichaffect the circulation are also numerous and notcompletely understood. Obviously, alterationin the volume of that portion of the extra-cellular fluid contained within the vascular sys-tem, the plasma, is intimately related to circu-

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latory function. Expansion of blood and plasmavolume, as when whole blood or concentratedalbumin is administered, may result in an in-crease in cardiac output in patients in shock63and in renal blood flow in normal subjects.64' 66Contraction of the blood and plasma volumemay lead to diminution of cardiac output, arte-rial pressure, renal blood flow, or generalizedperipheral vascular collapse.66 Abnormalities inthe extra- and intracellular fluids as a whole,are less well understood in regard to their effecton the circulation. Diminution of extracellularfluid volume resulting from dehydration, andespecially from sodium depletion, is closely as-sociated with collapse of the circulation. Thatthis relationship is not due alone to the con-comitant fall in plasma volume is suggested bythe following experimental evidence obtainedin dogs by one of the authors and his associ-ates.62' 67 Shock due to sodium depletion wasmore profound than that due to dehydrationalone; in the initial phases of sodium depletionthe cardiac output and arterial pressure fellabruptly well before the drop in plasma volume;restoration of extracellular fluid and plasmavolume alone, by the infusion of isotonic glu-cose solutions, did not restore the cardiac out-put. From these data it appeared that changesin total electrolyte concentration, and thereforein intracellular fluid volume, had some effecton the circulation, peripheral or central, otherthan that mediated through the plasma volume.Changes in the volume or composition of intra-cellular fluid have effects on the circulationunder a few other circumstances. Depletion ofintracellular potassium, and excess of cellularsodium in the myocardium, as produced byoverdosage of desoxycorticosterone, has beenreported to produce lesions which might resultin acute congestive heart failure.8 The samephenomenon has been suggested to occur inother types of clinical potassium deficiency.69' 70

In summary, from these observations it wouldseem that the third question asked in the intro-duction can be answered in the affirmative;that is, that body fluid distribution can affectboth circulatory and renal function. The ques-tion remains, does this occur in congestivefailure, and if so, how?

VARIOUS WAYS IN WHICH ABNORMALITIES OFFLUID DISTRIBUTION MAY PLAY A ROLE INTHE PATHOGENESIS OF CONGESTIVE FAILUREAbnormalities of fluid distribution in many

tissues may modify, secondarily, the circulatoryand renal factors in congestive failure. Circula-tory factors must be primary in the etiologyof congestive failure in patients with heartdisease, at least in a temporal sense; the placeof such factors in the more immediate sequenceof events is still open to discussion. Factors offluid distribution which may modify secondar-ily the circulatory disturbances have receivedless attention from investigators. From the pre-ceding discussion, however, it should be appar-ent that some of these possible modificationsoccur on the cellular level. Accordingly, in thediscussion which follows, particular emphasiswill be placed on disturbances in cellular me-tabolism and fluid composition of varioustissues, as they may play a role in the patho-genesis of congestive failure.For purposes of discussion some of these

hypothetic relationships are listed in table 1.Primary Relationships are concerned with car-diac dysfunction and its immediate sequelae.Cardiac dysfunction may be defined as a cardiacoutput which is inadequate in relation to thedemands of the body. A and B are the essentialrelationships of "forward" and "backward"failure. C introduces the possibility that a rela-tively inadequate output of the heart maymodify cellular metabolism by failing to main-tain an adequate supply of oxygen and othernutrients or to remove completely the productsof catabolism. Given this last result of an in-adequate cardiac output, a series of secondaryrelationships is postulated. In the first place,such a state of modified cellular metabolismmay lead to alteration of effective blood flowand effective blood volume between variousregions of the body. And in the second place,it may disturb the exchanges of electrolytesand water between the cells and extracellularfluid in various tissues. Such disturbances inturn may promote the edema of congestivefailure by direct effect on the cardiovascularsystem and on the peripheral tissues, or in-directly by humoral effects on the kidney. Someof the possible sites of these cellular disturb-

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ances are diagrammatically indicated by theletters a to e in figure 3. Obviously we aredealing with a set of complex interrelationshipsin which secondary effects may further aug-

TABLE 1. Hypothetic Relationships of Circulatory,Renal, and Body Flu2id Factors in the Production ofEdema in Congestive Heart Failure.

I. Primary relationshipsRelatively inadequate cardiac output and:A. diminished glomerular filtrationB. venous congestionC. modified cellular metabolism

(failure to supply oxygen and other nu-trients, failure to remove products of catab-olism, etc.)

II. Secondary relationshipsA. Modified cellular metabolism and regional

alterations in effective blood flow and bloodvolume:1) Relatively decreased renal blood flow

[IA]*2) Relatively decreased peripheral blood

flow [11B413) Relatively decreased cerebral blood flow

and volumeStimulation of a blood and interstitialvolume receptor [I1B21

B. Modified cellular metabolism and alterationsin cellular electrolytes and water:

1) Impairment of myocardial and peripheralvascular function (a)t, [I].

2) Increased tubular reabsorption of Na andH20 [IBIa) DCA from adrenal cortex (d)b) ADH from posterior pituitary (e)c) Local stimuli in renal tubular cells (c)

3) Fluid intake increased in relation to out-put (thirst and appetite) (f) [IB]

4) Direct effect on peripheral tissues (g)? Cellular depletion of potassium? Cellular overhvdration due to increasedcellular osmolaritv.

III. Tertiary relationshipsA. Modifications of I and II by therapy.

1) AMercurials, acting on IIB:2c, ?2b, ?3, ?4

* Figures in brackets indicate possible interrela-t ionships.

t Letters in parentheses refer to cellular loci dia-grammatically represented in figure 3.

ment primary causes. Some of these interrela-tionships which would create vicious cycles areindicated ill table 1 (by cross references inbrackets).

Alterations in regional blood flow may promoteedema. Anoxia is known to result in changes inblood flow between various regions of thebody.30 The stimulus presumably is initiatedon the cellular level and is effected in partthrough reflex vasomotor activity and in partthrough direct local action. Diminution of renalblood flow may cause a further fall in glomeru-lar filtration rate and so promote retention ofsalt and water. Diminution of peripheral bloodflow should lead to increased hypoxia of theperipheral tissues (see below). Harrison andco-workers,51 as mentioned above, have foundthat intracranial congestion is associated withincreased excretion of salt and water by thekidneys. On the basis of their experimentalwork they postulate a "volume receptor" inthe cranial cavity which conditions the renalexcretion of salt and water. These workerssuggest that in congestive heart failure intra-cranial blood volume is diminished by redis-tribution of blood to other parts of the body,and so stimulates the receptor to initiate therenal retention of salt and water. To such areceptor changes in blood volume or iii inter-stitial fluid volume are more likely to be thestimulus than are changes in cell volume. Ineither case, alterations in the circulation in thisregion of the body may be a critical factor.

Aside from influencing the blood flow tovarious regions of the body, modified cellularmetabolism leading to disturbances in waterand electrolyte content of the cell may be asecondary factor in the pathogenesis of conges-tive failure by a variety of mechanisms.

Secondary tissue fluid changes may affectdirectly function of the heart or peripheral vascu-lar system (fig. 3, a and b). This possibility issupported by the hemodynamic response citedabove62' 67 to the experimental depletion of so-dium leading to hyponatremia and intracellularoverhydration. Potassium depletion of the myo-cardium has also been reported to lead to acutecongestive failure.68-70 However, it has not beenestablished that such a vicious cycle occurs inthe congestive failure attendant upon chronicvalvular disease of the heart; coronary occlu-sion with myocardial infarction is a special casein this regard.

Increased renal tubular reabsorption of sodium

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and water is probably the result of secondarychanges in the cells of the receptors of certainendocrine glands, or of changes in the renaltubular cells themselves (fig. 3, c, d, e). Evidencehas been presented above for humoral factorswhich influence tubular transfers of water andelectrolytes in congestive heart failure. If ad-renal steroids are involved, their secretion re-quires a stimulatory mechanism, whether thepathway goes from the sympathetic nervoussystem through the secretion of epinephrine tothe production of adrenocorticotropic hormone(ACTH) by the anterior pituitary gland, orwhether the latter receives its stimulus fromthe central nervous system via the hypothala-mus. In either case a receptor tissue (fig. 3, d)is probably stimulated in the normal subjectby changes in the distribution of its water andelectrolytes; in the subject with congestive fail-ure the response may be altered by metabolicchanges in the receptor tissue or by stimuli ofa different nature, perhaps associated withstress. Antidiuretic hormone production by theposterior pituitary is initiated not only bycentral nervous system stimuli but by certainhypothalamic osmoreceptors as well (fig. 3, e).7'This is a clear example of fluid distribution in aremote tissue modifying renal function. Thefunctions of these osmoreceptors and how theymay he involved in congestive failure, at leastunder certain circumstances of therapy, arediscussed below. Finally, in the light of presentknowledge one can believe that renal tubulartransfers are conditioned by factors present inthe renal tubular cells themselves (fig. 3, c).These cells may share with those of peripheraltissues changes in volume and electrolyte com-position resulting from altered metabolic proc-esses. That such is the case in congestive fail-ure, however, has not been demonstrated.

The physiologic regulation of intake of waterand electrolytes (thirst and appetite) is probablyeffected through certain tissue factors, such ascellular hydration (fig. 3, f). These regulatingmechanisms appear to function in an abnormalway in congestive failure since the normal rela-tionships of intake to output are maladjustedduring the period of edema formation. Suchmay also be the case following prolonged ad-ministration of mercurial diuretics (see below).

Secondary changes in the peripheral tissues(muscle) may directly alter the exchange betweencells in these tissues and the immediate internalenvironment, the interstitial fluid (fig. 3, b). Evi-dence has been presented that transfers ofwater into and out of cells may be effectedwithout any primary change in extracellulartonicity and without any net transfer of solutesacross the cell boundary, that is, by changes ineffective osmolar concentration of the soluteswithin the cell. This evidence is of severalkinds. In intact man and animals it has beenshown experimentally72 13 that significant dis-crepancies may exist between the total waterbalance and the total sodium plus potassiumbalance of the body, discrepancies that, in theopinion of the authors, could only be explainedby changes in the osmotic activity of soluteswithin the intracellular phase. In another typeof experiment based on direct analysis of skele-tal muscle before and after certain manipula-tions of extracellular fluid, a similar discrepancywas found between the observed transfers ofwater and those predicted from the transfersof base.74 75 Other workers76 have observedphenomena that are most easily explained bysuch a process. Presumably such a change inthe osmotic activity of intracellular solutes isdue to changes in the degree of dissociation ofmolecular aggregates. Such changes are mostlikely conditioned by metabolic processes. Hill77has demonstrated that following stimulation ofa frog's muscle, under anaerobic conditions,there is an increase in its total effective osmolarconcentration and wshen oxygen is introducedinto this system, the total osmolar concentra-tion returns to its previous level. More recently,Robinson78 has found that transfers of waterin slices of rat kidney cortex are dependentupon oxygenation. The "active process" ofwater transfer which he postulates is probablythe process under discussion. Thus the evidenceis strong for the view that metabolic processesnot only condition differential exchanges ofsolutes across the cell boundary,2 but alsochanges in osmotic activity of solutes withinthe cell, and therefore that metabolic processescontrol the volume of intracellular water.

For these reasons it is not difficult to believethat such a factor as hypoxia, in congestive

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failure, might well condition directly the ex-changes of fluid in the peripheral tissue (fig.3, g) without a preliminary effect on eitherintake or renal output of salt and water. Thepossibility of such an occurrence is suggestedby the observations47 mentioned above whichrelated edema formation to anoxemia. Suchtransfers of fluid in the peripheral tissue wouldundoubtedly lead to secondary transfers else-where in the body but this fact should notdetract attention from the possibility that thefirst transfer took place in the periphery.

Therapeutic measures in congestive failure mayfurther modify the primary and secondary rela-tionships listed in table 1; this is especially trueof the prolonged use of mercurial diuretics. The

E ~~ ~~~~EIr---- ~ B

Ed~~ ~ ~~~ mu I +

mLC____ Circulatoryheart *--Vo. failure

E 4-

FIG. 4. Diagram of "systemic" dehydration in thepresence of edema: regional differences in distributionof bodv fluids.

already complex relationships of the physi-ologic and chemical factors in congestive failuremay be further complicated by at least onetherapeutic agent. Since mercury is an enzy-matic poison because of its ability to combinewith sulfhydryl groups, it is reasonable to lookfor its effects in congestive failure at the cellu-lar level, that is, among the secondary relation-ships in table 1. The problem posed by thehyponatremic mercury-fast patient in conges-tive failure exemplifies the extreme complexityof the relationships of the physiologic factorsinvolved. The remainder of the discussion isdevoted to a consideration of this special aspectof congestive failure.

"Systemic" sodium depletion following pro-longed mercurial therapy (the low-salt syndrome)

may augment the circulatory and renal failure.Changes in composition of extracellular fluidwith further deleterious effects in the circula-tion have been recognized for some time tooccur in the presence of prolonged administra-tion of mercurial diuretics. Klinghoffer79 de-scribed in four such patients the occurrence ofhemoconcentration and azotemia. These find-ings suggested a contraction of plasma volumeand an increased degree of renal insufficiencywhich probably was the result of a further dropin renal blood flow. Schroeder" has reported aseries of patients with similar findings andwith hypochloremia and hyponatremia, whoresponded to the administration of hypertonicsolutions of sodium chloride. This condition incardiacs he has designated as the "low-saltsyndrome." Presumably these patients have a"systemic" sodium depletion and dehydrationin the presence of localized or regional edema.It is easily understood how this paradoxic situ-ation can occur. During the administration ofmercury which inhibits the tubular reabsorp-tion of sodium, salt is lost from the only portionof the body fluids immediately available to thekidney, namely, the plasma flowing through it.If the circulation is adequate, edema fluid maybe mobilized to replace the salt and waterdeficits of the circulating plasma, and diuresisensues. If, however, for such reasons as im-paired cardiac action, increased hydrostaticpressure due to gravity, hypoalbuminemia, thatis, "prerenal deviation," the circulation is notable to effect a mass movement of fluid fromthe segregated pools of edema, then the rest ofthe "systemic" extracellular fluid is depleted,with further circulatory collapse instituting avicious cycle. The results of this sequence ofevents are represented diagrammatically in fig-ure 4.

The hyponatremia of the low-salt syndromeshould produce, in sequence: (1) intracellularoverhydration; (2) inhibition of antidiuretic hor-mone production (through Verney's osmorecep-tors) and inhibition of thirst; and (3) diuresis.The hyponatremia described as a cardinal signof the low-salt syndrome implies a state ofintracellular overhydration. This is a conditionwhich in normal subjects is associated withinhibition of the antidiuretic hormone (ADH)

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of the posterior pituitary and diuresis.7" It ispertinent, therefore, to speculate as to how theintracellular fluid may be altered in these cir-cumstances and how such alteration might inturn affect the circulation and renal function.

Evidence is presented in the papers whichare to follow that hyponatremia frequentlyoccurs in patients with congestive failure andthat it is usually associated with the adminis-tration of mercurial diuretics. In addition it isnot always associated with the "low-salt syn-drome" insofar as the latter is indicated by asuccessful response to hypertonic sodium solu-tions. If the removal of sodium from some por-tion of the body is not the major factor, someother mechanism must be invoked to accountfor the maintenance of a low concentration ofsodium and total electrolyte in the body fluidsin the presence of edema.The osmoreceptors of the posterior pituitary,

as described by Verney,7' represent one intra-cellular fluid in which changes of compositionmay materially affect the distribution of fluidsthroughout the body (fig. 3, e). When Verneyinjected in the. area of the supraoptic nucleihypertonic solutions of substances which didnot readilv cross the cell membrane, the diuresisof a standard water load was inhibited. Hepostulated that the osmotic effect of thesesolutions on the "osmoreceptor" cells is toreduce intracellular fluid volume with a conse-quent stimulation of the antidiuretic hormoneproduction by the posterior pituitary. The anti-diuretic hormone as a humoral agent then in-creases the reabsorption of water in the distaltubule of the kidney. If thirst is directly relatedto intracellular hydration,48 80, 81 wherever thereceptor of this stimulus is located, the effectof sodium loading on thirst and on antidiuretichormone production may be represented dia-grammatically as in figure 5A. The converse,the effect of water loading, has not been experi-mentally demonstrated by Verney, but for pur-poses of discussion may be assumed to holdtrue: intracellular overhydration results in in-hibition of antidiuretic hormone production,and abolition of thirst (fig. 5B). Accordingto this theory, cellular overhydration as theresult of sodium depletion should also inhibitantidiuretic hormone production and abolish

thirst (fig. 5C). In our previous experimentson sodium depletion,62 it was found that theabolition of thirst did occur, but diuresis didnot occur, apparently because of failure of thegeneral and renal circulation. In the "low-saltsyndrome" of systemic sodium depletion, thiscombination of circumstances should obtain(fig. 4). The administration of hypertonic so-dium solution should result in a diuresis of saltand water as the pattern of body fluids movesfrom that of relative sodium deficit (fig. 5C) inthe direction of that of sodium excess (fig. 5A)provided that improvement of circulatory effi-ciency occurs before the production of anti-diuretic hormone becomes too great.

E IA Sodium

excess lIlT

I I~~~~~~~~~~:U.~~~~~~~~~~~~ l~U

[B] TVI -E +

Antidiuretic hormone (ADH) +Th i r s t 4

(B) -I +E +

ADH - 4 diuresisThirst -

C Sodium A.[B)deficit [B]I ~~~~I4.

E -

ADH - -+ no diuresis, Thirst - If circ.foil.

FIG. 5. Diagram of the effects of changes in sodiumload and water load on the distribution of water be-tween the phases of body fluid; correlated with theexpected effects of antidiuretic hormone productionand thirst.

The lack of diuresis and the development ofthirst in hyponatremic cardiacs suggests an al-tered response of cellular receptors which setsthe total electrolyte concentration of body fluidsat a new level; changes in osmotic activity ofcellular solutes might produce such a result. Forthose edematous patients with hyponatremiawho develop thirst but do not have a diuresisfollowing the administration of hypertonic so-dium solutions, an alternative mechanism maybe hypothesized in the light of the above dis-cussion. As already mentioned, indirect evi-dence has been presented in the past by our-

selves and others72' 76 for the occurrence ofchanges in osmotic activity, or osmolarity, ofsolutes within the intracelluar p hase, changes

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which are independent of transfers to and fromthe extracellular fluid across the phase bound-ary. If a sufficient amount of intracellularsolute, most readily quantitated in terms ofthe cation or base, were osmotically inacti-vated, water would pass from the cellular phase.Under these circumstances the total concentra-tion of osmotically active electrolyte would belowered throughout both phases (fig. 6A), pro-vided the extra water were not excreted from theextracellular phase. But since the intracellularvolume is lowered rather than elevated, pro-duction of the antidiuretic hormone should bestimulated and the diuresis inhibited. Thus the

E IA Hypotonic ....---

*demao. : ~ fdue to E +cellulor e° ADH + -h antidiuresishypo- l Thirst +osmolarity 0vol. \osmoticolly inactivated bose

8 Hypotoni r-

edeaoF~hypertnIoI

[B]

E

ADHThirst

4+

+ + 4 ontidiuresis++ +4.

C Hypotonic r C(B]ede mao +

E +

2=' ADH - .-?diuresis, ifThirst - circulation

is adequate

FiuT. 6. Diagram of the theoretic effect that inac-tivation of osmotically active intracellular solutes (orbase) would have on the pattern of edema fluids:namely-, maintenance of hypotonic body fluids with-out the usual inhibition by intracellular overhydra-tion of antidiuretic hormone production and thirst;effect on such a situation of treatment with hvper~tonic sodium solution or with water.

concentrations of sodium and of total electro-lyte of the body fluids would be set at a sub-normal level in the presence of excess waterwdithout the usual stimulus for excretion of theextra water.

If such a process is operative in the hypona-tremic cardiac, the results of therapy, at least inpart, will depend upon the balance between im-provement of the peripheral circulation and pro-

duction of antidiuretic hormone. If the hypona-tremia of an edematous cardiac is due to thismechanism rather than to the renal loss ofsodium in excess of water, a different response

to the administration of hypertonic sodium

solutions would be anticipated. Such therapyshould raise the extracellular concentration ofelectrolyte and cause further intracellular de-hydration. If a systemic sodium depletion andvascular collapse is not being rectified, the onlyresult should be increased antidiuretic hormoneproduction and thirst even at hyponatremiclevels (fig. 6B). On the other hand, the admin-istration of water or hypotonic sodium solutionswould expand the intracellular fluid volumeand should so inhibit antidiuretic hormone pro-duction (figure 6C). This mechanism may bean important factor in the remarkable diuresesreported by Schemm52 to be the result of theadministration of water. Schemm has attrib-uted the response to the reduction of an ele-vated total osmolar concentration within thecell due to nonelectrolyte solutes. This conceptis difficult to accept in view of the experimentalevidence that solutes, such as urea, which dif-fuse freely across cell membranes have no effecton either thirst83 or on antidiuretic hormoneproduction.7" In any case, the hazard of thepure water treatment would seem to be that,while the intracellular volume is expanded, thetonicity or total electrolyte concentration ofthe body fluids is further depressed (figure 6C).Therefore, if this contributes to "systemic"sodium depletion and associated circulatoryinsufficiency, the benefit of any inhibition ofantidiuretic hormone may be negated by col-lapse of the circulation.In summary, it has been pointed out that in

congestive failure alterations in fluid distribu-tion in various tissues and organs may resultfrom modification of cellular metabolic proc-esses produced by circulatory dysfunction, andthat such alterations may in turn affect second-arily circulatory and renal function. These sec-ondary factors may be effective locally in themyocardium, the cells of the peripheral vascu-lar system, the cells of the renal tubule, orthe cells of peripheral tissues; they may condi-tion intake and output of water and electro-lytes through humoral mechanisms dependentupon stimuli in such tissues as the receptors ofthe anterior pituitary-adrenal cortex axis or inthe osmoreceptors of the posterior pituitarygland. These secondary factors appear to bemodified further by the therapeutic adminis-

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tratioln of mercury over long periods of timewhich may affect both peripheral and renalcirculation and the "setting" of the osmore-

ceptors.

SUMMARY AN-D CONCLUSIONS

In this discussion an attempt has been madeto review some of the factors which enter intothe chain of exkents leading from cardiac andcirculatory dysfunction to the congestive state.The relationship of circulatory to renal factorshas been discussed; abnormalities of tubular as

well as of glomerular function suggest thatendocrine and possibly other factors are in-volved in the sequence. In short, the homeo-static mechanisms which control body fluidvolume, unkniownt in part, may be functioninginl an abnormal way in congestive failure.

This consideration directs attention to therelationships of the state of fluid distributionin various tissues to the circulation and kidneys.Evidence has been found that intracellularas well as extracellular fluid abnormalities existin ongestive failure. Since such abnormalitiescertainly modify circulatory and renal functionin other conditions, it is reasonable to considerthat they do so in the edematous patient. Thereare various tissues and cells in which these sec-

ondary mechanisms may be initiated, given a

primary disturbance in cellular metabolismwhich is related to circulatory dysfunction.Fluid transfers may be affected directly bychanges in the myocardium, the renal tubularcells, and the peripheral tissues, and indirectlythrough hormonal mechanisms by changes inthe receptor cells of the adrenal cortex or theosmoreceptors of the posterior pituitary.Changes in cellular hydration may be related

to altered metabolic processes influencing thetransfers of electrolytes and the osmotic activ-ity of the solutes within the cells. Such changesoccurring in the osmoreceptors of the posterior.pituitary would affect antidiuretic hormoneproduction, and possibly the sensation of thirst.At least following the prolonged administrationof mercurial diuretics, some such mechanismappears to set a new level of total electrolytein body water.

ACKNOWLEDGMENTThe authors are especially indebted to MIrs. Alar)

Sawyer Squires for secretarial assistance in thepreparation of this series of papers.

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J. R. ELKINTON and R. D. SQUIRESConsiderations

The Distribution of Body Fluids In Congestive Heart Failure: I. Theoretic

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