Edema

Definition
Cinicallyapparentincreaseintheinterstitialfluidvolumeasaresultofanimbalancein
thefiltrationsystembetweenthecapillaryandinterstitialspaces.

Physiology
Totalbodywaterisdividedbetweentheintracellularandextracellularspaces.The
extracellularspace,whichcomprisesaboutonethirdoftotalbodywater,iscomposedof
theintravascularplasmavolume(25%)andtheextravascularinterstitialspace(75%).
Starlingdefinedthephysiologicforcesinvolvedinmaintainingthebalanceofwater
betweenthesetwocompartment,whichincludethegradientbetweenintravascularand
extravascularhydrostaticpressures,differencesinoncoticpressureswithintheinterstitial
spaceandplasma,andthehydraulicpermeabilityofthebloodvesselwall.Thelymphatic
systemcollectsfluidandfilteredproteinsfromtheinterstitialspaceandreturnsthemto
thevascularcompartment.Majorperturbationsinthisdelicatehomeostasisthatfavors
netfiltrationoutofthevascularspace,orimpairedreturnoffluidbylymphaticsfromthe
interstitialspace,willresultinedema.
Pathology
Starlingforces
Increasedvenouspressuresduetocentralorregionalvenousobstructionortoan
expansioninplasmavolumearetransmittedtothecapillarybed,therebyincreasing
hydrostaticpressureandpredisposingtoedemaConversely,localautoregulationby
smoothmusclesphinctersontheprecapillary(orarterial)sideprotectthecapillarybed cirrhosis,initiatesaneurohumoralcascadethatattemptstomaintaineffectivecirculating
fromincreasesinsystemicarterialpressure,whichexplainswhyhypertensivepatientsdo volume.Thiscascadereducesglomerularfiltrationrateviarenalvasoconstriction,
nothaveedemadespiteelevatedbloodpressure. increasessodiumreabsorptionproximallymediatedbyangiotensinIIandnorepinephrine,
Themajorcontributorstointerstitialoncoticpressurearemucopolysaccharides,filtered andincreasessodiumandwaterreabsorptioninthecollectingtubulesmediatedby
proteinssuchasalbumin,capillarywallproteinpermeability,andtherateoflymphatic aldosteroneandantidiuretichormone.Additionally,endotheliumderivedfactorssuchas
clearance.Changesincapillarywallpermeabilityaremediatedbycytokinessuchas nitricoxideandprostaglandinsareincreasinglyrecognizedasbeingimportantin
tumornecrosisfactor,interleukin1,andinterleukin10,aswellasbycirculating regulatinghomeostasis.Collectively,theylimitsodiumandwaterexcretion,thereby
vasodilatoryprostaglandinsandnitricoxide.Increasedvascularpermeabilityiscentralto promotingedemadevelopment.Overtime,theseresponsesbecomemaladaptive,
edemaresultingfromlocalinflammation(e.g.,insectbites),allergicreactions,andburns. leadingtoacycleoffurthersodiumandwaterretention.
Incontrast,natriureticpeptides,whicharereleasedintothecirculationinresponseto
Renalandneurohumoralfactors cardiacchamberdistentionorsodiumload,enhanceexcretionofsodiumandwaterby
Becausethetissuesconstitutingtheinterstitiumeasilyaccommodateseverallitersof thekidneys.Theyaugmentglomerularfiltration,inhibitsodiumreabsorptioninthe
fluid,apatientsweightmayincreasenearly10%beforepittingedemaisevident.The proximaltubule,inhibitreleaseofreninandaldosterone,andresultinarteriolarand
sourceofthisexpansionofinterstitialfluidisthebloodplasma.Becausenormalblood venousdilatation.Unfortunately,abnormalendorganresistancetonatriureticpeptides
plasmaisonlyabout3L,thediffusionoflargeamountsofwaterandelectrolytesintothe inevitablyoccursinchronicedematousstates,whichexplainsthesodiumretentionin
interstitialspacenecessitatestherenalretentionofsodiumandwatertomaintain theseconditionsdespitehighcirculatinglevelsofatrialnatriureticpeptide.
hemodynamicstability.Hence,bloodvolumeandnormalosmolalityaremaintained Etiologies
despitemovementoflargeamountsoffluidintotheextravascularspace.
Effectiveintravascularvolumedepletion,whichoccursinchronicheartfailureand

Heartfailure
Inheartfailure,anelevationinvenouspressurecausedbyventricularsystolicordiastolic
dysfunctionincreasescapillaryhydrostaticpressure.Theresultinglowoutputstate
activatestheaforementionedneurohumoralmechanismsthatmaintainarterialperfusion.
Iftheresultingextravasationoffluidoutpacestheabilityofthelymphaticsystemto
returnthisfluidtothevascularspace,edemawillresult.Withleftventricularfailure,this
manifestsaspulmonaryedema;whereaswithrightventricularfailure,thisleadsto
peripheraledema[6].Theseverityoftheedemamaybedisproportionatetothedegree
ofcentralvenouspressureelevationdependingonfactorssuchasimmobility,posture,
andvenousinsufficiency.
Constrictivepericarditis/restrictivecardiomyopathy
Thesignsofbothconstrictivepericarditisandrestrictivecardiomyopathyaresimilarto
thoseofrightheartfailure,namelyelevatedjugularvenouspressure,hepaticcongestion,
ascites,andperipheraledema,andtheironsetmaybeinsidious.Patientswithelevated
neckveinsoftenreceiveamisdiagnosisofprimaryhepaticcirrhosis.Apossiblediagnosis
ofconstrictionorrestrictionshouldbeconsideredinapatientpreventingwith
unexplainededema,elevatedjugularvenouspressure,andrelativelypreservedsystolic
function.Althoughechocardiographymayprovideindirectevidence,moreinvasive
studiessuchasrightheartcatheterizationortissuebiopsyareoftennecessarytomakea
conclusivediagnosis.
Nephroticsyndrome
Thenephroticsyndromecomprisesagroupofdisordersthatarecharacterizedbysevere
proteinuria,hypoalbuminemia,hyperlipidemia,andedema.Nephroticproteinuriaisoften
causedbydiabeticnephropathy,althoughitmayresultfromprimaryglomerulardisease
orlesscommonconditions.Althoughthesyndromehasbeenlongrecognized,the
mechanismofedemaformationisstilldebated.Thelongheldunderfilltheory
postulatesthatedemaresultsfromreducedcolloidoncoticpressureduetomassive
proteinlossbythekidneys,whichleadstotranslocationofwaterintotheinterstitial
space.Thereductionineffectivecirculatingvolumethentriggerstheefferent
mechanismsthatperpetuatethecycleofedemaformation.Althoughthismayoccurin
childrenwithacutenephrosis,itisnotthelikelymechanisminmostadults.Infact,most
patientswithnephroticsyndromehaveincreasedneurohumoralhormonelevels.These
findingssuggestthatprimarysaltretentionbythekidneyshassubstantialeffectsinmost
patients.Thelowplasmaoncoticpressureincreasestheamountofedemathatis
observedforanyincreaseinplasmavolumeandcentralvenouspressure.Therefore,
estimationofthecentralvenouspressureisveryimportantasaguidetodiuretictherapy.
Iftheplasmavolumeisreducedveryrapidlywithdiuretics,patientscandevelopacute
renalfailurewhilehavingsubstantialedema.
Hypoproteinemia
Hypoproteinemiacanoccurinseveralconditionsotherthannephroticsyndrome,
althoughthemechanismofedemaformationmaybesimilar.Theseetiologiesinclude
severenutritionaldeficiency(e.g.,kwashiorkor),proteinlosingenteropathies,andsevere
liverdiseasewherehepaticsyntheticfunctionisimpaired.Albuminisimportantfor
maintainingplasmaoncoticpressure,andalevelbelow2g/dLofplasmaoftenresultsin
edema.
Cirrhosis
Endstageliverdiseaseresultsinprofoundsaltandwaterretention.Althoughmostofthis
fluidretentionmanifestsintheperitonealcavityasascites,peripheraledemamay
becomeprominentinlaterstages,particularlywhenthereisseverehypoalbuminemia.As
inheartfailure,decreasedeffectivecirculatingvolumeinitiatesaneurohumoralcascade
ofeventsleadingtoincreasedsodiumandwaterreabsorptionbythekidneys.This
decreaseis,inpart,theresultofsplanchnicvasodilatationandarteriovenousfistula
formationthroughoutthebodythatreducevascularresistance.Unlikeheartfailure,
cardiacoutputisnormalorelevatedinthisformofhighoutputfailure.
Drugs
Medicationsmaycause,orexacerbate,peripheraledema.Antihypertensivedrugssuchas
calciumchannelblockersanddirectvasodilatorsaremostfrequentlyimplicated.Ofthe
calciumchannelblockers,thedihydropyridinesaremorelikelytoinduceperipheral
edemathanarethephenylalkylamineorbenzothiazepineclasses,purportedlybecauseof
moreselectivearteriolarvasodilatation.Thedirectvasodilatorssuchasminoxidiland
diazoxideenhancerenalsodiumreabsorptionthroughtheirbloodpressureeffectand
activationofthereninangiotensinaldosteronesystem.Angiotensinconvertingenzyme
inhibitors,incontrast,rarelycausedependentedema,suggestingthatinother
vasodilatorsangiotensinmayplayacentralroleinedemaformation.
Troglitazone,rosiglitazone,andpioglitazonehavebeenassociatedwithperipheral
andpulmonaryedema,andaregenerallycontraindicatedinpatientswithNewYork
HeartAssociationclassIIIorIVheartfailure.Theedemaispartlyattributedtothe
6%to8%increaseinplasmavolumeassociatedwithuseofthesedrugs.The
mechanismofedemaformation,however,isnotknown.Hence,useofthesedrugs
inpatientswithmilderformsofheartfailuremustbeweighedagainstthepotential
riskofworseningvolumeoverload.Suchpatientsshouldbemonitoredforchanges
inweightandfluidstatus.
Pregnancy
Peripheraledemaisevidentin80%ofnormalpregnancies,halfofwhichinvolvethelower
extremities.Themajorityofthisweightgainoccursduringthesecondtrimester.Several
factorsconducivetoedemaformationarepresentinthegravidpatient,suchasincreased
plasmavolumeandsodiumretention,decreasedplasmaproteinconcentration,increased allpatientswithmyxedema.Localizededemaoftheeyelids,face,anddorsumofthehand
capillaryhydrostaticpressurelateinpregnancybecauseofmechanicalcompressionofthe arenotedmorefrequently.Therearenumerousdirectandindirectbiochemical
internalvenacavaandiliacveins,increasedantinatriuretichormonessuchasaldosterone responsestohypothyroidismthataffectnearlyallorgansystems,andthemechanismof
anddesoxycorticosterone,andactivationofthereninangiotensinaldosteronesystem. myxedemaisnotfullyunderstood.Atthecapillarylevel,thereisincreasedpermeability
resultingintheaccumulationofproteinsandmucopolysaccharidesintheinterstitium,
Chronicvenousinsufficiency followedbysodiumandwater.Thereisaconcomitantexpansionintotalbodywaterand
Chronicvenousinsufficiencyoftenresultsfromlongstandingvenousvalvular sodium.
incompetencethatleadstovenoushypertension.Themostcommoncauseofvalvular
incompetenceisthesequelaofpriorclinicaloroccultdeepvenousthromboses.Asthe Idiopathicedema
thrombosisheals,valvesaredestroyed,leadingtoincompetencyandvenouswall Idiopathicedemadescribesapoorlyunderstoodsyndromeofabnormalfluidretention
distortion. thatprimarilyaffectspremenopausalwomen.Inattemptstodescribeitsprimary
Theedemamaybeunilateralorbilateral,althoughitisoftenasymmetric.Earlyinits features,theconditionhasalsobeentermedcyclicaledema,periodicedema,fluid
course,itissoftandpitting,whereasinthelaterstages,chronicvenousanddermal retentionsyndrome,ororthostaticedema.Thekeyfeaturesareperiodicepisodesof
changessuchasvaricosities,induration,fibrosis,andpigmentationdevelop.Symptoms edemainwomenwhohaveweightchangesthatarenotclearlyrelatedtothemenstrual
maybeexacerbatedbyheatorprolongedsittingorstanding.Theextremitiesare cycle.Symptomsareusuallydescribedasswellingofthehands,legs,orface,or
susceptibletosecondarycomplicationssuchasdermatitis,cellulitis,andstasisulceration. abdominalbloating,whichmaybereal,orperceivedbythepatient.Bydefinition,its
Venousstasisulcerstypicallyoccuraroundthemedialmalleoli. diagnosisismadeafterexcludingotherorganiccausesofwaterretention.Itismost
commoninthethirdandfourthdecadesoflife.Psychologicandemotionaldisturbances
Lymphedema arecommoncomorbidconditions.Concomitantmisuseofdiureticsorlaxativesisalso
Lymphedemaresultsfromimpairedlymphatictransportleadingtothepathologic commoninpatientswiththisdisorder.
accumulationofproteinrichlymphaticfluidintheinterstitium,mostcommonlyinthe
extremities.Secondarylymphademaisthemostcommonform.IntheUnitedStates, History,Signs,Investigation
edemaoftheupperextremityafteraxillarylymphnodedissectionisthemostcommon Organ History PhysicalExamination LaboratoryFindings
causeofacquiredlymphadema,whereasfilariasisisthemostcommoncauseworldwide, System
affectingmorethan90millionpeople. Cardiac Dyspneawith Elevatedjugular Elevatedureanitrogento
Withlongstandinglymphstasis,cutaneousandsubcutaneousfibrosisdevelopsintothe exertionprominent venouspressure, creatinineratiocommon;
classic,induratedpeaudorangeappearanceoftheskin.Thereispreferentialswellingof oftenassociatedwith ventricular(S3) elevateduricacid;serum
thedorsumofthefoot,withacharacteristicsquaredoffappearancetothetoes.This orthopneaor gallop;occasionally sodiumoftendiminished;
swellingresultsintheinabilitytotenttheskinonthedorsumofthedigitsoftheaffected paroxysmalnocturnal withdisplacedor liverenzymesoccasionally
extremity,alsoknownasStemmerssign.Dependingontheetiology,theedemamaybe dyspnea dyskineticapical elevatedwithhepatic
unilateralorbilateral.Evenwhenbilateral,itiscommonforthelymphedematobe pulse;peripheral congestion
asymmetricinseverity. cyanosis,cool
Lipedemaiscommonlymistakenforperipheraledemaorlymphedema.Inthiscondition, extremities,small
thelegswellingisduetoabnormalaccumulationoffattysubstancesinthesubcutaneous pulsepressurewhen
tissues,characteristicallysparingthefeet,andfoundalmostexclusivelyinyoungwomen. severe
Theonsetisusuallyinsidiousandoftenbecomesapparentshortlyafterpuberty.Thelack
ofinvolvementofthefeetandtheabsenceofStemmerssignhelptodistinguish
lipedemafromlymphedema. Hepatic Dyspneainfrequent, Frequently Ifsevere,reductionsinserum
exceptifassociated associatedwith albumin,cholesterol,other
Myxedema withsignificant ascites;jugular hepaticproteins(transferrin,
Peripheraledemamayoccurinthesettingofhyperthyroidismorhypothyroidism, degreeofascites; venouspressure fibrinogen);liverenzymes
althoughitismorecommonwiththyroidhormonedeficiency,occurringinabouthalfof mostoftenahistory normalorlow;blood elevated,dependingonthe
 ofethanolabuse pressurelowerthan causeandacuityofliver notdesirable.Acombinationofpatienteducation,sodiumrestriction,and,when
inrenalorcardiac injury;tendencytoward appropriate,theuseofdiureticsareoftenrequired.
disease;oneormore hypokalemia,respiratory Toreduceextracellularfluidvolume,anegativesodiumbalancemustbeachievedby
additionalsignsof alkalosis;macrocytosisfrom reducingsodiumintake,increasingexcretionofsodium,orboth.Ifsodiumintakeremains
chronicliverdisease folatedeficiency high,increasingsodiumexcretionmaynotbesufficienttodecreaseextracellularvolume.
(jaundice,palmar Reducingsodiumintakeisoftennotsufficient,anddiureticssuchasloopdiuretics,
erythema, thiazidediuretics,andpotassiumsparingdiureticsmaybeneeded.Theseclassesof
Dupuytren's diureticsactwithinthetubularlumentoinhibitsodiumreabsorptionwithinthenephron.
contracture,spider
angiomata,male Diuretics
gynecomastia; Loopdiureticsareusuallythemosteffectivefordiuresis.Becausetheirplasmahalflives
asterixisandother areshort(e.g.,1hourforbumetanide,1.5to2hoursforfurosemide,3to4hoursfor
signsof torsemide),severaldosesarerequiredperdaytomaintainnatriuresis.Themaximal
encephalopathy)may responsetoeachloopdiureticispatientspecific;hence,athresholdlevelofthedrugat
bepresent thesiteofactionmustbeattainedformaximalresponse.Exceedingthisthresholddose
willnotresultingreaterdiuresis.Similarly,ifanadequatedosefailstoachievea
response,changingtoadifferentloopdiureticwillnotbeefficaciousbecausethe
Renal Usuallychronic:may Bloodpressuremay mechanismsofactionarethesame.
Albuminuria,hypoalbuminemia;sometimes,
beassociatedwith beelevated; Thebioavailabilityofloopdiureticsisthesameinpatientswithrenalinsufficiencyandin
elevationofserumcreatinineandureanitrogen;
uremicsignsand hypertensiveor hyperkalemia,metabolicacidosis, normalpatients,butalargerdosemaybenecessarytoattainthethresholdamountof
symptoms,including diabeticretinopathy druginthetubularfluid.Reducingsodiumreabsorptioninthedistalnephronbyadding
hyperphosphatemia,hypocalcemia,anemia(usually
decreasedappetite, inselectedcases; normocytic) thiazideorpotassiumsparingdiureticsmayimprovediuresisinpatientswhoare

altered(metallicor nitrogenousfetor; refractorytoloopdiureticsalone.Sodiumretentioninpatientswithnephroticsyndrome
fishy)taste,altered periorbitaledema ishigh.Therefore,higherdosesofloopdiureticsareoftenrequiredtoachieveeffective
sleeppattern, maypredominate; sodiumexcretion,andtheadditionofathiazidediureticisoftennecessary.
difficulty pericardialfriction Patientswithcirrhosisoftenhavesecondaryhyperaldosteronism,andforthem
concentrating, rubinadvanced spironolactoneisacommonfirstchoicefordiuretictherapy.Theinitialdoseisusually50
restlesslegsor caseswithuremia mg/d,anditslonghalflifeallowsforoncedailydosing.Themaximumdoseis400mg/d.
myoclonus;dyspnea Inpatientsinwhomspironolactoneisinadequate,athiazideorloopdiureticmaybe
canbepresent,but added.Ifneeded,largevolumeparacentesescanbeperformedtoreducetheneedfor
generallyless higherdosesofdiuretics.Rapiddiuresisshouldbeavoidedincirrhoticpatients,especially
prominentthanin inthosewithoutmuchperipheraledemainwhomtheextravascularfluidisprimarily
heartfailure localizedasascites.Inthesepatients,onlytheperitonealcapillariesareavailableto
mobilizethefluid.Overlyaggressivediuresismaythenoutpacetheabilitytoreplenishthe
plasmavolume,precipitatingthehepatorenalsyndromeorhemodynamiccollapse.A
dailyrateofdiuresisofabout500ccisrecommended
Management
Treatment
Treatmentrequirestherecognitionandmanagementofunderlyingconditionsthat
predisposetotheformationofedema.OnlybycorrectingthedisruptionsinStarling
forcesthatleadtothecascadeofwaterretentioncanthecyclebehaltedandtheprocess
reversed.Inmanycases,theeliminationofedemaisnotpossible,whereasinsomeitis