JPediatr(RioJ).2014;90(2):99---101
www.jped.com.br
EDITORIAL
Vitamin
D
as
a
modifiable
risk
factor
in
critical
illness:
questions
and
answers
provided
by
observational
studies
夽
,
夽夽
Vitamina
D
como
um
fator
de
risco
modificável
em
doenc
¸as
graves:
perguntas
e
respostas
de
estudos
observacionais
J.
Dayre
McNally
DepartmentofPediatrics,FacultyofMedicine,UniversityofOttawa;Children’sHospitalofEasternOntario,Ottawa,Canada
Vitamin D is essential to optimal health. Studies dating back to the early 1900’s convincingly demonstrate that a state of vitamin D deficiency, acquired through limited sun exposure and avoidance of vitamin D-rich foods can lead to stunted growth, bone disease, and hypocalcemic seizures.Over thepastfew decades,arising bodyof epi-demiological literature has also suggested that vitamin D deficiency predisposestoa widevariety of disease states outsideof themusculoskeletalsystem. Forexample, vita-min D status has been associated withdiseases involving dysregulationoftheimmune(typeIdiabetes,cancer), car-diovascular(heartfailure,cardiomyopathy),andrespiratory systems(bronchiolitis,pneumonia).Strongbiological plau-sibility supportingtheseepidemiological findingshasbeen provided,includingbasicsciencestudiesshowingthe pres-enceofvitaminDreceptorsonalargenumberofdiversecell types(e.g.whitebloodcells,myocytes),andanimalstudies demonstratingdiseaseoccurrenceingenetically-(vitaminD
DOIoforiginalarticle:
http://dx.doi.org/10.1016/j.jped.2013.08.004
夽 Pleasecitethisarticleas:McNallyJD. VitaminDasa
modifi-ableriskfactorincriticalillness:questionsandanswersprovided byobservationalstudies.JPediatr(RioJ).2014;90:99---101.
夽夽SeepaperbyReyCetal.inpages135---42.
E-mail:[email protected]
receptorknockout)ornutritionally-inducedvitaminD defi-ciencystates.
As the pathophysiology of theimmune, cardiovascular, respiratory,andrenalsystemsiscentraltocriticalillness, itisnotsurprisingthatcliniciansandresearchershavealso hypothesizedthatvitaminDmaybeamodifiableriskfactor in the intensive care setting. Since the initial NEJM pub-lication in 2009 by Lee et al.,1 there have been dozens
of adult epidemiological studies on this subject, and the overwhelmingmajorityreportedhighvitamin Ddeficiency rates and statistical relationships with illness severity. In theadultrealm,interventionalstudiesareunderway,with thepublicationoftwopilotphaseIIstudiesevaluatingrapid restorationregimens2,3andtheinitiationofalarge
random-izedcontrolledtrial.4
Incomparison,theimportanceofvitaminDinpediatric criticalillness is significantly less studied, and the publi-cation by Rey et al. in this issue5 adds to this emerging
bodyofliterature.NotwithstandingthepublicationbyRey etal.thepediatric literatureonvitamin Din criticallyill children was summarized in a recent review.6 The initial
pediatricstudiesaddressingthisquestionwerepublishedin late2012.7,8 IncludingthepublicationbyReyetal.,there
arenowtwostudiesonmixedmedical/surgicalpopulations, twoonisolatedmedicalpopulations, andtwoonisolated cardiacsurgerypopulations.5,7---11 Althoughsomevariability
wasobserved,all studies reportclinicallysignificant vita-min Ddeficiency prevalence rates (30% to80%). The four
100 McNallyJD
studies involving post-operative cardiac surgery patients reportedstatisticallysignificantrelationshipsbetweenlow 25-hydroxyvitamin D (25OHD) andgreater illness severity. Thepictureislessclearforthestudiesonpediatricintensive careunitpopulations,withonlytwoofthefourstudies docu-mentingsuchastatisticallysignificantassociation.Although themostrecentstudybyReyetal.didnotpresentany sta-tisticallysignificantassociations,thereweresomepotential trendsnoted,andthestudywasatriskfortypeIIerrorgiven thesmallsamplesizeandunadjustedanalysis.
Does the optimization of vitamin D status prevent or speed recovery from pediatric critical illness? Multiple researchgroups,mostrecentlyReyetal.,haveperformed thestandard initialstudiesusedtoanswer research ques-tionsofthisvariety.Anevaluationoftheavailablestudies demonstratesthat,regardlessofgeography,manycritically illchildrenarevitaminDdeficient.Thisobservationwould appeartopresent anopportunity.Themissinginformation is whetherand towhat extent the natural history of dis-easeismodifiedby raisingvitaminD levels.Observational studieson nutrientsandhormones areoften usedto pre-dictthepotentialmagnitudeofeffectbycomparingillness courseingroups ofpatients withdifferentlevels. Regard-lessof whetherthe resultsshowthe desiredassociations, cliniciansandresearchersstruggletointerpretandcompare thefindingsfrombothsingularandgroupsofobservational studies. This is due tosmall sample size, patient hetero-geneity(withinandbetweenstudies),measurementerror, confoundingfactors,outcomeselection,statisticalanalysis, andreportingbiases.Inadditiontothestandardproblems associatedwithPICUstudiesofthisnature,thereareother problemsspecifictovitaminDthatfurthercomplicatesthe issue.First,althoughrecognizedastheappropriatemarker ofvitaminDstatusinmostpopulations,25OHDlevelsmay notaccurately reflect bodystores in critically illpatients (thosewith hypoparathyroidism, renal dysfunction, inter-stitialleakofbindingproteins,fluidshifts,dialysis).Ithas beensuggestedthatbloodconcentrationsoftheactive vita-minDhormonemightbetterreflectvitaminDaxisfunction, aquestionthatwillrequirefurtherstudies,whichwillalso suffer from the abovementioned problems. Second, asso-ciationstudiesintendedtoevaluateanddemonstratethat higher vitamin D levels prevent illness or speed recovery sufferfromalackofpatientswithblood25OHDlevelsthat representthetarget.Stateddifferently,itisnotpossibleto estimatethebenefitsofa25OHDlevelof100nmol/Lwhen fewofthestudyparticipantsachievethistarget.
WhatadviceshouldbegivenregardingvitaminD supple-mentation to clinicians who care for patients who are either at risk for critical illness or are critically ill? For now,itwouldappearprudenttoprovidepre-illness supple-mentationin a range knownto safely maintain 25OHD at 100nmol/L(1,000to2,000IU/day).12,13Therearespecific
populationsthatdeservespecialattentionandmayrequire higher supplementation doses to achieve desired vitamin D status (patients with renal dysfunction, malabsorp-tionsyndromes,anti-seizuremedications,cardiopulmonary bypass).14,15 With good compliance, a daily intake in the
1,000 to 4,000 IU range for two to three months should achievetargetvitaminDlevels.Analternativeapproachis requiredtooptimizevitaminDstatusintheactively criti-callyillpatientswhoarevitaminDdeficient.Whatisclear
isthatdailyadministrationoflowdosevitamin supplemen-tation (400 to 4,000 IU/day) will not restore levels in a beneficialtimeframe.Instead,clinicianswillneedto con-sider loadingdoses(orstoss therapy)ranging from50,000 to600,000IU,dependingonstartinglevelandweight.16---18
Given evidence (albeit largely from case reports/series) that high dosesmay causehypercalcemia,hypercalciuria, ornephrocalcinosis,vitaminDloadingdosescannotbe rec-ommended in critically ill children without clinical trial data.19,20Assuch,thenextstepsinthisemergingfieldare
patience(resultsoftheadultstosstherapyrandomized clini-caltrials)andcompletionofsmallerphaseIIdose-evaluation studiesinchildren.
Conflicts
of
interest
Theauthordeclaresnoconflictsofinterest.
References
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