w w w . r b h h . o r g
Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
Review
article
Nutritional
status
and
hyperglycemia
in
the
peritransplant
period:
a
review
of
associations
with
parenteral
nutrition
and
clinical
outcomes
Marina
Verdi
Schumacher
a,
Gustavo
Adolpho
Moreira
Faulhaber
b,∗aHospitaldeClínicasdePortoAlegre(HCPA),PortoAlegre,RS,Brazil
bUniversidadeFederaldoRioGrandedoSul(UFRGS),PortoAlegre,RS,Brazil
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r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received26July2016 Accepted9September2016 Availableonline21February2017
Keywords:
Hematopoieticstemcell transplantation Nutritionalsupport Parenteralnutrition Hyperglycemia
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Hematopoieticstem celltransplantationis anestablishedtreatment optionforvarious hematologicaldiseases.Thistherapyinvolvescomplexproceduresandisassociatedwith severalsystemiccomplications.Duetothetoxiceffectsoftheconditioningregimenused inallogeneictransplantations,patientsfrequentlysufferfromseveregastrointestinal com-plicationsandareunabletofeedthemselvesproperly.Thiscomplexclinicalscenariooften requiresspecializednutritionalsupport,anddespitetheincreasingnumberofstudies avail-able, many questionsremainregardingthebest waytofeedthesepatients. Parenteral nutritionhasbeentraditionallyindicatedwhentheeffectsongastrointestinalmucosaare significant;however,thetruebenefitsofthistypeofnutritioninreducingclinical com-plicationshavebeenquestioned.Hyperglycemiaisacommonconsequenceofparenteral nutritionthatseemstobecorrelatedtopoortransplantationoutcomesandahigherrisk ofinfections.Additionally,nutrition-relatedpre-transplantationriskfactorsarebeing stud-ied,suchasimpairednutritionalstatus,poorlycontrolleddiabetesmellitusandobesity.This reviewaimstodiscusssomeoftheserecentissues.Arealcaseofallogeneictransplantwas usedtoillustratethescenarioandtohighlightthemostimportanttopicsthatmotivated thisliteraturereview.
©2017Associac¸ ˜aoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.Published byElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
HSCT is widely used to treat hematological and non-hematologicalmalignancies.ComparedtoautologousHSCT, allogeneicHSCT(allo-HSCT)causesmoreseverenutritional
∗ Correspondingauthorat:DepartmentofInternalMedicine,HospitaldeClínicasdePortoAlegre(HCPA),RamiroBarcellos2350/700,
90035-903PortoAlegre,RS,Brazil.
E-mailaddress:gfaulhaber@hcpa.edu.br(G.A.MoreiraFaulhaber).
consequencesandsideeffectsduetoitsmoreintenseablative and immunosuppressive conditioning regimen. Mucositis, nausea and vomiting, diarrhea, poor oral intake, mal-absorption and prolonged malnutrition are some of the complicationsoftenobserved.1–3
http://dx.doi.org/10.1016/j.bjhh.2016.09.016
Therefore,adequatenutritionalsupportisparamount dur-ingall thephasesofthetransplant procedure,4,5 and isan importantmeasureforbetteroutcomesintheshortandlong term.6 Mostpatientsneedartificial nutritionatsomepoint andfordifferentlengthsoftime.Allo-HSCTpatients suffer-ing from severe gastrointestinal symptoms usuallyrequire prolonged support, frequentlyvia parenteralnutrition (PN) becauseofverypoororalintakeand intolerancetoenteral nutrition (EN).4–7 In cases of severe graft-versus-host dis-ease(GVHD)withgastrointestinalcomplications,theuseof PN usuallybecomes necessary again.8 Nevertheless, as PN isaninvasiveprocedureandnotfreeofrisks,itsuseinthe quitecomplexscenarioofallo-HSCThasbeenquestioned.9–11 RecentstudiesdemonstratethatPNcanactuallybeharmful under some circumstances, due to higher risk of hyper-glycemiaandbloodstreaminfections.12–14Inaddition,despite theincreasingnumberofstudies,thereisstillnoclear consen-susregardingthebenefitsofENversusPNinHSCTpatients.15 Thereare severalstudiesdemonstratingthe importance of a complete nutritional status assessment before the transplant.16–18 Associations between abnormal body mass index (BMI) and non-relapse mortality (NRM) have been documented.7,19–21Correlationsbetweenpre-transplantation comorbiditiesandpooroutcomes,especiallydiabetes melli-tus,havealsobeendiscussed.22
Thebriefcasescenariodescribedbelowisusedtoillustrate somedifficultsituationsthatcanbefoundinthecontextof HSCT.Theimportanceofadequate nutritionalsupport,the controversialfindingsintermsofthebestapproachandtype ofnutrition,andsomeofthedeleteriousconsequencesofPN inHSCTpatientsareemphasizedhere.Recentfindingsrelated tonutritionalassessment,pre-transplantationdiabetes mel-litusandobesityarealsoreviewed.
Clinical
vignette
WSA, a 27-year-old male with diagnosis of acute myeloid leukemia subtype M5 refractoryto multiple chemotherapy regimens,wasadmittedtotheHospitaldeClínicasdePorto Alegre for related mismatched allogeneic stem cell trans-plantation.Hewasobese(BMI:30.5kg/m2),anactivesmoker, andonanti-hypertensivetreatment.Hisperformancestatus was ECOG0. He received Busulfanand Cyclophosphamide plus thymoglobulin as the conditioning regimen, as well as cyclosporine and methotrexate for GVHD prophylaxis. Engraftmentoccurredaroundthethirdweekafter transplan-tation; it was followed by acute gastrointestinal (grade III) and hepatic (grade II) GVHD with diagnosis based on the NationalInstituteofHealth(NIH)consensuscriteria.23 This complicationwasrefractorytofirst-linecorticosteroid ther-apy(methylprednisolone2mg/kg)andpartiallyresponsiveto basiliximab(anti-CD25monoclonalantibody)andinfliximab (anti-TNFmonoclonalantibody).
Anindividuallycompounded PN wasinitiatedon Day 5 aftertransplantation dueto neutropenic enterocolitis with paralyticileusandoralmucositisgradeIV.ThePNwas calcu-latedbasedonthepatient’sbodyweightof90kgatthattime, toprovide30–35kcal/kg/day,atleast1.5gofprotein/kg/day and amaximumof1.0goflipids/kg/day.Thiscomposition
corresponded to20–25%oftotal calories comingfrom pro-tein (10%aminoacid solution),50–60%from dextrose(50% glucosemonohydratesolution)andupto30%oftotalcalories fromlipids(20%lipidemulsion).1Thisdietwasmaintainedfor approximatelythreeweeksbecauseofverypoororaltolerance andnosafeaccessfortubefeedingduetothrombocytopenia. However,thePNhadtobediscontinuedforshorttimesduring thisperiodbecauseofseverehyperglycemia.Thepatienthada mediumglycemiclevelofaround80–120mg/dLbeforestarting PN.Thiscomplication,relatedtotheuseofcorticosteroidsand immunosuppressants,becameclearlyworseafterthe intro-ductionofPNashisserumglucosepeakedat300–400mg/dL. Evenwithareductionoftheglucoseinfusionrate,reduction oftotalcaloricamountofPN to20–25kcal/kg/dayand high dosesofcontinuousIVinsulinadministration,theglycemia remained poorly controlled. The PN was interrupted. The patientrefusedtubefeeding,sooralnutritionwasinitiated accordingtohistolerance.Hehadseveralinfectious compli-cations,suchasbacterialsinusitisandpneumonia,anddied fromgram-negativesepsisthreemonthsafterhematopoietic stemcelltransplantation(HSCT).
Pre-transplantation
nutritional
assessment
HSCT involves an increase in nutritional and metabolic demandsthatispartiallyexplainedbythedeleteriouseffects of the conditioning regimenon the gastrointestinal tract.1 Furthermore,theoccurrenceoffever,infections,andthe pro-longedtimeofimmunosuppressioncreateahypermetabolic statethatcanfurtherexacerbatenutritionaldeficits.5,24Itis knownthatanimpairednutritionalstatusbefore transplanta-tioncanaffectcomplicationsandclinicaloutcomesofHSCT, inparticularallo-HSCT.16,19,20Inmalnourishedpatients,there isevidenceofincreasedmortalityrates,prolongedlengthof hospitalizationand delayedtimetoengraftment.Moreover, theNRMishigherfortheextremelyunderweight,overweight andobese.21,25
There are innumerous available nutritional assessment methods,althoughnonearespecificfortheHSCTpopulation. Screeningquestionnairescanbeusedwhencombinedwith a physical examination,biochemical markers, and anthro-pometry,i.e.,themeasurementofweight,height,skinfolds and circumferences. Single methods have limitations and are inefficient.18 Liu et al. evaluated and compared differ-entquestionnairesinpatientswithleukemia,andshoweda betterclinicalapplicabilityoftheNutritionalRiskScreening 2002questionnaire(NRS2002)todetectmalnutritionbefore transplantation.26,27 ThemaincomponentsoftheNRS2002 are:(1)severityofprimarydiseaseanditsimpacton nutri-tionalstatus,(2)recentchangesofbodyweight,(3)changes indietary intakeand(4) bodymassindex. ANRSscore≥3 definesnutritionalrisk,informationthatcancontributetothe planningofperitransplantnutritionalsupport.28
Thephase angle,onedatumobtainedfromthis procedure, has been correlated with worse clinical prognosis in vari-ousdiseases asareducedphaseanglecanreflectbodycell massloss,especiallymuscleloss.30 Thestudy showedthat patientswithextremelylowpre-transplantationphaseangles had anincreased riskofdeath inthe first two years after transplantation.29
Therefore,acompleteassessmentisaveryimportantstep priortoHSCT,andshouldcombineallavailabletoolsinorder to detect nutritional issues that can be improved prior to theprocedure. Also,thisapproachallowstheteamtoplan adequatenutritionalsupportinadvanceandtotake appro-priatemeasurestomaintainthissupportduringandafterthe procedure.11,16
Pre-transplantation
comorbidities
–
the
role
of
obesity
and
diabetes
mellitus
Apart from malnutrition and low body weight, tradition-ally associated with poor outcomes in cancer patients, otherprognosticfactorsassociatedtonutritionalstatushave been described recently. Among these, obesity and dia-betes mellitus seem to play an important role in HSCT patients.22,31–33 Sorror et al. established the hematopoietic cell transplantation-comorbidity index(HCT-CI), whichis a scoringsystem topredict the risk ofNRM after transplan-tation. Thisindex, which includesdysfunction ofdifferent organs,suchaspulmonary,hepatic,cardiac,andrenal dys-function, alsoincludesdiabetes and obesity as deleterious comorbidities(basedonaBMI>35kg/m2 inadults).34Ithas been validated inseveral countries asa predictor ofHSCT complications.35
There isa growing number of studies,albeit retrospec-tive studies, that show an association of high BMI before transplantationwithagreaterriskofGVHDandNRM.7,20,31,33 Gleimeretal.observedasignificantincreaseinNRMamong obesepatientssubmittedtoallo-HSCT.7Toconfirmthese find-ings,Nakaoetal.conductedameta-analysistoassesswhether overweightpatientssubmittedtoHSCTactuallyexperience worse outcomes.A statistically significant association was foundbetweenexcessofbodyweightandpooroutcomesafter allo-HSCT,butno significantimpactwas foundonsurvival inautologousHSCT.Thatcorrelationwasespeciallytruefor theoccurrenceofacuteGVHDamongoverweightpatients.31 Thepossiblereasonsinvolvedcould beinappropriatedoses ofconditioningregimenduetodifferentmedication pharma-cokineticsintheobese,thedoseofinfusedstemcellsandof GVHDprophylaxis.Inthiscase,theidealbodyweightcould beabetterpredictorofdoseadequacy.36Otherpossible fac-torsinvolvecytokine-relatedmechanisms,suchastheeffect ofT-cellproliferationandfunctiondrivenbyadipocytokines.31 Pre-transplantation diabetes mellitus has also been reportedasanimportantriskfactorforworsetransplantation outcomesandNRM.Asignificantlygreaternumberof inva-sivefungaldiseasesandimpairedneutrophilfunctionhave been describedin diabeticpatients submittedto HSCT.22,32 AlthoughTakanoetal.showedthatpre-engraftment hyper-glycemiacouldbeariskfactorforinfectiousdiseases,acute GVHDandNRM,hyperglycemiaaftertheprocedurecanalso
increasetheriskofsubsequentNRM.12,37,38 Fujietal., how-ever,statedthatitisstillunclearwhetherabettercontrolof diabetesmellituspriortoHSCTwouldactuallyreducethese complications,andfurtherresearchisstillnecessary.12
Specialized
nutritional
support
after
HSCT
–
enteral
versus
parenteral
nutrition
Theprolongedgastrointestinalsymptomsthat occurinthe first daysafterthe transplantation giverise totheneedof specializednutritionalsupport.Thefirst10–15daysare criti-calespeciallyduetoneutropenicmucositis,nauseaandpoor oralintake.4,24Itissuggestedthatmaintainingthefunctions ofthedigestivetract,evenwithsmallvolumesofnutrition, could bring beneficial effects in terms of maintenance of theimmunologicalgutbarrierandglucoselevelcontrol.39–41 However,the use oftubefeedingin thispopulation isstill beingstudiedand isnotstandard practice,mainlybecause of the challenges of establishing a safe enteral access in patients with severe mucositis, gastrointestinal tract dam-ageandthrombocytopenia.24 Whenthecalorictargetisnot achieved or the patient presents significant gastrointesti-nalintolerance,theuseofPNmaybejustifiedtominimize nutrient deficiencies and maintain body weight. However, its advantages and disadvantages are still under discus-sion considering the potentially higher riskof bacteremia, catheter-site infections, hyperglycemia and fluid overload observedinPNrecipients.10
TheuseofPN inHSCThasbeendescribed inthe litera-turesincethe1980sandthesepioneeringstudiesarestillused asreference.42,43In1987,Weisdorfetal.comparedPNversus intravenousdextrosesolutiontoadultandpediatricpatients undergoingallogeneicandautologousHSCTfromsevendays before cytoreductive chemotherapyuntil 28 days after the transplant.PatientsintheallogeneicgrouponPNhada bet-ter2-yearoverallsurvival,althoughpresentedahigherrate ofbacteremiacomparedtothecontrolgroup.Nodifferencein timetoengraftment,lengthofhospitalizationandincidence ofGVHDwereobserved.43Overthelastdecades,similar stud-ieshavebeenpublished.9,39,44–46Nevertheless,mostofthem hadheterogeneouspopulationsofchildrenandadults under-goingautologousandallogeneicHSCT,makingananalysisof theresultsadifficulttask.Loughetal.forexample,compared totalPN(TPN)andintravenous5%dextrosesolutioninadults submittedtobothtypesofHSCT;therewasatrendtowards morefluidoverload,longertimeoffeverandahigher num-berofpositivebloodculturesintheTPNarm.45 Muscaritoli et al.,in 1998,comparedglucose-basedand lipid-based PN inbothtypesoftransplant, demonstratingatrendtowards moreacuteGVHDandhyperglycemiaintheglucosegroup.46 Morerecently,Cetinetal.evaluatedtheeffectsofTPNversus partialPNinautologouspatients;theTPNgrouphadhigher ratesofhyperglycemia,moreinfectionsanddelayedplatelet engraftment.44 Therefore,asArfons etal.demonstrated,to constructclearrecommendationsabouttheuseofPNinthis scenarioisstillchallengingconsideringtheheterogeneityof theavailablestudies.10
the transplantation (Day 0 or 1) independently of oral tol-erance,oraccordingtothenutritionalneedsofthepatient. The former approach is less used, although some centers stillpreferthisformofnutritionalintervention:startingon thefirstdayafterallo-HSCTandcontinuingfor15–21days.1 Therefore,whentostartPNisanothermatterofcontroversy. TheEuropeanSocietyforClinicalNutritionandMetabolism (ESPEN)proposestoinitiatePNonceoralfeedingfallsbelow 60–70%ofrequirementsforthreeconsecutivedays,47andthis recommendationisfollowed bythe SociedadeBrasileirade Nutric¸ãoParenteraleEnteral(SBNPE).48 TheAmerican Soci-etyforParenteralandEnteralNutritionconsiders7–14daysan appropriatedefinitionof“prolongedperiodoftime”of unsatis-factoryoral/enteralnutritionbeforeestablishingPN.24Table1 showsthe currentrecommendations ofnutritional support and use of PN in HSCTfrom different societies and study groups.
WhenPNiscomparedtoEN,moststudiesshowedseveral benefitsofmaintainingtheuseofthedigestivetractduring thetransplantphases.39–41InthesameyearasWeisdorfetal. publishedtheirstudyonPN,Szelugaetal.conductedastudy tocompareENandPNinpediatricandadultHSCTpatients. Therewere nodifferencesbetweengroupsinterms of sur-vival,immunologicalrecovery,lengthofhospitalization,and GVHD;however,anon-statisticallysignificantdifferencewas observedintheincidenceofbacteremia,catheter-site infec-tions,hyperglycemiaandfluidoverloadinthePNpatients.11 Sincethen,agrowingnumberoftrialshavebeenconducted todemonstratethesafety andfeasibilityofENinthis con-text,butup-to-dateguidelineswithclearrecommendations arestilllacking.AccordingtoGuieseetal.,therearefew stud-iescomparingENtoPNamongallo-HSCTpatients,although theavailableevidenceshowsacleartrendofreductioninthe incidenceofacuteGVHDandlowinfection-relatedmortality withinthefirst100daysaftertransplantinpatientsreceiving EN.39,40 Theonly meta-analysis available until today, pub-lishedin2008,concludedthatthereisstillinsufficientdata todetermineclearbenefitsofENversusPNinpatients under-goingallo-HSCT.15 Evenwiththeselimitations,theauthors propose that EN should be adopted as the first choice for nutritional supportwhilethe gut remains functional, with supplementary PN beingadded onlywhen energy require-mentsarenotachievedorthereisaclearintolerancetotube feeding.15TheESPENalsosharestheserecommendations:PN shouldbereservedforuse inpatients withsevere mucosi-tis(grade3–4),prolongedileus,andintractablevomiting.47A prospectiverandomizedcontrolledtrialcomparingPNandEN aftermyeloablativeHSCTisongoinginFrance(NEPHAstudy), andhopefullywillelucidatethisimportantissueinthenear future.49
Post-transplantation
hyperglycemia:
the
role
of
parenteral
nutrition
HyperglycemiafrequentlyoccursafterHSCT,mainlybecause of the effects of glucocorticosteroids, immunosuppressive drugs and the use of PN.12,37,38 The hyperglycemic envi-ronment may cause a delay inneutrophil recovery, impair neutrophilfunction, promotegreater riskofinfections and
prolong engraftment times.50 Additionally, the metabolic alterations thatoccur inthe early phaseafter transplanta-tionresultinmoreendogenousglucoseproduction,increased insulinresistanceandanimpairedcapacitytooxidizeplasma glucose.51 Factorsthat were independentlyassociatedwith hyperglycemiaduringthefirsttendaysafterallo-HSCTwere greater BMI and insulin resistance, use of tacrolimus and glucocorticoids, myeloablative conditioning withtotal body irradiationandtheuseoftotalPN.37Ithasbeendemonstrated thattheoddsofdevelopinghyperglycemiaafterPNisnearly four-fold(oddsratio:3.9;95%confidenceinterval:2.7–5.5)that ofpatients notsubmittedtoPN aftercontrollingfordonor type,race,age,andconditioningchemotherapy.50
Ithasbeenhypothesizedthatthenegativeconsequences ofimpairedglucosecontrolintheinflammatorycascadecan also increase the risk of acute GVHD, which itself raises hyperglycemia even further, creating a vicious cycle.52,53 Gebremedhinetal.showedahigherincidenceofacuteGVHD after allo-HSCT when severe hyperglycemia was present. However,thisassociationvariedbycategoryofBMI:among normal-to-overweight subjects, severe hyperglycemia was markedlyassociatedwithacuteGVHD,andleanBMIseemed tobeaprotectivefactoragainstthiscomplication.37Fujietal. alsodemonstrated agreater cumulativeincidence ofgrade II–IV GVHD in patients presenting hyperglycemia (glucose levels>150mg/dL)duringtheneutropenicphaseafter trans-plant.Accordingtotheseauthors,itisreasonabletospeculate thattheincreasedproductionofinflammatorycytokinesby hyperglycemiacanactasariskfactorinthepathogenesisof acute GVHDandorgan dysfunction.12 According toSheean et al., PN has inherently greater risks of infections when comparedwithENorstandardoraldiets,andbecauseofits adverse consequences,severalauthorshavechallengedthe intuitiveconclusionthatPNisbeneficialandnecessaryduring HSCT.14Ahigherriskofcatheter-relatedbloodstream infec-tionsinPNrecipientsiswelldescribedintheliterature54as themicro-andmacronutrientcompositionofPNcan facili-tatethegrowthofmicroorganisms.55Furthermore,ithasbeen suggestedthattheseinfectiouscomplicationscouldalsobe related tobacterialtranslocationdueto atrophyofthe gut mucosaandgut-associatedlymphoidtissue,asaconsequence ofPNorabsenceofEN.56 However,accordingtoJeejeebhoy etal.,humanstudiesdidnotdemonstrateintestinalatrophy relatedtoPNandthereislittleevidencethatENcanprevent bacterialtranslocation.57
Table1–NutritionalsupportrecommendationsanduseofPNinHSCTbydifferentsocietiesandstudygroups. Indications forNST Energy requirements Protein requirements PN discontin-uation criteria Areasof uncertainty PNadverse effects
ASPEN9 Malnourishedpatients unableto
absorb/ingest adequatenutrientsfor 7–14days
CriteriatoinitiatePN notspecified
Notmentioned Not mentioned Afterstem cell engraftment when adequateEN ororalintake isfeasible
Benefitsofalipid basedPNvs. glucosebasedPN todecreaserisk ofGVHD Useofglutamine
Increasedmorbidity, morediarrhea,more hyperglycemia, delayedtimeto engraftment
ESPEN47 StartNSTif: -Undernourished -Inabilitytoeat>60% ofnutritionalneeds for>7days PNpreferredif increasedriskof hemorrhageand infectionrelatedto tubeplacement Ambulant patient: 30–35kcal/kg/day Bedridden patient: 20–25kcal/kg/day (recommenda-tionsforgeneral oncology patients) 1.2–2.0g/kg/day (recommen-dationsfor general oncology patients) Not mentioned Benefitsof glutamineand omega3 Notmentioned Italiangroup University La Sapienza, Rome2
PNroutinelyinitiated onDay-1ofallo-HSCT andcontinuedfor 15–21days.Oral intakenotallowed duringthisperiod
130–150%of basalenergy requirementsor 30–35kcal/kg/day
1.5g/kg/day Not mentioned
Benefitsofalipid basedPNin decreasingrisk ofacuteGVHD useofglutamine
Notmentioned
FNCLCC18 NSTindicatedto malnourished patients(>10%lossof bodyweight) irrespectiveofthe typeoftransplantor conditioning PNiforal/EN intolerance,GI obstructionorsevere mucositis
Non-protein calorieintakeof 25–35kcal/kg/day Daily nitrogen intake between200 and 250mg/kg Oraland/or ENableto provide>60% ofnutritional requirements
Benefitsofalipid basedPNin decreasingrisk ofacuteGVHD useofglutamine
Notmentioned Spanish group Univesity LaPaz, Madrid6
StartPNif: -Lossof>10%of initialweight -BMI<18.5kg/m2
-Oralintake<60–70% ofrequiredover3days
130–150%ofthe estimatedbasal energy requirements,or 30–50kcal/kg/day 1.5–2.0g/kg/day ofstandard aminoacid solution Oraldiet covers>50% ofdaily energyneeds Benefitsof glutamine, antioxidants (selenium, vitaminsCandE) andomega3
Catheter-related infections Atrophyofvilliand increaseinbacterial translocation
SBNPE48 StartPNif:
-Severemalnutrition athospitaladmission -7–10daysof inadequateoralintake -Weightloss>10% duringtreatment
130–150%of basalenergy requirementsor 30–35kcal/kg/day
1.5g/kg/day Oralintake and/orEN ableto provide>50% ofnutritional requirements
Timingtoinitiate PN:
-24–36hafter transplantation OR
-Whenoral intake<60–70% ofnutritional requirements
Morehyperglycemia, higherriskof infectionsand positiveblood cultures,prolonged hospitalizationand needoftransfusions
thattheglycemicgoalinnon-criticallyillpatientsreceiving TPNshouldbeatameanlevelof180mg/dL.52
Conclusions
Thisreviewaimedtodiscusssomerelevanttopicsrelatedto nutritionalstatus ofpatientssubmittedto HSCTand com-plications caused by PN in this population, in particular hyperglycemia and its adverse effects. Theamount of sci-entificevidenceregardingthebest nutritionalapproachfor HSCTpatientsisstillinsufficientandinconclusive,asthere isnoconsensusorclearrecommendationsregardingthe tim-ingandcriteriatoinitiateENandPN.Acompletenutritional assessmentpriortoHSCTisrecommendedbyallsocieties, asitgivesinformationessentialtobuildanutritionalsupport planfortheperitransplantperiod.
Despite the inherent risks of PN, and the insufficient amountofstudiesdemonstratingclearbenefitsofthistype ofnutritionintheHSCTpopulation,itcontinuestobe recom-mendedaspartoftransplantcare.Therefore,assessmentof riskfactorsforhyperglycemiapriortoHSCT,acarefulchoice oftheconditioningregimenandalleffortstoavoidprolonged PNinpatientsathigherriskforthiscomplicationcontribute tosuccessfulpost-transplantrecovery.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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s
1. AraiS,JagasiaM,StorerB,ChaiX,PidalaJ,CutlerC,etal.
Globalandorgan-specificchronicgraft-versus-hostdisease
severityaccordingtothe2005NIHConsensusCriteria.Blood.
2011;118(15):4242–9.
2. MuscaritoliM,GriecoG,CapriaS,IoriAP,RossiFanelliF.
Nutritionalandmetabolicsupportinpatientsundergoing
bonemarrowtransplantation.AmJClinNutr.
2002;75(2):183–90.
3. HabschmidtMG,BaconCA,GregoireMB,RasmussenHE.
Medicalnutritiontherapyprovidedtoadulthematopoietic
stemcelltransplantationpatients.NutrClinPract.
2012;27(5):655–60.
4. SoEJ,LeeJS,KimJY.Nutritionalintakeandnutritionalstatus
bythetypeofhematopoieticstemcelltransplantation.Clin
NutrRes.2012;1(1):3–12.
5. HerrmannVM,PetruskaPJ.Nutritionsupportinbonemarrow
transplantrecipients.NutrClinPractOffPublAmSoc
ParenterEnterNutr.1993;8(1):19–27.
6. Martin-SalcesM,dePazR,CanalesMA,MesejoA,
Hernandez-NavarroF.Nutritionalrecommendationsin
hematopoieticstemcelltransplantation.NutrBurbankLos
AngelCtyCalif.2008;24(7-8):769–75.
7. FujiS,TakanoK,MoriT,EtoT,TaniguchiS,OhashiK,etal.
Impactofpretransplantbodymassindexontheclinical
outcomeafterallogeneichematopoieticSCT.BoneMarrow
Transplant.2014;49(12):1505–12.
8. FujiS,EinseleH,SavaniBN,KappM.Systematicnutritional
supportinallogeneichematopoieticstemcelltransplant
recipients.BiolBloodMarrowTransplantJAmSocBlood
MarrowTransplant.2015;21(10):1707–13.
9.vanderMeijBS,deGraafP,WierdsmaNJ,LangiusJAE,
JanssenJJWM,vanLeeuwenPAM,etal.Nutritionalsupportin
patientswithGVHDofthedigestivetract:stateoftheart.
BoneMarrowTransplant.2013;48(4):474–82.
10.IestraJA,FibbeWE,ZwindermanAH,RomijnJA,KromhoutD.
Parenteralnutritionfollowingintensivecytotoxictherapy:an
exploratorystudyontheneedforparenteralnutritionafter
varioustreatmentapproachesforhaematological
malignancies.BoneMarrowTransplant.1999;23(9):933–9.
11.ArfonsLM,LazarusHM.Totalparenteralnutritionand
hematopoieticstemcelltransplantation:anexpensive
placebo?BoneMarrowTransplant.2005;36(4):281–8.
12.SzelugaDJ,StuartRK,BrookmeyerR,UtermohlenV,Santos
GW.Nutritionalsupportofbonemarrowtransplant
recipients:aprospective,randomizedclinicaltrialcomparing
totalparenteralnutritiontoanenteralfeedingprogram.
CancerRes.1987;47(12):3309–16.
13.FujiS,KimS-W,MoriS,FukudaT,KamiyaS,YamasakiS,etal.
Hyperglycemiaduringtheneutropenicperiodisassociated
withapooroutcomeinpatientsundergoingmyeloablative
allogeneichematopoieticstemcelltransplantation.
Transplantation.2007;84(7):814–20.
14.SarkisianS,FentonTR,ShaheenAA,RamanM.Parenteral
nutrition-associatedhyperglycemiainnoncriticallyill
inpatientsisassociatedwithhighermortality.CanJ
GastroenterolJCanGastroenterol.2010;24(7):453–7.
15.SheeanPM,BraunschweigC,RichE.Theincidenceof
hyperglycemiainhematopoieticstemcelltransplant
recipientsreceivingtotalparenteralnutrition:apilotstudy.J
AmDietAssoc.2004;104(9):1352–60.
16.MurraySM,PindoriaS.Nutritionsupportforbonemarrow
transplantpatients.CochraneDatabaseSystRev.
2009;(1):CD002920.
17.FerreiraEE,GuerraDC,BaluzK,deResendeFurtadoW,da
SilvaBouzasLF.Nutritionalstatusofpatientssubmittedto
transplantationofallogeneichematopoieticstemcells:a
retrospectivestudy.RevBrasHematolEHemoter.
2014;36(6):414–9.
18.RaynardB,NitenbergG,Gory-DelabaereG,BourhisJH,
BachmannP,BensadounRJ,etal.SummaryoftheStandards,
OptionsandRecommendationsfornutritionalsupportin
patientsundergoingbonemarrowtransplantation(2002).BrJ
Cancer.2003;89Suppl.1:S101–6.
19.WangB,YanX,CaiJ,WangY,LiuP.Nutritionalassessment
withdifferenttoolsinleukemiapatientsafterhematopoietic
stemcelltransplantation.ChinJCancerResChung-KuoYen
ChengYenChiu.2013;25(6):762–9.
20.DeegHJ,SeidelK,BruemmerB,PepeMS,AppelbaumFR.
Impactofpatientweightonnon-relapsemortalityafter
marrowtransplantation.BoneMarrowTransplant.
1995;15(3):461–8.
21.GleimerM,LiY,ChangL,PaczesnyS,HanauerDA,FrameDG,
etal.Baselinebodymassindexamongchildrenandadults
undergoingallogeneichematopoieticcelltransplantation:
clinicalcharacteristicsandoutcomes.BoneMarrow
Transplant.2015;50(3):402–10.
22.LeBlancK,RingdénO,RembergerM.Alowbodymassindex
iscorrelatedwithpoorsurvivalafterallogeneicstemcell
transplantation.Haematologica.2003;88(9):1044–52.
23.RadfarM,FaghihiT,HadjibabaieM,EbrahimiF,QorbaniM,
IravaniM,etal.Impactofpreexistingdiabetesmellituson
transplantationoutcomesinhematopoieticstemcell
transplantation.EndocrRes.2015;40(1):20–4.
24.AugustDA,HuhmannMB,AmericanSocietyforParenteral
andEnteralNutrition(A.S.P.E.N.)BoardofDirectors.A.S.P.E.N.
clinicalguidelines:nutritionsupporttherapyduringadult
transplantation.JPENJParenterEnteralNutr. 2009;33(5):472–500.
25.PereiraAZ,VictorES,VidalCampregherP,PiovacariSMF,
BernardoBarbanJS,PedreiraWL,etal.Highbodymassindex
amongpatientsundergoinghematopoieticstemcell
transplantation:resultsofacross-sectionalevaluationof
nutritionalstatusinaprivatehospital.NutrHosp.
2015;32(6):2874–9.
26.LiuP,YanX,WangB-S,XuX-D.Threemethodsassess
nutritionalstatusofleukemiapatientsbeforehematopoietic
stemcelltransplantation.ChinMedJ(Engl).2012;125(3):440–3.
27.LiuP,ZhangZ-F,CaiJ-J,WangB-S,YanX.NRS2002assesses
nutritionalstatusofleukemiapatientsundergoing
hematopoieticstemcelltransplantation.ChinJCancerRes
Chung-KuoYenChengYenChiu.2012;24(4):299–303.
28.KondrupJ,RasmussenHH,HambergO,StangaZ,AdHoc
ESPENWorkingGroup.Nutritionalriskscreening(NRS2002):
anewmethodbasedonananalysisofcontrolledclinical
trials.ClinNutrEdinbScotl.2003;22(3):321–36.
29.UrbainP,BirlingerJ,IhorstG,BiesalskiH-K,FinkeJ,BertzH.
Bodymassindexandbioelectricalimpedancephaseangleas
potentiallymodifiablenutritionalmarkersareindependent
riskfactorsforoutcomeinallogeneichematopoieticcell
transplantation.AnnHematol.2013;92(1):111–9.
30.daSilvaTK,BerbigierMC,RubinBdeA,MoraesRB,Corrêa
SouzaG,SchweigertPerryID.Phaseangleasaprognostic
markerinpatientswithcriticalillness.NutrClinPractOff
PublAmSocParenterEnterNutr.2015;30(2):261–5.
31.NakaoM,ChiharaD,NiimiA,UedaR,TanakaH,MorishimaY,
etal.Impactofbeingoverweightonoutcomesof
hematopoieticSCT:ameta-analysis.BoneMarrow
Transplant.2014;49(1):66–72.
32.TakanoK,FujiS,UchidaN,OgawaH,OhashiK,EtoT,etal.
Pre-transplantdiabetesmellitusisariskfactorfor
non-relapsemortality,especiallyinfection-relatedmortality,
afterallogeneichematopoieticSCT.BoneMarrowTransplant.
2015;50(4):553–8.
33.FujiS,KimS-W,YoshimuraK,AkiyamaH,OkamotoS,SaoH,
etal.Possibleassociationbetweenobesityand
posttransplantationcomplicationsincludinginfectious
diseasesandacutegraft-versus-hostdisease.BiolBlood
MarrowTransplantJAmSocBloodMarrowTransplant.
2009;15(1):73–82.
34.SorrorML,MarisMB,StorbR,BaronF,SandmaierBM,
MaloneyDG,etal.Hematopoieticcelltransplantation
(HCT)-specificcomorbidityindex:anewtoolforrisk
assessmentbeforeallogeneicHCT.Blood.2005;106(8):2912–9.
35.TeixeiraGM,BittencourtH,deMacedoAV,MartinhoGH,
ColosimoEA,RezendeSM.Assessingtheinfluenceof
differentcomorbiditiesindexesontheoutcomesof
allogeneichematopoieticstemcelltransplantationina
developingcountry.PLOSONE.2015;10(9):e0137390.
36.SinghalS,GordonLI,TallmanMS,WinterJN,EvensAM,Evens
AO,etal.Idealratherthanactualbodyweightshouldbeused
tocalculatecelldoseinallogeneichematopoieticstemcell
transplantation.BoneMarrowTransplant.2006;37(6):553–7.
37.GebremedhinE,BehrendtCE,NakamuraR,ParkerP,Salehian
B.Severehyperglycemiaimmediatelyafterallogeneic
hematopoieticstem-celltransplantationispredictiveofacute
graft-versus-hostdisease.Inflammation.2013;36(1):177–85.
38.HammerMJ,CasperC,GooleyTA,O’DonnellPV,BoeckhM,
HirschIB.Thecontributionofmalglycemiatomortality
amongallogeneichematopoieticcelltransplantrecipients.
BiolBloodMarrowTransplantJAmSocBloodMarrow
Transplant.2009;15(3):344–51.
39.GuièzeR,LemalR,CabrespineA,HermetE,TournilhacO,
CombalC,etal.Enteralversusparenteralnutritionalsupport
inallogeneichaematopoieticstem-celltransplantation.Clin
NutrEdinbScotl.2014;33(3):533–8.
40.SeguyD,BerthonC,MicolJ-B,DarréS,DalleJ-H,NeuvilleS,
etal.Enteralfeedingandearlyoutcomesofpatients
undergoingallogeneicstemcelltransplantationfollowing
myeloablativeconditioning.Transplantation.
2006;82(6):835–9.
41.SeguyD,DuhamelA,RejebMB,GomezE,BuhlND,BrunoB,
etal.Betteroutcomeofpatientsundergoingenteraltube
feedingaftermyeloablativeconditioningforallogeneicstem
celltransplantation.Transplantation.2012;94(3):287–94.
42.SchmidtGM,BlumeKG,BrossKJ,SpruceWE,WaldronJC,
LevineR.Parenteralnutritioninbonemarrowtransplant
recipients.ExpHematol.1980;8(4):506–11.
43.WeisdorfSA,LysneJ,WindD,HaakeRJ,SharpHL,GoldmanA,
etal.Positiveeffectofprophylactictotalparenteralnutrition
onlong-termoutcomeofbonemarrowtransplantation.
Transplantation.1987;43(6):833–8.
44.CetinT,ArpaciF,DereY,TuranM,OztürkB,KömürcüS,etal.
Totalparenteralnutritiondelaysplateletengraftmentin
patientswhoundergoautologoushematopoieticstemcell
transplantation.NutrBurbankLosAngelCtyCalif.
2002;18(7-8):599–603.
45.LoughM,WatkinsR,CampbellM,CarrK,BurnettA,Shenkin
A.Parenteralnutritioninbonemarrowtransplantation.Clin
NutrEdinbScotl.1990;9(2):97–101.
46.MuscaritoliM,ConversanoL,TorelliGF,ArceseW,CapriaS,
CangianoC,etal.Clinicalandmetaboliceffectsofdifferent
parenteralnutritionregimensinpatientsundergoing
allogeneicbonemarrowtransplantation.Transplantation.
1998;66(5):610–6.
47.BozzettiF,ArendsJ,LundholmK,MicklewrightA,ZurcherG,
MuscaritoliM,etal.ESPENguidelinesonparenteralnutrition:
non-surgicaloncology.ClinNutr.2009;28(4):445–54.
48.TerapiaNutricionalnoTransplantedeCélulaHematopoiética. SociedadeBrasileiradeNutric¸ãoParenteraleEnteral(SBNPE) eAssociac¸ãoBrasileiradeNutrologia(ABRAN).2011.
49.LemalR,CabrespineA,PereiraB,CombalC,RavinetA,
HermetE,etal.Couldenteralnutritionimprovetheoutcome
ofpatientswithhaematologicalmalignanciesundergoing
allogeneichaematopoieticstemcelltransplantation?Astudy
protocolforarandomizedcontrolledtrial(theNEPHAstudy).
Trials.2015;16:136.
50.SheeanPM,FreelsSA,HeltonWS,BraunschweigCA.Adverse
clinicalconsequencesofhyperglycemiafromtotalparenteral
nutritionexposureduringhematopoieticstemcell
transplantation.BiolBloodMarrowTransplantJAmSocBlood
MarrowTransplant.2006;12(6):656–64.
51.BraunschweigCL,LevyP,SheeanPM,WangX.Enteral
comparedwithparenteralnutrition:ameta-analysis.AmJ
ClinNutr.2001;74(4):534–42.
52.OlveiraG,TapiaMJ,OcónJ,Cabrejas-GómezC,
Ballesteros-PomarMD,Vidal-CasariegoA,etal.Parenteral
nutrition-associatedhyperglycemiainnon-criticallyill
inpatientsincreasestheriskofin-hospitalmortality
(multicenterstudy).DiabetesCare.2013;36(5):
1061–6.
53.TurinaM,FryDE,PolkHC.Acutehyperglycemiaandthe
innateimmunesystem:clinical,cellular,andmolecular
aspects.CritCareMed.2005;33(7):1624–33.
54.BeghettoMG,VictorinoJ,TeixeiraL,deAzevedoMJ.Parenteral
nutritionasariskfactorforcentralvenouscatheter-related
infection.JPENJParenterEnteralNutr.2005;29(5):367–73.
55.MachadoJD,SuenVM,FigueiredoJF,MarchiniJS.Biofilms,
infection,andparenteralnutritiontherapy.JPENJParenter
56.AnastasilakisCD,IoannidisO,GkiomisiAI,BotsiosD.
Artificialnutritionandintestinalmucosalbarrier
functionality.Digestion.2013;88(3):193–208.
57.JeejeebhoyKN.Totalparenteralnutrition:potionorpoison?
AmJClinNutr.2001;74(2):160–3.
58.SheeanP,BraunschweigC.Theincidenceandimpactof
dextrosedoseonhyperglycemiafromparenteralnutrition
(PN)exposureinhematopoieticstemcelltransplant(HSCT)
recipients.JPENJParenterEnteralNutr.2006;30(4):345–50.
59.vandenBergheG,WoutersP,WeekersF,VerwaestC,
BruyninckxF,SchetzM,etal.Intensiveinsulintherapyin
criticallyillpatients.NEnglJMed.2001;345(19):1359–67.
60.NICE-SUGARStudyInvestigators,FinferS,LiuB,ChittockDR,
NortonR,MyburghJA,etal.Hypoglycemiaandriskofdeath
