JPediatr(RioJ).2015;91(5):407---409
www.jped.com.br
EDITORIAL
IV
fluid
choices
in
children:
have
we
found
the
solution?
夽
,
夽夽
Escolhas
de
fluidos
IV
em
crianc
¸as:
encontramos
a
soluc
¸ão?
Karen
Choong
a,∗,
Sarah
McNab
b,c,daDepartmentofPediatrics,CriticalCare,ClinicalEpidemiologyandBiostatistics,McMasterUniversity,Hamilton,Canada bDepartmentofGeneralMedicine,RoyalChildren’sHospital,Australia
cDepartmentofPaediatrics,UniversityofMelbourne,Melbourne,Australia dMurdochChildren’sResearchInstitute,Melbourne,Australia
There have been at least 15 randomizedcontrolled trials (RCTs) publishedontheisotonic versushypotonic mainte-nance fluid debate in the last decade, the most recent ofwhich wasthetrial conductedby Valadãoetal.,1
pub-lished in this issue of Jornal de Pediatria. Based on a
concernthatchildrenundergoingsurgeryareatparticular
riskofhospital-acquiredhyponatremia,theseinvestigators
conducted asingle center, double-blindedRCT comparing
isotonic(150meq/Loressentiallya0.9%NaClsolution)toa
30meq/L(0.2%NaCl)hypotonicsolutioninchildren
under-goingappendectomy,fromthetimeofadmissionuntil48h
post-operatively.Withatotalof50patientsincludedintheir
perprotocolanalyses(23and27ineacharm,respectively),
theauthorsdidnotfindanystatisticallysignificant
differ-enceinserumsodiuminbothgroupsat24or48h.Theyalso
didnotobserveanydifferencesinthesecondaryoutcomes
of hypervolemia and other electrolyte disturbances. The
DOIoforiginalarticle:
http://dx.doi.org/10.1016/j.jped.2015.01.004
夽 Pleasecitethisarticleas:ChoongK,McNabS.IVfluidchoices
inchildren:havewefoundthesolution?JPediatr(RioJ).2015;91: 407---9.
夽夽
SeepaperbyValadãoetal.inpages428---34.
∗Correspondingauthor.
E-mail:choongk@mcmaster.ca(K.Choong).
authorstherefore concludedthat both hypotonic and
iso-tonicsolutionsareappropriateformaintainingintravenous
fluidchoicesinchildrenundergoingappendectomy.
The history of the debate around the most
appropri-ate choice of intravenous maintenance fluids in children
evolved from concerning case reports and observational
studiesinthe1990s,whichfueledopinion-basednarrative
reviewsin theearly2000s,suggesting aharmfulpotential
forsignificanthyponatremicencephalopathyandmortality
withhypotonicfluids.2 Thosein favorofisotonicsolutions
argued that fluids containing higher sodium (and
there-fore tonicity) reduce the risk of iatrogenic hyponatremia
and itssequelae in the setting of an inability to excrete
free water,3 while those in favor of hypotonic solutions
argued that iatrogenic hyponatremia is related to excess
fluidvolumeadministration, andnotadilutionaleffectof
free water intake, and that isotonic fluid increases the
risk of hypernatremia.4 The conclusions of experts in the
field at that time were invariably a call for more
rigor-ous, prospective evidence in this important area before
more definitive recommendations on safe fluid practices
couldbe made.5,6 Subsequently, an increasing number of
RCTsandatleastsixsystematicreviewsandmeta-analyses
published over the last ten years later have provided a
highergradeofevidencetoendthisdebate.5,7---10 The
find-ings and conclusions of this body of evidence have been
consistent. Compared to hypotonic maintenance fluids,
http://dx.doi.org/10.1016/j.jped.2015.05.001
408 ChoongK,McNabS
isotonicsolutionssignificantlyreducetheriskofiatrogenic
hyponatremia,particularly in the first 24h of
administra-tion,withsomeevidencethatthiseffectpersistsat48h.10,11
Isotonicsolutionsprotectagainsthyponatremiawithoutan
increasedrisk of hypernatremia in both medicaland
sur-gicalpatients, aswell asincritically andnon-criticallyill
children.10,12 While there are fewer trials comparing the
effectoffluidvolumeversustonicityintake,theevidence
todatealsosuggeststhatiatrogenichyponatremiaisrelated
tothemaintenancesolutiontonicity,ratherthanvolume.13
Inother words,restricting hypotonicfluidintakedoesnot
protectagainst hyponatremia when compared toisotonic
solutions. In fact, restricting the volumeof isotonic fluid
intake, while it reduces the risk of hyponatremia, may
not prevent its occurrence.11 Since the Cochrane review
onthissubject, whichwaspublishedinDecemberof2014
andincluded a total of 10RCTs in970 children, five new
RCTs were published, in addition to the trial by Valadão
etal.,1 enrollingover 1100 patients.11,12,14---16 The number
of childrenenrolled in clinical trials comparinghypotonic
toisotonic fluids has morethan doubled in the last year,
andcontinuetostrengthentheevidenceinfavorofisotonic
maintenancesolutions.Contrarytotheoriginal
recommen-dationsofHollidayandSegarandtotheconcernsproposed
earlier,4 isotonic fluids were proven to be safe and were
associatedwithareductionintheriskofhospital-acquired
hyponatremia.Ithasbeen suggestedthatthisreductionin
riskmayinfactbeunderestimated,asmanystudiestodate
excludedpatientswithbaselinehyponatremia.8
WhyaretheresultsofValadãoetal.’strial1contraryto
thisevidence?Whiletheauthorsconcludethattheirresults
suggestthereisnoincreaseinriskwitheitherfluidtype,we
cautionagainstthisinterpretationduetotheirsamplesize.
Thiswasasmallstudythatwasnotpoweredforthestated
primaryoutcome.There werethreeandfourwithdrawals
ineacharm;asthiswasnotanintentiontotreatanalysis,
itisuncleartheimpactthatthishadontheresults.A
dif-ferencebetweengroupsmaynothavebeendetectedasthe
timingofserumsodiummeasurementswas24and48hafter
surgery(notintervention),andhyponatraemiaismost
com-monlyreportedwithin24h ofintervention.10,12 Botharms
alsoreceivedasignificantamountofisotonicfluidspre-and
intra-operatively,whichpotentially dilutedtheirability to
detectadifferenceinserumsodium.Comparingmeanserum
sodiumin thissmall sample, asopposedto theincidence
of hyponatraemia, maynot be the most appropriate
out-cometoassessthesafetyofhypotonicversusisotonicfluid,
givena regressiontothemeanbias.17 The onlysignificant
differencedetectedbetweenbothgroupsisthehigher
pre-operativefluidbalanceinthehypotonicgroup;theauthors
suggestthatthiscontributedtohyponatremiaat baseline.
However,astheinterventiondurationwas48haftersurgery,
andtheir datashowednodifferenceinthepost-operative
fluidintakeorbalance,thisobservationmayhavebeendue
tochance.
While serum sodium was not significantly different in
thetwogroups, hyponatremiadiddevelop inanumberof
patients after exposure to hypotonic as well isotonic
flu-ids,andinpatientswhowerenormonatremicatbaseline.It
is important tonote that half (n=24) of the participants
in this trial were hyponatremic at baseline, of whom 15
(62.5%) normalized their serum sodium during the study
period,regardless ofthe administered solution.However,
theproportionofpatientswithhyponatremiaineachgroup
at baselineis unclear.Thisillustratesthatsodiumbalance
is not simply influencedby sodiumintake andtonicity of
maintenanceintravenousfluids,butismultifactorial.
Possi-bleresponsiblemechanismsincludethedilutionaleffectof
apositivebalanceoffreewatereitherfromadministration,
and/orandimpairedabilitytoexcretefreewaterasaresult
ofnon-osmoticantidiuretichormone(ADH)excretion,and
translocationalhyponatremiawithincreasedosmolargap.18
Unfortunately,thisstudydidnotincludemeasurementsof
ADH,urineosmolality,andelectrolytes,notallowingfor a
fullexplanationofthepossiblemechanismsfortheobserved
results.
Whilewecommendtheauthorsonconductingthistrial,
we cautionreaders against concludingthat,based onthe
lackofdemonstrabledifference,hypotonicsolutionsareas
safe as isotonic solutions. The overwhelming prospective
evidencetodateindicatesthatisotonicmaintenance
solu-tions aresaferthan hypotonicfluids in protectingagainst
hospital-acquired moderate and severe hyponatremia in
medical and surgical pediatric patients. If hyponatremia
waspurelya problemofdilution, thenall hypotonic
solu-tions shouldbeabandoned.While isotonicfluidis notthe
onlysolutionfor correctinglowsodium, itiscertainly the
safest empiric choice. Concerns regarding the potential
for harm associatedwithintravenous fluidcontaining less
than77mmol/L,togetherwithan accumulatingwealth of
prospectiveclinicaltrialevidencehasresultedinapractice
changeandamendednationalclinicalguidelines.19Ournext
debate is which isotonicfluid is superior, a balanced salt
solution or 0.9% NaCl.20 Studies to date have not
evalu-ated thepotentialforhyperchloremic metabolicacidemia
whenisotonicfluidsareadministeredatmaintenancerates.
This is a well-recognized sequelae of volume expansion
with 0.9% saline, and a growing concerngiven its
poten-tialassociation ofmorbidityandmortalityinthecritically
ill population.21 We emphasize thatthere is no ideal
sin-gle solution that can guarantee correction of electrolyte
abnormalities. Individualizingfluidprescriptions according
tothepatient’sphysiology,vigilancewithmonitoring,and
dose adjustment of fluidcomposition andvolume
accord-ing to therapeutic endpoints are key componentsto safe
intravenousfluidpracticesinchildren.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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