Coupled-plasma filtration and adsorption for severe burn patients with septic shock and acute kidney injury treated with renal replacement therapy

Coupled-plasma

filtration

and

adsorption

for

severe

burn

patients

with

septic

shock

and

acute

kidney

injury

treated

with

renal

replacement

therapy

Filippo

Mariano

*

,

Zsuzsanna

Hollo

’

,

Nadia

Depetris

,

Valeria

Malvasio

,

Alberto

Mella

,

Daniela

Bergamo

,

Anna

Pensa

,

Maurizio

Berardino

,

Maurizio

Stella

,

Luigi

Biancone

a_{Nephrology,DialysisandTransplantationU,DepartmentofGeneralandSpecializedMedicine,CityofHealthand}

Science,CTOHospital,Turin,Italy

b_{AnesthesiaandIntensiveCare3,DepartmentofAnesthesiaandIntensiveCare,CityofHealthandScience,}

CTOHospital,Turin,Italy

c

PlasticSurgeryandBurnCenter,DepartmentofGeneralandSpecializedSurgery,CityofHealthandScience,

CTOHospital,Turin,Italy

d_{DepartmentofMedicalSciences,UniversityofTurin,Turin,Italy}

a

b

s

t

r

a

c

t

Background: Coupled-plasma filtrationadsorption (CPFA)is a sorbent-based technology

aimedatremovingsolublemediatorsofsepticshock.Wepresentourexperienceontheuse

ofCPFAinsepticshocksevereburnpatientswithacutekidneyinjury(AKI)needingrenal

replacementtherapy(RRT)withthemaingoaltoevaluateefficacyandsafetyofCPFAinthis

specificsubsetofsepticshockpatients.

Methods:Inthisobservationalstudy,weretrospectivelyreviewedthemedicalnotesofall

burnpatientsadmittedtoouradultBurnCenterwhoreceivedCPFA,aspartoftheseptic

shocktreatmentrequiringRRT,betweenJanuary2001andDecember2017(CPFAgroup).

WecomparedCPFAgroupwithalltheburnpatientsadmittedtoourCenterinthesame

periodoftime,withthesamerangeofrelevantclinicalcharacteristics,whodevelopedAKI

and were treated with RRT, but not CPFA(control group). We collected demographic

characteristics,burnsize,SequentialOrganAssessmentFailure(SOFA)score,

microbiolog-icaldata,andpatientoutcome,intermsofin-hospitalmortalityrateandtheprobabilityof

survivalcalculatedusingtherevisedBauxscore.WealsocollecteddataregardingCPFA

safety(hemorrhagic episodes, catheterassociated-complications, hypersensitivity

reac-tions)andefficiency(numberanddurationofCPFAsessions,plasmatreatedamount,plasma

processeddose).

Results:39severeburnpatientsweretreatedwithCPFA(CPFAgroup)(meanage46.0years,

range40.0 56.0years;meanburnsize48.0%TBSA,range35.0 60.0%TBSA),and87patients

a

r

t

i

c

l

e

i

n

f

o

Acutekidneyinjury

Abbreviations:CPFA,Coupledplasmafiltrationandadsorption;AKI,Acutekidneyinjury;CRRT,Continuousrenalreplacementtherapy;

MAP,Meanarterialpressure;TBSA,Totalbodysurfacearea;MRSA,Methicillinresistantstaphylococcusaureus;RRT,Renalreplacement

therapy;RCA,Regionalcitrateanticoagulation.

* Correspondingauthorat:Nephrology,DialysisandTransplantationU,DepartmentofMedicalSciences,UniversityofTurin,AOUCityof

HealthandScience,CTOHospital,ViaG.Zuretti29,10126Turin,Italy.

E-mailaddress:[email protected](F.Mariano).

https://doi.org/10.1016/j.burns.2019.05.017

0305-4179/©2019 TheAuthors. Publishedby ElsevierLtd.This is anopen access articleunderthe CC BY-NC-ND license (http://

creativecommons.org/licenses/by-nc-nd/4.0/).

Available

online

at

www.sciencedirect.com

ScienceDirect

treatedwithRRT,butnotCPFA,whohadsimilarclinicalcharacteristics(controlgroup).

Observedmortalityratewas51.3%intheCPFAgroupand77.1%inthecontrolgroup(p0.004).

RegardingfactorsaffectingsurvivalintheCPFAgroup,SOFAscoreonthe1stdayofCPFA

resultedsignificant(OR2.016,95%CI,1.221 3.326;p<0.004)inthemultivariateanalysis

logisticmodel.

Conclusions:CPFAtreatmentforburnpatientswithAKI-RRTandsepticshock,sustainedby

bacterialstrainsnonorpoorlyresponsivetotherapy,wasassociatedwithalowermortality

rate,comparedtoRRTalone.However,furtherresearch,suchaslargeprospectivestudies,is

requiredtoclarifytheroleofCPFAinthetreatmentofburnswithsepticshockandAKI-RRT.

©2019TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCC

BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

1.

Introduction

Coupled-plasma filtration adsorption (CPFA) is a

sorbent-basedtechnologywithanextra-corporealcircuitconsistingof

aplasmafilter,aresincartridgeandahigh-fluxdialyzer[1].

CPFAisaimedatremovingsolubleendogenousinflammatory

mediators circulating in septic shocks and acute kidney

injuries(AKI)viaanextracorporealtreatment[1,2].CPFApilot

applicationsinhumansepticshockdemonstratedfavorable

effects,byimprovinghemodynamicstatus,reducing

norepi-nephrine requirement, and showing immunomodulation

properties[3 5].

Inburnpatients,AKIrequiringrenalreplacementtherapy

(AKI-RRT)duringsepticshocksrepresentsoneofthemost

prejudicialcomplications,stillburdenedbyahighmortality

rate [6 16]. CPFA has been described as a promising

emerging purification technique in burns, although there

isnolargestudyreportingitsapplicationinburnpatientsso

far[14].

After a preliminary experience of good hemodynamic

tolerance and metabolic management in burns patients

[17,18],startinginJanuary2001,weusedCPFAasanadjunctive

modalityforsevereburnpatientswithsepticshock,AKI-RRT

andnoclinicalresponsetoanappropriateantibiotictherapy.

InthisstudywepresentourexperienceontheuseofCPFA

in39severeburnpatientswithsepticshockandAKIneeding

RRTwiththemaingoaltoevaluateefficacyandsafetyofCPFA

inthisspecificsubsetofsepticshockpatients.Furthermore,

we present and examine aspects of the adopted CPFA

technique.

2.

Material

and

methods

Inthisobservationalstudy,weretrospectivelyreviewedthe

medicalnotesofallburnpatientsadmittedtoouradultBurn

Center who received CPFA, as part of the septic shock

treatmentrequiringRRT,betweenJanuary2001andDecember

2017(CPFAgroup).

InordertobetterevaluateefficacyandsafetyofCPFA,we

comparedCPFAgroupwithalltheburnpatientsadmittedto

ourCenterinthesameperiod,withthesamerangeofrelevant

clinicalcharacteristics,whodevelopedAKIandweretreated

withRRT,butnotCPFA(controlgroup).

We collected demographic characteristics, burn size in

termsof%oftotalbodysurfacearea(TBSA)burned,Sequential

OrganAssessmentFailure(SOFA)score,frequencyof

mechan-icalventilationtreatment,microbiologicaldata,andpatient

outcome, in terms of in-hospital mortality rate.Regarding

SOFAscore,braininjurywasexcludedforallpatientsinthe

CPFAgroupatBurnCenteradmission,andallofthemwere

sedatedthedaythatCPFAstarted.Assuspensionofsedation

was notpossibleforsafety reasons, theSOFAscore ofthe

centralnervoussystemwasconventionallyconsidered+1.

Theprobabilityofsurvivalwascalculatedineachpatient

usingtherevisedBauxscore[19].

WealsocollecteddataregardingCPFAsafety(hemorrhagic

episodes,catheterassociated-complications,hypersensitivity

reactions) and efficiency (number and duration of CPFA

sessions,andplasmaprocesseddose).

The study was conducted according to the Helsinki

Declaration and approved by the Ethics Committee ofour

Hospital (dossier n. CS2/908). Informed consent to the

proposed treatments and the consent to retrospectively

review the medical notes and analyze the collected data

wasobtainedfromthepatientsorsubstitutedecision-makers.

2.2. ManagementofsepticshockandAKI

Systemic treatment of burn patients and diagnosis and

treatmentofsepticshockwasmanagedbyamultidisciplinary

teamonthebasisofguidelinesinplaceatthattime[20 28].

RRT was startedwhen patientswereina trendoffluid

overloadnotresponsivetoconservativemanagement

includ-ing maximal diuretictherapyand: (1)oliguriaor (2)severe

hyperkalemia,or(3)severeacidosisor(4)uremic

complica-tions[20].

CPFAwaschosenasanadditionaltherapywhen:(1)the

patientswereinsepticshockwithAKI-RRTandmultiorgan

failure, and: (2) microbiological confirmation of the septic

eventbymeansofbloodcultureswaspositivefor

multidrug-resistantstrains,and:(3)therewasnoclinicalresponseafter

72hofappropriateantibiotictreatment.

2.3. CPFAtechnique

CPFA was performed with a dedicated machine that the

manufacturer updatedovertime(Multimat

B.IC/Lynda/Am-plya,Bellcospa,Mirandola,Italy).CPFAwasalwayscarriedout

by using a polyethersulfone plasma filter (0.5m2_{, MPS 05,}

polyethersulfone hemodialyzer (1.4m2_{, BLS814G, Bellco).}

Plasmafiltratewasadsorbedonanunselectivehydrophobic

resincartridge(140mlfor70g,withasurfaceofabout700m2_/g)

[1,17,18].

AccordingtoCPFAprotocol,bloodflowraterangingfrom

100to180ml/minandeffluentratesweresetbythetargetof

dialysis adequacy.Following themanufacturer instructions

overtimetheeffluentresultedfromhemodialysis,

hemodia-filtration,orhemofiltrationmodalities[1,5,17,18].Wesetan

exchangeof3 4l/hourofeffluentatthestarttoachievean

amountof30 42l/day,accomplishingthedialysistargetof20

25ml/kg/die[20].Thistargetwasirrespectiveofthepatient’s

residual renal function and dialysate/infusion proportion.

Moreover, as these rates were occasionally limited by the

efficiency and patency ofthe vascular access, a dedicated

nurse recorded the effective flow rates. According to the

manufacturer’s protocol, plasma filtration rate was

main-tainedbetween15 25%ofbloodflowrate.

ThevascularaccessofCPFAwasprovidedby12Fdouble

lumenvenouscatheterinsertedinthejugularorfemoralvein.

2.4. Anticoagulationstrategies

In order to provide CPFA effectively and safely, either

unfractionatedheparinorcitratewereusedfor

anticoagula-tionoftheextracorporealcircuit,onthebasisofthe

patient-s’characteristics,withthesupportofourpreviousexperiences

[13,17,18]. Specifically, the regional citrate anticoagulation

(RCA)strategywaspreferredifthepatientpresented(1)ahigh

bleeding risk (defined as bleeding alert in insertion site

catheter,or attracheostomy,or gastrointestinal tractor in

surgicalwounds)or(2)frankbleedingnecessitating

transfu-sion of packed red blood cells [13,17,18]. If none of these

conditions existed, anticoagulation was performed with

unfractionatedheparin.

If RCA was applied, an ACD-A dispersed solution was

infusedinpredilutionmodepreparedbynursesimmediately

beforeCPFAsessions,orwithaspecificbag(Citrate,Hospital

Service,Scarmagno,Italy:composition(inmmol/l)Na+148;K

+

1.5;Mg++0.75;Cl 108;citrate10;glucose5.5;bicarbonate10)

[13,17,18]. Subsequently, after 2012 citrate anticoagulation

wascarriedoutthroughacitrate-containingbagfollowingthe

manufacturer’sinstructions(Prismocitrate18/0,BaxterItalia,

Rome,Italy:composition(inmmol/l)Citrate18;Na+_140;Cl

86). Astandard sterilebicarbonate-containing solutionwas

used with calcium as an infusion (Prismasol 32, Hospal,

Mirandola,MO,Italy)orwithoutcalciumasdialysate(Ci Ca,

FreseniusMedicalCare,BadHomburg,Germany).

Inallpatients,acommercial10%calciumchloridesolution

wasinfusedbythemonitorheparinpumpinaseparatelineat

theendofthevenouscircuit[17,18].

If anticoagulation was achieved with unfractionated

heparin,thelatterwasadministeredpre-filterand

standard-ized to an initial bolus of 1250U followed by 1000U/h.

Subsequent adjustments were made accordingly to obtain

coagulation parameters of PTT>60s. A standard sterile

bicarbonate-containing solutionwas usedin theform ofa

dialysate/infusion(Prismasol32,Hospal,Mirandola,MO,Italy;

composition(mmol/l)Na+_140;K+_2.0;Ca++_2;Mg++_{0.75Cl :108;}

bicarbonate32;acetate4;glucose5.5).

2.5. StatisticalAnalysis

Continuousdataareexpressedasmedianwithquartiles(the

25thand75thpercentiles),andcategoricaldataasfrequencies

andpercentages.StudentT-test,Fisher’sexacttestorANOVA

withmulticomparisonNewman Keulstestwereusedwhen

appropriate.Multivariateanalysiswasperformedusing

logis-ticregressionforthetotalnumberofnonsurvivorpatientsto

determinetheeffectonthein-hospitalmortalityrateofthe

followingvariablesofinterest:age,andSOFAscoreatthestart

ofCPFA.

Kaplan Meier estimate of survival was constructed to

compare180-daysurvivalbetweenthepatientstreatedwith

RCA and those treated with unfractionated heparin

anti-coagulation. Cox’sF-test wasusedtotestthe differencein

survivalrates.

p<0.05 value was considered statistically significant.

Statistical computing and graphics were performed by

Statisticav.10.1(Statsoft,Tulsa,OK,USA).

3.

Results

FromJanuary2001toDecember2017,amongthe212patients

whounderwent RRT,39ofthem wereadditionallytreated

with CPFA (CPFAgroup),out of1520 severe burnpatients

admitted to our Burn Center. We identified 87 patients

(Controlgroup)whoweretreatedwithRRT,butnotCPFA,in

the same period of time, and had showed no significant

differencesintermsofburnsize,revisedBauxscore,gender,

septicshockincidence,requirementofmechanical

ventila-tionandtimeintervalfromadmissiontostartingofCPFAor

RRT(Table1).

Theoverallobservedmortalityratewas51.3%intheCPFA

groupand77.1%intheControlgroup(p0.004).

3.1. CPFAtreatment

InthegroupCPFA,patientswereaged46.0years(40.0 56.0;

median,the25thand75thpercentiles,range14 81years)with

aburnsizeof48.0%TBSA(35.0 60.0,range85%).Themedian

periodbetweenpatients’admissionandtheonsetofsepsis

was5.5days(4.5 7.0).Themedianperiodbetweenpatients’

admissionandRRTstartwas15.0days(7.0 23.0).

ThemainreasonsforstartinganRRTtreatmentwerefluid

overloadandoliguria(26patients,66.6%),followedbysevere

hyperkalemia (18 patients, 46.1%) and severe acidosis (16

patients,42.0%),anduremiccomplications(3patients,7.6%).

MostofpatientsoftheCPFAandcontrolgroupsweretreated

withpotentiallynephrotoxicdrugs(aminoglycosides,colistin,

vancomycin),andnoneofthepatientsunderwent

contrast-media procedures. No significant difference was found

betweenthe2groupsintheuseofnephrotoxicdrugs,lactate

levels,doseofvasopressorsandSOFAscoreattheonsetof

treatment,timefromshocktorenalfailureandoverallRRT

treatmentduration(Table1).

In16CPFApatientsnocomorbiditieswerefound.Inthe

remaining23patients,comorbiditiesincluded6casesofmajor

psychiatricdisorders,5casesofpolytrauma,3casesofchronic

(COPD),6casesofhypertensionand2casesofdiabetes.The

overall prevalence ofthe above comorbiditiesin the CPFA

groupwasnotsignificantlydifferentfromthatinthecontrol

group(p0.4045).

Amongatotalof70positiveculturesisolatedfromthese

patients’bloodandotherspecimensourcesthegram-negative

strainswerepredominant(47/70cultures).Thetop6

micro-organisms were Acinetobacter Baumanni (21 specimens),

Pseudomonas Aeruginosa (16 specimens), Staphylococcus

Aureus MR (6 specimens), Candida spp. (6 specimens),

CoagulaseNegativeStaphylococcus(5specimens)and

Sten-otrophomonasMaltophilia(4specimens).

AsshowninTable2,nonsurvivorsweresignificantlyolder

in the CPFA group (54 vs. 46years, p 0.012), and had

significantlyhigher SOFA score(13.0 vs. 11.0,p 0.005)and

revised-Bauxscore(119.9vs.103.0,p<0.041).Nosignificant

difference was found for burn size, days of CPFA and

continuousRRT(CRRT),andCPFAdose.Whilesearchingfor

factorsaffectingsurvivalintheCPFAgroup,weincludedthe

twofollowingpredictorsinthemultivariateanalysislogistic

model:SOFAscoreonthe1stdayofCPFA,andage.Ofthesetwo

predictors,SOFAscorewassignificant(OR2.016,95%CI,1.221

3.326; p<0.004), whereasp-value forageshoweda trend

towardssignificance(OR1.065,95%CI,0.997 1.139;p<0.059).

Fig. 1shows theclinical trendofhemodynamics(mean

arterial pressure (MAP), heart rate and norepinephrine

requirement), metabolic indexes (plasma lactate and pH)

andSOFAscorefornonsurvivorandsurvivorpatientsbefore

andafterinitiationofCPFAtherapy.LowervaluesofMAPand

pH, and higher norepinephrine requirements and lactate

plasma levels were observed in nonsurvivors (Fig. 1). In

survivorspatientsweobservedatrendtowardsaprogressive

improvement ofthe hemodynamic and laboratory

param-eters.Ninepatientsdiedwithinthe2nddayofCPFA.

Regardinganticoagulationstrategies,nosignificant

differ-ences werefoundforobservedmortalityrate,revisedBaux

score,SOFAscore,CRRTdayspost-admissionandnumberof

CPFA sessions/patient performed, (Table 3). However, the

patientsthatweretreatedwithunfractionatedheparin

anti-coagulationwereyoungerandwithhigherburnsize,whereas

thosethatweretreatedwithRCAwereolder(p<0.05)andwith

lowerburnsize(p0.06,Table4).

SurvivalanalysisbyKaplan Meyercurvesshowedatrend

towardsabettersurvivalforpatientsthatweretreatedwith

RCA in comparison to those treated with unfractionated

heparin,eventhoughnotsignificant(p0.1583,Cox’sF-test,

Fig.2).

Regarding CPFA flow rates, the session duration was

significantlylongerforpatientstreatedwithRCA,aswellas

the amount ofeffluent volume andnet fluidremoval.The

mediandoseofplasmaprocessedduringCPFA,normalizedto

patientweight,wassimilarinthetwogroups(Table4).

4.

Discussion

SevereburnpatientsrepresentaspecificmodelofAKIassociated

septic-shockin whichtheseverityoftheinitialinsultcanbe

quantifiedintermsofburnsizeandrevisedBauxscore,andthe

septic process develops predictably [12,16,25 29]. Moreover,

Table1–Demographiccharacteristicsof39septicshockburnpatientswithAKItreatedwithCPFA(CPFAgroup)andof87 burnpatientstreatedwithonlyRRT(Controlgroup).a

CPFAgroupb Controlgroupc p

Patients(n) 39 87

In-hospitalmortality(%,n) 51.3%,20 77.1%,67 0.004

Age(years) 46.0(40.0-56.0) 61.0(46.0-73.0) 0.003

Totalbodysurfacearea(%) 48.0(35.0-60.0) 40.0(30.0-60.0) 0.250

RevisedBauxscore 111.2(99.5-126.4) 121.7(102.9-133.4) 0.118

Genderratio(male%,n) 74.3%,29 60.9%,53 0.102

Septicshock(%,n) 100%,39 91.9%,80 0.337

Mechanicalventilation(%,n) 100%,39 94.2%,82 0.223

CPFA-RRT/RRTinterval(dayspost-admission) 17(9-25) 18(10-28) 0.268

Septicshock/AKIinterval(days) 5(4-7) 5(3-10) 0.938

CPFA-RRT/RRTduration(days) 5(3-13) 10(18-5) 0.111

Citrateanticoagulation(%,n) 51.3%,20 75.8%,66 0.012

SOFAscore(at1stdayoftreatment) 12(10-14) 12(10-14) 0.364

Lactate(mmol/l,at1stdayoftreatment) 2.0(1.4-2.5) 2.4(1.5-3.7) 0.127

Norepinephrin(ug/kg/min,at1stdayoftreatment) 0.40(0.20-0.57) 0.40(0.20-0.60) 0.762

Nephrotoxicdrugs(%,n) 69.3%,27 66.7%,58 0.773

Aminoglycosides 56.4%,22 52.8%,46 0.708

Colistin 30.8%,12 21.8%,19 0.278

Vancomycin 30.8%,12 26.4%,23 0.610

Dataaregivenasmedian(the25thand75thpercentiles)oraspercentagewhenappropriate.StudentT-testorFisher’sexacttestwasdonewhen appropriate.

a_{Controlgroup(n87)includedalltheburnpatientstreatedwithRRTfrom2000to2017,with:(1)atimeintervalfromadmissiontoRRT5days,and}

(2)therangevaluesofageof14and81years;and(3)%TBSArangeof85%.

b_{CPFA=coupled-plasmafiltrationadsorptionwithrenalreplacementtherapy.} c_{RRT=renalreplacementtherapyalone.}

despitetheimprovementsofsupportiveintensivecareandthe

optimizationofdialytictechniques,AKIinburnsepsisisstill

associatedwithahighriskofdeath[6 16].

IthasbeenhypothesizedthatCPFAinburnpatientscould

exertabeneficialimmunomodulatoryeffect[14],beingableto

removeexogenousandendogenousinflammatorymediators

throughaplasmaadsorptionmechanism[1 3].Nevertheless,

thereisnocleardemonstrationofasurvivalbenefitfromCPFA,

sofar.However,veryfewstudieshaveaddressedtheclinical

impactofCPFAonmortalityrates,andtheenrolledpatients

hadsepticshockofmultifactorialetiology[5].Theselectionof

patientsmaybecrucialfordemonstratingtheefficacyofthe

treatment.Evenifitwasrecentlyshownthattwosessionsof

CPFAinsevereburnpatients,inadditiontoroutinetreatment,

significantlydecreasedthelevelofdifferentcytokines[30],no

studyhasaddressedtheissueofCPFAclinicalefficacyina

selectedandspecificpopulation,suchassepticshocksevere

burnpatients.

Consideringthepossiblebenefitsand,atthesametime,the

lack of evidence, we decided to introduce CPFA as an

Fig.1–OutcomeofMAP,heartrate,norepinephrinerequirement,pH,bloodlactateandSOFAscoreinthefirstsixdaysofCPFA

forNonsurvivor(n20patients)andSurvivorspatients(n19patients).DataweretakenatthestartofCPFAdaysession.Dataof

Day1werethebaselinedataattime0ofCFFAcourse.Thenumberonthecolumnsindicatesthenumberofconsideredcasesat

eachtime.TheNonsurvivorpatientswere:20atday1,15atday2,11atday3,10atday4,8atday5,and8atday6.

Dataaregivenasmedian(the25thand75thpercentiles).ANOVAandpost-hocanalysiswithNewman Keulsmulticomparison

testwasdonebetweenNonsurvivorandSurvivorspatients(*p<0.05).MAP=meanarterialpressure.

Table2–Characteristics,clinicalparametersandoutcomeofnonsurvivorandsurvivorpatientstreatedwithCPFA(CPFA group).

Nonsurvivor Survivor p

Patients(n) 20 19

Age(years) 54(43 71) 46(30 51) 0.012

Totalbodysurfacearea(%) 49(35 65) 45(35 60) 0.815

RevisedBauxscore 119.9(105.9 131) 103.0(94.8 120.5) 0.041

Genderratio(male%,n) 65.0%,13 76.1%,16

Mechanicalventilation(%,n) 100,20 100,19

SOFAscore(at1stdayofCPFA) 13(12 14) 11(9 11) 0.005

Cardiovascular 4(4 4) 4(4 4) 0.547 Respiratory 3(2 3) 2(1 3) 0.031 Hematologic 1(0 2) 0(0 1) 0.045 Liver 2(1 2) 1(1 2) 0.147 Citrateanticoagulation(%,n) 45.0%,9 57.8%,11 CPFA(sessions) 3.5(1.5 7) 6(4 10) 0.205

CPFAdose(l/kg/day) 0.179(0.161 0.196) 0.171(0.138 0.180) 0.135

CRRTa_{(days) 10.5(3 17.5) 10(7 20) 0.892}

CRRTintervala_{(dayspost-admission) 16.5(8 24.5) 18(13 28) 0.907}

Dataaregivenasmedian(the25thand75thpercentiles)oraspercentagewhenappropriate.StudentT-testorFisher’sexacttestwasdonewhen appropriate.

adjunctivetherapyonlyforsevereburnpatientswithapoor

prognosis,suchthosesufferingfromsepticshockwithmulti

organ failure sustained by multi-drug resistant bacterial

strainsnotorpoorlyresponsivetoantibiotictherapy.

IntheCPFAgroupthemortalityratewas51.3%,lowerthan

themortalityrateinthecontrolgrouptreatedonlywithRRT,

andbetterincomparisontotheliteraturedata[6 13,16].This

resultsuggeststhatCPFAinburnpatientswithsevereseptic

shockandconcomitantAKIcouldprovideanactualbenefiton

theoutcomewhencomparedtostandardCRRTtreatment.

We applied logistic regression analysis on our data,

searchingforfactorsthathelppredictthesurvivalofpatients

treatedwithCPFA. Wefoundthat theSOFAscore wasthe

only significant parameter, whereas the age was near

significance.As also suggestedby the significantly higher

value in nonsurvivors than in survivors, the SOFA score

(Table2andFig.1)confirmedtobeareliablepredictorofthe

outcomeforburnpatients[24,31,32].Inthesameway,the

observedhighlactatelevels inthe firstfourdays ofCPFA,

when mortality peaked (see Fig. 2) reflected the fatal

outcome and confirmed lactate as a strong predictor of

mortality inseptic shockburn patients [33]. As shownin

Fig.1,theCPFApatientsofbothgroupshadslightlyelevated

levelsoflactate,whilehavinganextremelyhighmeanSOFA

scoreof>12.Thispuzzlingdiscrepancycouldbeduetosome

specific conditionsofburnpatients,such asinfectionand

organ dysfunction lasting a long time, the pathogenesis

sustainedby differentmicroorganismsandthe fluctuating

course of infective process. In addition, we analyzed the

presence of comorbidities [32,33]. We did not find a

differenceofoverallcomorbiditiesprevalencebetweenthe

twogroups,thusmakingthecomparisonreliable.

Asexpected,thepatientsofbothgroupsexperiencedan

intensiveuseofpotentiallynephrotoxicantibiotics.Therefore,

the AKI pathogenesis of our patients was likely to be

multifactorial.Besidesimmunologicalandinfectiousfactors

[29],AKIreflectedalsoadirecttubularantibiotictoxicity,and

bothsystemicandlocalhemodynamicderangements.

Table4–CPFAgroupflowratesaccordingtoanticoagulationprotocolwithCitrate(n20patients)andHeparin(n19patients) subgroups.

All Citrate-CPFA Heparin-CPFA pa

CPFAsessions 238 128 110

Sessions(no./patient) 5(2 8) 5(2 10) 5(3 7) 0.945

DurationofCPFAsession(hours) 8.0(7.0 9.0) 8.0(7.0 10.0) 7.5(7.0 8.0) 0.005

Hemorrhagicepisodes 6/238 0/128 6/110 0.005

Catheter-relatedcomplications 7/41 2/18 5/23 0.327

Hypersensitivityreactions 0/238 0/110 0/128

Bloodflowrate(ml/min) 150(140 160) 150(140 165) 150(150 160) 0.654

Circuitcitratemia(mmol/l) 3.9(3.4 4.5)

Unfractionatedheparin(Units/hour) 900(750 1200)

Effluentvolume(l/session) 22.5(19.5 27.0) 25.2(21.6 33.6) 21.0(18.0 24.0) 0.005 Netfluidremoval(l/session) 0.20(0.00 1.10) 0.70(0.00 1.10) 0.20(0.00 0.85) 0.024 Plasma-treated(l/session) 12.2(10.4 14.6) 12.6(10.4 16.3) 12.1(10.1 13.4) 0.006 Plasma-processeddose(l/kg/day) 0.175(0.144 0.198) 0.176(0.144 0.202) 0.174(0.145 0.196) 0.854

Dataareexpressedasmedian(the25thand75thpercentiles).

a_{StudentT-testorFisherexacttestwasdonebetweenCitrateandHeparingroupswhenappropriate.}

Table3–Demographiccharacteristicsof39severeburnsepticshockpatientsundergoingCPFA(CPFAgroup).Datawere givenaccordingtoanticoagulationprotocolwithCitrate(n20patients)andHeparin(n19patients).

Citrate-CPFA Heparin-CPFA

All Dead Alive All Dead Alive pa

Patients(n) 20 9 11 19 11 8 0.314

In-hospitalmortality(%) 45.0% 61.1%

Age(years) 50.5(43 62) 55(46 78) 46(40 55) 44(31 56) 45(37 60) 37(40 47) 0.049

Totalbodysurfacearea(TBSA,%) 45(35 52.5) 45(35 55) 45(35k50) 56(40 65) 50(40-80) 58(42 60) 0.062 RevisedBauxscore 108(99 122) 114(103 126) 104(99 121) 117(90 131) 124(108-138) 102(88 116) 0.756 SOFAscore(onthe1stdayofCPFA) 13.0(9 13) 13.0(12 15) 10.5(9 13) 11.5(10 14) 13.0(11 14) 10.5(9 11) 0.929

Genderratio(male%,n) 70.0%,14 44.4%,4 90.9%,10 78.9%,15 81.8%,9 75.0%,6 0.397

Mechanicalventilation(%,n) 100%,20 100%,10 100%,10 100%,19 100%,11 100%,7

CRRTinterval(dayspost-admission) 18.5(9 29.5) 21(7 28) 18(9 31) 15(9 21) 12(8 21) 17(14 24) 0.387

Dataaregivenasmedian(the25thand75thpercentiles).

WefurtherexploredsometechnicalaspectsoftheCPFA

technique.Specifically,wewantedtoseeiftheanticoagulation

strategy adopted in delivering CPFA could influence the

efficacy and safety ofthe treatment. The patients treated

with unfractionated heparin anticoagulation and those

treated with RCA had similar characteristics, even tough

patientstreatedwithunfractionatedheparincoagulationwere

youngerandhadhigherburnsize.Theobservedmortalitydid

notsignificantlydifferbetweenthetwogroups,evenifthe

Kaplan Meyercurvesofsurvivalshowedabettertrendfor

patients treated with RCA strategy (Cox’s F-test p 0.1583).

However,aspreviouslydescribedincontinuous

extracorpo-real treatment [13,17,18], during regional unfractionated

heparin anticoagulation hemorrhagic events were more

frequent.

Inthepresentpaperwereportedourclinicalexperience

withanewtreatmentoptionforaspecificICUpopulation,such

asburnpatientswithsepticshocksandpooroutcome,andthis

couldbethe strengthofourstudy,and likelyonepossible

reasonforthepositiveresults.Theimprovedsurvivalrateis

indeedfarfrombeingconclusiveandshouldbeconsideredasa

startingpointforfurtherstudies.CPFAinburnpatientswith

severesepticshock andconcomitant AKIcould providean

actualbenefitontheoutcome whencomparedtostandard

CRRTtreatment.Accordingtootherexperiences,thesedata

alsosuggestthattheactualbenefitdemonstrationofanew

treatmentoptioninICUpatientsisdeeplyrelatedtothechoice

ofappropriatepatients,withappropriateindications[34].

Werecognizethatourstudyhassomelimitations.First,

severeburnpatientssufferfromacomplexcondition,andthey

undergomultipleinterventions.Isolatingtheeffectofasingle

treatmentontheoutcomecouldbeimpossible.Secondly,the

numberofsubjectsislimitedinsuchspecificpopulation,and

treatedoveranextendedperiodoftimewhencomprehensive

burn care measures and team expertise have improved.

Thirdly,as suggestedby thehigh numberofdeathsinthe

first48h,themortalityratecouldhavebeenreducedwithan

earlierCPFAtreatment.Thisconsiderationwasalsosupported

bythestrongcorrelationoftheSOFAscoreasagoodpredictor

offataloutcome.

5.

Conclusion

CPFAtreatment forburnpatients withAKI-RRTandseptic

shock,sustainedbybacterialstrainsnon-orpoorlyresponsive

to therapy, was associated with a lower mortality rate

comparedtoRRT alone.However,furtherresearch,suchas

largeprospectivestudies,isrequiredtoclarifytheroleofCPFA

inthetreatmentofburnswithsepticshockandAKI-RRT.

Ethics

approval

and

consent

to

participate

ThestudywasapprovedbytheEthicalCommitteeoftheCityof

HealthandScienceofTurin(dossiern.CS2/908).

Availability

of

data

and

material

Thedatasetsusedandanalyzedduringthecurrentstudyare

availablefromthecorrespondingauthoronreasonablerequest.

Competing

interests

and

conflict

of

interest

Theauthors declarethat theyhavenocompeting interests

and/orconflictofinterest.

Funding

ThisworkwassupportedbyagranttoFMfromtheMinistero

dell’Istruzione,Universita’eRicerca(MIUR,ex60%),Italy.The

authorsdeclarenofinancialinterest.

Authors’

contributions

FM and ZH conceived the study, collected, analyzed and

interpretedthedata,andelaboratedthemanuscript.VM,AP,

AM,andDBperformedtheenrollmentofpatientsinthestudy.

LB,MB,andMSsupervisedthestudy,andNDcorrectedthe

finalversionofthemanuscript.Allauthorsreadandapproved

thefinalversionofthemanuscript.

Westatethattheresultspresentedinthispaperhavenot

beenpublishedpreviouslyinwholeorpart,exceptinabstract

format.

Acknowledgments

The authors wish to thank Dr. Luisa Tedeschi and all

colleaguesfortheirvaluablehelpinproofreading.

REFERENCES

[1]RoncoC,BrendolanA,d’IntiniV,RicciZ,WrattenML,Bellomo R.Coupledplasmafiltrationadsorption:rationale,technical developmentandearlyclinicalexperience.BloodPurif 2003;21:409 16.

[2]TettaC,GianottiL,CavaillonJM,WrattenML,FiniM,BragaM, etal.Coupledplasmafiltration-adsorptioninarabbitmodelof endotoxicshock.CritCareMed2000;28:1526 33.

[3]RoncoC,BrendolanA,LonnemannG,BellomoR,PiccinniP, DigitoA,etal.Apilotstudyofcoupledplasmafiltrationwith adsorptioninsepticshock.CritCareMed2002;30:1250 5.

[4]FormicaM,OlivieriC,LivigniS,CesanoG,ValleroA,MaioM, etal.Hemodynamicresponsetocoupled plasmafiltration-adsorptioninhumansepticshock.IntensiveCareMed 2003;29:703 8.

[5]LivigniS,BertoliniG,RossiC,FerrariF,GiardinoM,PozzatoM, etal.GiViTI:gruppoItalianoperlaValutazionedegliInterventi inTerapiaIntensiva(ItalianGroupfortheEvaluationof InterventionsinIntensiveCareMedicine).Efficacyofcoupled plasmafiltrationadsorption(CPFA)inpatientswithseptic shock:amulticenterrandomizedcontrolledclinicaltrial.BMJ Open2014;4(January(1)):e003536.

[6]LeblancM,ThibeaultY,QuerinS.Continuoushaemofiltration andhaemodiafiltrationforacuterenalfailureinseverely burnedpatients.Burns1997;23:160 5.

[7]HolmC,HorbrandF,vonDonnersmarckGH,MuhlbauerW. Acuterenalfailureinseverelyburnedpatients.Burns 1999;25:171 8.

[8]TremblayR,EthierJ,QuerinS,BeroniadeV,FalardeauP, LeblancM.Veno-venouscontinuousrenalreplacement therapyforburnedpatientswithacuterenalfailure.Burns 2000;26:638 43.

[9]ChungKK,LundyJB,MatsonJR,RenzEM,WhiteCE,KingBT, etal.Continuousvenovenoushemofiltrationinseverely burnedpatientswithacutekidneyinjury:acohortstudy.Crit Care2009;13(3):R62.

[10]SoltaniA,KarsidagS,GarnerW.Aten-yearexperiencewith hemodialysisinburnpatientsatLosAngelesCounty+USC MedicalCenter.JBurnCareRes2009;30:832 5.

[11]BrusselaersN,MonstreyS,ColpaertK,DecruyenaereJ,BlotSI, HosteEA.Outcomeofacutekidneyinjuryinsevereburns:a systematicreviewandmeta-analysis.IntensiveCareMed 2010;36:915 25.

[12]PalmieriT,LavrentievaA,GreenhalghDG.Acutekidneyinjury incriticallyillburnpatients.Riskfactors,progressionand impactonmortality.Burns2010;36:205 11.

[13]MarianoF,TedeschiL,MorselliM,StellaM,TrioloG.Normal citratemiaandmetabolictoleranceofcitrateanticoagulation forhemodiafiltrationinseveresepticshockburnpatients. IntensiveCareMed2010;36:1735 43.

[14]LindenK,StewartIJ,KreyerSF,ScaravilliV,CannonJW,Cancio LC,etal.Extracorporealbloodpurificationinburns:areview. Burns2014;40:1071 8.

[15]ChungKK,CoatesEC,SmithJr.DJ,KarlnoskiRA,HickersonWL, Arnold-RossAL,etal.Randomizedcontrolledevaluationof high-volumehemofiltrationinadultburnpatientswithseptic shockandacutekidneyinjury(RESCUE)investigators. High-volumehemofiltrationinadultburnpatientswithseptic shockandacutekidneyinjury:amulticenterrandomized controlledtrial.CritCare2017;21(1):289,doi:http://dx.doi.org/ 10.1186/s13054-017-1878-8.

[16]ClarkA,NeyraJA,MadniT,ImranJ,PhelanH,ArnoldoB,etal. Acutekidneyinjuryafterburn.Burns2017;43:898 908.

[17]MarianoF,TettaC,StellaM,BiolinoP,MilettoA,TrioloG. Regionalcitrateanticoagulationincriticallyillpatients treatedwithplasmafiltrationandadsorption.BloodPurif 2004;22:313 9.

[18]MarianoF,MorselliM,HolloZ,AgostiniF,StellaM,BianconeL. Citratepharmacokineticsathighlevelsofcircuitcitratemia duringcoupledplasmafiltrationadsorption.NephrolDial Transplant2015;30:1911 9.

[19]DokterJ,MeijsJ,OenIM,vanBaarME,vanderVliesCH,Boxma H.ExternalvalidationoftherevisedBauxscoreforthe predictionofmortalityinpatientswithacuteburninjury.J TraumaAcuteCareSurg2014;76:840 5.

[20]KellumJA,LameireN,KDIGOAKIGuidelineWorkGroup. Diagnosis,evaluation,andmanagementofacutekidney injury:aKDIGOsummary(Part1).CritCare2013;17(1):204.

[21]BoneRC,BalkRA,CerraFB,DellingerRP,FeinAM,KnausWA, etal.Definitionsforsepsisandorganfailureandguidelinesfor theuseofinnovativetherapiesinsepsis.TheACCP/SCCM ConsensusConferenceCommittee.AmericanCollegeofChest Physicians/SocietyofCriticalCareMedicine.Chest

1992;101:1644 55.

[22]LevyMM,FinkMP,MarshallJC,AbrahamE,AngusD,CookD, etal.Internationalsepsisdefinitionsconference.2001SCCM/ ESICM/ACCP/ATS/SISinternationalsepsisdefinitions conference.IntensiveCareMed2003;29:530 8.

[23]DellingerRP,CarletJM,MasurH,GerlachH,CalandraT,Cohen J,etal.SurvivingSepsisCampaignManagementGuidelines Committee.SurvivingSepsiscampaignguidelinesfor managementofseveresepsisandsepticshock.CritCareMed 2004;32:858 73.

[24]SingerM,DeutschmanCS,SeymourCW,Shankar-HariM, AnnaneD,BauerM,etal.Thethirdinternationalconsensus definitionsforSepsisandsepticshock(Sepsis-3).JAMA 2016;315(8):801 10.

[25]Evidence-basedGuidelinesGroup,A.B.A.,&ParadigmHealth Corporation.Practiceguidelinesforburncare.JBurnCare Rehabil2001;(Supplement,v xii):1S 69S.

[26]AmericanBurnAssociation&AmericanCollegeofSurgeons. Guidelinesfortheoperationofburncenters.JBurnCareRes 2007;28(1):134 41.

[27]ISBIPracticeGuidelinesCommittee,SteeringSubcommittee, AdvisorySubcommittee.ISBIpracticeguidelinesforburncare. Burns2016;42:953 1021.

[28]Europeanpracticeguidelinesforburncare.4thed....[Last

accessed31July2018]http://www.euroburn.org.

[29]MarianoF,CantaluppiV,StellaM,RomanazziGM,AssenzioB, CairoM,etal.Circulatingplasmafactorsinducetubularand glomerularalterationsinsepticburnspatients.CritCare 2008;12(2):R42.

[30]MengA,RenY,YangL,HeL,ZengS,LiuQ.Clinicalstudyon continuousplasmafiltrationabsorptiontreatmentforburn sepsis.ZhonghuaShaoShangZaZhi2014;30:310 4.

[31]VincentJL,deMendonçaA,CantraineF,MorenoR,TakalaJ, SuterPM,etal.UseoftheSOFAscoretoassesstheincidenceof organdysfunction/failureinintensivecareunits:resultsofa multicenter,prospectivestudy.Workinggroupon

“sepsis-relatedproblems”oftheEuropeanSocietyofIntensiveCare Medicine.CritCareMed1998;26:1793 800.

[32]BelbaMK,PetrelaEY,BelbaAG.Epidemiologyandoutcome analysisofsepsisandorgandysfunction/failureafterburns. Burns2017;43:1335 47.

[33]LavrentievaA,VoutsasV,KonoglouM,KaraliV,KoukiasaP, LoridasN,etal.DeterminantsofoutcomeinburnICUpatients withsepticshock.JBurnCareRes2017;38:e172 9.

[34]VincentJL.Recentnegativeclinicaltrialsinsepticpatients: maybeagoodthing?MinervaAnestesiol2015;81:122 4.