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275:S169-S184, 1998.Advan in Physiol EduSusan P. Bagby and William M. BennettOSMOLARITY/WATER REGULATIONDISORDERS OF TOTAL BODY FLUIDVOLUME/NA CONTENT REGULATION VERSUSDIFFERENTIATING DISORDERS OF ECF

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DIFFERENTIATING DISORDERS

OF ECF VOLUME/ NA CONTENT REGULATION

VERSUS DISORDERS OF TOTAL BODY FLUIDOSMOLARITY/ WATER REGULATION

Susan P. Bagby and William M. Bennett

Portland Veteran s Affairs Medical Center, Portlan d 97207; and Divi sion of

Nephrology/ Hypertension , Or egon Health Sciences Un iversity, Port lan d, Or egon 97201

When one is teaching students who are new to concepts of body fluid and

electrolyte regulation, a major challenge is to convey the separate but

interactive natureof the two systems that respectively regulate extracellular

fluid(ECF) volume/Nacontentandtotal bodyfluidosmolarity/water. Wehavedeveloped

a series of strategies/tools designed to both optimize conceptual understanding and

translate conceptsto clinical practice. These include 1) clear delineation of the distinct

differencesbetween thetwo homeostatic systems,reinforced in instructional objectives,

lectures, and small group sessions; 2) anticipation and direct confrontation of the

common Na content Na concentration error, soliciting student participation in

oustingthismisconception; 3) modificationof terminologyto clarifybodyfluid reality;4)

facilitation of active problem-based learning in small group sessions focused on clinical

casesof increasingcomplexity (50%of coursehours); 5) useof whole body/single-eyeful

graphicsto conveyessentialdetails within aclinically meaningful context; 6) standardiza-

tion of diagnostic algorithms and pathophysiological graphs across lecturersand coursecomponents; and 7) provision of hands-on instruction/practice in physical examination

of ECFvolume in parallel with conceptual learning, thus emphasizingtheimportanceof

the bedside exam in detecting disorders of ECF volume/Na content. These approaches

require an enthusiastic and well-prepared faculty committed to a high level of

consistency and are designed for second-year students with a solid basic science

background.

AM. J. PHYSIOL. 27 5 ( ADV. PHYSIOL. EDUC. 20): S169 S184 , 199 8.

In our collective years of teaching medical students,

no concept hasbeen morechallengingto convey than

theseparate-but-interactivenatureof thetwo distincthomeostatic systems that regulate extracellular fluid

(ECF) volume/ECF Na content on one hand versus

total body fluid (TBF) osmolarity/water on the other

hand. Few conceptual distinctions are so crucial to

safe clinical management of body fluid disorders.

Teaching this topic in the second year, and seeing

little evidence of useful retention by students in thethird year, convinced us that fresh approaches were

needed.

GOAL

Our goal is to train clinicians whose understanding offluid/electrolyte concepts permits differentiation ofclinical abnormalitiesof ECFvolume/Nacontent regu-lation from abnormalities of TBF osmolarity/water

A P S R E F R E S H E R C O U R S E R E P O R T

1043 - 4046 / 98 $5.00 COPYRIGHT 1998THE AMERICAN PHYSIOLOGICAL SOCIETY

VOLUME20: NUMBER 1 ADVANCESIN PHYSIOLOGY EDUCATION DECEMBER 1998

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regulation and leadsto appropriate treatment of thesedisorders, whether present alone or in combination.

By choice, we have focused on homeostasis at thelevel of thewhole organism and have, over theyears,deliberately omitted myriad important details at cellu-lar and molecular levels. On the other hand, ourapproach provides a framework for ready incorpora-tion of such details and can facilitate their conceptualintegration in courses designed for different levels ofcomplexity.

THE WORKING REALITY

Body-fluid osmolarity is regulated by hypothalamicsensors, which detect osmolarity, and by effectors,which modify water handling (intake and excretion).

Because water moves freely throughout the bodyfluids (crossing vascular and cellular boundariesreadily), this system regulates intracellular fluid (ICF)and ECF compartments as a single unit, the TBFcompartment. Thus, at steady state, theosmolarity ofICF and ECF are always equal. When disorders of TBFosmolarity/water regulation occur, ICF and ECFosmo-laritywill both bealtered.

Despite this dependable concordance of TBF osmolarregulation, the specific solute molecules that consti-tute the ICF versus ECF osmoles are distinct, and it isthe energy-dependent separation of these solutes at

thecell membranethat createstheICF/ECFboundary.Thissolute-based subcompartmentalizationof theTBFspace creates the possibility that the ICF and the ECFcompartments may change their respective volumeseitherconcordantly(whenwater or anoncompartmen-talized solute is in excess or deficit) or discordantly(when a compartmentalized solute is in excess ordeficit). For example, if water is ingested in excess (oran evenly distributed solutesuch as ureais ingested inexcess, triggering water retention), the increase inTBF water will be distributed to the ICF and ECFcompartments in proportion to their initial sizes; thustheir respective volumes will change proportionately(i.e., by a similar percent increase) with two-thirds ofthewater excess goinginto theICF and one-thirdintotheECF (Fig. 1, upper pathway).

In contrast, in response to theadditionof asolute thatis restricted to oneof thetwo compartments, homeo-statically retained waterafter equilibrationwill re-

side in the compartment containing the extra solute.To understand the impact of this aspect of osmoregu-lation on the ECF compartment, it is helpful toconsider what would happen to theECF Volume afterNaCl ingestion if no ECF volume/Na content regula-tory system were operative. When NaCl, which isconfined to the ECF, is ingested without water (Fig. 1,lower pathway), ECF hypertonicity transiently drawswater from the ICF and also activates thirst/waterretention. If water ingestion is prevented and osmoticequilibration viawater shifts proceedsto completion,the resulting TBF osmolarity is above normal butlower than the ECF osmolarity immediately after saltingestion. Furthermore, ECFvolumeis now increased,whereas ICF volume is decreased by the volume ofwater shifted to the ECF. This state exists until water

ingestion occurs; water will then be homeostaticallyretained in a volume sufficient to restoretheosmolar-ityof both ICF andECF to normal. To achieve this, thewater must be retained in sufficient quantity to re-place the volume of ICF water initially shifted to theECF (therebynormalizing ICF volume and osmolarity)andmust further increasetheECFwater byan amountsufficient to normalize ECF osmolarity. If there is stillno ability to regulate ECF volume or Na content, theingested NaCl would persist as excess ECF NaClcontent. The osmoregulatory system would thus re-tain sufficient water to dilute an elevated ECF Naconcentration (and osmolarity) to normal, mandating

that the total ECF water content be increased. Thus,compared with the status before NaCl ingestion, theentirevolumeof new water gained in ourhypotheti-cal system would exactly equal the volume of waterretained within the ECF by the osmotic action of thecompartmentalizedNaCl;therehasbeenno n etchangein theICF volume or osmolarity.

Thus if the TBF osmolarity/water regulating systemwere operative in isolation, with no mechanism formonitoring/modifyingECF volume, then thetransientECF hyperosmolarity after NaCl ingestion would beroutinely normalized at the expense of an increasedECF volume and ECF Na content (without change inICF volume or solute content). The wide range oftolerable Na intakes that we take for granted wouldlikely lead to hypertension, pulmonary edema, anddeath with stroke or heart failure as cumulativepositive NaCl balance ensued and obligated isotonicECFwater retention in response to osmoregulation.


VOLUME 20 : NUMBER 1 ADVANCES IN PHYSIOLOGY EDUCATION DECEMBER 1998

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Fortunately, operating in parallel with TBF osmoregu-lation, thebodyis equipped with aseparateregulatorysystem that limits both ECF volume expansion andcontraction, therebyprotecting the hemodynamicallycritical intravascular compartment from unopposed

osmoregulation. ECF volume is regulated by intravas-cular sensors, which detect mechanical stretch (thusvascular volume) and by effectors which modify ECFNa content. In fact, altering Na content of the ECFcompartment can effect a change in ECF volume only

FIG. 1.

Nested relationship of extracellular fluid (ECF) volume/Na content regulation

within domain of total body fluid osmoregulation: why separate ECF volume

regulation is mandatory. The ECF (inner box containing vascular ring) is located

within theTBF and is subjecttoTBF osmoregulation. Concordantresponses of ECF

and intracellular fluid (ICF) osmolarity and volume in response to water ingestion

(upper pathway) is contrasted with response to NaCl ingestion, initially without

water (lower pathway). NaCl restriction to ECF initially increases only ECF

osmolarity, causing water to shift from ICF to ECF. This lowers ICF volume, raises

ECF volume, and equalizes osmolarity in the2 compartmentsat an elevated level.High osmolarity activates osmoregulatory processes[thirst, antidiuretic hormone

(ADH)] and leads to water retention. Retained water restores TBF osmolarity to

normal and restores ICF volume to normal. However, ECF volume is increased;

assuming no Naexcretion, thevolume of extrawater retainedwill precisely equal

the volume of water required to normalize ECF osmolarity in presenceof higher

ECFNa content.That theECF(as acomponentof TBF) is subjecttoosmoregulation

an d that NaCl is confined to the ECF compartment together create the linkage

between ECF Na content and ECF volume (see text). If no ECF volume regulation

were available to independently protect the ECF compartment from unopposed

osmoregulatory activity, life-threatening ECFvolumeexpansions andcontractions

would ensue.In fact, theECF volume/Nacontentregulatory systemperfectly solves

this problem by sensing intravascular volumeand appropriately altering ECF Na

content via renal Na excretion with an isotonic amount of water. Consequently,

NaCl ingestion only transiently increases ECF volume and Na content. Even a

sustained increasein daily NaCl intake causes remarkably small increases in ECFvolume/Nacontent (F5%). Osm,osmolarity;[Na], Naconcentration; Vol, volume.



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because the ECF osmolarity is concomitantly regu-lated. When Na is added or lost, the osmolarity isreliably normalized by proportional changes in ECFwater. Because Na concentration is maintained con-stant byosmoregulation independent of Nacontent, achangein theNacontentof theECFcompartmentwillnecessarily lead to a change in the ECF volume.Accordingly, the ECF volume/Na content regulatorysystem, although physiologically independent withdistinct sensor/effector limbs, is in fact functionallyeffective only when operating within the context oftheosmolarity/water regulating system.

THE CHALLENGE

These concepts aremultidimensional and intrinsicallycomplex. However, three aspects present special

difficulty for students newly introduced to body fluidregulation.

First, serumNaconcentration, although sampledfromtheECFcompartment, is in fact asurrogatemeasureofTBF osmolarityand thusreflectsTBFosmolarity/waterhandling; Na concentration is (seemingly paradoxi-cally) n ot a measure of ECF Na content. Studentstypically make an intuitively powerful cognitive errorby viewing serum Na concentration as a measure ofECF Nacontent.Thestudent is usually unawareof thisintuitiveerror and of its power to thwart understand-ing. In our experience, this miscognition will con-

tinue to operate until unmasked and subjected toconscious scrutiny.

Second, learningis hamperedbytheingrainedclinicaluse of imprecise terminology that creates confusionbetween ECF volume/Na content regulation versusTBF osmolarity/water regulation. One example is thecommon shortening of ECF volume to the termvolume or Na/volume. We then expect studentsto figure out that this volume is a function of Nabalance; conversely, changes in water balance (thelogical measure of volume in any language) are notacknowledged to have major impact on Na/volume.The inappropriate use of such terms as dehydration/hydration to refer to ECFvolumedepletion/repletion(rather than appropriately to water excess/deficit) isanother example.

Third, even when these concepts are clearly con-veyed, we have commonly failed to provide the

crucial next step, translation to clinical practice.Students can often parrot body fluid informationcorrectly on tests but are unable to correctly applytheir information in the context of patient evaluationand treatment.

STRATEGIES

Strategies used to optimize learning are outlined inTable1.

Establish Separatebut InteractiveNature of ECFVolume/NaContent VersusOsmolarity/WaterRegulatory Systems

We have added a short lecture segment focusingentirely on the separate-but-interactive nature of the

two systems. Our writtenobjectives convey their dualnature and incorporate direct comparisons (Table 2and Fig. 2). This reinforces their duality and describestheir nested relationship (ECF compartment lo-cated within the TBF and regulated by both systems;ECF volume regulation via Na content change effec-tive only in presenceof osmolarity/water regulation).Thespecific circumstancesof their clinical interaction

TABLE 1

Strategiestooptimizelearning

1) Distinguish thetwo separate systems regulating extracel-

lular fluid (ECF) volume/Nacontent vs. total body fluid

osmolarity/H2O in terms of fluidcompartment regulation,sensors/effectors, clinical datafor diagnosisof abnormality,

and pointsof interaction.

2) Carefully definethe languageof fluid/electrolytes using ter-

minology that clarifies and reflectstheclinically crucial dif-

ferencesbetween thetwo homeostatic systems.

3) Directly confront theNa concentrationNacontent cog-

nitiveerror common to studentsnew to fluid/electrolyte

concepts;solicit thestudents participation in recognizing

and neutralizing thisintuitively powerful miscognition.

4) Provide clinical problemsolving experience in small group

sessions designedto translatebasic fluid/electrolytecon-

ceptsinto sound clinical reasoningandtherapeutic inter-

ventions.

5) Make use of wholebody graphsto bringkey pathophysi-

ological elementsinto one eyeful, thus visually imprinting

key details within aclinically meaningful context.6) Standardize pathophysiological graphs and diagnostic algo-

rithms; use thesame visual aidsin all lectures and small

group sessions.

7) Provide hands-on experience/instruction of physical exami-

nation of theECF volume to complement theconceptual

aspects and to demonstrate their clinical relevance and

applications.



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are defined (severe ECF volume disorders nonosmoti-callyactivateantidiuretic hormone(ADH)/waterreten-tion). Finally, the distinctly different types of clinicaldatarequired for diagnosis of therespectivedisorders(i.e., physical exam for ECF volume/Na content disor-ders vs. lab test for TBF osmolarity/water abnormali-

ties) (Fig. 2).

Define and UsePreciseClinical Language

To further optimize learning, we allot a half-hourlecture to precisely define the language of bodyfluid/electrolytes for both participating faculty andstudents. Specifically, we defineanduse ECF, ICF, andTBF as compartment designations and modify thetermvolume byoneof these designations. Wehavedropped the term total body water and speak ofTBF osmolarity/water regulation to emphasize theregulated compartment (TBF), the sensed parameter(osmolarity), and the responding parameter (waterhandling). In parallel, thetermECF volume/Na contentregulation indicates the comparable components ofthat system. When referring to measured osmolarity,we use TBF osmolarity to emphasize the compart-ment reflected despitethefact that it is determinedona sample of serum and reported as serum osmolar-ity. Finally, throughout the course components,

TABLE 2

Instructional objectives

Thestudent shouldbe ableto:

1) Distinguish between the osmolarity/water regulatorysystemand the ECF Na content/ECF volume regulatory

systemin terms of:

fluid compartmentthat is regulated,

parameter that is sensed,

type and location of thesensor(s),

factors which mediate the response,

typical responses, and

clinical information required to diagnosean abnormality.

2) Characterize theeffectsof changesin sodiumintake on:

ECFvolume and ECFNacontent,

renin-angiotensin systemcomponents(renin, ANG II , aldo-

sterone),

sympathetic neural activity,

atrial natriuretic factor (ANF),

renal Naand H2O handling,serumNa concentration,*and

intracellular fluid volume.*

3) Characterize theeffectsof ANG II and theimplicationsfor

ECF volume/Na content homeostasiswhen renin-angio-

tensin effects are pharmacologically blocked(angiotensin-

converting enzyme inhibitors, AT1-receptor blockers).

4) Specify and be able to appropriately utilizeclinical indica-

torsof volume statusfor thefollowingECFsubcompart-

ments: intravascular venous volume, intravascular arterial

volume, interstitial volume.

5) Characterizethe three classic clinical statesof edemaforma-

tion (congestiveheart failure, hepatic cirrhosis, and

nephrotic syndrome) in terms of:

primary abnormality,manner in which ECFvolume is abnormally distributed,

changein effective arterial blood volume,

major mechanisms of sodium retention, and

major mechanisms of edemaformation.

6) Usetheclassicclinical approach to differential diagnosis in a

patient with hyponatremiaor hypernatremiawith respect to:

TBF osmolarity,

hypo-, hyper-, or euvolemia of ECF,

pathophysiological mechanismand differential diagnosisin

each subcategory,

expected urinary Na, urinary osmolarity values, and

appropriatetherapeutic interventions.

7) Distinguish, in clinical conditionswith combined disorders

of ECFvolume/Nacontent regulation and TBF osmolarity/water regulation, therapeutic interventions that address

each of thetwo abnormalities.

8) Explain why serumNaconcentration cannot beusedas an

index of theECF Nacontent or of ECF volume.

*Included to forcethe student to consider theindependenceof ECF

volume/Nacontent regulation fromNaconcentration (i.e., osmolar-

ity/water) regulation.

FIG. 2.

Comparison of the 2 body fluid regulating systems.

Layout emphasizes differences in key regulatory com-

ponents. Visual symbols are included to reinforce

distinctly different types of information required forclinical diagnosis(Dx). TBFOsmis used(rather than

serum Osm or serum [Na]) to reinforce the fluid

compartment reflected (not fluid compartment

sampled) andto avoid evokingtheNaconcentration

Nacontenterror. Aldo,aldosterone;SNS,sympathetic

nervoussystem;ANF, atrial natriuretic factor.



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every mention of serumNa concentration is linkedwith themodifier index of TBF osmolarity.

Unmask theNaConcentration/ NaContentError

We believe it is necessary to actively and openlyconfront this intuitive error in multiple, differentlearning contexts so that, with time, a new andconceptually valid paradigmcan replace theold. Eventhis focused attention may not fully offset the powerof this cognitive association. Students need to under-stand the potential for serious clinical consequencesdue to this common error of clinical reasoning. In oursmall group sessions, any student comment or re-sponse that reveals the activity of the erroneousparadigm is welcomed by the faculty facilitator as an

opportunity to point out, nonjudgmentally and sup-portively, the power and the universality of thismisconception. With repeated supportive encourage-ment, students began to catch themselvesand eachother in their incorrect thought patterns. Finally, asthe replacement paradigm takes hold, students arereminded of thetenacity of themisconception and ofthe tendency of the old paradigm to recur over timewithout regular reinforcement of the new paradigm.Students are reassured that several years is not anunreasonable nor unusual prerequisite for full under-standing of these complex concepts and for their full

integration into clinical decision making.

ProvideCase-Based Clinical ProblemSolving Experience

Three two-hour case-oriented small group sessionsemploy active-learningtechniques, benefitfromexten-sive faculty preparation as facilitators, are sequencedin conceptual complexity, and includeobjectives plusprovision of detailed written summaries of key pointson completion of each session. Duringthese optional,ungraded exercises, students (912/group) are askedto divideinto three to four minigroups; each group isthen assigned oneof thewritten cases with accompa-nying questions. Twenty to thirty minutes are pro-vided within the session time frame for students towork through the questions posed. Faculty serve asfacilitators, answer generic questions to permitprogress, andoften respondbyposingother questionsto guide students pathophysiological thinkingbut donot provide theanswers to theformal case questions.

Each minigroup is thus asked to commit to an answerdespite uncertainty. Each minigroup then presentsitsassigned case to the whole group, steps through thepathophysiology, answers the questions posed, anddemonstratesrelevant calculations. Their answers arethen critiqued by their peers with faculty guidanceand corrective input as needed. (In contrast to classicproblem-based learning exercises, we feel that thefaculty facilitators for these sessions must also beexperts because of the complexity of the conceptsand the need for immediate recognition and correc-tion of student misconceptions.)

StandardizeAll Key Graphicsand AlgorithmsAcrossLectures and Small Group Sessions

Make each available as transparencies for both stu-

dentsandfacultyfacilitatorsto useasteachingtoolsinsmall groups(Fig. 18).

UseGraphsThat EmbodythePrincipleof WholeBodyin Single Eyeful

Graphics used to describe homeostatic systems arederived from the premise that incorporating thewhole organism into a single eyeful helps organizeand visually imprint details while preserving a clini-cally meaningful wholebody context (Figs. 3 and4).

Link Conceptual and Clinical PracticeAspects

of ECF Volume/NaContent Evaluation

Along with concepts developed in lectures and smallgroupcases, apractical lecturedescribingECFvolumeassessment by physical examination is immediatelyfollowed byahands-on exercise providingdemonstra-tion of physical exam skills and opportunities forpractice with immediatefeedback.

COURSE CHRONOLOGY AND CONTENT

Lecture: Review of PhysiologyECF Volume/NaContent and Water/ Osmolarity Homeostasis

This lecture is based on material covered in the firstyear.

OverviewLecture: TheClinical Languageof Fluid/Electrolytes

Solute and osmolar concentration units, body fluidcompartment definitions, and normal fluid compart-



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ment volumes and compositions are reviewed. Distri-bution of ingested water versus NaCl versus salinesolutions of varying concentration in normals are

presented in a semi-interactive format, providing anintroduction to thefirst small group sessions.

Small Group Case-Oriented Session A:Normal BodyFluid Physiology

The purpose ofsessi on A is to address quantitativedistribution of ingested salt/water in physiological

contexts, and thus to orient student thinkingin terms

of tracking ingested solutions (salt vs. water vs. NaCl

solutions) into specific body fluid compartments in a

whole person. (Cases and written summary of keypoints are available on request.) Studentsare asked to

revisit body fluid compartments, calculate the respec-

tivecompartmentvolumesbased on bodyweight,and

calculate how each changes with ingestion of water

only, salt only, or both in varying proportions. Stu-

dentsare encouraged to envision ingestedmilliequiva-

FIG. 3.

Normal ECF volume/Nacontent regulation in response to Na restriction. Focus is on the 2 major

regulatory components,SNSand renin-angiotensin system (RAS). A: afferent pathways. Intravascu-

lar stretch receptors (*) at central venous, central arterial, and renal afferent arteriolar sites are

depicted with respect to SNSactivation. Renin releaseis induced via indirect (via SNS) and direct

(renal baroreceptor and macula densa based) pathways, yielding ANG II formation. B: efferentpathways of ANG II/SNS actions to protect ECF volume. Hemodynamic actions of ANG II and

norepinephrine (viarenal SNStraffic) are presented in terms of their effects on proximal tubular

Na reabsorption as well as their circulatory effects to protect blood pressure [vasoconstriction,

venoconstriction (shiftingblood from venous to arterial circuits)]. Similarly, direct proximal and

distaltubular actionsof ANG II/aldosteroneandSNStraffictoconserveNaareemphasized,an effect

which limits further losses and, with availability of exogenous Na, can eventually restore normal

ECF volume/Na content. GI, gastrointestinal; AII, ANG II; HR, heart rate. Prox, proximal. PPT,

pressure in peritubular capillary; Fil Fx, filtration fraction; [Prot]PT, protein concentration in

peritubular capillary.



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lentsof salt andcubic centimetersof water in termsofvolumes of normal saline versus free (solute-free)water. This exercise emphasizes the clinical realitythat different fluids distribute into distinct compart-ments with dramatic consequences for therapeuticdecision making. This session also prepares the wayfor the subsequent small group sessions addressingclinical disordersof salt/water homeostasis andrequir-

ing estimation of body fluid compartment sizes andcalculation of water deficits.

Lecture: Dual Systemsof Body Fluid Regulation

Instructional objectives for the three major lecturesare presented in Table 2.

This lecture opens with a general description of thetwo homeostatic systems from a clinical perspective.Their uniqueness, their respective sensors/effectors,and their distinct requirements for clinical detectionare carefully outlined (Fig. 2). Three points of interac-tion are then described. First, the presence/normaloperation of theosmolarity/water regulatingsystemiswhat permits regulation of ECF Na content to alsoachieve regulation of the size of ECF volume. [Ex-

ample used: salt tablet ingestion, with stepwise re-sponses of the osmolarity/water regulatory system,followed by the activation of ECF Na/ECF volumeregulating systems (see above and Fig. 1)]. Second,primary abnormalities of the TBF osmolarity/waterregulating system, which include the ECF compart-ment in therelative excess or deficit of water, activateECF volume sensors and initiate ECF volume regula-tion; this protects the ECF volume from uncontrolledosmoregulation. Third, severe (pathological) reduc-tion in ECF volume or in effective arterial volumeactivates ADH secretion nonosmotically, thus recruit-ing a component of the osmolarity/water system to

protect ECF volume at the cost of impairing normalwater excretion capacity. This interaction underliesthe clinical approach to differential diagnosis of bodyfluid osmolarity/water disordersbased on thestatusoftheECFvolume.

The clinical indicatorsfor assessing thevolume statusof each of the ECF subcompartments are then intro-duced and explained. These include the jugular ve-nous pressure (JVP, an index of the venous compo-nent of vascular volume), arterial blood pressuremeasured supine and standing (postural BP, anindex of effective arterial volume), and edema (asevidence of excessive interstitial fluid volume andexcessivetotal ECFvolume). We establish this clinicalconnection early and reemphasize the crucial pointthat clinical diagnosis of ECF volume/Na contentdisorders depends primarily on the bedside exam.This is in distinct contrast to the clinical diagnosis of

FIG. 4.

Clinical disorders of ECF volume/Na content regulation

associatedwith expandedECFvolumeandgeneralizededema.

Congestive heart failure (CHF), hepatic cirrhosis, and ne-

phrotic syndrome are each reviewed as prototypes of the

mostcommonclinical entitiesrequiringclear understanding

of body fluid regulation. The central themefor understand-

ing disordered ECF volume regulation is maldistribution of

ECF volume, causing reduced effective arterial volume; thelatter is then sensed and transmitted to kidney as a need to

conserve Na/isotonic water. A: CHF. A dam concept con-

veys primary abnormality at level of heart and emphasizes

increased venous pressure with overt venous distension

(shiftingintravascular volume from arterial to venous sites)

and capillary fluid transportation (shifting intravascular

fluid to interstitial compartment). Reduced effective arterial

volume (sensed atcentral arterial and intrarenal sites) then

activates same mechanisms for renal Na retention outlined

in Fig. 3. JVP, jugular venous pressure; RV, right ventricle;

Pcap, capillary pressure; Cap H2O permeability, capillary

water permeability. B: hepatic cirrhosis.ECFmaldistribution

in response to a dam created byscarringin liver, increasing

portal and splanchnic venous pressure and distension, se-

questering excessive blood volume in this venous subcom-partment and causing transudation of intravascular fluid

from liver surface and splanchnic capillaries to produce

ascites. The ensuing reduction in effective arterial volume

activatesvenous, arterial,andintrarenal sensorsandinduces

Naretention. Intrasplanchnic arterial nitrous oxideproduc-

tion is noted asan additional mechanism sequesteringblood

volume in intrasplanchnic vascular bed. Finally, an intrahe-

patic hepatorenal sympathetic circuit and intrarenal Na-

retaining effects of hypoalbuminemia can beintroduced as

mechanistic elementsaccountingfor advancedstageknown

ashepatorenal syndrome. C: nephrotic syndrome. ECFmal-

distribution (not as clinically consistent in this entity) is a

shift from intravascular to interstitial compartment due to

lowered oncotic pressure of hypoalbuminemia. Additional

potential contribution of generalized loss of endothelial cellnegative-charge barrier (nil-change disease) is noted, with

concomitant prominenceof non-gravity-dependent sites of

edema (e.g., facial). In all 3 entities, the need to separately

assess adequacy of intravascular arterial compartment and

to maintain blood pressure and organ perfusion (despite

presenceof total ECFvolume/Nacontent excess) is stressed

in clinical management.



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TBF osmolarity/water abnormalities, which is basedsolely on a laboratory blood test (TBF osmolarity,measured as serum osmolality or estimated by serumNa concentration as an index of TBF osmolarity)(Fig. 2).

TheNaconcentrationNacontent cognitiveerrorand its clinical implications are then described (asoutlined in STRATEGIES). Its universality and power areacknowledged, and the students are encouraged toactively participate with faculty in detecting anderadicating this sneaky neural pathway that standsbetween thestudent and metabolic enlightenment.

An optional demonstration (which can be done usingcolor slides) involves hidden beakers of varying sizes,

each filled with fluid and representing an ECF volumeof distinct (low, normal, or high) size; each beakercontains adifferent concentration of solute(blue dye)that varies independent of beaker volume. Test tubescontaining equal aliquots from each beaker are pre-sented to thestudents, who are then asked to predictthe volume of the beaker (ECF volume) from thesoluteconcentration of thetest tubesample. Most willrecognize the fallacy of this effort when the task isthus presented. The similar fallacy of predicting ECFvolume or Na content from serum Na concentrationcan thenbeemphasized.

Lecture: Clinical Disorders of ECFVolume/NaContentRegulation

Once the duality of the two regulatory systems ispresented, the components of the ECF volume/ECFNa content regulating system is specifically outlinedusingwholebody/single-eyeful graphsto permit detailwhile retaining a whole body context (Fig. 3). Thecomponents of the ECF volume regulating system areinitially presented in sequential steps as aresponse toECF volume/Na content depletion. Thus initial activa-tion of low-pressurestretch receptorsandearly activa-tion of renal sympathetic nerve system (SNS) trafficleads to the initiation of renin release and bothcirculating and intrarenal ANG II formation (Fig. 3A).Subsequent ANG II and SNS actions on proximal Nareabsorption reduce distal NaCl delivery and thusactivatethemaculadensamechanismof renin release,bringing into play two of the three renin-activatingpathways(Fig. 3A). It is pointed out that activation ofthe renal baroreceptor by lowered pressure at the

afferent arteriole, while activatedin pathological statesof ECF volume depletion with hypotension, is notnecessarily activated in physiological states such asdietary Na restriction. Next, hemodynamic effects ofANG II areoutlined, includingand specifically understatesof circulatorystressadominantefferentarterio-lar constriction. This provides relativeprotection ofglomerularfiltration rate(GFR) viasustainingglomeru-lar capillary pressureand increasing filtration fraction.It is important to stress that GFR is not increased,rather it is decreased to a lesser degree than is renalblood flow (RBF). Increased filtration fraction yieldsincreased protein concentration and lowered hydro-static pressure in the peritubular capillary, thus alter-ing Starling forces to promote Na/water reabsorption.Finally, direct actions of ANG II, the SNS, and aldoste-

rone on respectively proximal and distal tubular Nareabsorption are reviewed(Fig. 3B).

(We do not emphasize pressure natriuresis as a physi-ological effector of ECF volume/Na content regula-tion, because this homeostatic system is extremelyeffectivein theabsenceofclini cally detectablechangesin blood pressure. This obviously does not excludeimportant intrarenal pressure changes. Pressure natri-uresis is instead presented in thecontext of long-termblood pressure regulation.)

Clinical indicators of ECF volume status are then

reviewed for expected changes in true ECF volumedepletion: reduced JVP (venous), postural hypoten-sion (arterial), or absent edema (interstitial). (Majorfocusing on physical exam details is deferred to adedicated lecture and clinical ECF volume examexercise on the following day.) A simple differentialdiagnosis of causes of ECF volume depletion is brieflyreviewed.

Students attention is then turned to disorders involv-ingECFvolume/Nacontentexcess(Fig.4). Physiologi-cal mechanisms of reducing ECF volume/Na contentare reviewed, including suppression of SNS, ANG II,and aldosterone together with activation of atrialnatriuretic factor (ANF). (Pressure natriuresis is ac-knowledged as a mechanism of blood pressure con-trol and is covered in lectures on blood pressureregulation; it is not included as a mechanism of ECFvolume/Na content regulation.) Discussion of condi-tions with truly generalized ECF volume excess (min-



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eralocorticoid excess, renal failure) logically falls here

butisdeferred to later lectureson secondaryhyperten-sion and renal failure, respectively. These categories

are thus noted for completeness, but primary atten-

tion is directed to the three classic states of general-

ized edemaformation: congestiveheart failure (CHF),hepatic cirrhosis, andnephrotic syndrome. Thepreced-

ing detailed description of the normal response to

dietary Na restriction/ECF volume depletion has alsoprovided the pathophysiological information neededto understand the systemic and renal responses tothese classic edematousstates. Each is presented as apathophysiological abnormality that leads to func-tional maldistribution of ECF volume and thereby todeficits of effective arterial volume; the latter thenactivates some or all of the same Na-retaining mecha-

nisms involved in true ECF volume/Na content deple-tion. A second and extremely important aspect ofthese complex clinical states is the typically discor-dant changes in individual ECF subcompartments.Thus effective arterial volume, as assessed by posturalBP changes, may be significantly decreased and organperfusion threatened despite an unequivocal increasein interstitial (and total ECF) volume as manifested byedema or ascites. It is crucial to equip students toclinically evaluate each ECF subcompartment sepa-rately and to acknowledge the clinical priority ofrestoringthearterial circuit andorgan perfusion whenit is threatened.

Congestive heart failure. CHF (Fig. 4A) is takenstepwisefromthefirst subnormal stroke volume withconsequent increased filling volume/pressures. In-creased venouspressuresdistend theveins, sequester-ing excess blood volume in thevenouscompartment;elevated hydrostatic pressure promotes transfer ofECF volume from vascular to interstitial compart-ments, augmented by increased circulating ANF. Theimpaired cardiac pump action creates a functionaldam at the level of the heart, initially producingineffective arterial volume at normal filling pres-sures. Accordingly, ECF volume is maldistributed attwo levels: arterial volume shifts to the venous side;and vascular volume is shifted to the interstitialcompartment. Inadequate arterial volume activatescentral arterial and renal components of the ECFvolume/Na content regulating system (e.g., arterialhigh-pressure stretch receptors with SNS response;macula densa and potentially renal baroreceptor

regulation of renin release). In addition to these

mechanisms of Na retention, mechanisms of edema

formation are outlined (increased venous/capillaryhydrostatic pressure,ANF-dependentincreasein endo-

thelial permeability). If pump dysfunction is not

severe, then the increased filling pressure can restorecardiac output,offsettingthedameffect at theexpenseof

increased pressures(i.e., compensated CHF).

Hepatic cirrhosis. Hepatic cirrhosis (Fig. 4B) isnextoutlined as an abnormality that creates a functionaldam within the liver, increasing intrahepatic sinusoi-dal and portal venous pressures. The increased pres-sure distends the veins, sequestering excess bloodvolume in the splanchnic venous circulation, andforms ascites by increasing hydrostatic force for fluid

transudation at the liver surface and across capillarybeds. In addition (and perhaps as a compensation forhigh venouspressure), excess nitric oxide-dependentvasodilation localized to the splanchnic circulationexpandssplanchnic arterial volumeandfurther seques-ters blood volume. These forces yield maldistributionof ECF volume at two levels: within the vascular tree(extrasplanchnic arterial to splanchnic venous arte-rial) and between vascular and interstitial/peritonealcompartments (from splanchnic venousto peritonealspace). Both, if uncompensated, would tendto stealvolume fromthe arterial tree, contributing to ineffec-tive arterial volume and activating all renal and sys-

temic componentsof ECF volume/Na content regula-tion, including the low-pressure central venouselements. Mechanismsof renal Naretention areempha-sized: reduced effective extrasplanchnic vascularvolume, intrahepatic activation of asympathetic hepa-torenal reflex circuit, and the direct intrarenal Na-retainingeffectsof commonly associatedhypoalbumin-emia. Mechanisms of generalized edema formationincludecompressiveeffectsof asciteson lower extrem-ity venous return andthelowered oncotic pressureofhypoalbuminemia.

Nephrotic syndrome. Finally, nephrotic syndrome(Fig. 4C) is presented asadisorder leadingto maldistri-bution of ECF volume fromintravascular to interstitialspace PLUSprimary renal Naretention in response tohypoalbuminemia. We use the example of lipoidnephrosis, wherein loss of endothelial cell negativecharges occur both at the glomerular capillary walland throughout the peripheral vasculature. Reducing



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thenatural charge-based barrier to albumin (an anion)leads not only to proteinuria but also to generalizedtransudation of albumin, reducing plasma oncoticpressure and redistributing ECF from vascular tointerstitial space. Unopposed, this reduction in intra-vascular volume would activate all componentsof theECF volume/Na content regulating system and thuscause secondary renal Na conservation and Na reten-tion together with water in isotonic amounts. Evi-dence for a direct intrarenal effects of hypoalbumin-emia to promote p r i m a r y renal Na retention is alsonoted, and the balance of these factors may vary,yielding a low (dominance of hypoalbuminemia),normal, or high (dominance of primary renal Naretention) intravascular subcompartment. Recentstud-ies have raised technical questions about methods

used to show increased vascular volume in somenephrotics. Nonetheless, expanded total ECF vol-ume/Nacontent, with edemaas thehallmark, remainsa classic finding in nephrotic syndrome, and theclinicianschallengeis to accurately assesstheintravas-cular subcompartment in planning therapeutic inter-vention. (Other aspects of nephrosis are addressed intherenal sectionof thecourse.)

Lecture: Disorders of TBFOsmolarity/Water

Regulation

Instructional objectives areoutlined in Table2.

The lecturebegins with abrief reminder of body fluid

spaces and their composition. The normal physiology

of osmotic regulation andwater balanceis reviewed in

detail because thisinformation is crucial to theunder-

standingof thedisorders(Fig.5). Acuteversuschronic

renal actions of ADH at the level of aquaporin recruit-

ment to theapical membranearebrieflyintroduced. It

is emphasized again that these disorders, typically

presenting as altered serum Na concentration (an

index of TBF osmolarity), are in fact abnormalities of

TBF osmolarity/water regulation and are n ot reflec-

tions of altered ECF Na content. This point is reiter-

ated in many different ways to the students, once

again directly confronting the Na concentration

Nacontent error.

A classic clinical approach to thedifferential diagnosis

ofhyponatremia is presented in depth, includingthe

requirement for clinical estimation of theECF volume

FIG. 5.

Normal TBF/osmolarity regulation. Excessversus deficit of water and its distribu-

tion to TBF compartment is shown, together with appropriate osmoregulatory

responsesthatsubsequently normalizeTBFosmolarity.



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to categorize hypoosmotic hyponatremias into hypo-,hyper-, and euvolemic subsets (Fig. 6). The generalmechanism of hyponatremia in each subset is intro-duced and linked to thetherapeutic approach in eachcase. Thus hypovolemic hyponatremia reflects thecapacityof severeECF volumedepletion to nonosmoti-

cally activate ADH secretion; this, together with re-duced GFR, impairs free water excretion at theexpense of hypoosmolarity. Correction requires ECFvolume repletion with NaCl and water. Hypervolemichyponatremia also reflects inadequate effective arte-rial blood volume, causing nonosmotic ADH stimula-

FIG. 6.

Clinical approach to patient with hyponatremia. Classic algorithm ad-

dresses1stthestatusof TBFosmolarity.Serum Na(asasurrogatemeasure

of TBF osmolarity) is misleadingin caseof hyperosmotic hyponatremia

due to, e.g., hyperglycemia (wherein TBF osmolarity is increased due toexcessglucosepathologically confinedto ECFcompartmentin absenceof

insulin). For truly hypoosmotic states, the 2nd stage in differential

diagnosisis bedsideexam for determinationof overall ECFvolumestatus.

Hypovolemic andhypervolemic hyponatremic categoriesshare 2 impor-

tant features: 1) thedisorder of TBF osmolarity/water regulation causing

hyponatremia is a secondary complication of a primary disturbance of

ECF volume/Na content regulation; and 2) mechanism of inappropriate

water retention in both categories is a nonosmotic stimulation of ADH

dueto severely impaired ineffectivearterial volumecoupledwith contin-

ued water ingestion. In contrast, the euvolemic category encompasses

primary disturbances of TBF osmolarity/water regulation. Routine treat-

ment in secondary categories combines correction of primary ECF

disorder (e.g., ECF volume/Na content repletion or improving cardiac

function in CHF), together with fluid restriction, the latter to prevent

worsening and chronically to achieve net negative water balance viainsensiblelosses.Continuedfluid restrictionis requiredwhen underlying

pathological factors are irreversible. In contrast, euvolemic/primary

disorders of TBF osmolarity/water regulation are treated by fluid restric-

tion. Regardless of ECF volume category, hyponatremia presenting with

central nervous system abnormality dictates consideration of more

aggressive initial treatment. (This algorithm is used in lectures and is

provided asanoverhead for all small group sessions.)BP, bloodpressure;

UNa, urine[Na]; Uosm, urine osmolarity;Rx, treatment.



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tion and impaired free water excretion. However, inthis case, total ECF volume/Na content is in excess,indicating discordant directional changes in the ECFsubcompartments (i.e., increase in total ECF volumebut decreasein theeffectivearterial subcompartment,and thus ECF maldistribution). These two categoriesof hyponatremia, hypo- and hypervolemic, are in factcomplications of, and thus secondary to, primarydisturbances of ECF volume/Na content regulationand are especially apt to occur when theprimary ECFdisorder is severe. In contrast, euvolemic hyponatre-m i a is a subset of disorders in which TBF osmolarity/water regulation is theprimarybodyfluiddisturbance,induced by inappropriate production of ADH or

ADH-like molecules or by other disturbances thatimpair renal freewater excretion.

A specific example of a prototypical disorder thatpresents with hyponatremia is then discussed indepth for each of the three subtypes (Fig. 6). Thesyndromeof inappropriateantidiuretic hormonesecre-tion (SIADH) is detailed as a type of euvolemichyponatremia. Simple pathophysiological diagramsare used to explain the pathogenesis of the disorder(Fig. 7). The inappropriately retained water distrib-utes evenly throughout the TBF. When the compo-nent retained within the ECF is sufficient to activatestretch receptors, activation of ECF volume/Na con-

FIG. 7.

Syndrome of inappropriate ADH (SIADH) as an example of euvolemic

hyponatremia. Diagram of pathogenesis of this disorder emphasizes failure

of normal negative-feedback loop (hypotonicity is unable to suppress

autonomous source of ADH secretion) resulting in continued elevation of

ADH, renal water retention, expansion of TBF compartment, and persistent

hypoosmolarity. ECF shares in positive water balance, leading to activation

of intravascular stretch receptors and suppression of SNS/RAS with activa-tion of ANF, promoting transientrenal Naexcretion and a finitenegative Na

balance. At new steady state, ECF volume is normal by clinical exam, and

normotension plusabsenceof edemaare characteristic features. Urinary Na

excretion will be accomplished normally, i.e., intake will equal output.

Because of a persistently concentrated urine (urine osmolarity G serum

osmolarity), normal daily Na load is contained in lower urine volume and

urine[Na]is thustypically high (butcan below if patientis salt restricted).



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tent regulation promotes transient Na loss, maintain-ing a steady-state ECF volume within a clinicallynormal range. Thus, although the ECF compartmentshares in the retained water/hypoosmolarity, the de-gree of ECF volume expansion under these circum-stances is homeostatically limited and not clinicallydetectable. We apply the term clinically euvolemicdespite the recognition that TBF is increased andsubtle ECFexpansion is present.

Similarly, specificexamplesof hypovolemic hyponatre-mia and hypervolemic hyponatremia are each re-viewed stepwise with emphasis on the mechanismofwater retention. It is emphasized again to thestudentsthat the hypo- and hypervolemic hyponatremias arevery common clinically and most often develop as a

complication of the primary ECF Volume/Na contentdisorders. Finally, a case of hypervolemic hyponatre-mia due to CHF is presented and the pathogenesisreviewed to demonstrate the simultaneous presenceof a TBF osmolarity/water disorder and an ECF vol-ume/Na content disorder in thesame patient (Fig. 4C)and the need to address their respective treatmentsseparately.

In a parallel manner, hypernatremia is discussed in

the context of a generalized clinical approach to the

patient (Fig. 8) with subcategorization based on clini-

cal assessment of the ECF volume status. Euvolemichypernatremia is discussed along with the types of

diabetesinsipidus, namely,pituitary and nephrogenic.

Because of its uncommon occurrence, hypernatremia

in the setting of ECF volume overload is mentioned

only briefly, whereas hypernatremia in the setting of

ECF volume depletion is discussed in more depth. In

these latter disorders, we emphasize that aNacontent

deficit is present (as shown by physical exam) and is

accompanied by a proportionally larger water deficit

(as manifested by the increased TBF osmolarity). We

also stress that restoring the intravascular compart-

ment of the ECF with normal saline, thus protecting

vital organ perfusion, is always given priority over

therapeutic manipulation of theosmolarity.

Asafinal synthesis, thedistinction between regulation

of excess and deficiency of ECF volume/Na content

and regulation of excess and deficiency of TBF osmo-

larity/water is onceagain revisited(Fig. 2).

FIG. 8.

Clinical approach to patient with hypernatremia. An algorithm paralleling

that in Fig. 6 is used. Because all hypernatremiasare hyperosmolar, the1st

tier (determining TBF osmolarity) is not required. Differential diagnosis

according to status of ECF volume exam with expected urine findings is

presented together with appropriatetherapeutic interventions.



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Case-Oriented Small Group Session B

Paper caseson ECF volume depletion/excess, hypona-tremia, and hypernatremia are provided using the

same format as outlined in Small Group Session A.

Lecture: Clinical Evaluation of ECFVolume

This practical session describes the standard physicalexamination of ECF volume, includingprocedures fordetermining and guidelines for interpreting jugularvenous pressure, postural BP changes, edema, andascites.

Small Group Session C: Hands-On ClinicalECF VolumeExam

This 2-hour session provides, for 50 students at each

of 2 sessions, 1012 stretcher stations, each with apatient volunteer, a stretcher with easily adjustableheadpiece, Hg manometer with three BP cuff sizes, acentimeter ruler, and a faculty member familiar withthepatient/volunteersfindingsandwith courseobjec-tives. Stationsare set up in wide hallwayssurroundingthe dialysis unit; two stations involve a stable dialysispatient undergoing hemodialysis. Students spend 1520 min per station; they are shown the findings in thefirst two stations encounteredandat subsequent stopsare asked to do their own exam and assess the status

of the ECF volume/Na content. Faculty are careful toacknowledge when jugular veins are not able to beevaluated and why. A faculty timekeeper kept thestudentgroupsmovingfrom station to station on time.

Case-Oriented Small Group Session D

Paper cases are provided in which somewhat morecomplex fluid/electrolyte challenges are presented.Students are encouraged not only to develop theirown conceptual analysis of thepatientsproblems butalso to extend their clinical wings by independentlycalculatingbody fluiddeficits/excesses and bywritingorders specifying types and volumes of fluids toadminister and over what time period they should beadministered.

The success of these instructional strategies andteaching tools is greatly dependent on a cadre ofdedicated faculty with substantial expertise in fluid/electrolyte issues, commitment to the preparationtimeessential to achieveconsistency, and uncommonenthusiasm. We have been privileged to work withsuch a group and gratefully acknowledge their manycontributions.

Address for reprint requests: S. P. Bagby, Portland VA Medical

Center, PO Box 1034, Portland,OR 97207.



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