【Guideline】 ガイドライン
Evidence-based Guidelines for the Use of Albumin Products Japan Society of Transfusion Medicine and Cell Therapy
Satoshi Yasumura1）, Shigeyoshi Makino2）, Masanori Matsumoto3）, Takehiro Kono4）, Shuichi Kino5）, Asashi Tanaka6）, Akemi Wakisaka7）, Yuji Yonemura8） and Tadashi Matsushita9）
Keywords:
AlbuminProducts,Hypoalbuminemia,Hemorrhagicshock,Severesepsis,
Therapeuticplasmaexchange
TableofContents 1. Introduction
2. TypesofAlbuminProductsandAssessmentofAdministration 3. HypoalbuminemiaandIndicationsofAlbumin
4. EffectsofDifferentAssaysonSerumAlbuminLevels
5. BenefitsandRecommendationsforAlbuminUsebyPathologicalCondition
(i) Hemorrhagicshock
(ii) Severesepsis
(iii) Ascitessecondarytolivercirrhosis
(iv) Nephriticsyndromewithrefractoryedemaorpulmonaryedema
(v) Extracorporealcirculationwithunstablehemodynamics
(vi) Therapeuticplasmaexchangenotrequiringthereplacementofcoagulationfactors
(vii) Severeburns
(viii) Pulmonaryedemaormarkededemaduetohypoproteinemia
(ix) Markedlydecreasedcirculatingplasmavolume
(x) Cerebralischemia(headinjury)
(xi) Heartsurgerywithcardiopulmonarybypass
(xii) Hypoalbuminemiawithstablehemodynamicsduringtheperioperativeperiod
(xiii) Pregnancy-inducedhypertension
(xiv) Inflammatoryboweldisease
(xv) Nutritionalsupportasasourceofprotein
(xvi) Terminallyillpatients
(xvii)Pathologicalconditionsthatarenoteligibleforotherplasmaexpanders
1）DepartmentofTransfusionMedicineandCellTherapy,ToyamaUniversityHospital 2）DepartmentofTransfusionMedicine,ToranomonHospital
3）DepartmentofBloodTransfusionMedicine,NaraMedicalUniversity 4）DivisionofTransfusionMedicine,OsakaMedicalCollegeHospital 5）JapaneseRedCrossSocietyHokkaidoBlockBloodCenter
6）DepartmentofTransfusionMedicine,TokyoMedicalUniversityHachiojiMedicalCenter 7）JapanBloodProductsOrganization
8）DepartmentofTransfusionMedicineandCellTherapy,KumamotoUniversityHospital 9）DepartmentofTransfusionMedicine,NagoyaUniversityHospital
〔Received:2017/07/04,Accepted:2017/08/25〕
1. Introduction
1) Purpose of the Development of the Guidelines
Albumin was introduced into clinical use in 1941 and has been widely used worldwide for about 70 years
becauseofitsefficacyandsafetyinpatientswithhypovolemicshockorthosewithmarkededema.“Guidelines
foruseofbloodproducts”weredevelopedin1999bytheMinistryofHealth,LabourandWelfareandhavebeen
amendedandrevised,buthavenotprovidedanyevidence-basedrecommendationlevels.Meanwhile,inrecent
years,studiesonalbuminanditsuseincriticallyillpatientshavebeenincreasinglypublishedandprovidedimpor- tantinsightsintoclinicaluseofalbuminforthetreatmentofdifferentpathologicalconditions.Thepurposeof
theseguidelinesistoprovidehealthcareprofessionalswithsupportinmakinganappropriatedecisionontheuse
ofalbumintopromotetheappropriateuseofalbuminandtoensurebettertreatment.Althoughtheseguidelines
areevidence-based,theymerelyprovideevidenceofresultsofclinicalstudiesanddonotguaranteetheuniversal
useofalbumin.Inclinicalpractice,albuminshouldbeusedbasedonanoveralljudgmentbyhealthcareprofes- sionalsandtheseguidelinesdonotrestricttheuseofalbumin.Inaddition,healthcareprofessionsortheseguide- linesarenotlegallyheld,regardlessofwhetherornottheuseofalbuminincludedintheseclinicalpractice
guidelinesisfollowed.
2) Background of the Development of the Guidelines
ThisprojectwasinitiatedastheLiteratureSearchProjectfortheDevelopmentofGuidelinesfortheAppropri- ateUseofAlbuminProducts,aresearchprojectfundedbytheHealthandLabourSciencesResearchGrants,in
March2012andhasbeen,since2013,takenovertotheTaskforcefortheDevelopmentofGuidelinesforAdmin- istrationofAlbuminProducts,asubcommitteeoftheGuidelinesCommitteeoftheJapanSocietyofTransfusion
MedicineandCellTherapy,andResearchontheDevelopmentofEvidence-basedGuidelinesforBloodTransfu- sion,aresearchprojectfundedbytheHealthandLabourScientificResearchGrants.MembersoftheTaskforce
fortheDevelopmentofGuidelinesforAdministrationofAlbuminProductswereelectedinmeetingsoftheboard
ofdirectorsinMay2013inconsiderationoftheirspecialty.
Guidelinescommitteemembers
●ResearchprojectfundedbytheHealthandLabourSciencesResearchGrants
“LiteratureSearchProjectfortheDevelopmentofGuidelinesfortheAppropriateUseofAlbuminProducts”
PrincipalInvestigator:ShigeyoshiMakino,ToranomonHospital
●ResearchprojectfundedbytheHealthandLabourSciencesResearchGrants
“ResearchontheDevelopmentofEvidence-basedGuidelinesforBloodTransfusionetc.”
PrincipalInvestigator:TadashiMatsushita,NagoyaUniversity
●GuidelinesCommittee,JapanSocietyofTransfusionMedicineandCellTherapy
TaskforcefortheDevelopmentofGuidelinesforAdministrationofAlbuminProductsExecutiveDirector:Yuji
Yonemura,KumamotoUniversity
Chairperson:SatoshiYasumura,UniversityofToyama
Member:ShuichiKino,(formerly)AsahikawaMedicalUniversity(May2013toMarch2014)(currently)Japanese
RedCrossSocietyHokkaidoBlockBloodCenter(April2014tonow) Member:TakehiroKono,OsakaMedicalCollege
Member:AsashiTanaka,TokyoMedicalUniversityHachiojiMedicalCenter Member:ShigeyoshiMakino,ToranomonHospital
Member:MasanoriMatsumoto,NaraMedicalUniversity
Member:AkemiWakisaka,(formerly)ChitosePlant,JapanBloodProductsOrganization(May2013toJuly2014)
(currently)CentralResearchLaboratory,JapanBloodProductsOrganization(August2014tonow) 3) Method of the Development of the Guidelines
Clinicalquestions(CQs)wereformulatedregardingatotalof17pathologicalconditions,includingindications
andinappropriateusesspecifiedinChapter5“Appropriateuseofalbuminproducts,”“GuidelinesforAdministra- tionofBloodProducts,”andasearchwasconductedbasedonatotalof3,059domesticandoverseaspaperson
albuminpublishedin1972to2014,ofwhich310paperswereincludedintheprimaryselection,asshowninthe
tablebelow.Otherimportantpublishedpapersorpapersnecessaryforformulatingstatementswereaddedas
hand-searchedpapersandlevelsofevidenceandgradesofrecommendationweredeterminedforeachCQaccord- ingtotheMindsHandbookforClinicalPracticeGuidelineDevelopment2014.Fortheseguidelines,aguidelines
committeememberwasassignedtoeachCQandthechairpersonwasresponsibleforoverallsupervision.
● Statusofthecollectionofpublishedpapers
Source YearofStartingSearch HitCountsofPapersonSearch NumberofPapersIncludedinthePrimarySelection
MEDLINE 1972 1,979 245
Cochrane 1992 881 26
JAMAS 1983 199 39
ImportantpapersthatweresearchedforeachCQwereincluded.Draftguidelineswerereviewedandmodified
bytheTaskforce.Subsequently,publiccommentswereinvitedonthesociety’swebsiteandanynecessarymodi- ficationsweremadeforthefinalizationoftheguidelines.
EvidencelevelsandgradesofrecommendationweredeterminedaccordingtotheMindsHandbookforClinical
Practice Guideline Development 20141）. The strength of recommendations was presented in two ways: “1”:
stronglyrecommendedand“2”:weaklyrecommended(suggested).Theoverallstrengthofevidenceacrossout- comes(A,B,C,D)wasputdownwiththeabovestrengthofrecommendations.
A(strong):stronglyconfidentoftheestimateofeffect B(moderate):moderatelyconfidentoftheestimateofeffect C(weak):limitedconfidenceoftheestimateofeffect D(veryweak):verylittleconfidentoftheestimateofeffect
4) Publication and Revision
TheseguidelinesarepubliclyavailableontheJournaloftheJapanSocietyofTransfusionMedicineandCell
Therapyandthesociety’swebsite.Theywillberevisedwithaccumulatingevidence.
5) Funding and Conflict of Interest
ThedevelopmentoftheseguidelineswasfundedbytheHealthandLabourSciencesResearchGrantsLitera- ture Search Project for the Development of Guidelines for the Appropriate Use of Albumin Products and
ResearchontheDevelopmentofEvidence-basedGuidelinesforBloodTransfusion.Thecontentoftheseguidelines
havenointerestinspecificprofitandnonprofitorganizations,drugmanufacturers,medicaldevicemanufacturers,
etc.,theguidelinescommitteemembersdeclaredthestatusofconflictofinteresttotheJapanSocietyofTransfu- sionMedicineandCellTherapy,andtheCOIcommitteeconfirmedtherewasnoconflictofinterest.
2. Types of Albumin Products and Assessment of Administration
Albuminproductsareavailableinanisotonic5%solutionandahypertonic20%to25%solution.Aheat-treated
humanplasmaproteinfraction(PPF),whichhasanalbuminconcentrationof≥4.4%andinwhichalbuminaccounts
for≥80%ofthetotalprotein,isalsoosmoticallyequivalenttonormalplasma.Isotonicalbuminproductsareused
forthereplacementofcirculatingplasmavolumeinhemorrhagicshock,severeburns,etc.,whileheat-treated
humanPPFis,inprinciple,contraindicatedinpatientsundergoingtherapeuticplasmaexchangenotrequiringthe
replacementofcoagulationfactorsorthoseundergoingcardiopulmonarybypassbecauseitcancausedecreased
bloodpressureinrarecases.Inaddition,itisadministeredatarateof≤5to8ml/minute.
Incontrast,hypertonicalbuminproducts,whichhaveacolloidosmoticpressure4to5timeshigherthanthat
ofplasma,aresuitableforthetreatmentofascitesorpulmonaryedemasecondarytohypoproteinemia.
Botheach250mlofa5%productandeach50mlofa25%productcontain12.5gofalbumin,whichisequiva- lenttotheamountofalbuminproduceddailyinadults.
Becausealbuminadministeredintravenouslyisevenlydispersedinthevascularcompartmentwithin10to15
minutesandevenlydistributedintheextravascularpoolwithin4to7days,thetransferofalbumintotheextra- vascularcompartmentaccountedfor60%oftheintravenousdose.When50ml(12.5g)ofa25%productisadmin- isteredtoanadultmaleweighing65kg,theexpectedincreaseinalbuminlevel(g/dl)canbecalculatedusingthe
followingequations,ontheassumptionthattheintravascularrecoveryofalbuminis40%:
Expectedincreaseinalbuminlevel(g/dl)
＝{doseofalbuminadministered(g)/circulatingplasmavolume(dl)}×0.4
(intravascularrecoveryofalbuminadministeredof40%)
＝{doseofalbuminadministered(g)/bodyweight(kg)×0.4dl}×0.4 (circulatingplasmavolume≒bodyweight(kg)×0.4dl)
＝{doseofalbuminadministered(g)/bodyweight(kg)}
＝{12.5(g)/65(kg)}≒ 0.2(g/dl)
However,becauseextravasationofalbuminisincreasedinmanypathologicalconditions,suchasmajorsurgery,
trauma,burns,sepsis,andshock,resultinginafurtherincreaseintheextravascularpool,theexpectedvalueis
notoftenobtained.Theresponsetoadministrationisassessedandbasedonmeasurementsofalbuminlevelsand
symptomaticimprovement.Therearereportsdemonstratingthatalbuminiseffectiveasmeasuredbytheassess- mentoforganfunctionsusingsequentialorganfailureassessment(SOFA)scoresoroxygenationinpatientswith
acutelunginjury2）3）.
3. Hypoalbuminemia and Indications of Albumin
Causesofhypoalbuminemiaincludehemorrhage,increasedcapillarypermeability,lossduetoexcessiverenal
excretionetc.,increasedmetabolism,decreasedhepaticsynthesis,anddilutionwithintraoperativefluidtherapy.
Innephriticsyndromeorprotein-losinggastrointestinaldisorders,lossofalbumincanleadtohypoproteinemia.In
highlyinvasivesurgery,sepsis,trauma,hepaticdisease,andmalignancy,decreasedsynthesisandleakageofalbu- mincantriggerhypoalbuminemia.Althoughserumalbuminlevelsareameasureofnutritionalstatusorprogno- sis, improvement of pathological conditions with the treatment of underlying diseases is given first priority
becausehypoalbuminemiaitselfisnotadverse.Albuminproductsareusedfortemporaryimprovementofpatho- logicalconditionsduetoacutehypoproteinemiaorpathologicalconditionsduetochronichypoproteinemiathat
aredifficulttomanagewithothertreatmentapproaches.
Althoughtherearemanyclinicalstudiesinwhichalbuminwasadministeredintheacutephasewithatarget
serumalbuminlevelof2.5to3.0g/dl,nosuperiorityofalbuminhasnotbeendemonstrated4）～6）.Itatleastappears
thatserumalbuminlevelsof≥2.5g/dldonothavetobemaintained.Inaddition,althoughsomeguidelinessetthe
target albumin level at 2.0 to 2.5 g/dl for hypoalbuminemia in various pathological conditions7）, there are no
thresholdsthathasreachedscientificconsensus.
Therefore,therearenoclearthresholdsforalbuminadministrationandtheuseofalbuminproductsisnot
indicatedforhypoalbuminemiaalone.Adecisiontousealbuminproductsshouldbemadeafterconsiderationof
diseaseandpatientconditions.
4. Effects of Different Assays on Serum Albumin Levels
Indiscussiondifferencesamongassays,thefollowingthreeaspectshavetobeconsidered:i)themagnitudeof
differencesinobservedvaluesamongassays,ii)theaccuracyofobservedvalueswitheachassay,andiii)which
assaycontrolledtrialswithahighevidenceleveluse.Forthei)above,theBCG(bromocresolgreen)methodhas
limitedaccuracybecauseofcross-reactionwithglobulinandprovideshighervaluesthanthemodifiedBCP(bro- mocresol purple) method. The proposal of the Japanese Society of Laboratory Medicine states that“It is
extremelydifficulttospecifyconversionformulasforbothmethodsbypathologicalconditionand,ifanalbumin
valueof≤3.5g/dlisobtainedwiththemodifiedBCPmethod,theobtainedvalueplus0.3g/dlshouldbeapproxi- matedastheestimatewiththeBCGmethod.”8）Fortheii)above,accordingtothereportontheresultsofquality
controlbytheJapanMedicalAssociationandJapaneseAssociationofMedicalTechnologists,thecoefficientof
variationofvaluesobtainedusingreagentsthatwereadoptedbymultiplefacilitieswasgenerallylessthan2%,
suggestingthattheaccuracywaswithintheacceptablerange9）.Incontrast,inoverseascountries,ithasbeen
notedthatthedegreeofinaccuracyofmeasuredalbuminlevelswasunacceptableandhastobeimproved10）.For
theiii)above,thereportsoflargecontrolledtrialsafter2000(e.g.,SAFEstudy,ALBIOSstudy)4）5）donotinclude
themethodofmeasurementandthereforethemethodsofmeasurementusedareunknown.Basedontheabove,
ithastobeconsidereddifficulttodeveloptheguidelinesofalbuminusebyassayatthistime.Instead,considering
thattherearenoclearthresholdlevelsforpathologicalconditionsthatareeligibleforalbuminproducts,the
necessityofalbuminproductsshouldbeconsidered,bearinginmindthatvaluesobtainedtheBCGmethodhave
limitedaccuracy.
5. Benefits and Recommendations for Albumin Use by Pathological Condition i) Hemorrhagic shock
● Statement
CQ1. Do patients with hemorrhagic shock benefit from
albumin? Grade EvidenceLevel Reference
Overseas Japan 1.Inpatientswithdecreasedintravascularvolumesecondaryto
trauma,surgery,etc.inwhomfluidtherapyisconsideredtobe
requiredtomaintainorexpandtheintravascularvolume,the
useofalbuminisnotassociatedwithimprovementinsurvival
comparedwiththeuseofcrystalloids.
1 A None＊ 4,11-14
2.Whenalbuminisusedforthereplacementforhypovolemia
secondarytotrauma,surgery,etc.,itcanpotentiallyimprove
morbidity. 2 C None＊ 15
＊Noclinicalstudywasavailable.
● Commentaries
Forthetreatmentofhypovolemiainducedbyhemorrhage,crystalloids,suchasnormalsalineandlactatedLin- ger’ssolution,andcolloidscapableofmaintainingplasmaoncoticpressure,suchashumanalbuminsolution,dex- transolution,andhydroxyethylstarch(HES)solution,areused.
In1998,theCochraneInjuryGroupAlbuminReviewersconductedameta-analysisofrandomizedcontrolled
trialscomparingalbuminversusotherfluidtherapiesincriticallyillpatientswithhypovolemiaduetohemorrhage
fromtraumaorsurgery11）.Theyfoundthatalbuminadministrationwasassociatedwithatrendforhighermortal- ity(relativerisk,1.46;95%confidenceinterval,0.97to2.22).Whenpatientswithburnandthosewithhypoalbumin- emia,whowerealsoanalyzed,wereincluded,itwasfoundthatalbuminadministrationwasassociatedwithhigher
mortality(relativerisk,1.68;95%confidenceinterval,1.07to2.67).
In2001,anothermeta-analysisofrandomizedcontrolledtrialscomparingalbuminadministrationversusother
fluidtherapieswasconducted12）.Therelativeriskformortalityinthegrouptreatedwithalbuminfortraumaor
surgerywas2.13(95%confidenceinterval,0.81to5.64).Whenalltheindications,suchasburns,hypoalbuminemia,
high-riskneonate,andascites,werepooled,therelativeriskformortalitywithalbuminadministrationwas1.11
(95%confidenceinterval,0.95to1.28),whichfailedtodemonstrateevidencethatalbuminadministrationincreased
mortality.
In2004,resultswerereportedfromaprospective,randomized,controlledtrialinwhich6,997ICUpatients
requiringintravascularbloodvolumereplacementreceived4%albuminsolutionornormalsaline(SAFEStudy)4）.
Theprimaryendpointofthisstudyismortalityat28daysandthesecondaryendpointsincludethenumberof
daysofICUstay,thenumberofdaysofhospitalstay,thenumberofdaysofmechanicalventilation,andthenum- berofdaysofrenal-replacementtherapy.Formortalityat28days,therelativeriskinthealbumingroupwas0.99
(95%confidenceinterval,0.91to1.09),thusprovidingnoevidencethat4%albuminsolutionissuperiortonormal
salineinICUpatientsrequiringintravascularbloodvolumereplacement(i.e.,normalsalineand4%albuminsolu- tionareequivalentwhenmortalityisusedasanendpoint).Inaddition,therewerenodifferencesbetweenthe
normalsalineand4%albumingroupsinthenumberofdaysofICUstay,numberofdaysofhospitalstay,number
ofdaysofmechanicalventilation,ornumberofdaysofrenal-replacementtherapy.Asubsequentanalysisofdata
fromtheSAFEstudyinvestigatedmortalityinpatientswith4%albuminsolutionornormalsaline,stratifiedby
baselinealbuminlevel(≤2.5g/dlor>2.5g/dl)andfoundnodifferencesinmortalityat28daysregardlessofbase- linealbuminlevel(oddsratio,0.87;95%confidenceinterval,0.73to1.05forpatientswithabaselinealbuminlevel
≤2.5g/dl;oddsratio,1.09;95%confidenceinterval,0.92to1.28forpatientswithabaselinealbuminlevel>2.5g/
dl)13）.
Themostrecentmeta-analysisincludingtheSAFEstudyconcludedthatforcriticallyillpatientswithhypovo- lemia,therewasnoevidencethatalbuminreducedmortalitywhencomparedwithcheaperfluids(oddsratio,1.02;
95%confidenceinterval,0.92to1.13)14）.Forcriticallyillpatientswithburnsorhypoalbuminemia,therewasasug- gestionthatalbuminadministrationmayincreasemortality.
Whencriticallyillpatientswithhypovolemiaduetohemorrhagefromtraumaorsurgeryreceivedalbuminor
otherfluidtherapies,morbiditywaslowerinthealbumingroup(relativerisk,0.58;95%confidenceinterval,0.40
to0.85)15）.
● Recommendation
1.Inpatientswithdecreasedintravascularvolumesecondarytotrauma,surgery,etc.inwhomfluidtherapyis
consideredtoberequiredtomaintainorexpandtheintravascularvolume,theuseofalbuminisnotassociated
withimprovementinmortalitycomparedwiththeuseofcrystalloids(strongrecommendationagainstuse,1A).
2.Whenalbuminisusedforthereplacementforhypovolemiasecondarytotrauma,surgery,etc.,itcanpoten- tiallyimprovemorbidity(2C).
ii) Severe sepsis
● Statement
CQ2.Dopatientswithseveresepsisbenefitfromalbumin? Grade EvidenceLevel Reference Overseas Japan
1.Inpatientswithseveresepsisorsepticshock,theuseofalbu- minisnotassociatedwithimprovementinmortalitycompared
withtheuseofcrystalloids. 1 B None＊ 4,5,16-18
2.Intheinitialtreatmentinpatientswithseveresepsis,albumin
administrationstabilizeshemodynamics. 2 C None＊ 4,5,16-18
＊Noclinicalstudywasavailable.
● Commentaries
IntheInternationalGuidelinesforManagementofSevereSepsisandSepticShockpublishedin2012,thefollow- ingrecommendationsregardingfluidtherapyinpatientswithseveresepsisareincluded16）:1)Werecommend
crystalloidsbeusedastheinitialfluidofchoicefortheresuscitationinpatientswithseveresepsisandseptic
shock (Grade of Recommendation 1, Evidence Level B); 2) We recommend against the use of hydroxyethyl
starches(HES)forfluidresuscitationofseveresepsisandsepticshock(GradeofRecommendation1,Evidence
LevelB);and3)Wesuggesttheuseofalbumininthefluidresuscitationofseveresepsisandsepticshockwhen
patientsrequiresubstantialamountsofcrystalloids(GradeofRecommendation2,EvidenceLevelC).
InasubgroupanalysisofpatientswithsepsisintheSAFEstudy,mortalityat28daystendedtobelower
amongpatientstreatedwith4%albuminthanamongpatientstreatedwithnormalsaline(relativerisk,0.87;95%
confidenceinterval,0.74to1.02;p=0.09)4）.Organfunctionsetc.werefurthercharacterizedinthissubgroup17）.Com- paredwiththenormalsalinegroup,thealbumingrouphadasignificantlylowerheartrateupto3daysoftreat- mentandasignificantlyhighercentralvenouspressure,buttherewerenosignificantdifferencesbetweenthe
groupsinthedurationofrenal-replacementtherapyorsequentialorganfailureassessment(SOFA)score.How- ever,whenbaselinecharacteristicswerealsoincluded,mortalityat28dayswassignificantlylowerinthealbumin
groupthaninthenormalsalinegroup,suggestingthatalbuminadministrationmightreducetheriskofdeathin
patientswithsepsis.
In2014,resultswerereportedfromarandomized,controlledtrial,involving1,818patients,whichinvestigated
thebenefitofalbumininpatientswithseveresepsisandsepticshock5）.Duringthefirst7days,thealbumingroup
hadahighermeanbloodpressureandlowernetfluidbalance.However,mortalitiesat28and90daysdidnot
differbetweenthegroups,indicatingthatalbumindidnotimprovetherateofsurvivalinpatientswithsevere
sepsis.Basedonanetworkmeta-analysis,whichcanevaluatetheeffectof3ormoretreatmentinterventions
simultaneously, albumin has been considered to contribute to survival to an equal or greater extent than
crystalloids18）.
● Recommendation
1.Inpatientswithseveresepsisorsepticshock,theuseofalbuminisnotassociatedwithimprovementinmor- talitycomparedwiththeuseofcrystalloids(strongrecommendationagainstuse,1B).
2.Intheinitialtreatmentinpatientswithseveresepsis,albuminadministrationstabilizeshemodynamics(2C).
iii) Ascites secondary to liver cirrhosis
● Statement
CQ3.Istheuseofalbumineffectiveinascitessecondarytoliver
cirrhosis? Grade EvidenceLevel Reference
Overseas Japan 1.Inpatientswithascitessecondarytolivercirrhosiswhoare
on diuretics, albumin increases the rate of disappearance of
ascites, prevents the recurrence of ascites, and improves the
rateofsurvival.
1 B None＊ 19,20
2.Albuminissuperiortootherplasmaexpandersinpreventing
circulatory failure and reducing mortality after large volume
paracentesis. 1 A None＊ 21-24
3. In patients with spontaneous bacterial peritonitis, albumin
improves systemic hemodynamics and prevents the develop-
mentofhepatorenalsyndrome. 1 A None＊ 25-28
4.Albuminincombinationwithinotropicagentsisaneffective
treatmentregimenforhepatorenalsyndrome.Improvementin
renalfunctionisobservedin65%ofpatientswithtype1hepa- torenalsyndrome.Albuminadministeredforthetreatmentof
hepatorenalsyndromebeforelivertransplantationisassociated
withimprovedprognosis.
1 A None＊ 29-31
＊Noclinicalstudywasavailable.
● Commentaries
Inpatientswithlivercirrhosis,thehalf-lifeofalbuminisprolongedanditscatabolismrateisalsoreduced,but
excessive administration of albumin induces isoleucine deficiency and causes impaired protein synthesis or
increasedalbumindegradation.Inaddition,fromastandpointofappropriateuse,ithasbeenbelievedthatchronic
administrationofalbuminshouldbeavoidedinpatientswithchronicliverdisease.However,theuseofhighdoses
ofalbuminthatarewellabovethelevelcoveredbyinsuranceinJapanisrecommendedinWesterncountries,
dependingontheconditionofdecompensatedcirrhosis.
1.Positionofalbuminforthetreatmentofascites
Casesofmarkededema,ascites,orpleuraleffusionindecompensatedcirrhosisarefirstmanagedwithsodium
andfluidrestrictionplusaldosteroneantagonistsandloopdiuretics,butcasesoftreatment-resistant,so-called
refractory,ascitesaretreatedforashorttimewithhypertonicalbuminproducts.Inparticular,markedhypoalbu- minemia(albuminlevel≤2.5g/dl)commonlydoesnotrespondtoanincreaseinthedoseofdiureticsandthusis
usuallytreatedincombinationwithhypertonicalbuminproductsthathavealowsodiumcontent.Albumin,which
isbeneficialinmaintainingplasmaosmoticpressureandenhancingtheeffectofdiuretics,increasestherateof
disappearanceofascites,preventstherecurrenceofascites19）,andimprovestherateofsurvivalinpatientswith
ascitessecondarytolivercirrhosiswhenadministeredonanoutpatientbasisforalongtime20）.Casesofrefractory
ascitesthatfailedtorespondtodrugsareeligibleforcell-freeandconcentratedascitesreinfusiontherapy,peri- toneo-venousshunt,ortransjugularintrahepaticportosystemicshunt.
2.Useofalbuminduringparacentesis
Refractoryasciteswithbreathingdifficultyormarkedabdominaldistensioniseligibleforparacentesis.Large
volume(≥4l)paracentesiscausesadverseeffectssecondarytodecreasedcirculatingplasmavolume,suchasrenal
impairment and hyponatremia, in approximately 30% of cases. Paracentesis-induced circulatory dysfunction
(PICD)isaccompaniedbymarkedrenalimpairmentandisassociatedwithdeath.Albuminhasbeenshowntohelp
preventtheseadverseeffects.Acomparisonofthegroupadministeredalbuminatadoseof40gper4to6lof
asciticfluidremovedandthegroupundergoingparacentesisalonefoundthatpatientsexperiencinghyponatremia
orrenalimpairmentafterthefirstparacentesishadapoorprognosis,indicatingthatalbuminadministrationwas
importanttopreventrenalimpairmentorelectrolyteabnormalityfollowinglargevolumeparacentesis21）.Albumin
hasbeencomparedwithothercolloidsolutionsforthereasonofitsexpensivenatureandPICDoccurredsignifi- cantlylessfrequentlyinpatientstreatedwithalbumin(18.5%)thaninthosereceivingdextran70(34.4%)orpoly- geline(37.8%)22）.AlthoughtherewasnodifferenceintheincidenceofPICDbetweenpatientsreceivingnormal
salineandalbuminwhen4to5lofasceticfluidwitheachparacentesisisremoved23）,albuminatadoseof8to10
gperlofasceticfluidiseffectiveiflargervolumeisremoved24）. 3.Useofalbumininspontaneousbacterialperitonitis(SBP)
Spontaneousbacterialperitonitissecondarytodecompensatedcirrhosisisalsoaconditionwithapoorprogno- sis.ItispredominantlycausedbyaerobicGram-negativebacteria,suchasE.coliandKlebsiella,andtreatedwith
3rd-generationcephemantibioticsorpenicillin.However,aclinicalstudycomparingthetreatmentwithcefotax- imealoneandincombinationwithalbuminshowedthatcoadministrationwithalbuminreducedthedevelopment
ofhepatorenalsyndrome(33%forcefotaximealonevs.10%forcefotaximeplusalbumin,p=0.002)andmortality
(29%forcefotaximealonevs.10%forcefotaximeplusalbumin,p=0.01)25）.Inthisstudy,albuminwasgivenata
doseof1.5gperkilogramofbodyweightwithin6hoursafterdiagnosis,followedby1gperkilogramofbody
weightonday3ofillness.Albuminisbeneficial,especiallyforpatientswithimpairedrenalfunction26）27）,andits
benefitsobservedbyameta-analysiswereappreciated28）. 4.Useofalbumininhepatorenalsyndrome(HRS)
Hepatorenalsyndromeisreferredtoasacuterenalfailureinpatientswithend-stagelivercirrhosisorhepatic
insufficiency,suchasfulminanthepatitis,butrepresentsfunctionalpre-renalfailurewithoutanyorganicorpatho- logicalchangesinrenaltissues.Hepatorenalsyndromeisclassifiedinto2types:type1showingrapidlyprogres- sivesymptomsofrenalfailureandtype2showingslowlyprogressiverenalfailure.Patientswithhepatorenal
syndromehasalowglomerularfiltrationrate(serumCr>1.5mg/dlor24-hourCCr<40ml/min),resultingin
oliguria.Inmanycases,hepatorenalsyndromeprogressesinanirreversiblemanner,isassociatedwithamortality
rateof≥90%,andisoneofthecausesofdeathinend-stagelivercirrhosis.Theuseofterlipressinandalbuminis
recommendedforthetreatmentoftype-1hepatorenalsyndrome29）30）.Improvementofrenalimpairmentisalso
notedin83%ofpatientswithcoadministrationofnorepinephrineandalbumin,whichrepresentsabeneficialtreat- mentregimenwhilewaitingforalivertransplant31）.
● Recommendation
1.Inpatientswithascitessecondarytolivercirrhosiswhoareondiuretics,albuminincreasestherateofdisap- pearanceofascites,preventstherecurrenceofascites,andimprovestherateofsurvivalafteralong-termadmin- istration(1B).
2.When≤4to5lofasceticfluidwitheachparacentesisisremoved,albuminisnotnecessarybecauseparacen- tesis-inducedcirculatorydysfunctioncanbemanagedwithelectrolytereplacement.Whenalargervolumeof
asciticfluidisremoved,ahypertonicalbuminsolutionatadoseof8to10gperlofasceticfluidiseffective(1A).
3.Spontaneousbacterialperitonitiswithrenalimpairmentbenefitsfromthetreatmentwithahypertonicalbu- minsolutionata1.5g/kgbodyweightwithin6hoursafterdiagnosis,followingby1g/kgbodyweightonday3
ofillness(1A).
4.Treatmentwithahypertonicalbuminsolutionandavasoconstrictoriseffectiveinimprovingtype-1hepa- torenalsyndrome.Albuminshouldbeadministeredatadoseof1g/kgbodyweightonday1and20to40g/body
weightonsubsequentdays,incombinationwithterlipressinandotherdrugs(1A).
iv) Nephritic syndrome with refractory edema or pulmonary edema
● Statement
CQ4.Isalbumintherapyeffectiveinnephriticsyndromewith
refractoryedemaorpulmonaryedema? Grade EvidenceLevel Reference
Overseas Japan Althoughalbuminisusedasanactofnecessityincombination
withadiuretic,itsefficacyistransient. 2 D D 32-35
● Commentaries
Useofalbumininnephriticsyndrome
Becausealbuminisrapidlyexcretedinurineafterdosinginpatientswithnephriticsyndrome,itsefficacyin
improvingrefractoryedemaisminimalandtransient32）33）.Instead,albuminhasreportedtoworsenrenalimpair- ment34）andisthusnotusedforimprovingedema35）.Inpatientswithnephriticsyndromewhohavedecreased
bloodpressureduetodecreasedcolloidosmoticpressureormassivepleuraleffusionorascitesresultinginbreath- ingdifficultyandwhohavebeendifficulttotreatwithotherapproaches,albuminisusedasanactofnecessityin
combinationwithadiuretic,butitsefficacyistransient,withlimitedreportsindicatingitsbenefits.
● Recommendation
Innephriticsyndromewithrefractoryedemaorpulmonaryedema,hypertonicalbuminisexpectedtoshow
onlytransientefficacyandisnotrecommendedwiththeexceptionofuseasanactofnecessity(2D).
v) Extracorporeal circulation with unstable hemodynamics
● Statement
CQ5.Istheuseofalbumineffectiveduringextracorporealcir- culation,suchashemodialysis,incaseswithunstablehemody-
namics(e.g.,inpatientswithdiabetes)? Grade EvidenceLevel Reference Overseas Japan
Althoughalbuminiseffective,normalsalineisthefirstchoice.
Dose adjustment of antihypertensive drugs, use of vasopres-
sors,orcontinuousdialysisisavailableasanalternative. 2 C None＊ 36-38
＊Noclinicalstudywasavailable.
● Commentaries
Useofalbuminduringextracorporealcirculation,suchashemodialysis,incaseswithunstablehemodynamics
(e.g.,inpatientswithdiabetes)
Dialysis-inducedhypotensionisacommoncomplicationofdialysisthatisduetodecreasedbloodvolume.It
presentswithsymptoms,suchasnausea,sweating,convulsion,anddizziness;ischaracterizedbyanabruptdrop
inbloodpressure;andhasbeentreatedwiththeadministrationofnormalsaline,albumin,isotoniccolloids,etc36）.
Knolletal.conductedadouble-blind,randomized,cross-overtrialdesignedtoevaluatethesuperiorityofalbumin
tonormalsalinein45patientswithahistoryofdialysis-inducedhypotensionandfoundnoevidenceofefficacyof
albuminwiththeexceptionthatthealbumingroupwasadministeredasmallervolumeofnormalsaline37）. Therearenoothertrialscomparingtheefficacyofalbuminwithotherfluidtherapies38）andthereforenormal
salineisthefirstchoiceforhypotensionduringdialysis.Inaddition,doseadjustmentofantihypertensivedrugs,
useofvasopressors,orcontinuousdialysisisavailableasanalternativetoalbuminindialysispatientswithunsta- blehemodynamics,includinghypotension.
● Recommendation
Inprinciple,theuseofisotonicalbuminisnotrecommendedduringextracorporealcirculation,suchashemodi- alysis,incaseswithunstablehemodynamics(e.g.,inpatientswithdiabetes)(weakrecommendationagainstuse,
2C).
vi) Therapeutic plasma exchange not requiring the replacement of coagulation factors
● Statement
CQ6.Istheuseofalbumineffectiveduringtherapeuticplasma
exchangenotrequiringthereplacementofcoagulationfactors
(e.g.,inautoimmuneneurologicaldisorders)? Grade EvidenceLevel Reference Overseas Japan
1. Therapeutic plasma exchange using albumin as a replace-
mentfluidisaneffectivetreatmentforneurologicaldisorders. 1 A None＊ 39-45 2.Therapeuticplasmaexchangeisbeneficialinremovinganti-
A or anti-B antibodies for ABO-incompatible transplantation
whenusedincombinationwithimmunosuppressantagents. 1 B None＊ 46 3.Inotherdiseases,therapeuticplasmaexchangeislesseffec-
tivethancausaltherapyandshowsonlytransientbenefits. 2 C None＊ 47,48
＊Noclinicalstudywasavailable.
● Commentaries
Therapeuticplasmaexchangenotrequiringthereplacementofcoagulationfactors
Plasmaexchange(PE)isatherapeuticprocedureinwhichaplasmafractionatorisusedtoseparatethepatient’s
bloodintoplasmaandbloodcellularcomponentsandreplacetheplasmacontainingpathogenicsubstanceswith
areplacementfluidinordertoremovethepathogenicsubstancesandhasbeenshowntobebeneficialinmany
diseases39）.IntherapeuticPEnotrequiringreplacementofplasmacomponents,adilutedalbuminreplacement
fluidisrecommendedratherthanfreshfrozenplasma(FFP)fromaviewpointofthepreventionofinfectionsand
simpleplasmaexchangeanddouble-filtrationplasmapheresis(DFPP)havebeenperformed40）.Heat-treatedhuman
plasmaproteinfractionis,inprinciple,notusedbecauseitmaycauseanaphylacticreactionstocontaminating
proteins,suchashypotension.
AhighevidencelevelisavailableregardingtheefficacyoftherapeuticPEinchronicinflammatorydemyelinat- ingpolyneuropathy(CIDP),Guillain-Barresyndrome(GBS),andacutemyastheniagravis41）.AlthoughPE,steroid
therapy,orhigh-dosegamma-globulintherapyisavailableforthetreatmentofCIDP,therearenodifferencesin
effectamongthesetreatmentsandtreatmentisselecteddependingonpathologicalconditions42）.Ameta-analysis
ofRCTshasshownthatPEprovidesshort-termsymptomaticimprovementinapproximately70%ofpatientswith
CDIP43）.PEisalsoeffectiveinGBS44）andatrialcomparingplasmawithalbuminasareplacementfluidhasindi- catedthattherearenodifferencesintreatmenteffectbetweenthemandthatalbuminreplacementhasalower
frequencyofcomplications45）.
PEandDFPPareperformedforremovinganti-Aoranti-BantibodiesinABO-incompatibletransplantationand
havebeenshowntobebeneficialwhenusedincombinationwithimmunosuppresants46）.
TherapeuticPEiseffectiveinacuteexacerbationofsteroid-refractorymultiplesclerosis47）.Inaddition,PEwas
used for immunoglobulin removal in multiple myeloma or macroglobulinemia and produced improvements in
renalfunctionandsurvivalrate48）.However,PEhasshownonlytransientefficacyinthesediseases.
● Recommendation
1.PEusinganisotonicordilutedhypertonicalbuminsolutionasareplacementfluid(1-to1.5-foldplasmavol- umepersession)isrecommendedforthetreatmentofneurologicaldisorders,suchasCIDPandGBS(1A).
2.PEusinganisotonicordilutedhypertonicalbuminsolutionasareplacementfluidisrecommendedforremov- inganti-Aoranti-BantibodiesinABO-incompatibletransplantationwhenusedincombinationwithimmunosup- pressantagents(1B).
3.Inprinciple,drugtherapyisusedinmultiplesclerosisorhematologicaldisorders(e.g.,multiplemyelomaor
macroglobulinemia)andtherapeuticPEisrestricted(2C).
vii) Severe burns
● Statement
CQ7.Istheuseofalbuminbeneficialforsevereburns? Grade EvidenceLevel Reference Overseas Japan
Albuminproductsareindicatedinburnsinvolving≥50%ofthe
totalbodysurfacearea. 2 C None＊ 49
Althoughsuchburnswithin18hoursofinjuryareusuallyman- agedwithextracellularfluid,albuminproductsareusedeven
within18hoursofinjuryifanalbuminlevelis<1.5g/dl. 2 B None＊ 50-53 Theefficacyofalbuminonsevereburns,lengthofstay,and
mortalityhasnotbeenproven. 1 B None＊ 49,54-58
＊Noclinicalstudywasavailable.
● Commentaries
1.Useofalbumininburnsinvolving≥50%ofthetotalbodysurfacearea
Regarding≥50%TBSA(%ofthetotalbodysurfacearea)burnsinchildren,thereisonlystudiesthatwere
publishedlongago,therearealimitednumberofcases,andalmostallcasesledtodeath,withnosurvivalbenefit
ofalbumindemonstrated.ApossiblereasonisthatPseudomonasaeruginosainfectionafterburnswasdifficultto
treat49）.InReference55,approximatelyhalfofpatientsinboththealbumingroupandthecontrolgrouphadpos- siblya≥50%TBSAandalbuminshowednobenefitsincardiopulmonaryfunctionorsurvival.
2.Extracellularfluidisusuallyusedwithin18hoursofinjury
Inprinciple,albuminadministrationisrecommendedtobestartedwithin24hoursofinjury.Plasmaproteins
otherthanalbuminhavebeenreportedtocauseshockorreducedbloodpressurewhenadministeredbybolus50）.
Albuminisconsideredtoextravasatewithin6to18hoursofinjury51）52）.
3.Albuminisindicatedevenwithin18hoursofinjuryifanalbuminlevelis<1.5g/dl
BasedonapaperonaburnedJehovah’switness53）whocouldendurealbuminlevelsdownto1.2g/dlwithout
administrationofbloodproducts,analbuminlevelof1.5g/dlwasconsideredappropriate.
4.Benefitsofalbumin
Althoughapaperreportedthatalbuminimprovedmorbidities58）,thestudyincludedonlyalimitednumberof
patients,with7patientsbothinthealbuminandcontrolgroups.Basedonotherpapersincludingmeta-analy- ses54）～57）,therewerenostatisticaldifferencesinmorbidity.Inaddition,thelengthofstay56）ormortalitywasnot
improved54）～58）.
● Recommendation
Nopaperprovidesevidenceoftheefficacyofalbumininsevereburnsanditsbenefitstolengthofstayand
mortality(strongrecommendationagainstuse,1B).Theuseofisotonicalbuminshouldbelimitedtocasesofa
serumalbuminlevelof<2.0g/dlafter18hoursofinjury(2B).
viii) Pulmonary edema or marked edema due to hypoproteinemia
● Statement
CQ8. Is the use of albumin effective in pulmonary edema or
markededemaduetohypoproteinemia? Grade EvidenceLevel Reference
Overseas Japan Albumin is beneficial only for diuretic-resistant pulmonary
edema or marked edema with marked hypoproteinemia, but
thereisnoevidenceofimprovedprognosis. 2 B None＊ 59-63
＊Noclinicalstudywasavailable.
● Commentaries
Placeofalbumininthetreatmentofpulmonaryedemaormarkededema
Casesofpulmonaryedemaormarkededemaarefirstmanagedwithsodiumandfluidrestrictionplusloop
diuretics.However,ifpatientsdonotrespondtohighdosesofdiureticsandhavecomorbidmarkedhypoalbumin- emia(albuminlevel≤2.0g/dl),thecombinationofadiureticandahypertonicalbuminproductisconsidered59）60）.
Itshouldbenotedthatthiscombinationtherapyisamatterofdisputeandpatientswhobenefitfromthetherapy
maybelimited61）62）.Thereisnoevidencethatalbuminproductsimproveprognosis63）.
● Recommendation
Inpatientswithtreatment-resistantpulmonaryedemaormarkededema,theuseofahypertonicalbuminprod- uctisconsideredonlyinthecaseofmarkedhypoalbuminemia(2B).
ix) Markedly decreased circulating plasma volume
● Statement
CQ9.Istheuseofalbumineffectiveinacutepancreatitisetc.
withmarkedlydecreasedcirculatingplasmavolume? Grade EvidenceLevel Reference Overseas Japan
Albuminadministrationisrecommendedinpatientswithshock
asaresultofmarkedlydecreasedcirculatingplasmavolume
secondarytoacutepancreatitis,intestinalobstruction,etc. 2 D D 64
● Commentaries
Circulatingplasmavolumeisdecreasedwhensystemicinflammatoryresponseinducedbypancreatitiscauses
increasedvascularpermeabilityorreducedcolloidosmoticpressureassociatedwithlossofproteins,whichfacili- tates the loss of extracellular fluid into the abdominal and thoracic cavities as well as the pancreatic area.
AlthoughtheClinicalPracticeGuidelinesfortheManagementofAcutePancreatitis201064）state“thepractical
regimen,includingtheratioofcrystalloidsandcolloidstobeused,shouldbeindividualizedonthebasisofan
overallassessmentofcentralvenouspressure,bloodpressure,urinaryoutput,hematocrit,serumtotalprotein
level,andothers,”thereisnoclearevidenceregardingtheefficacyofalbumininacutepancreatitis.Inaddition,
cautionshouldbeexercisedbecausealbuminadministeredincasesofincreasedvascularpermeabilityextrava- satesandinducesfluidretention,thuspossiblyleadingtoprolongededema.However,shocksecondarytomark- edlydecreasedcirculatingplasmavolumeiseligibleforisotonicalbuminproducts,ashypovolemicshockis.
● Recommendation
Anisotonicalbuminproductshouldbeusedincasesofshocksecondarytodecreasedcirculatingplasmavolume
associatedwithmedicaldisorders,suchasacutepancreatitis(2D).
x) Cerebral ischemia (head injury)
● Statement
CQ10 Grade EvidenceLevel Reference
Is the use of albumin effective in cerebral ischemia (head
injury)? Overseas Japan
1.Itcannotbesaidthatalbuminiseffectiveforfluidresuscita- tioninpatientswithtraumaticbraininjuryorinitialtreatment
of acute stroke. In the former, worsened prognosis has been
noted.
1 A None＊ 65,66
2.Albuminiseffectivetomaintaincirculatingbloodvolumein
vasospasmaftersubarachnoidhemorrhage. 2 C None＊ 67-69
＊Noclinicalstudywasavailable.
● Commentaries
1.Efficacyofalbuminincerebralischemia(headinjury)andprognosis
Amongpatientswithtraumaticbraininjurywhoreceivedfluidresuscitationfordecreasedcirculatingblood
volume,albuminwasassociatedwithahighermortalitythannormalsaline,especiallywiththedifferencereaching
significanceinpatientswithseverebraininjury65）.Inaddition,ithasbeennotedthatahypertonicalbuminproduct
atahighdose(2g/kg)fortheinitialtreatmentofacutestrokedoesnotimproveneurologicalprognosisandmay
increasetheincidenceofpulmonaryedemaorcerebralhemorrhage66）.
Crystalloidsarepreferentiallyusedtomaintainnormalcirculatingbloodvolumeincerebralvasospasmafter
subarachnoidhemorrhage.Althoughalbuminproductsarethesecondchoiceincasesofnon-responsetocrystal- loids,theyhavenodirecteffectoncerebralvasospasmandplayasupplementaryrolebymaintainingcirculating
bloodvolume67）.Triple-Htherapy(thecombinationofhypervolemia,hemodilution,andinducedhypertension)has
beenproposedfortheimprovementofdisturbedcerebralcirculationinducedbycerebralvasospasm,buteffects
ofaggressivefluidtherapyforcirculatingbloodvolumeexpansionarecontroversialandmaintenanceofnormal
circulatingbloodvolumehasrecentlybeenfavored68）69）.
● Recommendation
1.Albuminisnotrecommendedforfluidresuscitationinpatientswithtraumaticbraininjuryorinitialtreat- mentofacutestroke(strongrecommendationagainstuse,1A).
2.Theuseofisotonicalbuminshouldbeconsideredtomaintaincirculatingbloodvolumeincasesofvasospasm
aftersubarachnoidhemorrhagesthatdonotrespondtocrystalloids(2C).
xi) Heart surgery with cardiopulmonary bypass
● Statement
CQ11.Istheuseofalbumineffectiveduringheartsurgerywith
cardiopulmonarybypass? Grade EvidenceLevel Reference
Overseas Japan Thebenefitofusingalbuminasaprimingsolutionduringopen-
heart surgery with cardiopulmonary bypass has not been
proven. 2 D D 70-73,75
● Commentaries
Albuminhaslongbeenusedasaprimingsolutioninthecardiopulmonarybypasscircuitduringopen-heart
surgerywithcardiopulmonarybypass.Theusehastwomajorpurposes,i.e.,toreducetheactivationofplatelets
orcomplementsbycoatingthebloodcontactsurfaceofthecircuitandtopreventfluidleakagetotheextravas- cularcompartmentbymaintainingthecolloidosmoticpressureduringtheextracorporealcirculation.Forthe
former,thereductionoftheactivationofplateletsorcomplementsisnowachievedusingthebloodcontactsurface
ofthecircuitcoatedwithheparinormacromolecularpolymers.Therefore,albuminisusedmainlyforthelatter
purpose(maintainingthecolloidosmoticpressure).
Arandomized,controlledtrialcomparingalbuminandcrystalloidasaprimingsolutionforcardiopulmonary
bypassreportedthatthepostoperativefluidbalancewasbetterinthealbumingroup70）.However,therewereno
significantdifferencesinpostoperativeincreaseinbodyweight,althoughalbuminwasassociatedwithapostop- erativedecreaseinbodyweightandithasbeenreportedthattherearenostatisticaldifferencesinpostoperative
bloodloss,bloodtransfusionvolume,lengthofstayinICU,lengthofstayinhospital,ormortality71）～73）.Although
aJapaneseretrospectivestudyreportedthatalbuminasaprimingsolutionshouldbeusedwithcaution74）,itis
consideredthatsomeuseofalbuminisinevitableinchildrenwithhemodilution75）.
● Recommendation
Becausetherearealmostnostudiesprovidingevidenceoftheefficacyandbenefitsofisotonicalbumininlength
ofstayandmortalitywhenusedasaprimingsolutionduringopen-heartsurgerywithcardiopulmonarybypass,
albuminshouldbeusedwithcaution(2D).
xii) Hypoalbuminemia with stable hemodynamics during the perioperative period
● Statement
CQ12. Is the use of albumin is effective in hemodynamically
stablepatientswithhypoalbuminemiaduringtheperioperative
period? Grade EvidenceLevel Reference
Overseas Japan Theuseofalbuminisnoteffectiveinhemodynamicallystable
patients with hypoalbuminemia during the perioperative
period. 2 C None＊ 76,77
＊Noclinicalstudywasavailable.
● Commentaries
Duringtheperioperativeperiod,hypoalbuminemiamayoccursecondarytoincreasedvascularpermeability,
bodyfluiddilutionresultingfrombloodtransfusionorreducedalbuminproductionintheliver.Althoughitiswell
documentedthathypoalbuminemiaisapoorprognosticfactor76）,itremainsinconclusivewhethertheuseofalbu- mincanimprovethepatient’sprognosis.Manystudiesdesignedtoexaminetheeffectofalbuminduringthe
perioperativeperiodincludecriticallyillpatients,suchasICUpatients,butexcludepatientswithstablehemody- namics.TheresultofaChinese,prospective,single-center,controlledtrialcomparingalbuminwithnormalsaline
aftergastrointestinalsurgeryindicatedthattherewerenodifferencesintermsofrecoveryofserumalbumin
levelsorclinicaloutcomes77）.Inaddition,theefficacyoftheuseofalbuminremainsunknownevenincriticallyill
patients,suggestingthatmorecareshouldbetakeninhemodynamicallystablepatients.
● Recommendation
Theuseofalbuminisnotrecommendedinhemodynamicallystablepatientswithhypoalbuminemiaduringthe
perioperativeperiod(weakrecommendationagainstuse,2C).
xiii) Pregnancy-induced hypertension
● Statement
CQ13. Is the use of albumin effective in pregnancy-induced
hypertension? Grade EvidenceLevel Reference
Overseas Japan Theefficacyoftheuseofalbumininpregnancy-inducedhyper-
tensionisnotproven. 2 D D 78,79
● Commentaries
Inpregnancy-inducedhypertension,thepresenceofproteinuria,extravasation,etc.frequentlycausehypopro- teinemia.Whenhypertensionbecomesmoremarked,circulatingplasmavolumedecreases,leadingtohemocon- centration.Forthatreason,albuminproductswereusedforvolumeexpansioninthe1970s.However,excessively
high doses of albumin products increase the risk of pulmonary edema due to extravasation in patients with
pregnancy-inducedhypertension,whohaveincreasedvascularpermeability.Thus,albuminisindicatedincases
inwhichtheuseofanantihypertensivedrugreducesdiuresis,leadingtooliguria.Threetrialsconductedtodate
includedalimitedsamplesizeof61subjectsandfoundnoevidenceofefficacy.Reliabledatavolumeandmethod- ologiesareneeded78）.
Insummary,albuminisindicatedinonlylimitedcasesofpregnancy-inducedhypertensionandinsteadexces- siveadministrationmayworsendiseaseconditions79）.
● Recommendation
Isotonicalbuminmaybeindicatedincasesinwhichtheuseofanantihypertensivedrugreducesdiuresis,lead- ingtooliguria.Excessiveadministrationmayworsendiseaseconditions(2D).
xiv) Inflammatory bowel disease
● Statement
CQ14. Is the use of albumin effective in inflammatory bowel
disease? Grade EvidenceLevel Reference
Overseas Japan Theefficacyofalbuminininflammatoryboweldiseaseisnot
proven. 2 None＊ None＊ None＊
＊Noclinicalstudywasavailable.
● Commentaries
Hypoalbuminemiainpatientswithinflammatoryboweldiseaseoccursduetoundernutrition,inflammation,loss
ofproteinsfromtheintestinaltract,etc.Althoughalbuminisausefulindicatorofnutritionorprognosis80）81）,no
studieshavebeenreportedinwhichtheclinicalbenefitofalbumininhypoalbuminemiawasevaluated.Inprin- ciple,hypoalbuminemiaismanagedwithtreatmentofunderlyingdiseaseornutritiontherapy82）,andtheuseof
albuminisnotrecommended.
● Recommendation
Theuseofalbuminisnotrecommendedininflammatoryboweldisease(weakrecommendationagainstuse,2
None).
