DTIC ADA633551: Use of Procalcitonin for the Detection of Sepsis in the Critically Ill Burn Patient: A Systematic Review of the Literature

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4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER
Use of procalcitonin for the detection of sepsis in the critically ill burn
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patient: a systematic review of the literature
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Mann E. A., Wood G. L., Wade C. E.,
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United States Army Institute of Surgical Research, JBSA Fort Sam REPORT NUMBER
Houston, TX
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550 burns 37 (2011) 549 558
3.3. Burnspecificclinicaltrials ................................................................. 554
4. Discussion................................................................................... 556
Acknowledgements............................................................................ 557
References................................................................................... 557
1. Introduction 7 dayreturntobaseline[11].TherelativelyearlyriseofPCT
withalongplateauofupto24hafterresponsetosepsismakes
Severeburnfrequentlyresultsinmultipleorgandysfunction thismarkeridealforroutinedailymeasurement;asuddenrise
andsepsis[1].Thecauseofdeathin28 65%offatalburncases in PCT level is an indicator of sepsis onset [9]. The normal
hasbeenattributedtosepsis[2,3].Yetduetochronicbaseline serum value of PCT in a healthy individual without inflam
inflammatoryresponse[4]andimmunedysregulation[5]the mationislessthan0.05ng/mL[9].PCTlevelsassociatedwith
traditionalmarkersofacuteinfectionaredifficulttoidentifyin local infection,possiblesystemicinfection,sepsis,or severe
the burn patient. Consensus definitions for sepsis in the sepsisare:<0.5ng/mL,0.5 2ng/mL,2 10ng/mL,and>10ng/
criticallyillpopulationcouplecriteriaforsystemicinflamma mLrespectively[12].
toryresponsesyndrome(SIRS)withthedocumentedpresence Numerous clinical trials and meta analyses of ability to
ofinfection[6].However,theSIRScriteriaofmorethanoneof detectsepsisinacutelyandcriticallyillpopulationsusingPCT
thefollowingclinicalfindingsoftemperature>388Cor<368C; assay have produced promising results [13 15]. Multiple
heartrate(HR)>90beats/min;respiratoryrate(RR)>20/min studies specifically in the burn population have been
orPaCO <32mmHg;orwhitebloodcellcount(WBC)>12,000 performed[16 19].WhileEuropeanandAsiancountrieshave
2
or<4,000cells/ml arethenormforthehypermetabolicburn been the leaders in this new technology; widespread avail
patient [7]. A consensus panel for the American Burn abilityoruseofthePCTassayintheUnitedStatesislacking.A
Associationhasdevelopedspecificguidelinesforthediagnosis systematicreviewoftheliteraturewasconductedtoidentify
ofsepsisintheburnpatientthatincludehigherthresholdsfor evidencesupportinguseoftheprocalcitonindiagnostictestto
temperature(>398Cor<36.58C),HR(>110beats/min)andRR detectsepsisinthecriticallyillburnpatient.
(>25/min) in addition to presence of thrombocytopenia
(platelet count<100,000/mcl), and indications of insulin
resistance or feeding intolerance [7]. In addition to these 2. Methods
clinical indicators, documented presence of infection or
clinicalresponsetoantimicrobialsisrequired.Becausethese Toidentifyrelevantresearchregardingtheusefulnessofthe
guidelines are based on consensus and not founded in procalcitonintestintheearlydiagnosisofsepsisintheburn
prospectiveclinicalstudies,moreprecisemethodsofdetect patientasystematicreviewoftheliteraturewasperformed.
ing sepsis in this vulnerable population are necessary. MEDLINE, Cochrane Database, CINAHL, ProQuest, and SCO
Evidenceofanincreasedriskofmortalityintheburnpatient PUS electronic databases were searched in November 2009.
infectedwiththeubiquitouspathogenPseudomonasaeruginosa Combinations of the MeSH terms burn, procalcitonin, and
is suggested if appropriate antibiotic therapy is delayed for meta analysis were searched; reference lists for relevant
only2days[8]. articles were reviewed for additional pertinent articles. The
Detection of sepsis would be expedited if a simple, searchwaslimitedtostudiesofhumansubjects,clinicaltrials,
inexpensive test could be performed routinely, with a high andEnglishlanguage.Nolimitsfordatewereappliedtosearch
degree of accuracy in correctly differentiating sepsis from usingburnandprocalcitoninormeta analysisandprocalci
SIRS. Such an assay should improve the ability to identify tonin.Datelimitsof2004 2009wereappliedtothesearchof
severeinfection,guidetreatmentandreducethedurationof procalcitonin and infection as previously published articles
antibiotic exposure. Emergence of a test that meets these were included in one or more meta analyses or systematic
criteria is the assay of the procalcitonin (PCT) molecule, a reviews [13 15,20,21]. Studies considered for inclusion were
precursorofcalcitonin,producedinboththyroidalandextra performed with adult subjects, with an emphasis on burn
thyroidaltissues,includingadiposetissue[9].ReleaseofPCT injury but included other critically ill populations with the
occurs to varying degrees in response to bacterial infection, diagnosis of sepsis. Exclusion criteria included studies with
fungal infection, trauma, surgery and other types of condi the predominate focus on prediction of outcome, use of
tions. The greatest elevations of serum PCT occur in the procalcitonin test to guide antibiotic therapy, neonatal
presenceofbacterialinfectionandmulti organfailureresult subjectsoranimalstudies.
ing from trauma [10], and no change is found due to viral Thelevelofevidenceforeachstudywasdeterminedusing
infection[9].Comparedtoothersepsismarkersusedclinically the American Association of Critical Care Nurses Evidence
suchastumornecrosisfactor alpha(TNF a),interleukin 6(IL levelingsystem[22].Meta analysisisconsideredLevelA;well
6)orC reactiveprotein(CRP)thereactivepatternofPCThasan designedrandomizedcontrolledtrialswithconsistentresults
onsetwithin4hofresponsetoinfectionorinjury,peaksat6h Level B; and systematic reviews, descriptive studies or
withaplateauof8 24h,thenreturnstobaselinein2 3days. controlledtrialswithinconsistentresults LevelCevidence.
Thisiscomparedtoa90minonsetforTNF awithreturnto EachstudywasalsoevaluatedusingtheU.S.PreventiveTask
baselinein6h;a3 honsetforCRPwithreturntobaselinein Force Quality Rating Criteria for diagnostic accuracy studies
8h;anda12 24honsetforCRPwitha20 72 hplateauand3 [23]resultinginratingsofgood,fairorpoorbasedonrating
burns 37 (2011) 549 558 551
criteria.Thecriteriaincludedrelevanceofscreeningtest,use
of a credible reference standard, interpretation of reference
standard independent of screening test, in determinant
results handled in a reasonable manner, broad spectrum of
patientsincludedwithadequatesamplesize,andadministra
tionofareliablescreeningtest.
3. Results
A total of 19 articles were included in this review; the
systematic process of selection is described in Fig. 1(a c).
Four meta analyses [13 15,21] and 1 review of the literature
[20](Table1),wereretrieved.Studiesconductedafter2004and
not included in the meta analyses or systematic review
included1randomizedcontrolledtrial(RCT)[24],10prospec
tive observational studies [16 19,25 30], and 3 retrospective
reviews[31 33](Table2).Ofthese,5prospective[16 19,28]and
one retrospective study [33] were burn patient specific
(Table3).
3.1. Meta-analysesandreviewoftheliterature
Populations included in the meta analyses included emer
gencydepartment(ED)patients[13,21],surgicalandmedical
inpatients[14],andsurgicalandtraumapatients[15];febrile
neutropenicpatientswerethefocusofthereviewofliterature
[20]. Collectively these studies evaluated a range of 12 33
individualclinicaltrialsreportedfrom1996to2007,comprised
of a range of 1222 2335 subjects, with a subset of 486 603
pediatric subjects included in 3 of the systematic reviews.
Significantoverlapoccurredamongthesemeta analysesand
review of the literature as many of the same studies were
includedinmultiplereviews.Onlyonemeta analysisdeter
mined the PCT assay to fail to distinguish sepsis from SIRS
amongamixedsamplefromtheED,ICUandgeneralinpatient
units [21]; the other meta analyses determined a moderate
[13]abilityofPCTassaytoidentifysepsisinanEDpopulation,
andsuperiorityofPCToverCRPtoidentifybacterialinfection
orsepsisintheinpatientsetting[14,15].Theconclusionofthe Fig.1–(a–c)Flowdiagramsforincludedstudiesandsearch
literature review of PCT value in predicting sepsis in the criteria.
neutropenicpopulationdeterminedtheabilityoftheassayto
discriminateinfectiousetiologyinthissubsetofpatients[20].
Qualityoftheselectedmeta analysesappearstoberobust.
Each study described a comprehensive search strategy and CI, 9.1 27.1, p<0.0001) for PCT test when infection was
provided a flow diagram or grading criteria for included comparedwithnon septicSIRS.ThediagnosticORofthePCT
studies,statistical procedureswereconductedappropriately assayperformancetodiagnosesepsisreportedbyJonesetal.
althoughTangetal.[21]arrivedatcontradictoryconclusionof [13]was9.86(95%CI,5.72 17.02).Thesefindingsarecontrasted
PCTperformance compared totheothermeta analyses [13 tothoseofTangetal.[21]whereanORof7.79(95%CI,5.86
15]. The review of literature [20] did not include statistical 10.35)wascalculatedforthediagnosticabilityofPCTtestto
analysisbutarigoroussearchstrategyresultedininclusionof accuratelydiscriminatebetweensepsisandnon septicSIRS.
over 30 clinical studies of febrile neutropenic patients, a Simonetal.[14]reportedapooledsensitivityandspecificity
populationakintotheseverelyburnedpatientandthusthe for PCT assay of 88% and 81% respectively, compared to
studywasincludedinthisanalysis.Levelofevidencefor3of assessmentbyTangetal.[21]of71%and71%withareaunder
the meta analyses [13 15] was ‘‘A’’ (results from a meta thereceiveroperatingcurve(AUC)of0.78;thisvaluecontrasts
analysisthatconsistentlysupportaspecificaction),and‘‘C’’ withtheAUCreportedbyJonesetal.[13]of0.84.Thefindings
forthemeta analysisconductedbyTangetal.[21](systematic ofSakretal.[20]forthediagnosticabilityofthePCTassayto
reviewsormeta analyseswithinconsistentresults)[22]. detectsepsisinthefebrileneutropenicpopulationdetermine
Findings of the meta analyses resulted in differing con a cut off value of PCT >2ng/mL associated with sepsis and
clusions.Uzzanetal.[15]reportanoddsratio(OR)of15.7(95% septicshockandvaluesbetween1.0and2.0ng/mLtosuggest

556 burns 37 (2011) 549 558
reportbySachseetal.[33]describesa1.5ng/mLriseindaily decreasedtimetotreatment.Thus,itmayprovetobeusefulto
PCTlevelsassociatedwithonsetofsepticevents.Thestudyof utilizeCRPorPCTinterchangeablyintheburnpopulationto
pediatricburnpatientsfoundnoimprovementindetectionof expeditesepsistreatment.
sepsisusingPCTcomparedwithCRP,thediagnosticstandard ItwouldseemtheconclusionfromthisreviewofPCTassay
ofcareforthiscenter(sensitivity42.4%andspecificity88.8%) effectiveness in burns to be a promising adjunct to clinical
[28].Finally,Lavrentievaetal.[18]foundthePCTcut offlevel managementofsepticpatients.However,relianceonobser
of 1.5ng/mL to have the highest sensitivity and specificity vational and retrospective reviews to guide clinical care is
(82% and 91.2%, respectively) when contrasted with thresh tenuous at best. Well controlled clinical trials, preferably
oldsof2ng/mLand2.5ng/mL(66.6%and96.8%versus66.6% conducted in multiple centers will guide future knowledge
and97.6%,respectively).VonHeimburgetal.demonstrateda related to how PCT assay contributes to early identification
correlationbetweenincreasingTBSAandincreasingPCTlevel andtreatmentofburnsepsis.Theexpectationofsuchtrialsis
[19]. Overall a lack ofconsensusexists forutility ofthe PCT useoftheABAsepsiscriteria[7]toidentifysevereinfection,
assaytoreliablydetectsepsisintheburnspecificpopulation withvalidationoftheseparametersinaprospectivemanner.
duetothecontradictoryfindingsoftwo[17,28]ofthereviewed Asnoted,theseguidelinesarecurrentlythebestavailablebut
studies,despitepositivefindingsforPCTusein3prospective wereformulatedbyconsensusandrequirerobustsubstantia
[16,19,36]andoneretrospective[33]study. tion.
Improvedsensitivityandspecificityforpredictionofsepsis
maybeconferredwhenassayresultsarecoupledwithclinical
4. Discussion indicatorsinasystematicmanner.Inthemeantime,clinical
carewouldbesupportedwithroutinemeasurementofPCTon
Collectively,thebodyofavailableevidencesupportstheutility adailybasistodetectacutechangesinthebaselinelevelfor
ofPCTassayasanadjuncttosepsisdiagnosisinthecritically patients at high risk for sepsis. Such an assay requires a
illpopulation.Themeta analysisbyTangetal.[21]wasunable minimalbloodsample,theequivalentofroutinechemistryor
to support the clinical value of this test. However, the area hematological studies, and due to recent technological
undertheROCcurveforthepooledstudies(n 18)was0.78 advancesthisassaywillsoonbecomecost effective.Unfortu
(95%CI0.73 0.83),withadiagnosticORof7.79(95%CI5.86 nately, at many institutions PCT is processed elsewhere,
10.35).TheseauthorsdosuggesttheadditivevalueofthePCT taking several days for quantification with a cost of several
assay to contribute to clinical diagnosis of sepsis. Further hundred dollars. Certainly this constraint eliminates the
more,althoughconsensusisabsentwithintheburnliterature utilityofthisscreeningassaytodetectdailychangesinPCT
perhapsthesmallnumberofpatientsstudied,inclusionofa levelstoinitiateexpeditioustreatment.FederalDrugAdmin
pediatric study in this analysis,or theunderlyingmetabolic istrationapprovalfortheUnitedStatesispendingforasimple
complexityoftheseverelyburnedpatients confoundsthese semi quantitative test using a dip stick and colorimetric
findings. results that will be practical and cost effective. This test,
Oneprimaryinconsistencyintheburnspecificstudiesis PCT Q has been used in the emergency department and
relianceonareferencestandardfordiagnosissepsisintended demonstratedtobeafastandeffectivemethodofinitiating
foradifferentICUpopulation;theACCP/SCCMguidelines[6] antibiotictherapyinthatsetting[29].Svobodaetal.reporteda
describeSIRS,themetabolicbaselinefortheburnpatient[7]. correlationofr 0.92ofthePCT QwiththequantitativePCT
Use of an accepted standard for sepsis diagnosis for burn LUMItest1[24].TherangesofthePCT Qareclinicallyrelevant
patientsisnecessarytoguideanystudiesdirectedtowardthis tothethresholdsassociatedwithclinicallysignificantdegrees
uniquepopulation.ThestudybyBarqueetal.[17]reliedonthe of infection identified in the literature for local infection,
ACCP/SCCM sepsis guidelines which identify SIRS, yet the systemic infection (sepsis) and severe sepsis of 0.5, 2, and
populationstudiedwascomprisedofpredominatelyrespira 10ng/mLrespectively[29].
tory (18/47 subjects) and wound infections (15/47 subjects) OtherforthcomingtechnologywillmakeavailabilityofPCT
which are prone to improper diagnosis due to high rates of assaypracticalusingdevicessuchasTheranosTM(Theranos,
colonization.CoupledwiththeconservativePCTcutofflevelof Inc, Palo Alto, CA) point of care technology, a customizable
0.53ng/mL for sepsis determination this study may have deviceformultipleassaysthatincludesthePCTtest.Modules
utilized a population with mild to moderate infections not compatible with widely used core laboratory equipment to
representativeofseverelyillburnpatients[17]. provideon sitequantitativePCTassayareavailable,making
The pediatric population studiedby Neelyet al. [28] may routine screening of PCT a practical and clinically useful
sufferfromlackofanobjectivestandardforsepsisdiagnosis; adjunct to our current diagnosis and management of burn
thisstudyreliedonthesubjectivedeterminationofsepsisbya sepsis.
burnsurgeon.Furthermore,adramaticriseinPCTof5ng/mL Fortunately,routinescreeningofPCTconveysnoaddition
wasidentifiedasnecessaryfordiagnosisofsepsisbutmedian alpatientrisk,asthistestisnon invasive,requiringminimal
(25%,75%quartile)PCTforsepticandnon septicpatientswere phlebotomy, and will serve as an adjunct to routine clinical
reported as 6.7 (3.7, 31.2) vs. 2.1 (1.3, 5.7) (p<0.002) decision making. A large prospective multi center RCT is
respectively. Perhaps the 5ng/mL threshold was too ambi underway in Europe (planned enrollment n 1000 ICU
tious considering the moderate PCT levels for the septic patients) to determine the efficacy of guiding antibiotic
pediatric subjects. Finally, Neely et al. concluded with the therapyforinfectionusingdailyPCTlevels(TheProcalcitonin
suggestionthathadCRPnotbeentheburncenter’sstandardof and Survival Study PASS) [37], powered to determine
care for diagnosis of sepsis use of PCT would likely have mortality benefit of PCT guided therapy. A previous multi
burns 37 (2011) 549 558 557
center RCT conducted in the emergency department setting aspredictorsofbloodstreaminfectioninburnpatients.
(TheProHOSPRandomizedControlledTrial)determinedPCT ArchSurg2007;142(7):639 42.
[6] LevyMM,FinkMP,MarshallJC,AbrahamE,AngusD,Cook
guidedantibiotictherapyforlowerrespiratorytractinfections
DJ,etal.2001SCCM/ESICM/ACCP/ATS/SISInternational
reduced antibiotic exposure and associated adverse effects
sepsisdefinitionsconference.CritCareMed2003;31:1250 6.
with no increase of adverse outcomes [38]. These studies [7] GreenhalghDG,SaffleJR,HolmesJH,GamelliRL,Palmieri
support the premise that routine monitoring of PCT in the TL,HortonJW,etal.AmericanBurnAssociationconsensus
critically ill confers minimal risk, and promises benefits of conferencetodefinesepsisandinfectioninburns.JBurn
reduced exposure to antibiotic therapy, directed antibiotic CareRes2007;28:776 90.
[8] LodiseJrTP,PatelN,KwaA,GravesJ,FurunoJP,Graffunder
therapy,andthepotentialforreductioninmortalityassociat
E,etal.Predictorsof30 daymortalityamongpatientswith
edwithinfection.Theseareasforfutureresearchshouldbe
Pseudomonasaeruginosabloodstreaminfections:impactof
extended to the burn community, where risk of death from
delayedappropriateantibioticselection.AntimicrobAgents
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various research studies. As the overwhelming majority of
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includedstudieswereperformedoutsideoftheUnitedStates
injuredpatients.CritCareMed2000;28(4):950 7.
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[11] GabayC,KushnerI.Acute phaseproteinsandother
population may differ based on practice differences and systemicresponsestoinflammation.NEnglJMed
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