Haemodialysis

Online Clearance MonitoringAssuring the Desired Dose of Dialysis

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Contents

1.Foreword

2.Dialysisdose 2.1 Standardmethodsofdeterminationofthedialysisdose 2.1.1 UreaReductionRatio(URR) 2.1.2 Kt/V ClearanceK Effectivetreatmenttimet UreadistributionvolumeV 2.1.2.1 DeterminationofKt/Vusingbloodsamples Formalureakineticmodelling Single-poolKt/V(Daugirdasformula) Single-poolvariable-volumeKt/V Double-poolKt/V(dpKt/V)anditsapproximation: EquilibratedKt/V(eKt/V) 2.2 Theclinicalrelevanceofdialysisdose 2.3 Recommendationsfordialysisdoseandthefrequency ofmeasurementofdelivereddose

3.OnlineClearanceMonitoring–OCM®

3.1 ThemethodofOCM®operation 3.2 OCM®inONLINEplusHaemodiafiltrationtreatments

4.Optimisationofdialysisefficiency 4.1 Bloodflow 4.2 Dialysistime 4.3 Dialyser(Membranesurfacearea,lowflux/highflux) 4.4 Dialysateflowrate

5.MeasurementofplasmasodiumwithOCM®

6.FrequentlyAskedQuestionsaboutOCM®

7.References

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1. Foreword

OnlineClearanceMonitoring(OCM®)isastandardfeatureoftheFreseniusMedicalCareTherapySystem5008

thatprovidesanautomaticintradialyticmeasurementoftheeffective in-vivoureaclearanceK,thetotalcleared

bloodwatervolumeKt,thedelivereddoseofdialysisKt/Vandtheplasmasodiumconcentrationofthepatient.

WiththeOCM®itispossibletoeasilymonitortheseessentialparameterswithoutadditionalcostsduringregular

ONLINEHaemodiafiltrationineitherpre-orpost-dilutionmode,andduringhaemodialysistreatments.

TheOCM®helpsphysiciansandnursingstafftoensureanddocumentonaregularbasisthattherenalreplace-

menttherapymeetstherecommendedorrequiredqualitystandardswithouttheneedforadditionallaboratory

testsorexpenses.

ThisuserbrochureprovidesclinicalandtechnicalbackgroundinformationontheOCM®,describesitsoperation

andgivesrecommendationsfortheapplicationoftheOCM®.

4

2. Dialysis dose

Similar to the term “dose”, that defines the specific

quantityofamedicalproductordrugrequiredforthe

treatmentofapatient,thedialysisdosecanbedefined

as the quantity of dialysis treatment delivered for a

given period of time. In general the dialysis dose is

measuredbythecomparisonbetweenthebaselineand

finalconcentrationofadefinedsubstanceintheblood

ofthepatient.Themoreefficientthedialysissession,

thegreaterthereductionofthisgivensubstanceis.

Intheory,itispossibletodeterminehowefficientany

substancewhichispresentinthebloodhasbeenre-

movedduringdialysis.Eventhoughdifferentmethods

have been developed to measure the dialysis dose,

changesinureaconcentrationaremonitoredinorder

todeterminethedialysisdoseinstandardpractice.

2.1Standardmethodsofdeterminationofthedialysisdose

2.1.1UreaReductionRatio(URR)

Asimpleandcommonly-usedmethodofdetermining

thedoseofdialysisisthecalculationoftheUreaReduc-

tionRatio(URR).Thisinvolvesadirectcomparisonof

pre-andpostdialyticureaconcentrationsandshows

the percentage reduction of the urea concentration

duringdialysistreatment(1).

Inviewofthesimplicityofthemethod,URRisfrequently

usedtodeterminethedoseofdialysis,despitethefact

that the method has an in-built analytical weakness

whichmaycauseinaccurateresults.Incontrasttoother

methods,theURRmethoddoesnottakeintoaccount

thatureaisalsoremovedfromthebloodbyultrafiltration.

Cpost:postdialyticureaconcentration/Cpre:predialyticureaconcentration

Ultrafiltration leads toaveryefficient transferofurea

from the blood into the dialysate, but this does not

resultinadirectreductionoftheureaconcentrationin

theblood.Thisremovalofureaisnotaccountedforin

theURRmethod.ThegreatertheUFvolumeremoved

during dialysis, the more inaccurate the results of

dialysisdosecalculationbasedonURR(2,3).

2.1.2Kt/V

41:ThevariablesoftheKt/Vformula

TheformulaKt/V,whichisthemostcommonlyused

index of the adequacy of the dialysis treatment, is

a mathematical representation involving the blood

volume which has been completely cleared of urea

during a specified dialysis and the urea distribution

volumeofthepatientrequiringdetoxification.41

The variables of the Kt/V formula:

Clearance K

Aswell asbeing used as adiagnostic parameter in

renalfunctiontests,theterm“clearance”isalsoused

in renal replacement therapy.Theprimaryparameter

used to determine the volume of blood which has

beenpurifiedduringtreatment is theeffective in-vivo

clearance Keff (mL/min)42. Clearance is defined as

the (hypothetical) volume of blood which has been

totally “cleared” of a given substance each minute;

clearanceisthusexpressedasmL/min.

K x

V

t

Clearance(Manufacturer)

Dialysis time(Nephrologist)

Distribution volume(Patient)

5

URR = 100 1 - Cpost

Cpre ( )

In-vivo must be differentiated from

in-vitro clearance:

In-vitroclearancerepresentsthepurelydiffusiveclearance

achievedbyadialysertestedunderdefinedconditions

(asspecifiedinstandardEN1283)usingstandardised

aqueoussolutions.TheEN1283standardrequiresthat

measurementsbeconductedatapredefineddialysis

fluidflowratewithoutanyultrafiltration(thatis,without

aconvectiveclearancecomponent).Onlyonthebasis

ofthesenon-patient-specificlaboratorymeasurements

isitpossibletocompareclearancevaluesandthusthe

relativeefficiencyofindividualdialysers.In-vitroclear-

ance, i.e. the efficacyof adialyser under laboratory

conditions,isthusprimarilydeterminedbythedesign

featuresofthedialyseraswellasthemembranechar-

acteristics.

In-vitroclearancesofdialysers,ontheotherhand,are

measuredundertheactualdialysistreatmentconditions

involvingthepatient,generallybymeansofanalysisof

thebloodpriortoandafterpassingthedialyser:theterm

“wholebloodclearance”isthususedinthiscontext.

In-vivoclearancesaresubstantiallydifferentfromin-vitro

clearancesas,duringthedialysisofwholeblood,the

effectsof thecorpuscularbloodconstituents (mainly

theerythrocytes),thedissolvedplasmaproteins,andthe

adsorption of plasma proteins on the dialysis mem-

brane(the“secondarymembrane”)considerablyalters

thediffusionpropertiesofthedialysismembraneeven

underotherwisecomparablecircumstances.

In-vivoclearanceisthusinevitablylowerthanthestan-

dardisedin-vitroclearance,butdoesreflecttheactual

conditionsofthetreatmentandisthusofcentralimpor-

tanceforthedeterminationofdialysisefficiency.

Effective dialysis time t

Effectivedialysistimetistheactualdurationofdiffusive

blood detoxification (time of dialysis fluid flow in the

dialyserwiththebloodpumpoperating).Interruptions

to the dialysis treatment for therapeutic or technical

K=clearance(mL/min),QB=effectivebloodflow(mL/min),CBin=concentrationofinflowingblood,CBout=concentrationofoutflowingblood

K = QB CB in – CB out

CB in

6

In-vivo Clearance K influencedby:dialyser,effectiveblood(water)flow(considering

haematocrit),ultrafiltration,recirculation,dialysisfluidflow

Effective dialysis time t sometimesreducedduetoalarmsandbypassconditionsorprematureterminationofthetreatment

Urea distribution volume V dependentonbodysizeandcomposition,weight,ageandgenderofthepatient

42:ThedoseofdialysisKt/V isa resultof theeffective in-vivoureaclearanceK,theeffectivedialysistimetand theureadistributionvolumeV.

reasons are considered in the effective dialysis time

42. The effective dialysis time is, in most cases,

shorterthanthetotaldurationoftreatmentprovided.

Inanobservationalstudy,Seguraetal.havedemon-

stratedthat themeanprescribeddurationofdialysis

is generally not achieved inpractice. Thus, over the

period of 1 year, the loss of time and therefore of

efficiencyperpatientwasequivalenttothatof7whole

dialysissessions(4).

Urea distribution volume V

TheureadistributionvolumeVisequivalenttothetotal

bodyfluid,consistingoftheproportionofwaterinblood

(7%)aswellasthe interstitial (31%)and intracellular

volumecompartments(60%).Uponcommencementof

dialysis,ureaishomogeneouslydistributedthroughout

thebody;hence,more than90%of theureawhich

accumulatesinthehumanbodyisnotpresentinblood,

butintheinterstitialandintracellularvolumecompart-

ments. Thus, only with continuous diffusion of urea

fromthesecompartments into thebloodand further

transport into the extracorporeal circulation is the

largestproportionofureapresent in thebodymade

availablefordialysis.

Thelargerthebloodvolume(highbloodflowrate)which

reaches thedialyserduringa treatment sessionand

thelongerthedurationofthetime-dependentdiffusion

fromtheinterstitialandintercellularcompartmentsinto

theblood(adequatetreatmenttime),themoreefficient

thedialysistreatmentwillbe.

AmajoradvantageoftheKt/Vequationisthefactthat

ittakesintoaccounttheindividualbodyweightofthe

dialysispatient.PatientswiththesameKt/Varedetoxified

tothesameextenteveniftheyhavemarkedlydifferent

bodyweights.Dialysistreatmentscanthusbecompared

intermsoftheeliminationeffectusingtheKt/Vmethod.

The following examples should help explain the

use of the Kt/V concept:

AssumingKtis20litres,thismeansthat20Lofblood

haveleftthedialyserafterbeingclearedofurea.How-

ever,thisinformationdoesnotyettelluswhichdialysis

dosethepatienthasreceived.Inthecaseofapatient

withaureadistribution volumeVof30L, acleared

blood volumeof 20 L hasquite adifferentmeaning

thaninthecaseofapatientwithaureadistributionvol-

umeof40L.IfKt/Visequalto1,thismeansthatthe

volumeofbloodwhichhasbeencompletelycleared

ofureainthedialyserisexactlyequivalenttotheurea

distributionvolumeof thepatient. Inapatientwitha

distributionvolumeof40L,Ktmustbeequalto40L

sothattheresultoftheformulaKt/Visalso1.IftheKt

valueisonly20L,theKt/Vvaluewouldbe0.5.

EvenifKt/Visequalto1,thisdoesnotmeanthatthe

total body fluid or the total urea distribution volume

ofthepatient isfreeofurea,butonlythat,usingthe

exampleabove,40Lbloodhaveleftthedialyserafter

beingfreedofurea.IfKt/Vis1.0,aureaconcentration

of approximately 36 – 37%, relative to the baseline

value,remainsafterdialysis.

2.1.2.1DeterminationofKt/Vusingbloodsamples

Therearevariousmethodswhichcanbeusedtode-

termineKt/V inpractice.Thesediffer in termsof the

underlyingmathematicalmodelsusedtopredictand

determineureakinetics(inotherwords,thechangesin

thebloodureaconcentrationofthepatientovertime).

Somemethodsinvolveverycomplexcalculationsand

requireappropriatesoftwareprogrammes.

7

Formal urea kinetic modelling

Themostcomplex,butatthesametimemostprecise

methodofdeterminationofKt/V is theso-calledfor-

malureakineticmodelling(5,6).This requiresaccurate

measurementof:

•ureaorBUN(BloodUreaNitrogen):concentrations

priortoandafterthefirstdialysissessionoftheweek,

andureaorBUNconcentrationspriortothesecond

dialysissessionoftheweek(assumingthreetreat-

mentsareprovidedperweek)

• thebodyweightofthepatientpriortoandafterthe

firstdialysissessionoftheweek

• theactualeffectivetreatmenttime(nottheprescribed

durationofdialysisandnotthetimefromconnection

toanddisconnectionfromthedialysismachine)

• theeffectiveureaclearanceofthedialyserasmeasured

atthedialysiscentre(notthevalueforin-vitroclearance

quotedbythemanufacturer).

Ureakineticmodellingisareproduciblemethodwhich

notonly allowscalculationof thedialysisdoseKt/V,

butalsoof theparameternPCR (normalisedProtein

CatabolicRate),animportantmarkerofthenutritional

statusofthepatient.Moreover,ureakineticmodelling

allowstheexactcalculationofthepatient-specificurea

distributionvolumesothattheindividualdialysispre-

scriptioncanbegivenonthebasisofmeasureddata.

Themaindisadvantageof theureakineticmodelling

methodisthelogisticalaspect.Someparameters,such

astheeffectiveclearanceachievedbyadialyser,are

difficult tomeasure in clinical practice and the effort

required to obtain and process the necessary data

canbeconsiderableinlargedialysiscentres.

Morerecently,atwopointureakineticmodelhasbeen

validated which is based on only two measurements

ofureaorBUNinsteadofthree,priortoandafterthe

dialysis session and which supplies precise results

withamarkedreductionoflogisticaleffort(7).

Single-pool Kt/V (Daugirdas formula)

The best alternative to the urea kinetic modelling

method, also based on analysis of blood samples,

isprovidedbytheformulaforthecalculationofKt/V

developedbyJ.T.Daugirdas(8).

Single-pool variable volume Kt/V

Mostwidelyusedatpresent is the following formula

forcalculatingKt/V:

Thismathematicalmodel,whichusesthenaturalloga-

rithm tocalculateKt/V,providessufficientlyaccurate

resultsoverthefullrangeofstandardKt/Vvalues(9,10).

Inaddition,theDaugirdasformulatakesintoaccount

thechangeinpatientvolumecausedbyultrafiltration

anditscontributiontoconvectiveureaelimination.

ln:naturallogarithm,R:ratioofpostdialytic÷predialyticBUN,t:effectivedialysistimeinhours,Uf:ultrafiltrationvolumeinlitres,W:weightofthepatientafterdialysisinkg.

43:Bloodureanitrogenconcentrationatthebeginning(1),attheend(2) and60minutesaftertheend(3)ofaHDtreatment

Kt/Vsp = -ln (R – 0.008 x t) + (4 – 3.5 x R) x Uf/W

BUN

conc

entr

atio

n [m

g/dl

] ICV

ICV

ICV

ECV+blood

ICV: Intracellular volume

ECV: Extracellular volume

ECV+blood

ECV+blood

Time [min]

Single pool variablevolume Kt/V (spKt/V)

Equilibrated Kt/V(eKt/V)

“Rebound”

End of treatment

8

Double-pool Kt/V (dpKt/V) and its approximation:

equilibrated Kt/V (eKt/V)

Asinthecaseoftheother(notdiscussedhere)single-

pool models, the Daugirdas formula considers the

body,forthepurposesofmathematicalmodellingas

a single unified fluid pool, and does not take into

account the differences in rates of urea transfer

between the three fluid compartments blood plas-

ma, extracellular space and intracellular space. This

difference inthetransferrateofurea isdescribedas

thedouble-pooleffect.

Withincreasingefficiencyofthedialyser,itispossible

thatureaiseliminatedmorerapidlyfromthebloodthan

itcandiffusefromthecellsintotheblood.Duetothis

relativedelayofureamovementfromcellsintoblood,

the intracellular compartment becomes a non-equilib-

ratedreservoirforurea,andthisaspectisnottakeninto

accountinthesingle-poolmodelsforureakinetics(9,12,13).

Hence,oncompletionofadialysistreatment,theintra-

cellular urea concentration is greater than in blood

plasma,andthediffusionofureafromcellsintoblood

nevertheless continues for approximately 30 – 60

minutesaftertheendoftreatment43.Thisphenom-

enon is called urea rebound(14,15). If this intracellular

ureapoolislargeoncompletionofdialysisandisnot

takenintoaccount,theeffectivedialysisdoseKt/Vwill

beoverestimated.Thiseffect isparticularlymarkedif

high performance dialysers are used in combination

withashortdurationofdialysis(16).

In addition to the relative delay of transfer of urea

betweenthevariousbodycompartments,themarked

differencesinbloodperfusionoforgansalsocontribute

tothereboundeffect.Itshouldbeborneinmindthat

70%oftotalbodywater,andthusalsourea,ispresent

inbodyorganswitha relatively lowbloodperfusion,

suchasskinandmusclesatrest.Astheseurea-rich

organshaveonlyarelativelylowbloodflow,theircon-

tribution to the totalplasmaureawhich reaches the

extracorporeal circulation is less than thatof organs

with lowureaconcentrationsbuthavinghigherrates

ofbloodperfusion.Organswith lowbloodperfusion

thereforealsoconstituteafurtherureareservoir.Inthe

initial 30 minutes after completion of dialysis, the

concentrationequilibrationagainleadstoarebound,

thusanincreaseinbloodureaconcentration.

The extent of total urea rebound can differ greatly

betweenindividualpatients.Inastudyconductedby

Leblancetal.(15), themean rebound, thepercentage

increaseinpostdialyticureaconcentration30minutes

after dialysis, in comparison with that immediately

aftercompletionofdialysis,was17%.

Ifthisreboundeffectistakenintoaccountinthecal-

culationofthedialysisdose,theresultantKt/Vvalueis

referredtoasequilibratedKt/V(abbreviatedtoeKt/V).

Onaverage,equilibratedsingle-poolKt/V(eKt/V)is0.2

lowerthannon-equilibratedsingle-poolKt/V(17,18).

InordertoobtainanexactvalueforequilibratedKt/V,

theBUNconcentrationshouldideallybemeasured30

minutes after completion of dialysis, but this is, un-

fortunately,notpracticableinroutinepracticesofout-

patient haemodialysis centres. In order toovercome

thisproblem,various formulaehavebeendeveloped

which,afterathirdblood(urea)samplehasbeentaken

during the dialysis session (usually after 70 minutes

dialysis),allowthepostdialyticequilibratedureacon-

centration to be approximatively calculated(16,19). The

additionaleffortrequiredtoobtainathirdblood(urea)

sample has meant that this method has not been

widelyaccepted.

Daugirdashasalsodevelopedaformulawhichallows

theresultsofcalculationofsingle-poolKt/Vtobeextra-

polated to equilibrated Kt/V(20). Formula 1 (artKt/V) is

applicable if an arterial postdialytic urea value from

anarterio-venousaccessisavailable,whileformula2

(venKt/V)shouldbeusedifamixedvenousureavalue

fromaveno-venousaccessisavailable:

9

Thekeyadvantageoftheseformulaeisthatonlytwo

bloodsamplesarerequiredforthecalculationofthe

equilibratedKt/V.

The following table shows the relationship between

single-poolKt/V(spKt/V)valuesandequilibratedKt/V

values(eKt/V)relativetothedurationoftreatment.

2.2 The clinical relevance of the dialysis dose

Ifdialysisdoseisdetermined,itispossibletoprescribe

andsubsequentlymonitorthedialysistreatmentonthe

basis of clinical parameters. A significant correlation

betweentheaveragedelivereddialysisdoseandpatient

mortalityrateshasbeendemonstratedinmanyclinical

studies(1,21–29).All these studies reiterate the fact that

thehigherthedelivereddoseofdialysis,thelowerthe

patientmortalityrates.

TheNCDSstudy(30)wasthefirstlong-termstudywhich

investigatedthecorrelationbetweendialysisdoseand

therapeuticoutcome.Theresultsnotonlydemonstrated

astatisticalrelationshipbetweenureaeliminationand

mortality,butalsoallowedGotch&Sargenttodevelop

theureakineticmodellingmethodanddefinetheKt/V.

In2002,Portetal.publishedanobservationalstudy

ofmajorimportanceontheeffectofdelivereddialysis

doseontheriskofmortality(31).

Inthisretrospectivestudy,thedatafor45.967USpa-

tients who had commenced chronic haemodialysis

therapybetweenApril1997andDecember1998were

examined44.

Inordertonotmasktherelationshipbetweenmortality

riskanddialysisdosebytheseparateriskfactor“body

weightofthepatient”,patientswereinitiallysortedinto

threebodyweightgroups–small,mediumandlarge.

The relationship between mortality risk and dialysis

dosewasthenanalysedseparatelyforeachofthese

body weight groups. The result was confirmed over

thewholerangeofdialysisdosesanalysed:thehigher

thedelivereddialysisdose,thelowertherateofpatient

mortality.Thisstudyalsoshowedthatthereisnospecific

maximum dose above which no further decrease in

patientmortalitycanbeachieved.Thismeansthatduring

each dialysis treatment, it is advisable to deliver the

highestdialysisdosepossible.

Otherclinicalaspects,suchastheerythropoietin(EPO)

requirement,canalsobeinfluencedbythedialysisdose

Kt/V. Inastudypublished in2001, theEPOrequire-

mentoftwopatientgroupswithdifferentKt/Vvalues

44:Dialysisdoseandbodymassindexarestronglyassociatedwithsurvival in haemodialysis patients. Retrospective analysis of data from 45.967 US hemodialysispatientsstartingdialysisduringApril1997 throughDecember 1998(adaptedfrom(31)).

Small

MediumLarge

Annu

al a

djus

ted

deat

h ra

tes

[%]

* p<0.05 compared to next lower URR group

Size of circle reflects number of patients per group

Dose Category

*

**

*

*

*

**

*

Small BMI < 23.2 kg/m 2

Medium BMI 23.2 – 27.8 kg/m2

Large BMI > 27.8 kg/m 2

Ratio of single-pool Kt/V (spKt/V) and equilibrated Kt/V (eKt/V)as a function of treatment time (t)

eKt/V

spKTt/V 2.0 hrs 2.5 hrs 3.0 hrs 3.5 hrs 4.0 hrs 4.5 hrs 5.0 hrs

1.0 0.73 0.79 0.83 0.86 0.88 0.90 0.91

1.1 0.80 0.87 0.91 0.94 0.97 0.98 1.00

1.2 0.87 0.94 0.99 1.02 1.05 1.07 1.09

1.3 0.94 1.02 1.07 1.11 1.14 1.16 1.17

1.4 1.01 1.09 1.15 1.19 1.22 1.24 1.26

1.5 1.08 1.17 1.23 1.27 1.31 1.33 1.35

1.6 1.15 1.25 1.31 1.36 1.39 1.42 1.44

Table 1:

10

T:dialysistreatmenttimeinhours,t:dialysistimeinminutes

(1) equilibrated or eKt/V = artKt/Vsp – (0.6 x artKt/Vsp/T) + 0.03 (2) equilibrated or eKt/V = venKt/Vsp – (0.47 x venKt/Vsp/T) + 0.02

wascompared(32).Measuredhaematocritwas identi-

cal,at35±1.5%, inthetwoinvestigatedgroups,A

andB,althoughgroupAreceiveddialysisatalowKt/V

<1.2andgroupBreceiveddialysisatahighKt/V>1.4

45.WhilegroupA(Kt/V<1.2)hadanEPOrequirement

of183±95U/kg/week,patientgroupBwithitshigh

Kt/V (>1.4) required only 86 ± 33 U/kg/week. This

studyshowsthatifasufficientlyhighdialysisdoseis

delivered,thiscanhaveapositiveeffectontheoverall

clinicalconditionof thepatient,which, in turn, is re-

flectedinareductionoftheEPOrequirement.

2.3 Recommendations for dialysis dose and the frequency of measurement of delivered doseAsageneralrule,itisthetaskofthetreatingnephro-

logist,toprescribetheformanddoseofdialysistreat-

ment,taking intoaccountthespecificclinical factors

oftheindividualpatient.

Averycomprehensivecollectionofrecommendations

fortheprescriptionofdialysiswasfirstprovidedbythe

USNationalKidneyFoundation (NKF) in theirguide-

linesonadequatehaemodialysistreatment.TheDOQI

guidelineswerepublished in1997andsubsequently

updated as the K/DOQI guidelines (Kidney Disease

Outcomes Quality Initiative) in 2000(33). The European

BestPracticeGuidelinesforHaemodialysis(EBPGPart1)

were introduced in 2002 and represent the current

consensus on best practices and dialysis adequacy

amongsttheEuropeannephrologicalcommunity(67).

The respective recommendations regarding dia-

lysis dose are specified as follows:

•The delivered dialysis dose should be regularly

measuredandmonitored–atleastmonthlyusinga

standardisedmethod

•Thedelivereddialysisdoseshouldbeexpressedas

equilibratedKt/V(eKt/V)orassingle-poolKt/V(spKt/V)

•Theminimumdosepersessiononathrice-weekly

scheduleshouldbeeKt/V≥1.20(spKt/V~1.4)

TheEBPGforHaemodialysisareconsideredtobethe

referenceguidelines inEuropeandhavebeenadop-

tedortakenasthebasisforthepreparationofnational

guidelines.

Ithasbecomeoneofthemainaimsofhaemodialysis

treatment,particularlyintheUS,todeliverahighKt/V

dialysisdose. IntheUS,theaveragedeliveredKt/V

dialysisdosecontinuouslyincreasedintheperiod1986

to1999from0.9totoday’sfigureofgreaterthan1.4.

TheprescriptionofanadequateKt/Vnotonlyrepre-

sentsthemathematicallystandardisedspecificationof

averifiable therapygoal,but isaqualitycriterion for

dialysistherapyitselfbecauseofthefrequentlydescri-

beddirectcorrelationbetweendialysisdoseandpatient

mortality(1,21–29).Theregularmeasurementofdelivered

Kt/V is thus an important aspect of medical quality

assurance.Todate,however,theneedtoextensively

sample urea concentrations, and the associated

logistical and financial requirements, has made it

difficult toconductclosemonitoringofdoseoreven

tomeasuredelivereddoseineachsession.Asanauto-

matedprocedure,whichisnotbasedonaurea/blood

sampling method, the Online Clearance Monitoring

(OCM®)hasmadeitpossibletomeasuredialysisdose

easily without additional expenses during on-going

dialysistreatmentsateverysession.

45:TheinfluenceofahighKt/VontheweeklyEPO-dose(adaptedfrom(32)).

EPO

dose

[U/k

g/w

eek] Group A

Hct: 35%

Group BHct: 35%

EPO dose

11

The Online Clearance Monitoring (OCM®) is a stan-

dardfeatureintegratedintheFreseniusMedicalCare

5008TherapySystem.Itprovidesautomaticintradia-

lyticmeasurementofthedelivereddialysisdoseKt/V,

theeffective in-vivoureaclearance,theaccumulated

cleared plasma volume Kt and the plasma sodium

concentration of the patient. OCM® can be applied

during regular ONLINEplus haemodiafiltration treat-

mentsinpreorpostdilutionmodeaswellasduring

standardhaemodialysis.

ThedialysisdosedeterminedbytheOnlineClearance

Monitoring(OCM®)isequivalenttoasingle-poolKt/V

(spKt/V).

3.1 The method of OCM® operation

To achieve the objective of developing a low cost

methodofmonitoringclearance,itwasnecessaryto

moveawayfromthecost-intensiveconceptofenzy-

maticureaanalysis. Insearchingforanalternative,a

substancewasconsideredwhich ispresent in large

quantities in the dialysis fluid and where changes in

concentrationscanbemeasuredby the sensors in-

stalled within the dialysis machine – namely ionised

sodium.Sodiumionsrepresentthelargestproportion

offreelymobileelectrolytesinthedialysisfluidandtheir

3. Online Clearance Monitoring – OCM®

OCM®screenduringaHDFtreatment

concentrationessentiallydeterminesthetotalconduc-

tivityofthedialysisfluid.

Althoughthesmall,positively-chargedsodiumiondif-

fersfromthenon-chargedand largerureamolecule,

bothparticlesexhibitcomparable in-vitroand in-vivo

diffusion characteristics across a synthetic dialysis

membrane, i.e. their specific diffusion coefficient is

almost identical at 37°C (Na+: 1.94 x 10 – 5 cm2/s,

Urea:2.20x10–5cm2/s46(34)).Under realdialysis

conditions,thedifferenceinclearanceisevensmaller

than thedifferenceofdiffusioncoefficientssince the

clearanceislimitedbybloodanddialysateflowrates

andnotby thediffusionprocessacross thedialyser

membrane.

Bymeansofindirectdeterminationofionconcentra-

tions in the haemodialysis solution (measurement of

conductivityattheinflowandoutflowofthedialyser)it

istechnicallypossibletodeterminethediffusionprofile

ofsodiumionsacrossthedialysismembraneandthus

calculatethedialysanceorionicclearance(D).Onthe

basisofthedialysanceofsodiumions,the“diffusibi-

lity”ofureathroughthemembrane(permeability)and

thusureaclearancecanbedetermined(35).

For accurate measurement of sodium dialysance,

conductivity sensor cells have been installed in the

inflowandoutflowlinesofthedialysertomeasurethe

conductivityof thedialysisfluid (prior to thedialyser)

andinthedialysate(afterthedialyser)(36).

46:OCM® isbasedon theequivalenceofelectrolyteandureaclearance(adaptedfrom(34))

Elec

trol

yte

clea

ranc

e [m

l/min

]

Urea clearance [ml/min]

aqueous solutions

Coefficients of diffusion at 37°C[cm2/s]

Na+ Urea1.94 x 10-5 2.20 x 10-5

12

In order to achieve adetectablediffusionof sodium

ions across the membrane, the otherwise moderate

diffusiongradientof sodiumbetween thebloodand

dialysisfluidsidesofthedialysermustbetemporarily

increased.

Forthispurpose,thedialysismachineinducesashort

termpulsetoincrease(ordecrease)thesodiumcon-

centration in thedialysisfluid, therebyresulting inan

increase in diffusion of sodium ions into the blood

compartment or in the reverse direction48. Assu-

mingthattheconductivitypulsedoesnotexceedthe

specifiedconductivitylimits,alternatepulsesincrease

anddecreaseconductivitytoensurethatthesodium

balanceremainsasneutralaspossible(37–44).

Thisshort-termincreaseintheconductivityofthedia-

lysisfluidpriortoenteringthedialyserissubsequently

reducedbydiffusionofaportionof thesodium ions

across the dialysis membrane into the blood of the

patientduring thepassage through thedialyser.The

dynamicinputconductivitysignal(pulse)atthedialyser

inflow is continuously monitored by the conductivity

sensorinstalledatthatposition:thesignalattheoutflow

of the dialyser is registered by an equivalent sensor

positionedthere.Therelativeareasunderthecurves

for the two recorded conductivity signals reflect the

diffusionofsodiumionsacrossthedialysermembrane.

Thelowerthevalueofoutflowconductivitycompared

toinflowconductivity,thegreatertheamountofsodium

thathasdiffusedfromthehaemodialysissolutioninto

the blood compartment as a result of the diffusion

gradientor, inotherwords, themorepermeable the

dialysismembraneforsodiumis(45).

Asurea–aspostulatedabove–hasadiffusionprofile

similartothatofthesodiumion,ureaclearancecanbe

determined(usingappropriatecorrectionfactors)irre-

spectiveoftheactualconcentrationofureaintheblood.

Steiletal.wereabletodemonstratein1993thatthe

dialysanceisdirectlyproportionaltoureaclearance(35).

Theyshowedhowcloselymeasured ionicclearance

correlateswithmeasuredureaclearance.Inavalidation

studyconductedin2001,Kuhlmannetal.produced

clinical evidence that dialysance also correlates with

ureaclearancein-vivo,andthatitcanbedetermined

accuratelywithina very lowanalytical error rangeof

only±5%bytheOCM®49(39).Asacomparison:the

analytical error for the determination of urea in the

laboratoryisapprox.±7%.Inbothoftheabove-men-

tioned investigations, itwaspossibletodemonstrate

thatthecorrelationbetweenelectrolyteclearanceand

theclearancevaluesforureadeterminedusingstan-

dardmethodsisalmost ideal.Themajorityofresults

lie,withsufficientprecision,onthelineofidentityand

thecorrelationvaluer isclosetotheidealvalueof1

(if all values for ionic clearance and laboratory data

48:OnlineClearanceMonitoring isoperatingwithashort-termdynamic conductivitypulse

Inle

t/Ou

tlet c

ondu

ctiv

ity

[mS/

cm]

Dialysis Time [secs]

ytivitcudnoc tel

Rec.

tuOytivitcudnoc telnI

Recirculation

13

QDQB

Cd inCb out

Cd outCb in

Dialyser

Blood pumpBlood inflow

Blood outflow

Fistula

Dialysate outflow

Dialysis fluid inflow

Conductivity cell “out”

Conductivity cell “in”

47:Thediagramshowsthelocationofthe2conductivitycellsoftheOCM®

clearancewereexactly identical,all resultswouldbe

ontheidealline).Themajorityofvaluesarewithinan

errorrangeofonly±5–6%.

ThroughfurtherimprovementsoftheOnlineClearance

Monitoring®method,Goldauetal.reportedinafurther

seriesofanalysisin2002animprovedlevelofprecision

ofbelowthe5%errorlimit(45).

Theprecisionoftheconductivitymonitoringisdeter-

mined,amongotherfactors,bythestabilityoftheplasma

sodiumconcentrationduringmeasurement.The less

variation in the plasma sodium concentration of the

patientduringthemeasurementcycle,themorepre-

cisetheresult is.Forthisreason,thetimeintervalof

conductivity variation is kept as short aspossible in

theOCM®technique.

Withthiscomparativelyshort(butstillsufficientlylong)

measurementofdialysateconductivityatthedialyser

outflow,notonlythesodiumdialysanceofthedialyser,

butalsothenegativeeffectsoftotalrecirculation(fis-

tula recirculation plus cardiopulmonary recirculation)

canbedetermined48.Evenaftertheconductivitypulse

inthedialysatehasfadedout,recirculatingbloodtrans-

portsrecirculatingsodiumionstothedialyserwhich,

dependingontheconcentrationintheblood,willdiffuse

backintothedialysate.Consequentlythisresultsina

lessfavourableratiooftheareasundertheconductivity

curves,andthustoareductioninclearanceequivalent

tothecontributionmadebyrecirculation.Althoughitis

notpossibletoproduceactualfiguresforrecirculation

fromtheOCM®,theeffectistakenintoaccountinthe

calculationofeffectivein-vivoclearance.

TheOCM®determinesclearance “online”during the

entire treatment period, i.e. with no time lapse and

atpredefinedmeasurement intervals.Thenumberof

measurementcyclestobeperformedduringthetreat-

mentcanbepre-selectedwithincertainlimits(see5008

Operator’sManual).Inaddition,theOCM®iscapable

ofdetectingadjustmentstobloodand/ordialysateflow

rateswithin1minuteandthenimmediatelyrecalculates

thecorrespondingnewclearancevalues.Thismeans

thattheeffectsofanyalterationtotreatmentparameters

on actual clearance can be continuously monitored

duringanongoingsession.

Inaddition to theureaclearanceK, thedata for the

currenteffectivedialysistimetareobtainedfromthe

FreseniusMedicalCareTherapySystem5008andare

included in the calculation of the dialysis dose. The

effectivedialysistimetisdefinedasthetimeinwhich

physicaldialyticprocessesbetweenthebloodofthe

patient and the dialysis fluid occur. The time of any

interruption of treatment for technical or therapeutic

reasonsandthedurationofpreparationandreinfusion

procedures are not included: only the “true” dialysis

time(diffusiontime)istakenintoaccount.

Onthebasisofthetwomeasuredparameters–urea

clearance and effective dialysis time – the OCM®

calculates the cumulative water volume contained

withinthebloodKxt(inlitres)whichhasbeencleared

ofurea,which isequivalent to thatproportionof the

circulating blood from which all urea has been re-

movedduringdialysis:Kxt=x(L).

14

49: Correlation of electrolyte clearance measured by the OCM® and bloodureaclearance

Electrolyte clearance OCM® [ml/min]

Bloo

d ur

ea c

lear

ance

[ml/m

in]

Error K: ± 5%

It isnotonlypossibletoderivetheVofapatientby

calculation,but thisparametercanalsobeprecisely

measured. In clinical routine, the bioimpedance

spectroscopytechniqueortheureakineticmodelling

method described in section 2 above can be used.

Oncethismeasuredvalueisavailable,itcanbedirectly

entered into the data-entry menu of the OCM®: the

informationnecessary for theanthropometric formulae

(age,gender,etc.)isthen,ofcourse,nolongerrequired.

TheanthropometricformulaeallowVtobesimplyand

quicklyestimated,buttheresultsrepresentonlyastan-

dardised mean value for the population as a whole.

Deviationsattributabletoindividualfactors,suchasan

above-averageproportionoffatormuscletissue,are

notaccountedfor.Insomecases,theremaybemarked

differencesbetween thevalue forVcalculatedusing

theWatsonformulaandthemeasuredvalueforV.

Kloppenburgetal.havedemonstrated,inacompara-

tivestudy,thattheresultsforureadistributionvolume

VcalculatedusingtheanthropometricWatsonformula

regularlyexceedthemeasuredVofthesamepatient

by26%(50).Thus,ifthevalueforVobtainedusingthe

Watsonformulaisusedinsteadofameasuredvalue

forcalculationofKt/V,theachievedKt/Visfrequently

underestimated.

InorderthattheKt/Vvaluecanbedeterminedbydi-

vision of the result for K x t by the urea distribution

volumeV,theoperatormustenteranappropriateva-

luefortheureadistributionvolumeVoftheindividual

dialysispatient.

The easiest method of estimating urea distribution

volumeV is touse theanthropometric formulaede-

veloped by Watson(48), Hume-Weyers(49) and Mellits-

Cheek(70), the latter being especially adapted for

children below the age of 16. All formulae can be

selectedintheOCM®menuofthe5008.TheWatson

formulacalculates theVofapatienton thebasisof

bodyweight,height,ageandgender411.

The Hume-Weyers formula requires information on

bodyweight,heightandthegenderofthepatient;in-

formationonageisnotrequired.Forinformationonthe

Mellits-CheekformulapleaserefertotheFAQsection.

411:AcalculatortoestimatetheureadistributionvolumeVaccordingto anthropometricformulaeisintegratedintheOCM®

15

410: To calculate theKt/V theOCM®measuresKand the5008Therapy Systemmeasurestheexacteffectivedialysistimet;theuserhastoenterthe patient’sV

Effective clearance:accurately knownfrom OCM® (±6%)

Effective dialysis time:precisely known fromthe 5008

Normally unknown

V from anthropometric data (Watson,Hume-Weyers ...),large deviationslead to an approximate Kt/VV from a previous Urea Kinetic Modelling procedure (DCTool ), leads tothe best results for Kt/V (± 0.1 Kt/V)V from other methods, e.g. bioimpedance

K x

V

t

MaleVurea = 2.447 - 0.09516 x age + 0.1074 x height + 0.3362 x weight

FemaleVurea = -2.097 + 0.1069 x height + 0.2466 x weight

ureaprofileofahaemodialysispatientbasedontwo

blood samples (pre andpostdialytic) using the sing-

le-pool variable volume method(7). Important data

relevant to the dialysis and nutritional status of the

patient, such as urea distribution volume, Kt/V and

proteincatabolicrate(PCR)arederivedfromthis.The

DCTool programme differs from the standard urea

kineticprogrammesinthat,insteadofcalculatingtheo-

reticalclearanceonthebasisofbloodanddialysate

flowrates, theeffective in-vivoclearance–averaged

for the treatment as a whole – as measured by the

OCM®isusedformodelling.

Forthedeterminationoftheureadistributionvolume

ofapatientusingtheDCTool,thebasicpatientdata

and information on treatment regimen needs to be

entered.Thenonedialysis treatment isselectedand

the relatedmain treatment andOCM®data (i.e. the

averageeffective in-vivoclearance) togetherwiththe

pre-andpostdialyticureavaluesfrombloodsamples,

areenteredintheDCToolprogramme.Withthisinfor-

mation,theDCToolconductsanureakineticanalysis

anddeterminesaprecisevaluefortheureadistribution

volumeV;apartfromotherveryinterestingdoseand

nutritionalparameters.OncethisassessedvalueforV

isavailable, itcanbeentereddirectly intotheOCM®

template,savedonthePatientCardandishenceavail-

ableforsubsequenttreatments.ThisenablestheOCM®

tocalculateanexactvalueforspKt/Vwithanerror<0.1

foreachroutinedialysissessionconductedoveralon-

InordertodetermineanexactvalueforspKt/Vusing

theOCM®,itisalwayspreferabletoenterthemeasured

ureadistributionvolumeratherthanananthropomet-

rically-derivedV.

With the software “Dose Calculation Tool” (DCTool),

Fresenius Medical Care provides the OCM® user

with an uncomplicated and precise instrument for

the accurate calculation of patient-specific urea dis-

tribution volume V using treatment and laboratory

data. The DCTool is a urea kinetic modelling (UKM)

software programme based on 2 point urea kinetic

modelling. The programme determines the weekly

413:OCM®offersmanyadvantagesincomparisonwiththeconventionalmethodfortheKt/Vmeasurement

16

The conventional procedure today Aspects 5008 with OCM® option

Kt/V ≥ 1.2... 1.8

Frequency

Control

Effort

Accuracy of K

Handling

Quality assurance

Blood samples (expensive)

Once a month/quarterly

Retrospective

Staff, syringes, lab time, cost and energy

6 – 8 %

Inconvenient

Unpractical and uncommon

Dialysate; K and t (no additional costs)

In every session

Continuous, online

None

6 %

Automatic

Standard!

412: DCTool is a urea kinetic modelling software to precisely calculatetheureadistributionvolumeofthepatient

gertimeperiod(upto6monthsforstablepatients)(66).

Itispossibletoconvertthissingle-poolKt/Vdetermined

bytheOCM®toaneKt/V(≈doublepoolKt/V)using

the formulae provided in section 2.1. Alternatively,

eKt/Vvaluesarealsoshowninthetable1onpage10.

In order to ensure that the V value is appropriately

updated,itisadvisabletorepeatureakineticmodel-

lingcalculationswithDCToolwithintheframeworkof

routinelaboratorytestsevery6–12weeks.

Inclinicalstudiesinwhich40treatmentsand151treat-

mentswereanalysed,itwasshownthattheDCTool-

methodprovidedtheoptimumvaluefortheureadistri-

butionvolumeofapatient(51,52,66)andthat theresults

agree well with the total body water measured with

bioimpedancespectroscopy.

The use of the OCM® functionality and DCTool in

combinationmakesitpossibletodeterminetheexact

valueforspKt/Vduringeachroutinedialysis.

Theparametersrelevanttotherapymonitoring,includ-

ing the OCM® measurement results, are displayed

inaclearoverviewwithamulti-coloureddiagramon

the touch screen of the 5008 Therapy System. The

clearance K is displayed during the course of the

treatmentasabluelineinthe“OCM®diagram”graphic,

soarethecurrentandabsolutevaluesforK,Kt/Vor

KtandGoal-Kt/V.Inaddition,thecumulativeKt/V(red

line)orKt(blackline)arevisualisedinrelationtotheset

Kt/Vtarget(greenline).

3.2 OCM® in ONLINEplus Haemodiafiltra- tion treatments

ONLINE Haemodiafiltration (HDF) with its numerous

positiveeffectsonuraemia-relatedcardiovascularrisk

factors,isacknowledgedasthemosteffectivedialysis

treatment modality that comes closest to the elimi-

nationprofileofthenaturalkidney. Inparticular,HDF

showssuperiorclearancesincomparisontostandard

haemodialysisintheremovalofmiddlemolecules.In

selectedEuropeancountries,upto30–40%ofthe

dialysis population is treated with ONLINE HDF, the

averagehoweverbeingaround10%(61).

Several studies have demonstrated clinical advan-

tagesoftheONLINEHDFtreatmentmodalitysuchas

an increased dose of dialysis, a reduced risk of ß2-

microglobulin-associated amyloidosis(62,63), a positive

influence on the treatment of anaemia(64) and im-

proved intradialytic cardiovascular stability(65). The

results of two recent studies even demonstrate that

patients treated with ONLINE HDF had a significant

35%reductionofmortalityriskcomparedtopatients

treatedwithstandardhaemodialysis(68,69).

The precision of the OCM® clearance measurement

under ONLINE HDF conditions has been validated

in-vitro and in clinical experiments by Canaud et al.

(HôpitalLapeyronie,Montpellier,France;publicationin

KIpending(71)). Intheseinvestigations,anerrorrange

of6% for theclearancemeasurementof theOCM®

systemduringONLINEplusHDFwasreported.

WiththeintroductionofOnlineClearanceMonitoringin

ONLINEplusHaemodiafiltrationit ispossibletoeasily

monitor the dose of dialysis during highly efficient,

convectivetreatments.

17

414: The OCM® display: The blue line indicates the urea clearance, the cumulatingKt/Visdisplayedbytheredline,theGoal-Kt/Visvisualisedasa greenline.

4.1 Blood flow

Theextentofureaclearanceachievedduringdialysis

isdeterminedlargelybytheeffectivebloodflowrate.

Increasingthebloodflowrateisthusaveryeffective

method of increasing dialysis efficiency(53). Figure 15

illustrates that in the blood flow rate range 0 – 600

mL/min, the increase inureaclearance isproportional

tothe increaseinbloodflowrate.Underthespecified

conditions,e.g.withtheFreseniusMedicalCareFX60

dialyser,anincreaseinbloodflowratefrom200mL/min

to400mL/minresultsinanincreaseinureaclearance

by 65%, while an increase in blood flow rate from

150mL/minto300mL/minresultsinanimprovement

of82%.Butevenmoderate increases inbloodflow

rateby50mL/min–from250mL/minto300mL/min

Theefficiencyofeachhaemodialysistreatmentisdeterminedbythefollowingfourparameters:

• theeffectiveextracorporealbloodflow

• theactualdialysistime

• theeffectiveureaclearanceachievedbythedialyser

• thedialysateflowrate

Itisessentialtoachievetheappropriatebalanceoftheseparametersinordertoensurethatadequatedialysistreat-

mentisprovidedandalsotoensurethattheresourcesavailableareeconomicallyutilised.

415:UreaclearanceofFreseniusMedicalCareFX60dialyseratdifferentbloodflowrates

4. Optimisation of dialysis efficiency

– under standard conditions of dialysis lead to an

increaseintheureaclearanceofapproximately15%.

When prescribing the required blood flow, and par-

ticularly when increasing blood flow, the individual

vascularaccessofeachpatientmustbeconsidered.

Thefistulabloodflowrate(averageflowrateinradio-

cephalic fistula is approximately 500 – 900 mL/min)

shouldalwaysmarkedlyexceedthatoftheextracor-

porealbloodflowrateinthedialyser,otherwisethere

is the risk that recirculation, which compromises

efficiency,maybeinduced.Recirculationoccurswhen

blood that has already been cleared of toxins flows,

counter to thenaturaldirectionof flow in thefistula,

out of the venous cannula directly into the arterial

cannula and mixes with non-purified blood. Recirc-

ulating blood has only a low toxin load prior to its

repeated passage through the dialyser. As a result,

thetoxinremovalpertimeunitisreducedanddialysis

efficiencydecreases.

Thereare,however,variousdevicesavailable,suchas

theBlood Temperature Monitor (BTM),obtainable

as an optional extra to the 5008 Therapy System,

which can automatically measure recirculation at a

pre-selected blood flow rate. In case of a signifi-

cantdropinthemeasuredclearancevalues(≥20%)

during the same treatment or compared to the

previous one stored on the 5008 PatientCard, a

BTM recirculation measurement can be automati-

callyinitiatedbytheOCM®.

Urea

cle

aran

ce [m

L/m

in]

Blood flow [mL/min]

Dialysate flow 500 mL/min

18

Since the OCM® conducts the clearance measure-

mentonthedialysatesideonly,theaccuracyofKis

notinfluencedbydeviationsinthebloodflowrate.In

thecaseofbloodordialysateflowchangesinbetween

twosubsequentmeasurements,theOCM®isableto

account for thesechangesbyusingamathematical

estimateforKunderthenewconditions.

4.2 Dialysis time

As thedialysis time t is adirect variable in theKt/V

formula,itisimportanttoensurethatasufficientlylong

effectivedialysistimeisdeliveredtoensureprovisionof

anadequatedialysisdose.Itisessentialtoprescribe

a sufficiently long treatment timewhich, by avoiding

all interruptions caused by alarms or other delays,

should,asfaraspossible,alsorepresenttheeffective

dialysistime.

TheDOQIguidelines,forexample,take intoaccount

the discrepancy between prescribed and effective

treatmenttime,whichfrequentlyoccursasaresultof

undesirable interruptions inthedialysistreatment,by

recommendingprescriptionofaslightlyincreasedKt/V

valueof1.3ifaKt/Vof1.2istobeachieved(33). Ina

studypublishedin2001,J.Leonetal.investigatedthe

dialysisprescriptionsfor721dialysispatients(54).They

foundthatin15%ofpatientsthedialysisprescription

wastoolowtoachievetheminimumdoseofKt/V1.2

as recommended in theDOQI guidelines. They also

concluded that in this patient group, a prolongation

of treatment by up to 30 minutes (depending on

patient) would have resulted in the delivery of an

adequatedialysisdosein75%ofthecases.

Thisresultshowsthatevenamoderateprolongation

oftreatmenttimecanbeanessentialfactorinensur-

ing delivery of an adequate dialysis dose. Individual

prolongationof treatment time should thus seriously

betakenintoconsideration,despitethedifficultiesof

incorporatingthisinshiftschedulesandtheunwilling-

nessofpatientstoanincreaseinthedialysistime.

19

4.3 Dialyser (Membrane surface area, low flux/high flux)

Thedialyser itselfplaysan important role in theeffi-

ciencyofdialysistreatment.Theuseofadialyserwith

thehighestpossibleureaclearanceisrequiredforop-

timisationofthedialysistreatment.Asarepresentative

ofotherlowmolecularweightsubstances,ureaisone

ofthemostimportantmarkersubstancesindialysis.

Theureaclearanceisnotonlydeterminedbytheactive

surfaceareaofthemembrane,butalsobythemembrane

permeability(highorlowflux)andtheconstructionof

thedialyseritself.Figure16showstheincreaseinurea

clearanceunderthegivenconditions(bloodflowrate:

300mL/min,dialysateflowrate:500mL/min)inrelation

toanincreaseintheeffectivemembranesurfacearea.

Underidenticalconditions,ureaclearanceisimproved

bychangingfromlowfluxtohighfluxdialysers.Touti-

liseagivendialyserto itsfullcapacity, it is important

toconsidertherelationshipbetweeneffectivesurface

areaand theachievablebloodflow (see instructions

foruse:re-commendedbloodflowrange).

416:UreaclearanceofFreseniusMedicalCare lowandhighfluxdialysers asfunctionoftheeffectivesurface

4.4 Dialysate flow rate

Itistheconcentrationgradientbetweenthebloodand

dialysate which mainly determines the diffusion rate

duringhaemodialysis.Thelargertheflowoffresh,toxin-

free dialysis fluid through the dialyser, the larger the

removaloftoxinsbydiffusionis(55).

In many dialysis centres, a dialysis fluid flow rate of

500mL/minisusedbydefaultinhaemodialysistreat-

ments,althoughoptimalsoluteclearanceswouldal-

readybeachievedatlowerdialysisfluidflowrates.As

showninfigure17,atadialysateflowrateequaltothe

bloodflowrate,approximately90%ofthemaximum

solute clearance is already achieved. Thus, much

higherdialysis fluid flow rateswouldnotsignificantly

contributetoincreasesinclearancesandaretherefore

notnecessaryfromaneconomicalpointofview.

The5008TherapySystemofferstheAutoFlowfunc-

tion,whichautomaticallyadjuststhedialysisfluidflow

rateinordertoderiveanoptimalratiobetweenblood

flowrateanddialysisfluidflowrate.Anypotentialeffects

onlowmolecular(e.g.urea)clearancecanhoweverbe

monitored with OCM®, thus providing another very

meaningfulfunctionforfurthertreatmentoptimisation,

e.g.bymeansofincreasedbloodflowand/orperform-

ingONLINEHDF.

Urea

cle

aran

ce [m

L/m

in]

Effective dialyser surface [m2]

QB: 300 mL/min

1700,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0 2,2 2,4

180

190

200

210

220

230

240

QD: 500 mL/min

FX-class high flux range FX-class low flux range

417:UreaclearanceofaFX60dialyserasfunctionofbloodanddialysate flow.Thehigherthebloodflowthehigheristhepositiveeffectofincreasingthe dialysisfluidflowonureaclearance

In v

itro

urea

cle

aran

ce F

X 60

[mL/

min

]

Dialysate flow [mL/min]

Blood flow

20

QB: 300 mL/minQD: 500 mL/min

Theprerequisite for aneffectivedialysis treatment is

anappropriatebalancebetweenbloodflowrate,dia-

lysateflowrate,treatmenttimeandthedialyserused.

Forthispurpose,FreseniusMedicalCarehasdeveloped

appropriatesoftwareintheformoftheClearanceCal-

culationTool(CCT),whichmakesitpossibletocompare

theefficacyofFreseniusMedicalCaredialysersunder

diversepredefinedtreatmentconditions.

418:TheCCTClearanceCalculationToolisasoftwarefortheplanningof haemodialysistreatments.CCTallowsaclearanceestimationofanyFresenius MedicalCaredialyseroverthefullrangeoftreatmentconditions

21

Inadditiontothedelivereddialysisdose,theOCM®also

measures the levelofplasmasodiumof thepatient.

This information is a useful aid in the appropriate

therapeutic adjustment of the sodium concentration

of the dialysis fluid to the individual plasma sodium

levelofthepatient.

In a clinically stable haemodialysis patient, there is

physiologicalequilibriumbetweenthequantityofsalt

ingested with the nutrition and the quantity of NaCl

removedduringhaemodialysis.

Therearetwomechanismsofintradialyticremovalof

NaCl:ultrafiltration(UF)anddiffusion.

Theelectrolytecompositionoftheultrafiltrateremoved

forthepurposesofdehydrationofthepatientisvery

similartothatofbloodplasma,theNaClconcentration

intheultrafiltratevariesfrompatienttopatient inthe

approximaterange135–140mmol/L.Thequantityof

NaClremovedduringultrafiltrationdependsdirectlyon

thevolumeofUFremoved;thehigherthevolumeofUF,

thegreaterthequantityofNaClremovedfromthepatient.

Diffusion is even more effective than ultrafiltration in

theremovalofNaCl,thoughinthiscasemaintenance

ofaneffectiveconcentrationgradientbetweenblood

anddialysatesidesisrequired.

IftheconcentrationofNaClavailableforfreediffusion

inthebloodplasmaofthepatientishigherthaninthe

dialysisfluid, there isaflowofNaCl fromblood into

dialysis fluid;NaCl is removed from thepatient. The

oppositecan,ofcourse,alsooccur:iftheconcentra-

tionofNaClinthedialysisfluidishigherthaninblood

plasma,itdiffusesfromthedialysisfluidintotheblood

andthereisdialysis-inducedsalt-loading.

Theconcentrationofsodiuminthedialysisfluidthus

determineswhetherthesodiumbalanceispositiveor

negativeduringhaemodialysistreatment.

5. Measurement of plasma sodium with the OCM®

Variousstudieshavedemonstratedthatrestrictionof

sodium intake has a favourable effect on long term

bloodpressurecontrolindialysispatients;lowsodium

content inthedialysate,providedthis istoleratedby

thepatient,canassistindietarycontrolofsodiumin-

take(57–59).Krautzigetal.havedemonstratedthatwith

lowsodiumintake,itispossibletoreduce,orevendis-

continue,theuseofanti-hypertensivemedication(60).

However, if adialysatewithanon-physiological, low

sodium concentration is used, this can frequently

trigger intolerance reactions, such as hypotension,

tirednessandcramps.

Conversely,theuseofadialysatewithanon-physio-

logical, high concentrationof sodiummay improve

blood pressure stability during dialysis, but also in-

creasesthepatient’sthirstandresultsinasubsequent

increase in fluid intake by the patient. This, in its

turn, leads to increased overhydration and long-term

hypertension in the patient. Figure 20 summarises

theadvantagesanddisadvantagesofhighand low

sodiumconcentrationsinthedialysate.

Individualprescriptionofthesodiumconcentrationofthe

dialysisfluidalwaysrequiresachievingacompromise

between long-termbeneficial bloodpressure control

(withlowdialysisfluidsodium)andtheshort-termad-

vantageofbettercardiovascularstabilityduringtreat-

ment (with high dialysis fluid sodium). Hence, when

419:Acuteandchronic effectsofdifferent sodiumconcentrations in the dialysisfluid

Acute effects

cardiovascular stabilitythirst

extracellular dehydrationplasma osmolality

disequilibriumhypotension

Chronic effects

Chronic volume overloadhypertension

blood pressure control

Na145

Na138

Na130

+ ––

–––– +

–

22

decidingontheoptimumconcentrationofsodiumin

thedialysisfluid,thenephrologistshouldconsiderthe

predialyticplasmasodium,thegeneralstatusandthe

cardiovascularstabilityofthepatient.

Figure20showstheeffectsofahaemodialysistreat-

mentontheplasmasodiumconcentrationinindividual

patients(meanvaluesfor10treatmentsarequoted).

Whiletherewaslittlefluctuationinplasmasodiumlevels

inpatients1and2(thedialysisfluidusedforboththese

patientshadasodiumconcentrationof140mmol/L),

plasma sodium levels in patients 3 and 4 (here the

specifieddialysisfluidsodiumconcentrationwas142

mmol/L)increasedby2.5–3mmol/Lduringdialysis.

How can the OCM® be used for measurement of

plasma sodium?

TheOCM®determinessodiumconcentrationsatthe

dialysateinflowandoutflowbymonitoringconductivity.

Thedifferencebetweenthetwovalues,inrelationtothe

dialysateflowrate,showstherateofflowofsodium

intooroutofthepatient.Usingthevalueforclearance

asmeasuredbytheOCM®,theplasmaconcentration

ofsodiumcanbecalculated. In thisway, theOCM®

derivesavalueforplasmasodiumfromeachclearance

measurement.Theresultisadjustedusingcorrection

420: Example of a plasma sodium profile of 4 HD patients measured byOCM®

factorssothatthedisplayedvalueforplasmasodium

isequivalenttothatobtainedbymeansofflamepho-

tometryassay.

Smallabsolutedifferencesbetweentheplasmasodium

concentration determined by the dialysis machine

using this non-invasive method and the results

of laboratory analysis canbeexplainedbydeviations

of the measurement and calibration instruments

used. Of more clinical relevance, however, is the

change inplasmasodiumconcentrationduringdialy-

sis–withitsassociatedeffects–relativetopredialytic

baselineplasmasodium.Usingthedataforchanges

inplasmasodiumovertimeregisteredbythedialysis

machine, it can be determined whether the patient

is being loaded with sodium from the dialysis fluid

(plasma sodium concentration increase) or whether

too much sodium is being removed from the blood

(plasma sodium concentration falls), or whether the

sodiumconcentrationofthehaemodialysissolutionis

appropriateforthepatient(e.g.atendencytocons-

tantplasmasodiumconcentrations).OnlineClearance

Monitoring(OCM®)canassisttoappropriatelyadjust

thesodiumconcentrationof thehaemodialysissolu-

tionduringtheongoingtreatment.

Theplasmasodiumconcentrationovertimeisdisplayed

asaredlineintheUF-Na-Diagramofthe5008.Atlow

flowconditions(QB≤80mL/min;QD<300mL/min),

theplasmasodiumconcentrationisnotdisplayed.The

accuracyofthevaluedisplayedisfurthermorestrongly

affectedbytheexistenceoffistularecirculation.

421:ThekineticsoftheplasmasodiumconcentrationinthecourseofaHDtreatmentcanbedisplayedbytheOCM®(redline)

Plas

ma-

Na [m

mol

/l]

Pat 1 (Dial.-Na: 140 mmol/l)Pat 2 (Dial.-Na: 140 mmol/l)Pat 3 (Dial.-Na: 142 mmol/l)Pat 4 (Dial.-Na: 142 mmol/l)

23

1.IsKt/VasmeasuredbytheOCM®asingle-poolor

double-poolKt/V?

TheKt/VvaluedeterminedbytheOCM®isasingle-pool

Kt/V (spKt/V). It ispossible toconvert thesingle-pool

Kt/VdeterminedbytheOCM®toaneKt/V(≈equilibrated

or double pool Kt/V) using the formulae provided in

Section 2.1.2.1 Alternatively, eKt/V values are also

showninthetableonpage10.

2. In a comparison conducted at a dialysis centre, it

wasobservedthattheOCM®Kt/Vwas10%lowerthan

theKt/Vmeasuredonthebloodside:whatisthecause

ofthisdiscrepancy?

Suchadifferenceisfrequentlyseenifthevalueforurea

distributionvolumeVusedforKt/Vcalculationbythe

OCM®hasbeenestimatedusingtheWatsonformula.

TheanthropometricWatsonformulatendstooveresti-

matetheureadistributionvolumeindialysispatients.As

thepreciselymeasuredresult forKxtdeterminedby

theOCM®isthendividedbyanincorrectlyhighvalue

forV,thisresultsinanunderestimationofthedelivered

dialysisdose(Kt/V).Thisproblemcanbeavoidedifthe

valueforVisdeterminedmorepreciselyusingabioim-

pedancespectroscopy(BIS)techniqueorureakinetic

modelling (e.g.with theaidofDCTool)–seeSection

3–and this valuebeingentered into theOCM®and

storedonthePatientCardforfutureuse.

3.Whatisthesignificanceofhaematocritforthecalcu-

lationofclearanceandplasmasodiumconcentrations?

Whatalternativeisthereifnorecentvalueforhaema-

tocritisavailableforapatient?Couldanestimatedvalue

forhaematocritresultinaninaccurateresultforKt/V?

The haematocrit is required to calculate the effective

flowofwatercontainedwithintheblood(=plasmawa-

ter+intracellularwater)andsubsequentlytheeffective

Kt/V(Comment:HctdoesnothaveanyinfluenceonK,

sinceonlydialysate-sidequantitiesareused todeter-

mineit.Rather,itenterstheestimationformulaincase

6. Frequently Asked Questions about the OCM®

ofabloodflowchangebetween2measurements).Ifan

estimatedHctwhichdeviatesfromtheactualHctofthe

patientisenteredintheOCM®template,thiswillhave

littleeffecton theaccuracyof thevalue forclearance

calculatedby theOCM®. If, for example, theentered

value forHct is 10%higher or lower than the actual

valueforHct,thereisonlya2–3%changeinthere-

sultforclearance.IfnovalueforHctisenteredpriorto

commencementoftreatment,theOCM®automatically

assumesahypotheticalvalueof35%.Incasea5008

Blood Volume Monitor (BVM) isusedsimultaneously

withtheOCM®,thecontinuouslymeasuredHctvaluecan

beautomaticallytransferredfromtheBVMtotheOCM®.

4.WhyistheclearancemeasuredbytheOCM®frequen-

tlylowerthanclearancemeasuredonthebloodside?

This occurs if a simplified method of whole blood

clearance measurement is performed on the blood

side, where the full blood flow value QB is used

for blood side calculation of clearance, while the

OCM® correctly uses the effective flow of water

contained within the blood (= plasma water + intra-

cellularwater). Theeffective flowofwatercontained

within the blood is equivalent to the effective blood

flow x 0.87. The factor 0.87 takes into account the

characteristic composition of human blood. If the

effectiveflowofwatercontainedwithinthebloodisnot

usedforbloodsidecalculationofclearance,therecan

beaninappropriateoverestimationofureaclearance

byupto25%comparedwiththeeffectiveclearance

whichisaccuratelymeasuredbytheOCM®.

5.CouldtheaccuracyofOCM®measurementsbeim-

pairedifequipmentisnotdisinfectedbetweeneachdi-

alysistreatment?

In theory, throughout dialysis deposits may occur on

theconductivitysensorsoftheOCM®justasinanyof

the other components of the hydraulic system of a

dialysismachine.Toavoidthisproblem,itismandatory

todisinfect theequipmentaftereachdialysissession.

24

The risk of an inaccurate clearance measurement is

thusexcluded.

6. Does the accuracy of the OCM® depend on the

membranematerialusedinthedialyser?

Noevidencehasbeenfoundtodatethattheaccuracy

of the clearance measurement by the OCM® is influ-

encedbythetypeofdialysermembraneused.

7.CanOCM®measurementbestartedduringon-going

dialysistreatment?

Inprinciple,theOCM®canbestartedatanytimeduring

on-goingtreatment.If,however,morethan80minutes

havepassedsincetreatmentwasstartedwithoutasuc-

cessfulOCM®measurementperformed,thesystemwill

notcalculateKtandKt/V.Itwouldnotbeworthwhileex-

trapolatingbackwards,astheremayhavebeenmarked

changesinclearancesincetheinitiationoftreatment.

8.Isitpossibletocalculatetheureadistributionvolume

ofchildrenusingtheWatsonformula?

TheMellits-CheekformularatherthantheWatsonfor-

mulashouldbeusedforanthropometricestimationof

Vinchildren:

Forboyswithaheight<132.7cm:

V=-1.927+0.465xbodyweight(kg)

+0.045xheight(cm)

Forboyswithaheight>132.7cm:

V=-21.993+0.465xbodyweight(kg)

+0.209xheight(cm)

Forgirlswithaheight<110.8cm:

V=0.076+0.507xbodyweight(kg)

+0.013xheight(cm)

Forgirlswithaheight>110.8cm:

V=-10.313+0.252xbodyweight(kg)

+0.154xheight(cm)

Inorder toobtainaprecise value forV in children, a

bioimpedancemeasurementorureakineticmodelling

(e.g.withDCTool)ispreferable.

9. How does one take into account an amputation

whencalculatingureadistributionvolume?

Urea distribution volume V in amputated dialysis pa-

tients should not be estimated using anthropometric

formulae(suchastheWatsonformula),butshouldbe

determinedbyabioimpedancemeasurementorurea

kineticmodelling(DCTool).

10.CanOCM®alsobeusedduringONLINEHDF?

OCM®canbeusedduringregularONLINEplusHaemo-

dialfitrationtreatmentsineitherpost-orpredilutionmode

butduetothemissingdialysateflowinthedialysernot

inONLINE-HFnorinSingle-Needlemodes.

25

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Fresenius Medical Care Deutschland GmbH · 61346 Bad Homburg v. d. H. · Germany · Phone: +49 (0) 6172-609-0 · Fax: +49 (0) 6172-609-2191Head office: Else-Kröner-Straße 1 · 61352 Bad Homburg v. d. H.

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