Rev. Bras. Anestesiol. vol.65 número4

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REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

OfficialPublicationoftheBrazilianSocietyofAnesthesiology www.sba.com.br

REVIEW

ARTICLE

Colloids

versus

crystalloids

in

objective-guided

fluid

therapy,

systematic

review

and

meta-analysis.

Too

early

or

too

late

to

draw

conclusions

Javier

Ripollés

a,∗

,

Ángel

Espinosa

b

,

Rubén

Casans

c

,

Ana

Tirado

a

,

Alfredo

Abad

d

,

Cristina

Fernández

e

,

José

Calvo

f

a_Anestesia_y_{Reanimación,}_Hospital_{Universitario}_Infanta_Leonor,_Madrid,_Spain

b_Thorax_{Anesthesiology}_and_Intensive_Care_Consultant,_Thorax_Centrum,_Karlskrona,_Sweden c_Hospital_Clínico_{Universitario}_Lozano_Blesa,_Zaragoza,_Spain

d_Anestesia_y_{Reanimación,}_Hospital_{Universitario}_La_Paz,_Madrid,_Spain

e_Universidad_Complutense_de_Madrid,_Unidad_de_Metodología_de_la_{Investigación}_y_{Epidemiología}_clínica,_Servicio_de_Medicina

Preventiva,HospitalClínicoSanCarlos,Madrid,Spain

f_Universidad_Complutense_de_Madrid,_Hospital_{Universitario}_Infanta_Leonor,_Madrid,_Spain

Received29May2014;accepted3July2014 Availableonline3May2015

KEYWORDS

Fluidtherapy; Objective-guided fluidtherapy; Colloids;

Hydroxyethylstarch; Crystalloids;

Systematicreview; Meta-analysis

Abstract

Introduction:SeveralclinicaltrialsonGoaldirectedfluid therapy(GDFT)werecarried out,

manyofthoseusingcolloidsinordertooptimizethepreload.AfterthedecisionofEuropean MedicinesAgency,thereissuchcontroversyregardingitsuse,benefits,andpossiblecontribution torenalfailure.Theobjectiveofthissystematicreviewandmeta-analysisistocomparetheuse oflast-generationcolloids,derivedfromcorn,withcrystalloidsinGDFTtodetermineassociated complicationsandmortality.

Methods:AbibliographicresearchwascarriedoutinMEDLINEPubMed,EMBASEandCochrane

Library,corroboratingrandomizedclinicaltrialswherecrystalloidsarecomparedtocolloidsin GDFTformajornon-cardiacsurgeryinadults.

Results:One hundred thirtyreferenceswere foundand amongthose 38were selected and

29 analyzed;ofthese,sixwereincludedfor systematicreviewandmeta-analysis,including 390patients.Itwasobservedthattheuseofcolloids isnotassociated withtheincrease of complications,butratherwithatendencytoahighermortality(RR[95%CI]3.87[1.121---13.38];

I2₌_0.0%;_p₌_0.635).

∗_{Corresponding}_author.

E-mails:ripo542@gmail.com,ripo542@hotmail.com(J.Ripollés). http://dx.doi.org/10.1016/j.bjane.2014.07.018

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Conclusions:Becauseofthelimitationsofthismeta-analysisduetothesmallnumberof ran-domizedclinicaltrialsandpatientsincluded,theresultsshouldbetakencautiously,andthe performanceofnewrandomizedclinicaltrialsisproposed,withenoughstatisticalpower, com-paringbalancedandunbalancedcolloidstobalancedandunbalancedcrystalloids,followingthe protocolsofGDFT,consideringcurrentguidelinesandsuggestionsmadebygroupsofexperts. ©2014SociedadeBrasileiradeAnestesiologia.PublishedbyElsevier EditoraLtda.Allrights reserved.

PALAVRAS-CHAVE

Hidratacão; Hidratacãoguiada porobjetivos; Coloides; Derivadosde HidroxietilAmido; Soluc¸õesIsotônicas; Revisãosistemática; Metanálise

Coloidesversus cristaloidesemfluidoterapiaguiadaporobjetivos,revisão sistemáticaemetanálise.Demasiadamentecedooudemasiadamentetardepara obterconclusões

Resumo

Introduc¸ão:Foramrealizadosmúltiplosensaiosclínicosemfluidoterapiaguiadaporobjetivos

(FGO),sendomuitosdelescomousodecoloidesparaotimizaçãodapré-carga.Apósadecisão daAgenciaEuropeadeMedicamento,existeaindacontrovérsiasobresuautilização,benefícios epossívelcontribuiçãoparaafalênciarenal.Oobjetivodestarevisãosistemáticaemetanálise écompararousodecoloidesdeúltimageração,derivadosdemilho,comcristaloidesemFGO paradeterminarascomplicaçõeseamortalidadeassociadas.

Métodos: Realizac¸ão deuma busca bibliográfica em MEDLINE Pubmed, EMBASE eBiblioteca

Cochrane comprovando ensaios clínicos aleatórios nos quais se comparamcristaloides com coloidesdentrodeFGOparacirurgianãocardíacadegrandeporteemadultos.

Resultados: Foramobtidas130referênciasdasquaisseselecionaram38e29foramanalizadas;

destas,seisforamincluídaspara revisãosistemáticaemetanálise,incluindo 390pacientes. Observou-sequeousodecoloidesnãoestáassociadoaumaumentodecomplicac¸õesmassim comumatendênciaamaiormortalidade(RR[IC95%]3,87[1,121-13,38];I2₌_0,0%;_p₌_0,635).

Conclusões:Devido às limitac¸ões desta metanálise em decorrência do número escasso de

ensaiosclínicosaleatóriosepacientesincluídos,osresultadosdevemserusadoscomcautela,e propõe-searealizac¸ãodenovosensaiosclínicosaleatórios,compotênciaestatísticasuficiente naquelesemquesecomparamcoloidesbalanceadosenãobalanceadoscomcristaloides bal-anceadosenãobalanceados,dentrodeprotocolosdeFGO,respeitandoasindicac¸õesatuaise assugestõesemitidaspelosgruposdeespecialistas.

Introduction

Recently, several clinical trials have been published, as wellasmeta-analysis1---11_in_which_it_was_demonstrated_that

theuseofperioperativegoal-directedfluidtherapy(GDFT)

decreasespost-surgical2---9,11 _{complications,} _hospital_stay2,3

andmortality.1,7,8_The_GDFT _is_based_on_preload

optimiza-tionwiththeuseoffluids,inotropesand/orvasoconstrictors

throughalgorithmsdesignedforthispurpose,toachievea

particulartargetofstrokevolume(SV),cardiacindexor

oxy-gen delivery. The ultimate goal of this optimization is to

avoidfluidoverload,aswellashypoperfusionandhypoxia.12

Froma pathophysiologicalpoint ofview, hemodynamic

stabilizationwithcolloidsshouldresultinasmalleramount

ofliquidadministrated,13 _and_a_shorter_time_in _which_the

patientwouldfindhim/herselfinarelativepositionof

hypo-volemiaandpossibletissuehypoperfusion.14

Afterexaminingtheavailableevidence,andbasedmainly

on3 studies,15---17 _in_June ₂₀₁₃_the_{Pharmacovigilance}_Risk

Assessment Committeeof the European MedicinesAgency

concludedthatthebenefitsoftheuseofcolloids

(hydrox-yethylstarches [HES]) were smaller than their risks,18 _in

the same way as the Food and Drug Administration

rec-ommended to avoid its use in patients with sepsis and

in patients with renal insufficiency (RI).19 _These

conclu-sions were based on studies of patients with sepsis, not

inthecontextofintraoperativehemodynamicstabilization

from bleeding or relative hypovolemia, and the

possibil-ity of extrapolating the findings is debatable. Recently

Gillies etal.,20 _after _performing_a _systematic _review _and

meta-analysis in which colloids were compared with

dif-ferentkindsof liquids, concludedthat theuse ofHES did

not increase mortality, hospital stay, RI or the need for

extrarenalclearance20_;_however,_in _this_{meta-analysis}

col-loids are not comparedwith crystalloids in studies which

usedaGDFTalgorithmandincludedonlythreerandomized

controlled trials (RCTs), in which colloids were compared

(3)

this systematic review and meta-analysis is to determine

whethertheuseofthelatestgenerationofcolloidsderived

fromcorn (HE6%:130/0.4)for hemodynamicoptimization

inGDFTreducespostoperativecomplicationsandmortality.

Material

and

methods

Selectioncriteria

The studies were searched according to the following

selectioncriteriaandaccordingtothePRISMA/CONSORT24

methodology.

1. Participants: adult patients were included (>18 years)

undergoing scheduled noncardiac surgery. The studies

werenotlimitedaccordingtosurgicalrisk.

2. Typesofintervention: intraoperativeGDFTwhich

com-pares the use of crystalloids with colloids derived

from last generation corn (6% HE: 130/0.4), defining

that asthe hemodynamic monitoring that enables the

implementation of a hemodynamic optimization

algo-rithm based on the use of liquids, inotropes and/or

vasopressorstoachievenormalorsupernormal

hemody-namic values. Pulmonary artery catheter-guided GDFT

isexcluded,aswellasGDFTguidedbytransesophageal

echocardiographyorobsoletetechnology.Thosestudies

comparingHESwithcolloid instroke volume(SV)

opti-mizationwithoutcontributingwithoutcomesdefinedfor

this meta-analysiswere excluded. It is limited to

col-loids derived from low molecular weightcorn (HE 6%:

130/0.4).

3. Typesofcomparison:thosestudiescomparingGDFTwith

colloids to GDFT with crystalloids were selected for

analysis.Weexcludedthosestudiescomparingbalanced

versus unbalanced solutions. Those RCTs comparing a

monitoringtechnologywithanother,andthoseRCTs

com-paringdifferenttypesofhemodynamicalgorithms.

4. Outcomes: The primary outcome is the postoperative

complicationsandmortality.

5. Typesof studies: RCTsin which intraoperatoryGDFTis

performedinmajorschedulednoncardiacsurgery.

Informationsources

Different strategies of search were used (last updatedin

March2014)toidentifyrelevantstudiesthatmetthe

inclu-sion criteria in EMBASE, MEDLINE and Cochrane Library.

There was no restriction regarding publication date. The

searchwaslimitedtoarticlespublishedinEnglish.An

addi-tionalmanualsearchwasperformedwiththeaimthatevery

studypublishedwasanalyzed.

Searchitems

The search was performed using the following keywords

‘‘FluidTherapy’’(Mesh)AND‘‘HydroxyethylStarch

Deriva-tives’’(Mesh)AND‘‘IsotonicSolutions’’(Mesh).

Studyselectionanddataextraction

Two independent researchers assessed each title and

abstractinordertoruleouttheirrelevantRCTsandidentify

thosepotentiallyrelevant;thesewerethoroughlyanalyzed

selectingthosethatmettheinclusioncriteriasetoutabove.

TheextractionofdatafromtheincludedRCTswascarried

outbytworesearchersandanydiscrepancyrequiredanew

analysis,aswellasconfirmationbyathirdinvestigator.

Data extraction included characteristics of included

patients(ASA,age),typeofsurgery,typeofhemodynamic

monitoring,algorithmused,useoffluids,inotropesand/or

vasopressors,andgeneral,respiratory,infectiousand

surgi-calcomplications,transfusionandmortality.Dataextraction

wasrevisedbytheauthorsinordertoavoiderrorsindata

transcription.

Outcomes

Theprimaryoutcomeofthestudywasoverallcomplications

andmortality.

Abstract

measures

and

analysis

method

Statisticalanalysis

Weused Stata12.0 statistical softwareto perform

statis-ticalanalysis.Themeta-analysiswasperformedbyinverse

variationmethodfordichotomousoutcomesandcontinuous

data,results arepresented asrelativerisk (RR) with95%

confidenceinterval(CI95%)Themethodofmeandifference

wasusedwithamodelofrandomeffects.Forestplotswere

constructedconsideringp<0.05asstatisticallysignificant.

Theheterogeneityofthestudieswasevaluatedby

statisti-calI2_;_I2_values_are_defined_as_little_{heterogeneous,}_25---50%

moderatelyheterogeneous; and above 50% little

homoge-neous.2testforheterogeneitywasperformed,considering

statisticalsignificancep<0.01.

Thosestudieswherecomplicationsormortalityareequal

tozero cannotbe included inthe creationof forestplots

forstatisticalpurposes.Toevaluatetheagreementinbias

assessmentoftheauthor’skappastatisticswasused.

Results

Studyselection

Wefound130referencesinelectronicdatabases,ofwhich

38 were reviewed; of these, 29 RCTs were analyzed and

those which did not meet the inclusion criteria were

excluded.FinallysixRCTs21,25---29 _were_included. _RCTs_were

notfound in manualsearch. Atotal of 390 patientswere

included in thismeta-analysis. InFig. 1the flowchart for

selectingarticlesisshown.

Biasesriskevaluationinindividualstudies

Twoindependentresearcherscarriedoutthequality

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Table1 Evaluationofbiasesriskinisolatedstudies.

Study Year

Random-ization

Randomization sequence description

Double-blind

Blindness description

Missing description

Total Comments

Senagore etal.25

2009 1 1 1 0 0 3 Studynot

designedto detect complications noreffectof liquid

administration Zhang

etal.26

2012 1 1 0 0 1 3

Feldheiser etal.21

2013 1 1 1 1 1 5 Notdesignedto

analyze complications Yates

etal.27

2014 1 1 1 1 1 5

Lindroos etal.28

analyze complications Lindroos

etal.29

analyze complications

todescribethequalityofthestudiesbyassessingfive

ele-mentsof randomization, blindnessand application of the

protocol,withascoreof1---5;ahigh-qualitytrialistheone

whichhasascoreof5.ThisassessmentisshowninTable1.

130 references

92 articles eliminated, nonhuman, nonadult

38 articles for exhaustive

review

29 RCT for analysis

6 RCT for systematic review and metanalysis

23 studies are excluded since they do not meed

inclusion criteria 9 articles excluded: they

are not RCT

Figure1 Flowchartofarticlesincluded.

Characteristicsofstudiesincluded

The selected articles describe the results of those RCTs

that assess the useof colloids (6% HE:130/0.4, balanced

orunbalanced)versuscrystalloid(balancedorunbalanced)

inintraoperativeGDFTinprogrammednoncardiacsurgery,

thosewhichincludethepostoperativecomplicationsand/or

mortalityastheprimaryoutcome.Thecharacteristicsofthe

RCTsincludedareshowninTable2.

Ofsix RCTs analyzed, threeRCTs25---27 _were _carried _out

in gastrointestinal surgery; two in neurosurgery28,29 _and

one in gynecological surgery.21 _In _five _of _the _six _RCTs

included21,25---27,29_mortality_and_{complications}21,25---27,29_were

described. Twenty-eight were included in a systematic

review and meta-analysis as they describe decrease in

transfusion, which may be interpreted as a

complica-tion.OnlytwoRCTsdescribepostoperativerenalfailureas

complication.21,27

The GDFT was performed with two CardioQ® _in _two

RCT,21,25_in _two_cases _with_Flotrac®28,29 _with_LiDCO_Rapid®

inonecase27_and_through_calculation_of_pulse_pressure

vari-ationinanothercase.26 _The_{characteristics}_of_the_patients

includedareshowninTable3.

ThequalityoftheRCTsvaluedbyJadadscoreisshown

in Table 2,aswell asRCTs fundingincluded inthe

meta-analysis. Table 1 presents the description of the possible

biases.Onekappaagreementof90%wasfound intherisk

assessmentbetweenthetworesearchers.

Table4shows thestudies analyzedbut notincluded in

themeta-analysisbecausetheydidnotmeettheinclusion

criteriapreviouslydescribed.23,31---36_Senagore_et_al.25

com-pared the standard fluid therapy withGDFT withcolloids

(5)

Table2 CharacteristicsofRCTincluded.

Study Year Population Intervention Comparer Outcomes

Senagore etal.25

2009 Adult

patients Undergoing colorectal surgery

GDFTthroughCardioQ®_based

onalgorithmofmaximization ofSVwithHES(Voluven®_);

n=21

GDFTthrough CardioQ®_based_on

algorithmof maximizationof SVwithRinger lactate;n=21

Hospitalstay. Parametersof recuperationof bowelfunction. Complications Zhang etal.26

2012 Adult patients undergoing gastroin-testinal surgery

GDFTbasedonoptimization PPV<10%withHE;n=20

GDFTbasedon optimizationof PPV<10%with Ringerlactate; n=20

Hospitalstay. Parametersof recuperationof bowelfunction. Complications Feldheiser etal.21

2013 Adult

patients undergoing ovary surgery

GDFTthroughCardioQ®_based

onmaximizationalgorithmof SVwithbalancedHES (Volulyte®_),_{vasoconstrictors}

andinotropesforIC>2.5; n=24

GDFTthrough CardioQ®_based_on

maximization algorithmofSV withbalanced crystalloids (Jonosteril®_),

vasoconstrictors andinotropesfor CI>2.5;n=24

Totalfluids administered intraoperatively. Catecholamines administered. Hospitalstay. Complications Yates etal.27

2014 Adult

patients undergoing colorectal surgery

GDFTthroughLiDCORapid®

basedonalgorithmof

optimizationofSVV(SVV<10%) withHESanddopexamine; n=104

GDFTthrough LiDCORapid®

basedon algorithmof optimizationof SVV(SVV<10%) withRinger lactateand dopexamine; n=98

Gastrointestinal complicationson day5. Postoperative complications. Hospitalstay. Analytical parametersof coagulation Lindroos etal.28

2014 Adult

patients undergoing prone neu-rosurgery

GDFTthroughFlotrac®_based

onalgorithmofmaximization ofSVwithHES;n=15

GDFTthrough Flotrac®_based_on

algorithmof maximizationof SVwithRinger acetate;n=15

Fluidsnecessary forhemodynamic stabilization. Coagulation changes Lindroos etal.29

2013 Adult

patients undergoing neuro-surgery

GDFTthroughFlotrac®_based

onalgorithmofmaximization ofSVwithHESand

vasopressors;n=14

GDFTthrough Flotrac®_based_on

algorithmof maximizationof SVwithRinger acetateand vasopressors; n=14

Fluidsnecessary forhemodynamic stabilization. Coagulation changes

Study Design Jadadscore Conclusions Funds Country

Senagore etal.25

Monocentric Double-blind RCT

3 TheuseofGDFTwithCardioQ®

doesisnotbeneficialandis moreexpensivethan conventional.GDFTwith colloidsisnotbeneficial

Deltexmedical USA

Zhang etal.26

Monocentric RCT

3 TheuseofGDFTwithcolloids improvestheparametersof bowelfunctionanddecreases hospitalstay

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Table2 (Continued)

Study Design Jadadscore Conclusions Funds Country

Feldheiser etal.21

5 TheuseofGDFTwithcolloids provideshigherhemodynamic stability,withnoincreaseof riskofARF,anddecreasesFFP transfusions

FreseniusKabi Germany

Yates etal.27

5 TheuseofHEinGDFTdoesnot providecrystalloid-related benefits,exceptforalower balanceoffluidsinthefirst 24h

FreseniusKabi United Kingdom

Lindroos etal.28

Monocentric RCT

3 TheuseofGDFTwithHES decreasesthefluids administered.The

administrationof400ccofHES leadstochangesin

thromboelastogram

Notdeclared Finland

Lindroos etal.29

Monocentric RCT

3 TheuseofGDFTwithcolloids allowsdecreasingthe

perioperativeadministrationof fluidsandwaterbalance

HelsinkiUniversity Finland

RCT,randomizedclinicaltrial;GDFT,Goal-directedfluidtherapy;HES,hydroxyethylstarches;CI,cardiacindex;ARF,acuterenalfailure;

FFP,freshfrozenplasma;PPV,pulsepressurevariation;SV,strokevolume;SVV,strokevolumevariation.

(Ringerlactate)in GDFTbasedonaSV optimization

algo-rithmby CardioQ® _in_low-risk _patients _undergoing

laparo-scopic segmentalcolectomy within an enhanced recovery

program (fast track).37 _In _those _cases _where _no _SV

opti-mizationwasachievedwith20mLkg−1_HE_6%,_Ringer_lactate

wasused,notexceedingtherecommendeddosesand

indi-cations. They found a significant decrease in the amount

of liquid needed to get the optimal SV (863±850mL vs.

Table3 Characteristicsofpatientsincluded.

Study Year Surgery Monitoring ASA Age SI

dura-tion

Risk Describes mortality

Describes ARL

Describes complications Senagore

etal.25

2009 Colorectal CardioQ® _ND _ND ₁₄₃_vs.

150

High Yes No Yes

Zhang

etal.26

2012 Gastrointestinal Arterial I/IIvs.I 52.8vs.

53.3

183vs.

190

Low Yes No Yes

Feldheiser21 ₂₀₁₃ _{Gynecological} _CardioQ®

II/IIIvs.III 58vs.52 272vs.

242

Moderate-High

Yes Yes Yes

Yatesetal.27 ₂₀₁₄ _Colorectal _LiDCO

Rapid® II

vs.II 72vs.70 ND

Moderate-High

Yes Yes Yes

Lindroos

etal.28

2014 Neurosurgery Flotrac®

IIvs.II 55vs.52 169vs.

132

High No No No

Lindroos

etal.29

2013 Neurosurgery Flotrac®

IIIvs.III 40vs.43 145vs.

146

High Yes No Yes

ARL,AcuteRenalLesion;SI,surgicalintervention;ND,nodata.

Table4 Studiesanalyzedbutnotincludedinthemeta-analysis.

Study N Reasonforexclusion

Krebbeletal.31 ₄₀ _Balanced_and_unbalanced_solutions_are_compared

Kotakeetal.32 ₃₅ _A_colloid_different_from_HE_6%:_130/0.4_is_used

L’Hermiteetal.33 ₅₆ _Does_not_include_{complications}_or_mortality_as_primary_result

Dehneetal.34 ₆₀ _A_colloid_different_from_HE_6%:_130/0.4_is_used._GDFT_is_not_performed

Godetetal.35 ₆₅ _GDFT_is_not_performed

Guoetal.36 ₄₂ _A_colloid_different_from_HE_6%:_130/0.4_is_used._GDFT_is_not_performed

Hungetal.23 ₈₄ _GDFT_is_not_performed

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389±289mL;p<0.05).IntheHESgroupmorecomplications

werepresentedthoughnotsignificantly,andtherewasonly

adeceasedpatientinthestudy,correspondingtoHESgroup.

Theprimaryoutcomeofthestudywastohospitalstay;itis

notdesignedfor analysisofmajorcomplicationsanddoes

notdescribecasesofpostoperativerenalfailureorhowitis

defined.

Zhangetal.26 _compared_restrictive_fluid_therapy

proto-colswithGDFTwithcolloids(HE6%:130/0.4)orcrystalloids

(Ringerlactate)inGDFTbasedonpulsepressurevariation

optimization algorithm, in low-risk patients (ASA I-II and

estimated blood loss <500mL)undergoing gastrointestinal

surgery, including gastrectomy and segmental colectomy.

Therewerenoreportsthatthemaximumpermissibledoses

of colloid wereexceeded, andin any case it wasusedin

patientswithRI.Theyfoundasignificantdecreaseintheuse

ofintra-operativevasoconstrictors,andadecreasein

recov-erytimeofbowelfunctionfortheHES group(86.2±7.2h

vs. 95.4±9.1h; p<0.001); likewise, a decrease in

hos-pital stay in the HES group was detected (9.1±1.4 vs.

11.9±1.2days; p<0.001). There were no differences in

complications between both groups, and no patient died

duringthestudy.

Yates et al.27 _compared _the _use _of _colloids _(HE _6%:

130/0.4 balanced) versus crystalloids in GDFT throughSV

optimization and maintenance of stroke volume variation

<10% using LiDCORapid in patients at moderate-high risk

undergoingcolorectalsurgery.Themaximumdoseusedwas

HE50mLkg−1_using_a_balanced_gelatin_(Geloplasma®_,

Frese-niusKabi,Germany)incaseswherethatdosewasexceeded.

AHESgrouppatientandapatientfromthecrystalloidgroup

had RI. Patients included in the HES group received less

intraoperativefluid,whilepatientsinthecrystalloidgroup

receivedmorefluidsanddemandedhigherdose ofgelatin

tobeoptimized.Duringsurgery,therewasnodifferencein

theuseofvasopressors.Theprimaryoutcomeofthisstudy

wasthe intestinalfunction recoverytime, withno

differ-ences found within the groups. There were nosignificant

differences in post-operatory complications, norin

hospi-tal stay. It shouldbe noted that fourpatients in the HES

groupdevelopedacuteRIpostoperatively,whileonlytwoof

thecrystalloidgrouphadit.FivepatientsofHEgroup,and

twointhecrystalloidgroupdied.Weanalyzedthesystemic

inflammatoryresponsebyIL-6analysis,withnodifferences

betweengroups.

Feldheiser etal.21 _compared_balanced _colloids_(HE _6%:

Volulyte,FreseniusKabi,Germany)versusbalanced

crystal-loids(Jonosteril,FreseniusKabi,Germany)inGDFTbasedon

theoptimizationofSVandmaintenanceofthecardiacindex

>2.5mLkgmin−1_,_monitored_with_CardioQ® _in_low_to

mod-eraterisk patientsrequiringcytoreductiveresectionovary

surgery. Theuse ofHES waslimitedtothe maximum

rec-ommended dose, using fresh frozen plasma, when it was

exceeded.TheuseofHESenabledbetterhemodynamic

sta-bilization,inlesstimeandwithlessliquid,andasignificant

decreaseoffreshfrozenplasmaunits;however,therewere

no significant differences in postoperative complications,

hospitalstayormortality,althoughthestudyisnotdesigned

forthispurpose, withtheprimaryresultofthetotalfluids

administeredduringtheintraoperativeperiod.

Lindroos et al.28 _compared _the _use _of _colloids _(HE

6%:130/0.4unbalanced)withbalancedcrystalloid(Ringer

acetate)inGDFT basedonSVoptimizationwithfluidsand

vasopressors,whichis monitoredwithFlotrac® _in _low-risk

patientsundergoingneurosurgery intheproneposition.It

has been shown that the need for administration of

flu-idswas25%higher thanwithcrystalloidthan withcolloid

toachieve hemodynamicstabilization. Therewereno

sig-nificantdifferencesin hospitalstay orin complications.A

patientoftheHES group receivedtransfusionofred cells

concentrate.Nodeathswerereportedinthestudy.There

werenoreportsthatthemaximumpermissibledosesof

col-loidswereexceedednorofpostoperativeRI.

In anotherRCT in neurosurgery,Lindroos etal.29

com-paredtheuseofcolloids(HE6%:130/0.4unbalanced)with

balancedcrystalloid(Ringer acetate)withthe sameGDFT

algorithminpatients undergoingcraniotomyinthesitting

position; similarly, they found a smaller decrease of

liq-uids used for hemodynamic stabilization (<34%) with the

useof colloids, although therewere nosignificant

differ-encesfoundinpostoperativecomplicationsorhospitalstay;

theydidnotreportpostoperativeRInormortalitydata,thus

assumingthattherewerenodeaths.Thereisnoreportthat

maximumpermissibledosesofcolloidswereexceeded.

Primary

outcomes

Totalcomplications

OfthesixRCTsanalyzed,onlytwodescribethetotal

asso-ciatedcomplications.Nodifferenceswerefound,norwere

thereanyevidencethattheuseofcolloidswasassociated

withcomplications(RR:1.17;95%CI:0.86---1.61)(Fig.2).

Mortality

Mortalitywas assessedon threeof six RCTsanalyzed. We

foundatrendtowardincreasedmortalityinfavorofGDFT

with colloids (RR: 3.87---1.121; 95% CI: 13---38; I2₌_0.0%;

p=0.635),andinthethreestudiesincludedahigher

mor-talityinthecolloidgroupcomparedtocrystalloidgroupis

estimated.Thereisnoheterogeneity,althoughitmayseem

toexistatendencytopublishpositiveresults(Fig.3).

Discussion

ThecomparisonofcolloidsandcrystalloidsinGDFTwas

per-formedinmultiplesurgicalprocedureswithdifferenttypes

ofhemodynamicmonitoring,withdifferentalgorithms,and

achieving goals through different methods; as well as in

patientswithdifferentsurgicalrisk.

Themainresultsofthismeta-analysisare:(1)Thereare

nodifferencesinpostoperativecomplicationswiththeuse

ofGDFTwithcolloidsorcrystalloids;(2)Thereisatendency

tohighermortalityassociatedwithGDFTwithcolloids;(3)

InthestudiesanalyzedtheRIisnotdeterminedasaprimary

outcome or in accordance with internationally accepted

criteria,soitisnotpossibletodrawconclusionsregarding

theRIassociatedwiththeuseofcolloids.Itisworthnoting

thatthehighnumberofcomplicationsthatareindicatedin

thestudybySenagoreetal.25 _largely_correspond_to_minor

(8)

Senagore et al (2009)

Feldheiser (2012)

Yates et al (2013)

Zhang et al (2012)

Lindroos et al (2013)

Overall (I = 0.0%, 2 P=.635) ID

Study Mortality

Favor coloide Favor cristaloide

RR (95% Cl) Weight

%

3.00 (0.13, 69.70) 16.34

16.34 11.00 (0.64, 188.55)

2.36 (0.47, 11.86)

3.87 (1.12, 13.38)

0.00

100.00 (Excluded)

(Excluded)

67.31

–1 1 10

Figure2 Colloidsversuscrystalloids.Mortality.

andthat thisstudy has asprimaryoutcome hospitalstay.

Itisnotdesignedforanalysisofmajorcomplications.The

causeofdeathintheHESgroupisnotdescribed.Thesame

occursin the study by Yatesetal.27 _where _the _causes _of

deatharenotindicated,andtheRCTisnotdesignedforthe

analysisofcomplications;and,ontheotherhand,patientsin

thecrystalloidgroupshowedahigherbaselineoxygen

trans-portation(554vs.496;p=0.01),while fourpatientshada

postoperativeacuteRIintheHESgroupandonlytwointhe

crystalloidgroup.

Zhang et al (2012)

Feldheiser (2012) Yates et al (2013)

Lindroos et al (2013)

Overall (I 2 = 0.0%, P=.489) Senagore et al (2009)

0.80 (0.25, 2.55)

0.00

100.00 1.22 (0.88, 1.70)

(Excluded)

1.17 (0.86, 1.61)

0.00 88.40 11.60 RR (95% Cl) Weight

%

Favor coloide Favor cristaloide ID

Study Complications

–1 1 10

(9)

Feldheiser et al.21 _reported _a _trend _toward _increased

mortality(5vs.0;p=0.051),althoughthesedeaths

corre-spondtotumorprogression,andarenotdirectlyrelatedto

thehemodynamicalgorithm.RIisnotindicatedasa

postop-erativecomplication.StudiesbyLindroosetal.28,29_are_not

designedfortheanalysisofcomplicationsanditisassumed

thatthereisnopublicationbias,thatis,nodeathsduringthe

studyoritsfollow-up.Theresultsofthismeta-analysisshow

thatthereisatrendtowardincreasedmortalitywiththeuse

ofGDFTwithcolloids,although,asdescribedabove,thisis

notdirectlyrelatedtotheintervention,sinceasignificant

reductionincomplicationsisobtained.Themaintenanceof

an adequatecardiac outputcouldleadtomaintenanceof

immune function and protect the organs that are at risk

ofintraoperative hypoperfusion,38 _particularly_in

gastroin-testinalsurgery;itwasdemonstratedthattheuseofGDFT

withcolloidsimprovestheflowofthesuperiormesenteric

arteryby20%,andthemicrocirculationinthe

gastrointesti-nalmucosa39_by_up_to_40%;_thus,_a_decrease_of_{complications}

associatedwiththeuseofcolloidswouldbeexpected;

how-ever,thisisnotconfirmedwiththeexistingevidence.

Moreover, studies in healthy subjects have shown that

bloodflowoftheperianastomoticcolonicmucosaissimilar

tothefluidtherapywithcolloidsorcristalloids.40

The basic premiseof the GDFT consistsof ensuringan

optimal blood volume;the association of restrictive fluid

therapy41 _with _the_{identification} _of _optimal _preload_or _of

those patients who increased their SV through a volume

load (respondent to fluids) implies relative hypovolemia;

thequickcorrectionof thisproblemisessentialtoensure

correct tissue perfusion. This a priori should be faster

with colloids, since, as demonstrated in healthy patients

and animal models, the proportion of liquid required to

achieveagoalofhemodynamicstabilizationis1:442_;

how-ever,thiscannotbeconfirmedbythedataobtainedinthis

meta-analysisnor can bedemonstrated withrecent

stud-iesspecificallydesignedtodetermine it.33 _The_association

ofRIwiththeuseofcolloidsinthesurgicalfieldcouldnot

be demonstrated,20,43 _and_in _particular _in _GDFT _it _can _be

demonstrated,sincenoRCTanalyzedthisasaprimary

out-come;thus,itisnotpossibletodrawconclusionswithregard

tocolloidsassociationwithrenalfailureinsurgicalpatients

whounderwentGDFT.

Implicationsforinvestigation

Currently,therearetwoRCTsin whichGDFTwithcolloids

iscomparedwiththatwithcrystalloids inlargeabdominal

surgery,oneintheUSA‘‘EffectofGoal-DirectedCrystalloid

VersusColloid AdministrationonMajor Postoperative

Mor-bidity’’(NCT01195883)inwhichtheyexpecttoanalyze1112

patients,and withplannedcompletiondate onNovember

2014;andanotherinAustria,Europe,‘‘CrystalloidsVersus

ColloidsDuringSurgery(CC)’’(NCT00517127),with

comple-tionexpectedto2016,andthataimstorecruit400patients.

Bothwere approvedbeforetheresolution of the

Phar-macovigilanceRiskAssessmentCommitteeandtheFoodand

DrugAdministration.ThecompletionandpublicationofRCT,

andtheperformanceoffutureclinicaltrialsinthisareaare

essential.

InfutureRCTs,itwouldbeadvisabletofollowthe

sugges-tionsprovidedbyMeybohmetal.44_adapted_to_the_operating

environment:limit the use of colloids for initial

hemody-namic stabilization in cases where there is hypovolemia

through GDTF algorithms in order to avoid situations of

hypovolemiaandhypervolemia,consideringinallcasesthe

maximumpermissibledoses;andavoidtheadministrationof

theseinpatientswithRI,andperformingadequatepatient

monitoring.

Moreover,duetothecontroversygeneratedbythe

Phar-macovigilanceRiskAssessmentCommittee,infutureclinical

trials the determination of renal function will be

neces-sary with the use of internationally validated scales (IRA

andRIFLE),becausetheyallowtohomogenizecriteriaand

measurethisdysfunctionclinicalbehavior,45,46_and_also_the

performanceof this procedureswithbalanced and

unbal-ancedcolloids,asthiscouldbeadeterminingfactor.

Thus,morewell-designedmulticenterstudiesare

neces-sarywithsufficientstatisticalpowertocomparecrystalloid

versuscolloidasfluidtherapyinGDFT,accordingtothe

rec-ommendationsprovided by Meybohm etal.44 _adapted _for

the surgical environment and in different surgical

proce-duresthatenabletheclarificationofthecurrentcontroversy

surroundingtheuseofcolloids.

Limitations

AstheliteraturesearchwaslimitedtoPubMedandEMBASE;

therecouldbestudiesthatwerenotanalyzedinthis

meta-analysis.

Thestatisticalpowerofthismeta-analysistodetectan

effectoncomplicationsandmortalityisverylimitedbythe

lowrateofcomplications andmortality,aswell asdue to

thelimitednumberofincludedstudiesandpatients.

AsintheRCTthatwereincludedtheRIisnotaprimary

outcome,conclusionsinthisfieldcannotbeobtained.

DuetotheheterogeneityofsurgeriesinwhichtheRCTs

were performed, the data obtained in this meta-analysis

shouldbe evaluatedtogether with the individualanalysis

ofeachRCTincluded.

Thus, the results of this meta-analysis, and especially

thosewhichrefer tomortality, shouldtherefore betaken

withcaution.

Conclusions

Despite the major limitations found, this meta-analysis

shows that the use of the latest generation of colloids

derivedfromcorn(6%HE:130/0.4)intheGDFTwith

algo-rithms which optimizesthe preload toavoid situations of

relativehypovolemiathatcouldleadtotissuehypoperfusion

does not increase postoperative complications; however,

thereisatendencytohighermortalitywiththeuseofthese

regardingtheuseofcrystalloids.Althoughthereisatrendto

increasedmortality,theauthorsconsiderthat,giventhelow

numberofRCTsandpatientsincluded,thisconclusionshould

betakenwithcaution,anditisessentialtocarryoutnew

RCTstoconfirmit,withsufficientstatisticalpowerinthose

comparingbalanced tounbalancedcolloids withbalanced

andunbalancedcrystalloidswithinGDFTprotocols,inthose

inwhichrestrictivefluidtherapy isheld,andthatinclude

theuseofvasoconstrictorsandinotropesintheactive

(10)

currentindicationsandsuggestionsprovidedbythegroups

ofspecialists.44_Clearly,_survival_is_the_most_important_goal,

andisaprimaryresultinRCTthatisextremelydifficultto

analyze,giventhelowincidenceofitinthesurgicalfield;

therefore,futureRCTsshouldhavesufficientsamplesizein

ordertodeterminetheinfluenceofadministeredliquidin

it.

Authorship

JRplannedthismeta-analysiswithJC,madetheliterature

search,analyzedthe results,wrotethe meta-analysisand

sentthemanuscript.

AEandATparticipatedintheliteraturesearchand

selec-tionofarticles.

RCparticipatedintheassessmentofarticlesincludedand

inthemanuscriptwriting.

JC planned the meta-analysis with JR, supervised the

workinallitsphases,andcorrectedthetextuptothefinal

conclusion.

SCworkedonstatistics.

Alltheauthorsreadandapprovedthemanuscript.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgments

Theauthors wishtoexpresstheir gratitudetothe

profes-sionalsatBibliotecaProfessionaldelHospitalUniversitario

InfantaLeonor(Madrid).

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