selenium for sepsis - amazon s3 · 2018-07-10 · 72 selenium in guidelines 74 biosyn arzneimittel...

Selenium for sepsis

selenase®

• improves selenium status

• eliminatesseleniumdeficiency

• reducesmortality

we are research

High dose for sepsis – so that selenium works

Day1

Treatmentideallybeginswithin 6 hours after admission to the ICU

asbolus 2,0001–3 µg Se

thenascontinuousinfusion

1,6001–3 µg Se

at least 7days

maintenance therapy

1,6001–3µgSe/Day

Literature1ManzanaresWetal.2012,CritCare;16:R662HuangTSetal.2013,PLoSOne8:e544313AlhazzaniWetal.2013,CritCareMed41:1555–1564

selenase® for sepsis• Ahighdoseseleniumbolussignificantlyreducesthedeathrateforsepsispatientsby27%.[1]

• Ahighdoseof≥1,000μgseleniumassodiumselenitepentahydrate(selenase®) perdaysignificantlyreducesthemortalityby23%.[1]

• Amaintenancetherapyof≥7dayssignificantlyimprovessurvival.[1]

[1]HuangTS,ShyuYC,ChenHY,LinLM,LoCY,YuanSS,ChenPJ.PLoSOne.2013;8(1):e54431.doi:10.1371/journal.pone.0054431Effectofparenteralseleniumsupplementationincriticallyillpatients:asystematicreviewandmeta-analy-sis.http://www.ncbi.nlm.nih.gov/pubmed/23372722

Summary2

http://www.ncbi.nlm.nih.gov/pubmed/22534505




Miscibility

Yes No

• 5%glucosesolution

• Ringersolution

• Carbohydratesolutions (stability72hours(3days))

• Colloidal volume expander solutions (stability72hours(3days))

• Electrolytesolutionswithincreased potassiumconcentration(stability 48hours(2days))

• Crystalloidelectrolytesolutions (stability48hours(2days))

• Aminoacidsolutionswithoutcysteine(stability36hours(1.5days))

• Fat emulsions (stability24hours(1day))

• Vitaminsolutions(withoutvitaminC)

• Cytostaticagentsolutions[1]

• Aminoacidsolutions thatcontaincysteine[2]

• Solutions thatcontainglutathione(GSH)[3]

• Vitamin solutions thatcontainvitaminC[4]

[1]selenase®shouldgenerallybeadministered1hour beforecytostaticagentapplicationfortimelyincorporationintheendogenousprotectivesystems.

[2,3]SHgroupsreacttoNa-selenite;Na-selenitecan nolongersatisfyitstaskasaradicalscavenger

[4]Selenium(Se+IV)insodiumseleniteisreducedbyvitaminCtotheelementaryselenium(Se0)andistherebyineffective.

Literature: RobinsonMF,ThomsonCD,HuemmerPK.NZMedJ.1985Aug14;98(784):627-9.Effectofamegadoseof ascorbicacid,amealandorangejuiceontheabsorption ofseleniumassodiumselenite. http://www.ncbi.nlm.nih.gov/pubmed/3861972

IpC.JNatlCancerInst.1986Jul;77(1):299-303.InteractionofvitaminCandseleniumsupplementationinthemodifica-tionofmammarycarcinogenesisinrats. http://www.ncbi.nlm.nih.gov/pubmed/3088312

Summary 3



Productsforinjectiontherapy

Prescriptiononly

selenase® 100µg proinjectione

selenase® T proinjectione

100 µg Selenium / ampoule

500 µg Selenium / injectionvial

10(N2)and50ampoules with2mlsolutionforinjection

2,10(N2),30(3×10)and50 (5×10)glassvialswith10mlsolution forinjection

selenase® 100 µg / T: Active substance: Sodium selenite pentahydrate, 50 µg selenium per ml. Indications: Clinically proven selenium deficiency that cannot be compensated by nutritional sour-ces. Selenium deficiencies may occur as a result of states of maldigestion and malabsorption, as well as in malnutrition (e.g. due to complete parenteral nutrition). Composition: selenase® 100 µg pro injectione: 1 ampoule of 2 ml solution for injection contains: 0.333 mg sodium selenite pentahydrate, corresponding to 100 µg (micrograms) selenium. selenase® T pro injectione: 1 injection vial of 10 ml / 20 ml solution for injection contains: 1.67 mg / 3.33 mg sodium selenite pentahydrate, corresponding to 500 µg / 1000 µg selenium. selenase® 100 µg peroral: 1 drinking ampoule of 2 ml oral solution contains: 0.333 mg sodium selenite pentahydrate, corresponding to 100 µg selenium. selenase® T peroral: 1 ml oral solution contains: 0.167 mg sodium selenite pentahydrate, corresponding to 50 µg selenium. Excipients: Sodium chloride, hydrochloric acid, water for injections. Contra-indications: Selenium poisoning. Undesirable effects: None known to date if the medicinal product is administered according to prescription. selenase® 100 µg / T pro injectione: General disorders and administration site conditions: Frequency not known (cannot be estimated from the available data): After intramuscular administration local pain at the site of administration has been reported. Form of administration, size of packages: selenase® 100 µg pro injectione: 10 or 50 ampoules of 2 ml solution for injection. selenase® T pro injectione: 2 or 10 injection vials of 10 ml solution for injection, hospital-size pack 30 (3 x 10) or 50 (5 x 10) injection vials of 10 ml solution for injection, 2 or 10 injection vials of 20 ml solution for injection, hospital-size pack 30 (3 x 10) or 50 (5 x 10) injection vials of 20 ml solution for injection. selenase® 100 µg peroral: 20, 60, 90 or 100 ampoules of 2 ml oral solution. selenase® T peroral: 10 drinking bottles of 10 ml oral solution plus one measuring cup. 10/14 e

8 Generalfactsaboutsepsis

8 Sepsis:Incidence

10 Theproblem:Diagnosis

10 Theproblem:Costs

12 Details on sepsis

12 SepsisinEurope

14 MajorinfluenceoforganfailureonICUmortalityrates

16 ICUmortalityratesignificantlyhigherinsepsispatients

18 Postoperative sepsis

20 Selenium and sepsis

21 Seleniumleveldeclinesincorrelationtosepsisseverity

22 SeleniumconcentrationisinverselycorrelatedwithAPACHEIIandSAPSIIscores

23 Minimumseleniumconcentration:independentpredictorofICUmortality

24 Wheredoesseleniuminterveneintheprocessofsepsis?

26 WhicheffectdoesROSproductionhaveonsurvival?

26 Whydoestheseleniumstatusdeclineinpatientswithsepsis?

28 Whyisearlyadministrationofsodiumselenitecrucial(within≤6hours)?

30 Whyinjectsodiumseleniteasbolus?

32 selenase® for sepsis

34 Metaanalysisof9sepsistrials

42 Pilotstudy

46 SICtrial(SeleniuminIntensiveCare)

52 Various trials

68 Overview of trials

72 Additionalinformation

72 Selenium in guidelines

74 biosynArzneimittelGmbH

5Content

Sepsis

General Germanyregistersover175,000sepsispatientseachyear

Despitemedicalprogressingeneral,thesenumberskeeprising

Diagnosisisencumberedbynon-specificsymptomsandalackofgenerallyvalidbiomarkers

Exorbitantcostsfortreatingsepsispatients

Details on sepsis

CorrelationbetweenICUmortalityandsepsisincidenceinEurope

OrganfailurestronglyaffectsICUmortalityrate

Thenumberoffailedorgansincreasessignificantlyinseveresepsis

Increasingnumberofpostoperativesepsiscases

Selenium and sepsis

Seleniumleveldeclinesincorrelationwithsepsisseverity

SeleniumconcentrationisinverselycorrelatedwithAPACHEIIandSAPSIIscores

Minimumseleniumconcentrationisanindependentpredictor ofICUmortality

Cut-offvalueof36µg/lseleniuminserumforsepsispatients

Early(≤6hours)administrationofselenase®iscrucial

Abolusadministrationreversesthepro-inflammatorystateviaanearly,transient,pro-oxidativeeffectofhigh-dosesodiumselenite

Summary

Summary6

selenase® for sepsis

Metaanalysis Parenteralsodiumselenitetreatmentsignificantlyreducestotalmortalityrateby17%(p=0.04)

Highersignificantreductionofmortalitywhenabolusisadministered (−27%;p=0.01),amaintenancetherapy≥7days(−23%;p=0.01) andadosingof≥1,000µgseleniumassodiumselenite-pentahydrate(selenase®)perday(−23%;p=0.04)

Pilotstudy Supplementation with selenase®increasestheseleniumlevel to values within the normal range

selenase®supplementationsignificantlyreducesmortality inpatientswithAPACHEIIIscore>53

SIC trial Significantreductioninmortalityintheselenase®-supplemented groupby14.3%(p=0.049)

Significantreductioninmortalityinthesubgroups(septicshock,APACHEIII≥102,>3organfailure)intheselenase®-supplementedgroup byupto26%

Various trials Possiblecorrelationbetweenseleniumsupplementationandprocalcitonin

Supplementationwithhigh-dosesodiumselenitereducestheincidence ofnosocomialpneumoniaandimprovessepsisseverity

SIGNETtrial:Fewernewinfectionsinpatientsreceivingselenase® supplementationfor>5days

REDOXStrial:Comparedtoglutamine,seleniumdoesnothaveanynegati-veeffectonmortality,althoughthebeneficialeffectofseleniumsupplemen-tationisreducedbythelackofseleniumdeficiency

Significantlymorecriticallyillpatientsintheinterventiongroupimpacted theanalysisoftheretrospectivetrialonseleniumsupplementation in patients with severe sepsis

Summary 7

Generalfactsaboutsepsis

Generalinformation

• Germanyregistersover175,000sepsispatientseachyear

• Despitemedicalprogressingeneral,thesenumberskeeprising

• Diagnosisisencumberedbynon-specificsymptomsandalackofgenerallyvalidbiomarkers

• Exorbitantcostsfortreatingsepsispatients

Sepsis:HighincidencerateSepsisinvolvesacomplexsystemicinflammatoryreactionaffectingtheentirebodyandimpairstissue,organsand therebyallvitalfunctions.Ifsepsisis notdiagnosedandtreatedinatimelymanner,itwillinvariablyleadtosepticshock,multipleorganfailureanddeath.One third to one half of all patients do notsurvivesepsis.

Sepsisisthemostcommoninfection-re-latedcauseofdeath.Olderfiguresrepor-ted1.5millionsepsispatientsannuallyworldwide[1].InGermany,theincidence is154,000peryear(Fig.1)[2].Newpub-licationsevenreported175,000cases[1].However, the experts meanwhile assume thatapprox.18millionpeopleperyearbecomeafflictedgiventhatthemajority

ofdeathsascribedtoHIV/AIDS,malaria,pneumoniaandotherinfectiousdiseasesaremostlikelyattributabletosepsis[3].

Despitegeneralprogressinmedicine,thesenumbersarerisingdramatically.Thenumberofsepsiscasestreatedinhospitalhavedoubledoverthepast 10years[4]andmeanwhileexceedthenumberofhospitaladmissionsduetoheartattacks(Fig.2)[5,6].Only20–40%ofsepsispatientsacquiredtheirsepsisoutside of the hospital [7].Bycontrast, forexample,theincidenceofpostopera-tivesepsisintheUSAtripledfrom1997to2006.


Fig.

1Incidenceandmortalityofsepsis dependingonage.[10]

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2Morehospitaladmissionsduetosepsis thantomyocardiacinfarction.[5,6]

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9Generalfactsaboutsepsis

Sepsis:problematicdiagnosticsThediagnosisisfrequentlyconfirmed toolatebecausetheclinicalsymptomsandlaboratoryvalues(bodytemperature, heartrate,respiratoryrateandwhitebloodcellcount)arerelativelynon-spe-cificandcanoccurinalargenumberofotherdiseasesaswell.Particularlyinchildren,thesesymptomsarelessmeaningfulbecausetheonsetofsepsissymptomsisusuallyverysubtle,withtheclinicalpicturesuddenlyworseningdramatically.

Thehighrateofmisdiagnosesorcasesdiagnosedafteritwastoolateisattribu-tabletodeficitsstillexistinginthedefi-nitionofthecondition,insufficientdiag-nosticcriteriaandfrequentlyinsufficientcompliancewithclinicalguidelines.Anadditionalproblemis,thatforadiagnosisusingbloodparameters(“biomarkers”),therearestillnogenerallyapprovedbiomarkers,incontrasttootheracutedi-seases.Somenationalandinternationalguidelinesrecommendprocalcitoninforguidingantibiotictherapyandverifyingdiagnosisofsepsis.

Sepsis:HighcostsBetween1997and2008,inflation-correc-tedcostsofhospitaltreatmentforsepsispatientsroseannuallybyanaverageof11.9%toapprox.$14.6billionin2008[6].Thesenumbersdonottakeintoaccountthecostsforlong-termeffects,becausetheyaresofarunknown.Sepsissurvi-vorssufferfromalargenumberofseverephysical,cognitiveandmentalproblems,whichleadtoamortalityrisktwiceas

highasthatofapopulationcontrolgroupeven5yearsaftersurvivingsepsis[8].

Overthepast10years,themeancostsfor hospital treatment per sepsis patient increasedinthesamemagnitudetoacurrentlevelofapprox.€55,000inGer-manyaswell[9].


Literature

1 Rangel-FraustoMS,PittetD,CostiganM,HwangT,DavisCS,WenzelRP.JAMA.1995Jan11;273(2):117-23.Thenaturalhistoryofthesystemicinflammatoryresponsesyndrome(SIRS).Aprospectivestudy.

2

BrunkhorstFM,EngelC,ReinhartK,BoneH.-G,BrunkhorstR,BurchardiH,EckhardtK.-U,ForstH,GerlachH,GrondS,GründlingM,HuhleG,OppertM,OlthoffD,QuintelM,RagallerM,RossaintR,SeegerW,StüberF,WeilerN,WelteT,andLoefflerM.fortheGermanCompetenceNetworkSepsis(SepNet).EpidemiologyofseveresepsisandsepticshockinGermany–resultsfromtheGerman„Prevalence“StudyCriticalCare2005;9(Suppl1):S83.

3InternationalOrganizationsDeclareSepsisaMedicalEmergency.Issuedbyanexpertpanelrepresenting20adultandpediatricintensivecaresocieties,October4th2010.2010:Pressrelease.Availablefrom:http://www.prnewswi-re.com/news-releases/international-organizations-declare-sepsis-a-global-medical-emergency-104142073.html

4KumarG,KumarN,TanejaA,KaleekalT,TarimaS,McGinleyE,JimenezE,MohanA,KhanRA,WhittleJ,Ja-cobsE,NanchalR;MilwaukeeInitiativeinCriticalCareOutcomesResearchGroupofInvestigators.Chest.2011Nov;140(5):1223-31.doi:10.1378/chest.11-0352.Nationwidetrendsofseveresepsisinthe21stcentury(2000-2007).

5YehRW,SidneyS,ChandraM,SorelM,SelbyJV,GoAS.NEnglJMed.2010Jun10;362(23):2155-65.doi:10.1056/NEJMoa0908610.Populationtrendsintheincidenceandoutcomesofacutemyocardialinfarction.

6 HallMJ,WilliamsSN,DeFrancesCJ,GolosinskiyA.NCHSDataBrief.2011Jun;(62):1-8.Inpatientcareforsep-ticemiaorsepsis:achallengeforpatientsandhospitals.

7BealeR,ReinhartK,BrunkhorstFM,DobbG,LevyM,MartinG,MartinC,RamseyG,SilvaE,ValletB,VincentJL,JanesJM,SarwatS,WilliamsMD;PROGRESSAdvisoryBoard.Infection.2009Jun;37(3):222-32.doi:10.1007/s15010-008-8203-z.PromotingGlobalResearchExcellenceinSevereSepsis(PROGRESS):lessonsfromaninternationalsepsisregistry.

8 AngusDC.JAMA.2010Oct27;304(16):1833-4.doi:10.1001/jama.2010.1546.Thelingeringconsequencesofsepsis:ahiddenpublichealthdisaster?

9VincentJL,SakrY,SprungCL,RanieriVM,ReinhartK,GerlachH,MorenoR,CarletJ,LeGallJR,PayenD;SepsisOccurrenceinAcutelyIllPatientsInvestigators.CritCareMed.2006Feb;34(2):344-53.SepsisinEuropeanintensivecareunits:resultsoftheSOAPstudy.

10AngusDC,Linde-ZwirbleWT,LidickerJ,ClermontG,CarcilloJ,PinskyMR;EpidemiologyofseveresepsisintheUnitedStates:analysisofincidence,outcome,andassociatedcostsofcare.CritCareMed.2001Jul;29(7):1303-10.

11 HeubleinS,HartmannM,HagelS,HutagalungR,BrunkhorstFM;EpidemiologiederSepsisindeutschenKranken-häusern-eineAnalyseadministrativerDaten.Intensiv-News2013(1)1-5.

11Generalfactsaboutsepsis


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098346/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098346/

http://www.prnewswire.com/news-releases/international-organizations-declare-sepsis-a-global-medical-emergency-104142073.html

http://www.prnewswire.com/news-releases/international-organizations-declare-sepsis-a-global-medical-emergency-104142073.html










Details on sepsis

Generalinformation

• CorrelationbetweenICUmortalityandsepsisincidenceinEurope

• OrganfailurestronglyaffectsICUmortalityrate

• Thenumberoffailedorgansincreasessignificantlyinseveresepsis

• Increasingnumberofpostoperativesepsiscases

SepsisinEuropeMoreexactfiguresonthetopicofsepsisinEuropecanbefoundintheSOPAtrial2006 [1].

Europe-wide,37%ofpatientshadsep-sisduringtheirICUstay.Thisnumber ofpatientsillustratesthehighprevalenceofsepsis.Thiscombinedwiththefact,thatthesepsismortalityrateineurope is27%duringanICUstayandincreasesto50%inseveresepsis,showsclearlyhowimportantthetopicofsepsisis, eveninindustrializednationswithverygoodmedicalcare.

Alargeproportionofsepsispatientsdisplayaseveresepsis(79%)and39%evensufferfromsepticshock.Thatme-ansthat15%ofallpatientsadmittedtoanICUsufferedfromsepticshock.

ICUmortalityinsepsispatientsrangesbetween10%inSwitzerlandand35%inItaly;Germanyhas16%,thesecondlowestICUmortalityrate.ThehospitalmortalityinpatientswithsepsisinGer-manyandSwitzerlandwaslowestat20%,withtheNetherlandsregisteringthehighestat47%.AclearcorrelationbetweenoverallICUmortalityandthesepsisrateisevidentacrossthedifferentcountries(Fig.1).Overall,ICUmortalityinpatientswithsepsiswassignificantlyhigher than in patients without sepsis (27%vs.14%;p<0.001).Inpatientswithseveresepsisand/orsepticshock,ICUmortalityincreasedonaverageto32.2%and54.1%,respectively(Fig.2).InGermany,ICUmortalityinseveresep-siswas24%.


Fig.

1CorrelationbetweenICUmortalityofallpatients andsepsisincidenceinEurope.[1]

Switzerland

Germany

Countries licensed for selenase®

Countries not licensed for selenase®

Belgium

SpainAustria

ScandinaviaGreece

France

Eastern EuropeNetherlands

UK + Ireland

Portugal

Italy

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Y = 0.51 x - 0.11R2 = 0.80

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Fig.

2ComparisonofsepsisincidenceinICUpatients withICUmortalityinEurope.[1]

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No sepsis Sepsis Severe sepsis Septic shock

ICU mortality

13Details on sepsis

Fig.

3SignificantlyincreasingICUmortalityinpatients withorganfailureandseveresepsis.[1]

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Majorinfluenceoforganfailure onICUmortalityratesAtICUadmission,81%ofpatientsdis-playedorganfailure[1].41%ofthesepa-tientshadsepsis.In38%ofICUpatientswithoutsepsis,noorganfailureoccurred.Also,ICUmortalityinthisgroupwasbarely2%.Intheremaining62%ofICUpatientswithoutsepsisbutwithorganfai-lure,ICUmortalityincreasedto21%.Incomparison,allICUpatientswithseveresepsis had organ failure, and ICU morta-lityincreasedfurthersignificantlyto32%(p<0.01)(Fig.3).

Independent of an existing sepsis, there wasadirectconnectionbetweenthenumberoffailedorgansandICUmorta-lity(Fig.4).Inpatientswithnoorganfai-lureatICUadmission,theICUmortalitywas6%.Inpatientswith4ormorefailedorgans,ICUmortalityincreasedto65%.


Fig.

4FrequencyoforganfailureatICUadmission andthecorrespondingICUmortality.[1]

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15Details on sepsis

Literature

1VincentJL,SakrY,SprungCL,RanieriVM,ReinhartK,GerlachH,MorenoR,CarletJ,LeGallJR,PayenD;SepsisOccurrenceinAcutelyIllPatientsInvestigators.CritCareMed.2006Feb;34(2):344-53.SepsisinEuropeanintensivecareunits:resultsoftheSOAPstudy.

2BatemanBT,SchmidtU,BermanMF,BittnerEA.Anesthesiology.2010Apr;112(4):917-25.doi:10.1097/ALN.0b013e3181cea3d0.Temporaltrendsintheepidemiologyofseverepostoperativesepsisafterelectivesurgery:alarge,nationwidesample.

Fig.

5Thenumberoffailingorgansissignificantlyincreased insepsispatients.[1]

70%

57%

25%28%

38%

12%

24%

4% 13%

60%

50%

40%

30%

20%

10%

0%

1 2 3 ≥4

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10%

0%

No sepsis Severe sepsis

Number of organ failures

p < 0.001 p < 0.001 p < 0.001 p < 0.001

ICUmortalityratesignificantlyhigher in sepsis patientsSeveresepsisdoesnotimpactICUmor-talityratedependingonthenumberoffailingorgans.Butthenumberoforgansthatfailinsepsispatientsissignificantlyincreased(Fig.5).Therefore,ICUmorta-lityinICUpatientswithseveresepsisisstillsignificantlyhighercomparedtotho-

sewithoutsepsis,butwithorganfailure.Ifthefrequencyofmultipleorganfailure(MOF)couldbeloweredinpatientswithsepsis,thehighmortalityrateinthisgroupofpatientswouldalsobemarkedlyreduced.




Diagnosticcriteriaforsepsis

Accordingto:ReinhartK,BrunkhorstFM,BoneHGetal.[Prevention,diagnosis,treatment,andfollow-upcareofsepsis.FirstrevisionoftheS2k.GuidelinesoftheGermanSepsisSociety(DSG)andtheGermanInterdisciplinaryAssociationforIntensiveandEmergencyCareMedicine(DIVI)].*Anaesthesist2010;59:347–370.

Sepsis Severe sepsis Septicshock

Evidence ofaninfection



SIRS SIRS SIRS

Acuteorgan dysfunction

Cardiovascular instability

Evidenceofaninfection:Diagnosisofinfectionbasedonmicrobiologicalprooforclinicalcriteria

Systemicinflammatoryresponsesyndrome(SIRS)– atleast2ofthefollowingcriteria:Fever (≥38°C)orhypothermia (≤36°C),confirmedthroughrectal,intravascularorintravesicaldetermination

Tachycardia withaheartrate≥90/min

Tachypnea (respiratoryrate≥20/min)or hyperventilation(PaCO2≤4.3kPa/≤33mmHg)

Leukocytosis (≥12,000/mm3) or leukopenia (≤4,000/mm3)or≥10%immatureneutrophilsinthedifferentialbloodcount

Acuteorgandysfunction–atleast1ofthefollowingcriteria:Acute encephalopathy: Reducedvigilance,disorientation,agitation,delirium.

Relative or absolute thrombocytopenia:Dropinplateletcount>30%within24hoursorplateletcount≤100,000/mm3.Thrombocytopeniaduetoacutebleedingorimmunologicalcausesmustberuledout.Arterial hypoxemia: PaO2≤10kPa(≤75mmHg)inroomairoraPaO2/FiO2ratio≤33kPa(≤250mmHg)onoxygen.Overtcardiacorpulmonarydiseaseasthecauseofthehypoxemiamustberuledout.Renal dysfunction: Diuresisof≤0.5ml/kg/hforatleast2hoursdespiteadequatevolumereplacementand/orariseinserumcreatininetomorethantwicethereferencerange.

Metabolic acidosis: Baseexcess≤5mmol/lorlactateconcentrationmorethan1.5timesthereferencerange.

Cardiovascularinstability:

Systolicarterialbloodpressure≤90mmHgand/ormeanarterialbloodpressure≤65mmHglastingforatleast1houroruseofvasopressorrequiredtostabilizesystolicarterialbloodpressure≥90mmHgorarterialmeanpressure≥65mmHg.Hypotensiondespiteadequatevolumeresuscitationnotexplainedbyothercauses.

17Details on sepsis

http://link.springer.com/article/10.1007/s00101-010-1719-5

Fig.

6Significantincreaseinpostoperativesepsis from1997–2006.[2]

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Postoperative sepsis Sepsisisamajorcauseofpostope-rativemortality.Atrialconductedin2010investigatedthedevelopmentofpostoperativesepsisfrom1997–2006usingthelargestpatientdatabaseintheUSA(morethan2millionpatients)[2].Duringtheanalysisperiod,theincidenceofpostoperativesepsisincreasedfrom0.7%to1.3%(p<0.001)andofseverepostoperativesepsisfrom0.3%to0.9%(p<0.001)(Fig.6).Thehigherincreasedrate of severe postoperative sepsis was foundinallsurgicalinterventioncatego-ries(Fig.7).Acountertrendwasobser-

vedforhospitalmortalityrate.Themor-talityratedeclinedfrom44.4%in1997to34%in2006(p<0.001)(Fig.8).Evenafteraccountingforpotentialconfoun-ders, a multivariate regression model showedadeclineinmortality(OR0.94;95%CI,0.93–0.95peryearincreaseinthetrialperiod;p<0.001).Overall,thedeclineinmortalitycannotcompensatetheincreaseinpostoperativesepsis.Thereforethenumberofdeathsfrompostoperativestressincreases.


Fig.

7Increasednumberofseverepostoperativesepsis isindependentofthetypeofsurgicalintervention.[2]

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810%reducedmortalitybetween1997–2006 inseverepostoperativesepsis.[2]

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19Details on sepsis

Selenium and sepsis

Generalinformation

• Seleniumleveldeclinesincorrelationwithsepsisseverity

• SeleniumconcentrationisinverselycorrelatedwithAPACHEII andSAPSIIscores

• Minimumseleniumconcentrationisanindependentpredictor ofICUmortality

• Cut-offvalueof36µg/lseleniuminserumforsepsispatients

• Early(≤6hours)administrationofselenase®iscrucial

• Abolusadministrationreversesthepro-inflammatorystateviaanearly,transient,pro-oxidativeeffectofhigh-dosesodiumselenite


Seleniumleveldeclines incorrelationwithsepsisseverityOnetrialconductedin2007compared45ICUpatientswithSIRS(systemicin-flammatoryresponsesyndrome),mainlyaftercardiacsurgery,withagroupof 15ICUpatientswithoutSIRS[1].The 45patientsweresubdividedintothefollowinggroupsSIRS,severeSIRSandseveresepsisorsepticshock:SIRS(n=15),severeSIRS(n=15),severesepsisorsepticshock(n=15).AlreadyatICUadmission,92%ofallpatients

hadaserumseleniumvaluebelowtheGermanreferencerange.DuringtheirICUstay,theseleniumconcentrationcontinuedtodeclineinallgroupsexceptforthecontrolgroupwithoutSIRS.Themean serum selenium levels at ICU ad-missioncorrelatednegativelywithsepsisseverity(Fig.1).

Fig.

1Serum selenium levels in sepsis patients at ICU admission declinedependingonsepsisseverity.[1]

90

30

40

50

60

70

80

20

10

0Severe SIRS*

Seru

m s

elen

ium

leve

l µg/

l

SIRS* Severe sepsis/Septic shock

p < 0.05p < 0.05

p < 0.05

Reference value ≥ 80 µg/l

21Selenium and sepsis

SeleniumconcentrationisinverselycorrelatedwithAPACHEIIandSAPSIIscoresMinimumserumseleniumconcentra-tionisinverselycorrelatedwithmaxi-mumnumberofleucocytes(R2=0.22;p<0.01),maximumserumCreactiveprotein(CRP)(R2=0.28;p<0.01),maximumserumprocalcitonin(PCT)(R2=0.3;p<0.01)andmaximumseruminterleukin6(IL-6)(R2=0.42;p<0.01).

APACHEIIandSAPSIIscores,bothin-dicatorsforinflammationandthedegreeoforganfailureduringanICUstay,corre-latedinverselywiththeminimumserumseleniumvalue(APACHEII:R2=0.31;p<0.01;SAPSII:R2=0.29;p<0.01)(Fig.2).Furthermoretheminimumserumseleniumconcentrationisinverselycor-related with the maximum degree of org-andysfunctionrespectivelyfailureduringanICUstay(R2=0.42;p<0.01).

Fig.

2Inversecorrelationofserumseleniumlevels withAPACHEIIandSAPSIIscores.[1]

50

30

40

20

10

0

60

40

50

30

20

10

0Severe SIRS*

Sco

re p

oint

s

SIRS* Severe sepsis/Septic shock

Min

imal

ser

um s

elen

ium

con

cent

ratio

n [µ

g/l]

SAPS II-Score

Minimalserum selenium concentration

APACHE II-Score

*SIRS=systemicinflammatoryresponsesyndrome


Minimumseleniumconcentration: independentpredictorofICUmortalityBoththeinitialserumseleniumvalueaswell as the minimum serum selenium concentrationweresignificantlylowerinnon-survivingcomparedtosurvivingpatients(Fig.3).Areceiveroperatingcharacteristic(ROC)analysisforpredic-tingICUmortalityshowedthattheSAPSIIscore(AUC=0.903;95%CI:0.819–0.987,p<0.01)andminimumserumseleniumconcentration(AUC=0.867;95%CI:0.753–0.981,p<0.01)werethemostsignificantpredictivefactors.

Acut-offvaluefortheminimumserumseleniumconcentrationwasset.Acut-offvalueof36µg/lseleniuminserumhasasensitivityof89%,specificityof71%andpositivepredictivevalueof35%.Mostimportantly,however,ithasanegativepredictivevalueof95%.

Thereforetheprobabilitytodieincreasesbelow36µg/lseleniuminserum.

Fig.

3The serum selenium level in surviving patients issignificantlyhigher.[1]

100

40

60

80

20

0Non-survivors (9)

Serum selenium concentrationat ICU admission (µg/l)

Survivors (51)

p < 0.05

Non-survivors (9)Survivors (51)

p < 0.05

100

40

60

80

20

0

Minimal serum selenium concentration (µg/l)


Cytokines:

TNFα IL-1 IL-6

Invasion of bacteria

and toxins

NF-κB activation

iNOSActivation of coagulation

NO

Tissue damage

Multiple organ dysfunction (MOD)

Multiple organ failure (MOF)

Neurological abnormalities

Fever Tachycardia

Leukocytosis

Purpura Petechia

Disseminated intravascular

coagulation (DIC)

Hypotension Cardiovascular hyporeactivity

Tissue hypoperfusion Hypoxia

Se [13]

Se [13]

Signaling processes


Invasion of bacteria

and toxins

NF-κB activation

COX-2 5-LO Adhesion molecules

Prostaglandins Leukotrienes

Thromboxanes

Neutrophil infiltration + activation

ROS

Endothelial injury

Tissue damage

Death

Capillary leakage

Se [13]

Se [16]

Se [17]

Se [16]

Selenium-Supplementatium[References]

Effectofselenium

Fig.

4Wheredoesseleniumintervene intheprocessofsepsis?

Signaling processes


WhicheffectdoesROSproduction haveonsurvival?Huetetal.conductedatrialinvestigatingtheextenttowhichtheproductionofre-activeoxygenspecies(ROS)correlateswiththeseverityofsepticshock[2].Forthispurpose,naivehumanumbilicalveinendothelialcells(HUVEC)weretreatedwithplasmacollectedfrom21patientswithsepticshockandtheinducedROSproductionwasquantified.Comparedtocontrols,theplasma-inducedROSproductionbyHUVECwassignificantly

higherinsepticshockandROSproducti-onsignificantlycorrelatedwiththeSAPSIIscore(p=0.028)andtheSOFAscore(p=0.0012).Moreover,ROSproductioninnon-survivorswassignificantlyhig-hercomparedtosurvivors(p=0.0015)(Fig.5).TheseresultsdemonstratethatanearlyreductionofROSproduction,asitcanbeachievedbyapplicationofselenase®,canincreasethechanceofsurvivalofsepticpatients.

Whydoestheseleniumstatusdecline inpatientswithsepsis?Clinicalsepsisisassociatedwithasignificantdecreaseinseleniumlevel[3,4].Lipopolysaccharides(LPS)arekeyplayersinthedevelopmentofsepsis.Thesetoxiccompoundsareproducedwhenattackingbacteriadivide,butalsowhenantibioticsactivelyattackpatho-gens.AninjectionofLPSinratsinducesanacute-phaseresponseandleadstosignificantlyreducedserumandliverselenium values [4].Severalrecenttrialshavebeenabletoelucidatesomeoftheunderlyingmechanisms.Itwasdemons-tratedthatanLPS-inducedacute-phaseresponseleadstoareductioninseleno-proteinbiosynthesisintheliver[5].TheliveristhemainlocationofbiosynthesisofselenoproteinP,whichisreleasedintothe plasma and transports selenium to

othertissues.ThehumanselenoproteinPpromoterisnegativelyregulatedbypro-inflammatorycytokinesinhumanhepatocytes[6].

Insepsis,apathogeniccyclemaybetriggeredinwhichselenoproteinPsyn-thesisintheliverisdiminishedbysepsisandinflammatorycytokines.Thislowersselenium status in other tissues as well, increasingoxidativestresswhichfurtheramplifiestheinflammatoryresponse (Fig.6).Fortheimmunesystem,thismeans that a low selenium status notonlydiminishesthetransportcapaci-tyofthelymphocytesandthecellsof theinnateimmunesystem,butalsoleadstostress-inducedlymphopenia[7].


Fig.

5SignificantdifferenceinROSproductioninsurviving andnon-survivingpatients(p=0.0015).[2]

ROS productionNon-survivors

ROS ProductionSurvivors

Course of illness

Fig.

6Cyclicreductionofseleniumlevelinsepsis andinterventionofseleniumsupplementationinthiscycle.[8]

SepsisorLPS-treatment

DecreasedSelenium transport to tissues

Lossofcirculatingselenium-containingproteinsvialeaky

vessels

Liver downregulates Selenoprotein P

expression

Increasedoxidativestress

Selenium supplementation

Pathogeniccykle ofstressinduced immune suppression

Secretionof IL-6andTNFα

Se Se


Whyisearlyadministrationofsodium selenite crucial(within≤6hours)?Levyetal.demonstratedthatoxidationofcytochromecbymyocardiaccytochromecoxidaseiscompletelyinhibitedearlyinsepsis.Myocardiaccytochromecoxida-seistheterminaloxidaseintheelectrontransportchain[9].Thisoxidativestressinmitochondrialeadstomitochondrialdysfunctionandisirreversibleafter48hoursaftertheonsetoftissuehypoxia(Fig.7).Irreversibleinhibitiondisruptsoxidativephosphorylation,whichleadstosepsis-associatedcardiacdepressi-on.Foraneffectiveantioxidantstrategy,seleniummustbeadministeredassoonaspossibleafteronsetofsepsis.

InaphaseIdose-escalatingclinicaltrial, it was shown that the glutathione concentrationwasnotdecreasedbyincreasingseleniumdoseinseverelyill

patients(p=0.03)[10].Furthermore,anincreasingseleniumdosedecreasedtheconcentrationsofthiobarbituricacidreactivesubstances(TBARS)significant-ly(p=0.03)andthusloweredoxidativestress.Motoyamaetal.showedthatin-creasingTBARSconcentrationsinsepsispatientscorrelatedwithahigherSOFAscore(p<0.001)[11].PlasmaTBARSconcentrationwassignificantlyhigherin sepsis patients with multi organ failu-re(MOF)thaninpatientswithoutMOF(57.1%vs.15.8%,p<0.001).AnalysisoftheratioofmitochondrialDNAasanindirectmarkerofmitochondriafunctionshowed,thatthefunctionofmitochond-riasimprovedwithincreasingseleniumdosage(p=0.001)(Fig.8)[10].


Fig.

8

Onlyahighseleniumdosageimprovesmitochondrialfunction,reducesoxidativestressandincreasesantioxidativecapacityinsepsis.[10]

GSH level stays stable

antioxidative capacity

TBARS (thiobarbituric acid

reactive substances)

oxidative stress

mitochondrial DNA

mitochondrial function

Selenium

Fig.

7Irreversibleinhibitionofthecytochromecoxidaseafter48hoursinseveresepsis.[9,10,x]

0h

6h

24h

48h

competitive inhibition of cytochrome c oxidase

organ failure

antioxidant concentration ↓

ROS ↑

non-competitive inhibition of cytochrome c oxidase

irreversible mitochondrial damage

oxidation of mitochondrial DNA

[x]BrealeyD,KaryampudiS,JacquesTS,NovelliM,StidwillR,TaylorV,SmolenskiRT,SingerM.AmJPhysiolRegulIntegrCompPhysiol.2004Mar;286(3):R491-7.Mitochondrialdysfunction inalong-termrodentmodelofsepsisandorganfailure.



Whyinjectsodiumseleniteasbolus?Theeffectofabolusinjectionof2,000µgseleniumassodiumselenitepentahydra-tewascomparedtoacontinousinfusionof4µg/kgperhourinanexperimentalanimal model for sepsis in sheep [12].Onlythebolusshowedapositiveeffecton sepsis progression, although the overalldosiswascomparable.Thelikelyexplanationforthisisanearlytransientpro-oxidativeeffectofsodiumselenite,thatcanbeusedastherapeuticstrategytoreversethepro-inflammatorystateexistinginseveresepsisandsepticshock.Thisexcessivepro-inflammato-rystateischarakterizedbyhighlevels

ofcirculatingcytokinesandROS,pha-gocytichyperactivityofleucocytesduetodelayedapoptosis,andaprolongedNFkBactivation.

AbolusinjectionintheearlyphaseofsepticshockinhibitsNF-κBbindingtoDNAviastabilizationofdisulfidebonds.This regulates gene expression and synthesisofpro-inflammatorycytokines[13].Additionallyabolusadministrationinducesapoptosisandcytotoxicityin activated,pro-inflammatorycellsalongwithadirectvirucidalorbactericidaleffect[14,15].

High dose for sepsis – so that selenium works

Day1

Treatmentideallybeginswithin 6 hours after admission to the ICU

asbolus 2,0001–3 µg Se

thenascontinuousinfusion

1,6001–3 µg Se

at least 7days

maintenance therapy

1,6001–3µgSe/Day

Literature1ManzanaresWetal.2012,CritCare;16:R662HuangTSetal.2013,PLoSOne8:e544313AlhazzaniWetal.2013,CritCareMed41:1555–1564





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2HuetO,ObataR,AubronC,Spraul-DavitA,CharpentierJ,LaplaceC,Nguyen-KhoaT,ContiM,VicautE,MiraJP,DuranteauJ.CritCareMed.2007Mar;35(3):821-6.Plasma-inducedendothelialoxidativestressisrelatedtotheseverityofsepticshock.

3HollenbachB,MorgenthalerNG,StruckJ,AlonsoC,BergmannA,KöhrleJ,SchomburgL.JTraceElemMedBiol.2008;22(1):24-32.doi:10.1016/j.jtemb.2007.11.003.NewassayforthemeasurementofselenoproteinPasasep-sisbiomarkerfromserum.

4 MaehiraF,LuyoGA,MiyagiI,OshiroM,YamaneN,KubaM,NakazatoY.ClinChimActa.2002Feb;316(1-2):137-46.Alterationsofserumseleniumconcentrationsintheacutephaseofpathologicalconditions.

5RenkoK,HofmannPJ,StoedterM,HollenbachB,BehrendsT,KöhrleJ,SchweizerU,SchomburgL.FASEBJ.2009Jun;23(6):1758-65.doi:10.1096/fj.08-119370.Down-regulationofthehepaticselenoproteinbiosynthesismachineryimpairsseleniummetabolismduringtheacutephaseresponseinmice.

6 DreherI,JakobsTC,KöhrleJ.JBiolChem.1997Nov14;272(46):29364-71.CloningandcharacterizationofthehumanselenoproteinPpromoter.ResponseofselenoproteinPexpressiontocytokinesinlivercells.

7

CarcilloJA,DeanJM,HolubkovR,BergerJ,MeertKL,AnandKJ,ZimmermanJ,NewthCJ,HarrisonR,BurrJ,WillsonDF,NicholsonC;EuniceKennedyShriverNationalInstituteofChildHealthandHumanDevelop-ment(NICHD)CollaborativePediatricCriticalCareResearchNetwork(CPCCRN).PediatrCritCareMed.2012Mar;13(2):165-73.doi:10.1097/PCC.0b013e31823896ae.Therandomizedcomparativepediatriccriticalillnessstress-inducedimmunesuppression(CRISIS)preventiontrial.

8 HuangZ,RoseAH,HoffmannPR.AntioxidRedoxSignal.2012Apr1;16(7):705-43.doi:10.1089/ars.2011.4145Theroleofseleniumininflammationandimmunity:frommolecularmechanismstotherapeuticopportunities.

9 LevyRJ,VijayasarathyC,RajNR,AvadhaniNG,DeutschmanCS.Shock.2004Feb;21(2):110-4.CompetitiveandnoncompetitiveinhibitionofmyocardialcytochromeCoxidaseinsepsis.

10HeylandDK,DhaliwalmR,DayA,DroverJ,CoteH,WischmeyerP.JPENJParenterEnteralNutr.2007Mar-Apr;31(2):109-18.Optimizingthedoseofglutaminedipeptidesandantioxidantsincriticallyillpatients:aphaseIdose-findingstudy.

11 MotoyamaT,OkamotoK,KukitaI,HamaguchiM,KinoshitaY,OgawaH.CritCareMed.2003Apr;31(4):1048-52.Possibleroleofincreasedoxidantstressinmultipleorganfailureaftersystemicinflammatoryresponsesyndrome.

12WangZ,ForcevilleX,VanAntwerpenP,PiagnerelliM,AhishakiyeD,MacoursP,DeBackerD,NeveJ,VincentJL.Shock.2009Aug;32(2):140-6.doi:10.1097/SHK.0b013e318193c35d.Alarge-bolusinjection,butnotcontinuousinfusionofsodiumseleniteimprovesoutcomeinperitonitis.

13 MatthewsJR,WakasugiN,VirelizierJL,YodoiJ,HayRT.NucleicAcidsRes.1992Aug11;20(15):3821-30.Thiore-doxinregulatestheDNAbindingactivityofNF-kappaBbyreductionofadisulphidebondinvolvingcysteine62.

14 SpallholzJE.BiomedEnvironSci.1997Sep;10(2-3):260-70.Freeradicalgenerationbyseleniumcompoundsandtheirprooxidanttoxicity.

15 StewartMS,SpallholzJE,NeldnerKH,PenceBC.FreeRadicBiolMed.1999Jan;26(1-2):42-8.Seleniumcom-poundshavedisparateabilitiestoimposeoxidativestressandinduceapoptosis.

16 MattmillerSA,CarlsonBA,SordilloLM.JNutrSci.2013Aug29;2:e28.doi:10.1017/jns.2013.17.eCollection2013.Regulationofinflammationbyseleniumandselenoproteins:impactoneicosanoidbiosynthesis.

17 RaymanMP.Lancet.2012Mar31;379(9822):1256-68.doi:10.1016/S0140-6736(11)61452-9
























selenase® for sepsis

Generalinformation

• Supplementationwithsodiumseleniteincreasestheseleniumlevelto values within the normal range

• Significantreductioninmortalityintheselenium-supplementedgroup

• Possiblecorrelationbetweenseleniumsupplementation andprocalcitonin[4]

• Supplementationwithhigh-dosesodiumselenitereducestheinciden-ceofnosocomialpneumoniaandimprovessepsisseverity


Metaanalysis Parenteralsodiumselenitetreatmentsignificantlyreducestotalmortalityrateby17%(p=0.04)

Highersignificantreductionofmortalitywhenabolusisadministered (−27%;p=0.01),amaintenancetherapy≥7days(−23%;p=0.01) andadosingof≥1,000µgseleniumassodiumselenite-pentahydrate(selenase®)perday(−23%;p=0.04)

Pilotstudy Supplementation with selenase®increasestheseleniumleveltovalueswithin the normal range

selenase®supplementationsignificantlyreducesmortalityinpatientswithAPACHEIIIscore>53

SIC trial Significantreductioninmortalityintheselenase®-supplementedgroup by14.3%(p=0.049)

Significantreductioninmortalityinthesubgroups(septicshock, APACHEIII≥102,>3organfailure)intheselenase®-supplemented groupbyupto26%

Various trials

Possiblecorrelationbetweenselenase®supplementationandprocalcitonin

Supplementationwithhigh-dosesodiumselenitereducestheincidence ofnosocomialpneumoniaandimprovessepsisseverity

SIGNETtrial:Fewernewinfectionsinpatientsreceivingselenase® supple-mentationfor>5days

REDOXStrial:Comparedtoglutamine,seleniumdoesnothaveanynegati-veeffectonmortality,althoughthebeneficialeffectofseleniumsupplemen-tationisreducedbythelackofseleniumdeficiency

Significantlymorecriticallyillpatientsintheinterventiongroupimpactedtheanalysisoftheretrospectivetrialonseleniumsupplementationinpatientswith severe sepsis

33selenase® for sepsis

Parenteralsodiumselenitetreatmentsignificantly reducestotalmortalityby17%(p=0.04).

Twelvetrialswereincludedinthemetaanalysis,wherebythemetaanalysiswascarriedoutinnineofthese(Table1)[3].Intotal,965patientstookpartintheninestudies;482participantsreceiveda sodium selenite supplementation and 483aplacebo.Atotalof148patients(30.7%)diedintheinterventiongroup,while180participants(37.3%)diedintheplacebogroup.Themortalityvariedgreatlybetweenthestudies,from24%to52%.Alsotheadministrationschemedifferedconsiderably,bothwithrespectto the duration and dose as well as the strategy.Theuseofsodiumselenitewas

uniformastheonlyapprovedseleniumformforthedrugproduct,wherebymorethanhalfofthetrialswerecarriedoutwith selenase®.Alltrialshadalowriskof“detectionbias”,sincemortalitywasdefinedastheresult.Inaddition,mosttrialshadalowriskof“attritionbias”e.g.protocolnoncompliance.

Intotal,themetaanalysisshowsthataparenteral sodium selenite supplementa-tionsignificantlyreducestotalmortality (RR0.83,95%CI0.70-0.99;p=0.04).

Meta analysis of 9 sepsis trials Withcorrectapplication,sodiumselenitesignificantly reducesmortality.

Generalinformation

• Alarge-bolusinjectionsignificantlyreducedmortality insepsispatientsby27%

• Maintenancetherapylasting≥7dayssignificantlyimproved theprobabilityofsurvival

• Ahighdoseof≥1,000µgseleniumintheformofsodiumselenitepentahydrate(selenase®)perdaysignificantlyreducedmortality by23%

Sepsis34 selenase® for sepsis

Tab.

1 Includedtrials

Zimmermannetal.

selenase®

ZimmermannT,AlbrechtS,KuhneH,VogelsangU,GrutzmannR,etal.(1997)[Seleniumadministrationinpatientswithsepsissyndrome.Apros-pectiverandomizedstudy].MedKlin(Munich)92Suppl3:3–4.

Angstwurmetal.

selenase®

AngstwurmMW,SchottdorfJ,SchopohlJ,GaertnerR(1999)Seleniumreplacementinpatientswithseveresystemicinflammatoryresponsesyn-dromeimprovesclinicaloutcome.CritCareMed27:1807–1813.

Mishraetal. MishraV,BainesM,PerrySE,McLaughlinPJ,CarsonJ,etal.(2007)Ef-fectofseleniumsupplementationonbiochemicalmarkersandoutcomeincriticallyillpatients.ClinNutr26:41–50.

Angstwurmetal.

selenase®

AngstwurmMW,EngelmannL,ZimmermannT,LehmannC,SpesCH,etal.(2007)SeleniuminIntensiveCare(SIC):resultsofaprospectiveran-domized,placebo-controlled,multiple-centerstudyinpatientswithseveresystemicinflammatoryresponsesyndrome,sepsis,andsepticshock.Crit CareMed35:118–126.

Forcevilleetal. ForcevilleX,LaviolleB,AnnaneD,VitouxD,BleichnerG,etal.(2007)Effectsofhighdosesofselenium,assodiumselenite,insepticshock:aplacebocontrolled,randomized,double-blind,phaseIIstudy.Crit Care 11:R73.ForcevilleX(2007)Effectsofhighdosesofselenium,assodiumselenite,insepticshockpatientsaplacebo-controlled,randomized,dou-ble-blind,multi-centerphaseIIstudy–seleniumandsepsis.JTraceElemMedBiol21Suppl1:62–65.

Montoyaetal. MontoyaGCHL,VillalobosSJA,OlveraGC,AguirreSJ,FrancoGJ(2009)Anti-inflammatoryeffectofseleniuminsepticpatients.RevAsocMexMedCrityTerInt23:199–205

Andrewsetal.

selenase®

AndrewsPJ,AvenellA,NobleDW,CampbellMK,CroalBL,etal.(2011)Randomisedtrialofglutamine,selenium,orboth,tosupplementparenteralnutritionforcriticallyillpatients.BMJ342:d1542.

Valentaetal.

selenase®

ValentaJ,BrodskaH,DrabekT,HendlJ,KazdaA(2011)High-doseseleni-umsubstitutioninsepsis:aprospectiverandomizedclinicaltrial.Intensive CareMed37:808–815.

Manzanaresetal. ManzanaresW,BiestroA,TorreMH,GalussoF,FacchinG,etal.(2011)Highdoseseleniumreducesventilator-associatedpneumoniaandillnessseverityincriticallyillpatientswithsystemicinflammation.Intensive Care Med37:1120–1127.

selenase®:Studieswerecarriedoutwithselenase®

Sepsis 35selenase® for sepsis















Fig.

1Positivesignificantimpactofseleniumassodiumselenite ontotalmortalityintheeventofsepsis.[changedaccordingto1]

Day 16h Day 2 Day 3 Day 4

Nosocomial infections

Day 5 Day 6 Day 7 Day 10 – 14

Without sodium selenitesupplementation

Survival

Late Death

Early death

At ICU-admission (< 6 h):Bolus: 2,000 µg Se as sodium selenite► Mortality rate ↓(RR 0.73; p = 0.01) [3] overwhelming immune response

Impaired immunity

Minimum 5 days Se as sodium selenite► New infections ↓(RR 0.53; p = 0.03) [2]

Minimum 7 days Se as sodium selenite► Mortality rate ↓(RR 0.77; p = 0.01) [3]

With sodium selenitesupplementation

Se = selenium

Immunosuppression

Immune response

Pro

-infla

mat

ory

Ant

i-inf

lam

ator

y

Hom

oeos

tasi

s

Viral reactivation

Bolus2,000 µg Seas sodium

selenite

1,600 µg Seas sodium selenite

per day

Metaanalysis(9studies,n=965)[3]Asodiumselenitesupplementationsignificantly reducesmortalityforsepsispatients(RR(relativerisk)0.83CI(confidenceinterval)0.77-0.99;p=0.04)


Meta analysis of 9 sepsis trialsAhigh-dosebolussignificantlyreducesmortality insepsispatientsby27%.

Abolusintheearlyphaseofsepsishasseveraleffects:

1.Down-regulationofthesynthesis ofpro-inflammatorycytokines

2.Apoptosisandcytotoxicityinactivatedpro-inflammatorycells

3.DirectvirucidalandbactericidaleffectsTheseeffectspreventanuncheckedimmuneresponse(cytokinestorm)andthusanearlydeathfromsepsis(Fig.1).

Inacomparisonofthesodiumselenitesupplementationwithabolustoaso-diumselenitetherapywithoutabolus,alowermortalitycouldbeshownintheinterventiongroupwithbolus(−7%; p=0.14).Aparenteralsodiumselenitesupplementationwithbolus,however,reducedthetotalmortalitywithahighersignificance(RR0.73,95%CI0.58-0.94;p=0.01).

Amaintenancetherapyof≥7dayssignificantly improvestheprobabilityofsurvival.

Theimpactofthedurationoftreatmentonmortalitywasdeterminedbymeans ofuni-variant“randomeffectsmeta-re-gression”analysis.Astatisticallysignifi-cantassociationbetweentherelativeriskofmortalityanddurationoftreatment

(Fig.2)wastherebydemonstrated. Asodiumselenitesupplementation of≥7daysreducedtotalmortality by23%(RR0.77,95%CI0.63-0.94; p=0.01).


Fig.

2Dependencyoftherelativerisk(RR) on the duration of treatment [3]

–1.00 5 10

6.5 days

15 20 25 30

–0.5

0.0

0.5

1.0

Treatment duration (days)

Log(

RR

)

Everycirclerepresentsonetrial,wherebythesizeofthestudycorrelateswiththesizeofthecircle.Anegativeeffect(circlebelowtheregressionplot)standsforthereductionofthemortalityrate.


Meta analysis of 9 sepsis trialsAhighdosingof≥1,000µgselenium assodiumselenite-pentahydrateperday significantlyreducesmortalityby23%.

Intheirmetaanalysis,Huangetal.dis-tinguishedbetweensodiumselenitesup-plementation with a high selenium dose (≥1,000µg/day)andalowdose(<1,000µg/day).Adosingof≥1,000µgseleniumperdaysignificantlyreducedthetotalmortality(RR0.77,95%CI0.61-0.99; p=0.04).Inacomparisonofseveralsepsistrials,Manzanaresetal.couldshowthatonlyahighsodiumselenitesupplementation(2,000µgbolus(day1)and1,600µg/dayselenium(day2–10))

sufficestoelevateserumseleniumcon-centrationintothelowreferencerangeortoincreasetheactivityofglutathioneperoxidase3toaphysiologicallevel(Fig.3)[4].Alowsodiumselenitetherapy(1,200µgbolus(day1)and800µg/day(day2–10))isneitherinthepositiontosufficientlyincreasetheserumseleniumconcentrationnortosufficientlyinfluencetheactivityofglutathioneperoxidase3(Fig.4).

Fig.

3

Development of the serum selenium concentrationforhighandlow-dosed sodium selenite supplementation [4]

10

0 2 4 6 8 10

3020

5040

807060

13012011010090

Days

Ser

um s

elen

ium

con

cent

ratio

n (µ

g/l)

low-dosed sodium selenitehigh-dosed sodium selenite


Fig.

4

Increaseofglutathioneperoxidase3activity toaphysiologicalleveltakesplaceonly withahigh-dosesodiumselenitesupplementation[4]

0.00 2 4 6 8 10

0.4

0.2

0.8

0.6

1.4

1.2

1.0

2.0

1.8

1.6

Days

GP

x-3-

activ

ity (U

/ml)

low-dosed sodium selenitehigh-dosed sodium selenite

Sepsis StudienSepsis 41selenase® for sepsis

Pilot studySupplementation with selenase®increases the selenium level to values within the normal range

Acontrolled,randomized,prospective,open-labelpilottrialanalyzedtheeffectsof selenase®supplementationinSIRSpatients [1].Theselenase®-supplementedgroup(n=21)receiveddescendingdo-ses of selenase®of535µgseleniumperdayfor3days,285µgseleniumperdayfor3days,155µgseleniumperdayfor 3days,and35µgseleniumperdaythe-reafter.Thecontrolgroup(n=21)recei-ved35µg/dayseleniumduringtheentiretreatmentperiod.

Theserumseleniumconcentrationswerebelowthedefinedreferencevalueforseleniumingermany(80µg/lseleniuminserum)atadmissiontotheICU.Glutathi-oneperoxidaseactivitywasalsosignifi-cantlytoolow.Whiletheserumseleniumlevelsinthecontrolgroupdidnotchangeovertheobservationperiod,theserumseleniumconcentrationincreasedinthenormalrangefromday3intheselena-se®-supplementedgroup(Fig.5). ThedatashowthatSIRSpatientsneed aseleniumdose>500µgtoreachnor-malrangeandthat155µgselenium perdayisnotsufficienttomaintain alownormallevelalreadyachieved.


Fig.

5

Significantincreaseinserumseleniumconcentration in the selenase®-supplementedgroup inthereferencerange.[6]

100

90

30

40

50

60

70

80

20

10

03 7

Days

Seru

m s

elen

ium

con

cent

ratio

n in

[µg/

l]

0 14

p < 0.001

p < 0.001Reference rangep = 0.003

selenase®-supplemented group Control group


Pilot studySupplementation with selenase® improvesclinicaloutcomesinSIRSpatients

Inbothgroups,thebaselineAPACHEIIIscorewasthesameanddecreasedduringtheirICUstay.However,the APACHEIIIscoreintheselenase®-sup-plementedgroupimprovedsignifiantlymorepronounced(day7:p=0.019; day14:p=0.041).Moreover,only12%of the patients in the selenase®-supple-mentedgroupbut42%inthecontrolgrouphadahigherAPACHEIIIscoreonday14comparedtoICUadmission(p<0.05).

Mortalityatdischargefromthehospitalwas33.4%intheselenase®-supplemen-tedgroupand52.4%inthecontrolgroup(p=0.135)(Fig.6).AcomparisonofpatientswithanAPACHEIIIscore>53highlightsthebeneficialeffectofselena-se®onmortalityrate.Althoughthepati-entpopulationinthissubgroupanalysiswasreducedto20(selenase®-supple-mentedgroup(n=11)andcontrolgroup(n=9)),therewasasignificantdecreaseinmortalityintheselenase®-supplemen-tedgroup(4of11patients(36%))versusthecontrolgroup(8of9patients(89%))(p=0.0053)(Fig.7).


Fig.

6

Intention-to-treatanalysisofsurvivaltime in the selenase®-supplementedgroup(n=21) andcontrolgroup(n=21). [5]

100

40

60

80

2020 40 60 80 100

Sur

viva

l (%

)

0

Control

selenase®

p = 0.135

Survival time (days)

Fig.

7

Intention-to-treatanalysisofsurvivaltimeinpatientswithanAPACHEIIIscore>53(selenase®-supplementedgroup(n=11)andcontrolgroup(n=9)).[5]

100

40

60

80

2020 40 60 80 1000

p = 0.0053

Sur

viva

l (%

)

Survival time (days)

Control

selenase®


SIC trial (Selenium in Intensive Care)Phase III trial with selenase®

Aprospective,randomized,double-blind,multicenterphaseIIItrialconductedat 11intensivecareunitsinGermany,ana-lyzedwhethertheresultsobtainedinthepilotstudywerereproducibleinapha-se III trial [2].Overall,249patientswithSIRS,sepsis,septicshockandanAPA-CHEIIIscore>70wererandomized.The selenase® doses administered were increasedtoa30-minutebolusinfusion of1,000µgselenium,followedby1,000µg/dayseleniumasacontinuousinfusionfor14days.Intheplacebogroup,adoseofupto100µg/daysele-nium was allowed with the parenteral nutrition.

Elevenofthe249randomizedpatientswereexcludedforvariousreasons.Thus,theintention-to-treatanalysisincluded238patients(Fig.8).Another49ofthese238patientshadtobeexcludedfurtherfortheper-protocolanalysiseitherbecauseinclusioncriteriawerenotmet(n=14)orduetosevereviolations ofthetrialprotocol(n=35).Therefore, theper-protocolanalysisonlycovered189patients,92intheselenase®-treatedgroupand97intheplacebogroup.


Fig.

8 StudyprofileoftheSICtrial. [6]

Randomizedpatients

N=249

• 5consentwithdrawn• 1suicide• 2 lost for follow up• 1non-compliant• 2 termination of treatment

• 14ex/inclusioncriteriafailure• 30trialdrugadministrationfailure• 5additionalseleniumsubstitutions >100µg/day

Intention-to-treatanalysis

N=238

Per-Protocolanalysis

N=189

selenase®- supplemented

group

N=116

selenase®- supplemented

group

N=92

Placebogroup

N=122

Placebogroup

N=97


SIC trialSignificantlyincreasedseleniumvalue in the selenase®-supplementedgrouponly.

The SIC trial also showed that seleni-umvaluesatICUadmissionwereverylow(Table2).Theseleniumconcen-trationincreasedsignificantlyintheselenase®-supplementedgrouponly(p<0.001).Despitehigh-dosedailyselenase® supplementation, the medi-anseleniumvaluesonlyincreasedto161.9µg/lseleniumintheserumand144.5µg/lseleniuminwholebloodonthelastday(day14)ofselenase® supplementation.Aftercompletingtheintervention,theseleniumleveldecrea-sedmarkedlywithinaweek(Fig.9).Inthetrial,nospecificadversereactionswereattributedtosupplementationwithhigh-doseselenase®.Overall,therewasnosignificantdifferenceintheadver-sereactionsintheinterventiongroup(90.2%)andtheplacebogroup(96%).

Thepositiveeffectofselenase® supple-mentationshowedinboththeseleniumconcentrationinbloodandtheglutathio-

neperoxidaseactivity.Bothparametersincreasedfromsuboptimalbaselinevaluesduringinterventionanddecrea-sedagainsignficantlyafterendingtheselenase®supplementation(Fig.9).Thecurvecharacteristicsreveals,thatanoptimalseleniumsupplyduringandaftersepsisisnotsufficient,whenaseleniumdosage,asiscurrentlyusedinparenteralnutritionrespectivelynormalnutrition,isapplied.Simultaneouslytheincreaseinglutathionperoxidaseactivityduringinterventionwith1,000µgseleniumasselenase®showsthatadailyseleniumintakeof100µginsepsispatientsdoesnot result in a plateau of selenopro-teinactivity,butincreasestillendingofintervention.Afterselenase® supplemen-tationtheglutathioneperoxidaseacitivtydecreasedagain,thoughthepatientsstillrecievedupto100µgseleniumwithparenteralnutrition.

Tab.

2Comparisonofseleniumconcentrationintheselenase®- supplementedversustheplacebogroupp<0.001.[2]

selenase®-supplemented group

Placebogroup

SerumseleniumconcentrationatICUadmissioninallrandomizedpatients(n=249)

37.9±18.2µg/l 36.3±12.6µg/l

SeleniumconcentrationinwholebloodatICUadmissioninallrandomizedpatients(n=249)

58.4±17.4µg/l 58.4±12.6µg/l

SerumseleniumconcentrationatICUadmissioninpatientsincludedintheper-protocolanalysis(n=189)

37.9µg/l 35.5µg/l

Serumseleniumconcentrationafter14days 161.9µg/l 47.4µg/l

Seleniumconcentrationinwholebloodafter14days

144.5µg/l 64.0µg/l


Fig.

9

Developmentofseleniumconcentration andglutathioneperoxidaseactivity during and after selenase®supplementation.[6]

selenase® Placebo group

selenase® Placebo group

End of selenase®

supplementation

Day 10

20406080

100120140160180200220240

Day 3 Day 7 Day 14 Day 21 Day 28

Day 1100120140160180200220240260280300320340

Day 3 Day 7 Day 14 Day 21 Day 28

Reference range

Glutathione peroxidase activity

in healthy europeans: 196 - 477 U/L[x]

Sel

eniu

m c

once

ntra

tion

in w

hole

blo

od [µ

g/l]

Glu

tath

ione

per

oxid

ase

activ

ity [U

/l]

End of selenase®

supplementation

[x]AlegríaA,BarberáR,ClementeG,FarréR,GarcíaMJ,LagardaMJ.JTraceElemMedBiol.1996Dec;10(4):223-8.SeleniumandglutathioneperoxidasereferencevaluesinwholebloodandplasmaofareferencepopulationlivinginValencia,Spain.



SIC trialSignificantreductioninmortality in the selenase®-supplementedgroup

Intheintention-to-treatanalysis(n=238),46of116patientsintheselenase®-supplementedgroupdiedand61of122intheplacebogroup.Thus,selenase®supplementationreducedmortalitynon-significantlyby10.3%(p=0.109;OR,0.66;95%CI,0.39-1.10)(Fig.10).Meanoverallsurvivalincrea-sedfrom17.6daysintheplacebogroupto20.3daysintheinterventiongroup(p=0.098)(Fig.11).

AspreviouslymentionedintheSICtrialdescription,49patientswereexcludedfromtheper-protocolanalysis.Eithertheinclusioncriteriawerenotmet(n=14)

orsevereviolationsofthetrialprotocoloccurred(n=35).Therefore,theper-pro-tocolanalysisonlycovered189patients,92intheselenase®-treatedgroupand97intheplacebogroup.

Intheper-protocolanalysis,28-daysmortalitydecreasedsignificantlyfrom56.7%to42.4%intheselenase®-sup-plementedgroup(p=0.049;OR,0,.56;CI,0.32-1.00)(Fig.12).Meanoverallsurvivalincreasedfrom16.4daysintheplacebogroupto19.7daysintheinter-ventiongroup(p=0.048)(Fig.13).

Fig.

1028-daysmortalityintheintention-to-treatanalysis(n=238). [6]

70

20

30

10

40

60

50

0

Mor

talit

y %

p = 0.109

50 %

39.7 %

-10.3 %

Placebo selenase®

Fig.

1228-daysmortalityinthe per-protocolanalysis(n=189).[6]

70

20

30

10

40

60

50

0Placebo selenase®

Mor

talit

y %

p = 0.049

-14.3 %56.7 %

42.4 %


Fig.

11 Survivaltimeintheintention-to-treatanalysis.[6]

100

25

50

75

021 28

Days

Sur

viva

l %

0 7 14

Placebo ≤ 100 µg Se/day

selenase® ≥ 1,000 µg Se/day

p = 0.098

n = 116

n = 122

Fig.

13 Survivaltimeintheper-protocolanalysis.[6]

100

25

50

75

021 28

Days

Sur

viva

l %

0 7 14

n = 92

n = 97

p = 0.048Placebo ≤ 100 µg Se/day

selenase® ≥ 1,000 µg Se/day


SIC trialSignificantreductioninmortalityinthesubgroups of the selenase®-supplementedgroup

Thetrialplanhadalreadyincludedasubgroupanalysis.PatientswithanAPACHEIIIscore>102(n=27ineachgroup)benefitedevenmorefromaselenase®supplementation(Fig.14).28-daysmortalitydecreasedinthissubgroupby25.9%from81.5%to55.6%(p=0.04;OR,0.28;95%CI,0.08-0.97).Inpatientswithsepticshock,28-daysmortalitydecreasedby26.2%from66.7%intheplacebogroup(30of45) to40.5%intheselenase®-supplemented

group(15of37patients)(p=0.018; OR,0.34;95%CI,0.14-0.84).Inpati-ents with more than triple organ failure, 28-daysmortalitydecreasedby22.6%inthecomparisonbetweentheinterventiongroup(42.5%;17of40patients)andtheplacebogroup(65.1%;28of43patients)(p=0.039;OR,0.40;95%CI0.16-0.96).Thesubgroupanalysishighlightsthefact,thatthebeneficialeffectbyselena-se®supplementationincreaseswithsepsisseverity.

SÉRÉNITÉ trialComparisonofSICandSÉRÉNITÉtrials

LikeSIC,theSÉRÉNITÉtrialwasaprospective,randomized,double-blind,multicentertrialconductedinFrance.However,thistrialonlyincludedatotalof60patients,i.e.aquarterofthenumberin the SIC trial [7].Thestudyincludedonlypatientswithseveresepticshock.Whilethe SIC trial enrolled patients within 6

hours after ICU admission and adminis-teredabolusinfusiondirectlyaftertrialenrollment,90%ofthepatientsintheSÉRÉNITÉtrialwereenrolledwithin 48hoursofICUadmission.Furthermore,aboluswasnotgiven.Instead,4,000µgseleniumwereadministeredasacontin-uousinfusion.Thesignificanceofabolus

Fig.

14Considerablyreduced28-daysmortalityintheselenase®-supplementedgroupacrossthepredefinedsubgroupsintheSICtrial.[6]

Reductioninmortality NNT (Numberneededtotreat)

SIC trial total -14.3% (p=0.049) =7

definedsubgroups:

Septicshock -26.2% (p=0.018) =4

APACHEIII>102 -25.9% (p=0.040) =4

>3organfailure -22.6% (p=0.039) =4-5


Fig.

15MortalityintheSÉRÉNITÉtrialinthesodiumselenite-supplemented andplacebogroup.[7]

1

0.9

0.3

0.4

0.5

0.6

0.7

0.8

0.2

0.1

030 60 90 120 150 180

p = 0.691

240210 270 300 330 360

Days

Pro

babi

lity

of s

urvi

val

0

Sodium selenite

Placebo

consistsofimprovingtheseleniumstatusofthesepsispatientasearlyandasrap-idlyaspossible.Thisenablesthebodytofightoxidativestress,andtohaveanan-ti-inflammatoryeffect.Theconsiderablylater and slower administration of sodium selenitewasnotabletocompensatetheresultingdamageeventhoughtwicetheamountofsodiumselenitewasused.IntheSÉRÉNITÉtrial,theseleniumvaluewas not measured at ICU admission nor overthecourseofthestudy.Therefore,itisnotpossibletoverifythepatients’seleniumconcentrationatICUadmis-sion.Sincemanystudieshaveshownthat the selenium value at ICU admission isinverselycorrelatedwithmortality,thequestionarisesastowhetherthepatientcohortintheSÉRÉNITÉtrialwasmoreseverelyillthanintheSICtrial.Another

differencewastheshorterdailyseleniumsupplementationgivenfor9versus14days.Here,aswell,thereisnowaytoverifywhicheffecttheshorterseleniumsupplementation had on the selenium value;whethertheseleniumconcentra-tiondecreasedbelowreferencerangeaftertheinterventionended,respectivelytowhichdegree.Inviewofthesediffer-ence,itisnosurprisethatareductioninmortalitywaslackingintheseleni-um-supplementedgroup(Fig.15). In the SÉRÉNITÉ trial, no adverse reactions were attributed to selenium. This is particularly noteworthy be-cause 4,000 µg selenium were given on day 1, without any adverse effects on the patients.


Valenta et al., 2011Evidenceofacorrelationbetween selenase®supplementationandprocalcitonin(PCT)

ThetrialbyValentaetal.in2011,pro-ducedanotherinterestingresult[8].Thisprospective,randomized,open-label,single-centreclinicaltrialenrolled150patientswithSIRS/sepsisandaSOFAscoreof>5.75patientsweresupple-mentedwith1,000µgselenium(selena-se®)onday1and500µgondays2–14,administeredasa30-minuteinfusioninthemorning.Patientsinboth,theinterventiongroupandthecontrolgroupreceivedastandarddoseof<75µg/day seleniumwiththeirparenteralnutrition.

Thistrialalsorevealed3effectsofselenase®supplementation:

• In the intervention group, the selenium value and the glutathione peroxidase activityincreasedfromaverylow baselinevalueinthereferencerangeascomparedtothecontrolgroup (Fig.16).

• Patientsinbothgroupssurviving 28daysshowedatrendforahigherserumseleniumlevelcomparedtonon-survivors(59.2±45.7vs.56.1 ±44.2µg/l;p=0.068).

• Despitethehigh-doseselenase® supplementation,nospecificadversereactionsortoxiceffectsoccurred.Only17ofthe799serumseleniumsamplestakenfrom9patientsintheintervention group showed selenium valuesabovethereferencerange(163.4±14.2µg/l,referencerange80–120µg/l).All9patientssurvived.

Thistrialalsoshowedanegativecorrela-tionbetweenserumseleniumlevelandseveralinflammatorymarkersandsepsisseverityatICUadmission(Table3).


Fig.

16Developmentofserumseleniumconcentrationduringselenase® supplementationcomparedtothecontrolgroup.[8]

120

60

80

100

40

20

0

Days

Seru

m s

elen

ium

con

cent

ratio

n [µ

g/l]

1 3

p < 0.001

p < 0.001

p < 0.001

p < 0.001p < 0.001

p < 0.001

5 70 1410

Reference range

selenase® Control

Tab.

3NegativecorrelationbetweentheserumseleniumlevelatICUadmission, inflammatorymarkersandsepsisseverity.[8]

r-value p-value

Procalcitonin(PCT) -0.172 0.035

C-reactiveprotein(CRP) -0.187 0.022

SOFAscore -0.277 0.001


Thetrialshowednosignificantdifferencein28-daysmortalitybetweeninterven-tionvs.controlgroup(25.3%vs.32%;p=0.367).Asubgroupanalysispro-ducedatrendtoalowermortalityintheselenase®-supplementedgroupforpati-entswithAPACHEIIscore>28(32.6%vs.51.6%;p=0.100).

However,Valentaetal.madeaninteres-tingdiscoveryinthistrial.Thecompa-risonofPCTandCRPvaluesbetweentheinterventionandtheplacebogroupshowedadecreaseofbothvaluesinde-

pendentlyofselenase® supplementation overthecourseofthe14daysobservati-onperiod.Butthereductionintheinter-ventiongroupwasmorepronounced. ForPCT,thedifferencebetweentheselenase®-supplementedgroupandthecontrolgrouponday7wasevensigni-ficant(Fig.17).These data suggest a biological interaction between seleni-um and PCT.


Fig.

17

SignificantlygreaterdecreaseinPCTintheselenase®-supplementedgroup. Therewasnosignificantdifference,despitethedifferenceinPCTvaluesbetweenthetwogroupsonday0(p=0.108).[8]

1.8

0.6

0.8

1

1.2

1.4

1.6

0.4

0.2

07

p = 0.003

p = 0.009

p = 0.06p = 0.004

p < 0.05

Days

PC

T [µ

g/l]

0 14

Reference range

selenase®

Control


Manzanares et al., 2011Supplementationwithhigh-dosesodiumselenitereducestheincidenceofnosocomialpneumoniaandimprovessepsisseverity

Thisplacebo-controlled,randomizedpro-spective,single-blindphaseIItrialenrol-led35patientswithSIRSandAPACHEIIscoresof≥15[9].Theinterventiongroupreceivedabolusof2,000µgseleniumand1,600µg/dayforanother10days.Bothgroupsreceivedanaverageof 77respectively73µg/dayseleniumenterally.

Inthesodiumselenite-supplementedgroup,theincidenceofearlyventila-tor-associatedpneumoniawassignifi-cantlyreducedby31%(p=0.04)(Fig.18).Theincidenceofnosocomialpneu-moniawasalsoreducedintheinter-ventiongroupby19%(p=0.03).Theauthorsattributedthisbeneficialeffecttotheadministeredlargebolus,becauseallthreeeffectsofabolusadministrationcaninfluencethedevelopmentofearlyventilator-associatedpneumonia.

• ReversibleinhibitionofNF-κBbindingtoDNA

• Apoptosisandcytotoxicityinactivated,pro-inflammatorycells

• DirectvirucidalorbactericidaleffectEarlyventilator-associatedpneumoniaintheICUisamajorcauseofmorbidity,mortalityandcosts.Areductionintheincidenceofearlyventilator-associatedpneumonia via sodium selenite might makeanimportantcontribution.

Furthermore,theSOFAscorewasreducedinthesodiumselenite-supple-mentedgroupversustheplacebogrouponday10(p=0.0001).WhiletheSOFAscoreintheinterventiongroupcontinuedtosignificantlydeclinefromday3today10,theSOFAscoreintheplacebogroupremainedvirtuallythesame(Fig.19).


Fig.

18Sodiumselenitereducedtheprobabilityforapatient toacquirenosocomialpneumonia.[9]

1

0.4

0.2

0.6

0.8

08 124 16 20 24 28

Days

0

p = 0.024Prob

abilit

y of

rem

aini

ng fr

ee o

f ho

spita

l-acq

uire

d pn

eum

onia

with

in th

e fir

st 2

8 da

ys

Sodium selenite

Placebo

Fig.

19Sodiumselenitesignificantlyimprovedsepsisseverity basedontheSOFAvalue(p=0.0001).[9]

2 4 6 8 1000

3

6

9

12

1

4

7

10

2

5

8

11

13

SO

FA s

core

(mea

n va

lue

± S

D)

Days

Placebo

Sodium selenite


SIGNET trialFewernewinfectionsinpatientsreceivingselenase® supplementationfor>5days

TheSIGNETtrialwasarandomized,double-blinded,factorial,controlledmulticentertrialwith502participants[6].Becauseofthefactorialdesign,thepa-tientswererandomizedtothefollowingstudyarms:Placebogroup(n=125)parenteralnutritioncontainingstandardformulation; selenase®group(n=127)standard formulation with addition of 500μgselenium;glutaminegroup(n=126)formulationincluding20.2gglutamine; selenase® + glutamine group (n=125)formulationwithadditionof500µgseleniumand20.2gglutamine.

Only56%ofthepatientshadsepsis. The selenase®-supplementedgroup showedadecreasedrateofnewin-fectionsby5%(p=0.24)incontrasttoglutaminesupplementation.selenase® supplementationsignificantlyreducednewinfectionsinpatientswhorecei-vedinterventionfor≥5daysby13%(p=0.03)(Fig.20).


Fig.

20Atleast5daysselenase® supplementation significantlyreducednewinfections.[10]

80

70

20

30

10

40

60

50

0Placebo selenase® ≥ 5 days

(n = 251)

Infe

ctio

ns %

p = 0.03

72.3 %

58.9 %

-13.4 %


REDOXS trialComparedtoglutamine,seleniumdidnothaveany negativeeffectonmortality,althoughthebeneficial effectofseleniumsupplementationwasreduced bythelackofseleniumdeficiency

TheREDOXStrialwasarandomized,controlled,double-blind,2x2factorial,multicentertrialwith1,223severelyillpatients with multiple organ failure [11].Within24hoursafterICUadmission,thepatientsreceivedeitherglutamine,anti-oxidants(including500µgseleniumasselenase®),bothorplaceboforamaxi-mumof28days(Table4).

Onlyin31%ofpatientstheprimarydiagnosis was sepsis at ICU admissi-on.Comparedtoothersepsistrials,theselenium value at ICU admission was not outsidethenormalrangeinanyofthe66analyzedtrialpatients.Itisnotknownwhether these patients were sepsis pati-ents.However,themedianserumsele-nium level at 86 µg/l in the antioxidant groupand80µg/linthenon-antioxidantgroupwasfarabovethemeansinsepsispatientsat30–40µg/lseleniumintheserum.TheaforementionedsepsistrialswereexclusivelyconductedinEuropewhere the average selenium level in the populationisclearlybelowthereferencerangeof80µg/lseleniumintheserum.TheREDOXStrialwasconductedboth

inCanada,theUSAandEurope.BothinCanadaandtheUSA,theseleniumstatusismarkedlyabovethereferencerangeof80µg/l.

In the antioxidant group, the selenium valueintheserumincreasedsignificantly(p<0.001),whereastheseleniumstatusinthenon-antioxidantgrouponlyshowedaslightincrease(Table5).Despitethesignificantincreaseinseleniumcon-centration,theauthorsreportedthatthemedianseleniumlevelinbothgroupsremained within the normal range at all measurementtimepoints.

Supplementation with antioxidants had noeffecton28-daysmortality(30.8%vs.28.8%;p=0.48).Inadditiontotheabove-mentionedrestrictionsintheRE-DOXStrial,thepositiveeffectofseleni-ummighthavebeennegatedbythelateinitiation of supplementation with antio-xidants, the too low selenium dose and theinteractionofvitaminCwithseleniumduetoitsconcurrentadministration.


Tab.

5 Increaseinserumseleniumvalueintheantioxidantgroup.[11]

Antioxidants No antioxidantsp-value

n median[Q1,Q3](µg/l) n median[Q1,Q3](µg/l)

ICUday1 31 86(71–98) 30 80(65–85) 0.08

ICUday4 28 142(137–164) 26 85(67–95) <0.0001

ICUday7 25 156(134–174) 19 89(82–107) <0.0001

Tab.

4 TrialarmsintheREDOXStrial.[11]

Trial arm Number Supplementation Administration

1 Glutamine(Gln) 3030.5gGln/kgbodyweight Parenteral

30gGln Enteral

2Antioxidants(AOX)

308

500µgseleniumasselenase® Parenteral

300µgselenium,20mgzinc,500mgvitaminE,10mgbeta-carotene,1,500mgvitaminC

Enteral

3 Gln+AOX 310 1+2

4 Placebo 302 −


Sakr et al., 2014Doctorsgiveselenase®primarilyseverlyillpatients

Inalargeretrospectivestudyconductedin2014,Sakretal.analyzedtheeffectofaseleniumsupplementationin1,047pa-tients with severe sepsis treated over a periodofmorethan6yearsinasurgicalICU [12].Duetotheretrospectivenatureofthestudy,theselenium-supplementedgrouphadonly413(39%)patients.Thecontrolgroupreceived100µg/daysele-niumandselenium-supplementedgroupreceivedabolusof1,000µgselenium(selenase®)and1,000µg/dayselenium(selenase®)foramaximumof14days.

Themediandurationofadjuvantseleni-umtherapywas8days(IQR=4–12).Thetwogroupspresentedwithsignifi-cantlydifferentpatientcharacteristics.Particularly,thehigherSAPSIIscore(50.8vs.47.7,p=0.001)andthehigherproportionofpatientswithcancer(32.4%vs.24.6%;p=0.005)mayhaveaffectedthestudyanalysis.Thisisalsoevidentintheparametersmeasuredtotestinflam-mationandorganfunction(C-reactiveprotein,PCT,bloodlactate)(Table6).

Dosurgicalsepsispatientsneedadifferent(higher) dosagethanmedicalsepsispatients?

It is known that, among other things, asurgicalinterventiontriggersoxidativestresswhichsignificantlyheightensthebody’sseleniumconsumptionduringandaftersurgery.Itcanthereforebeassu-medthat,toachievethesamebeneficialeffect,surgicalsepsispatientsrequirehigherseleniumdosesthanmedicalsepsispatients.Astrialsonseleniumsupplementationincardiacsurgeryhaveshown, without selenium supplementati-

onsurgerycausestheseleniumconcent-rationtodecreasebyaroundonequarterofthebaselinevalue.Inthisstudy, thefactthatnoseleniumlevelsweremeasuredorstatedmakesitimpossibletodrawconclusionsastowhethersele-niumconcentrationatICUadmissioninsurgicalsepsispatientswaslowerthaninmedicalsepsispatients.

Tab.

6Significantlydifferentpatientcharacteristics intheseleniumandcontrolgroup.[12]

Characteristics Control group Selenium group p-value

SAPSII 47.7±17 50.8±17.7 0.001

Cancer 24.6% 32.4% 0.005

C-reactiveprotein 78(13–193) 146(46–235) <0.0001

Procalcitonin 2.3(0.7–7.2) 3.7(0.9–12.9) <0.0001

Bloodlactate 2.5(1.6–5.3) 2.9(1.7–5.6) 0.031


Literature

1HotchkissRS,MonneretG,PayenD.LancetInfectDis.2013Mar;13(3):260-8.doi:10.1016/S1473-3099(13)70001-X.Immunosuppressioninsepsis:anovelunderstandingofthedisorderandanewtherapeuticapproach.

2AndrewsPJ,AvenellA,NobleDW,CampbellMK,CroalBL,SimpsonWG,ValeLD,BattisonCG,Jenkins-onDJ,CookJA;ScottishIntensivecareGlutamineorseleNiumEvaluativeTrialTrialsGroup.BMJ.2011Mar17;342:d1542.doi:10.1136/bmj.d1542.Randomisedtrialofglutamine,selenium,orboth,tosupplementparenteralnutritionforcriticallyillpatients.

3HuangTS,ShyuYC,ChenHY,LinLM,LoCY,YuanSS,ChenPJ.PLoSOne.2013;8(1):e54431.doi:10.1371/jour-nal.pone.0054431Effectofparenteralseleniumsupplementationincriticallyillpatients:asystematicreviewandmeta-analysis.

4 ManzanaresW,HardyG.CurrOpinClinNutrMetabCare.2009May;12(3):273-80.doi:10.1097/MCO.0b013e-32832a0cc2.Seleniumsupplementationinthecriticallyill:posologyandpharmacokinetics.

5 AngstwurmMW,SchottdorfJ,SchopohlJ,GaertnerR.CritCareMed.1999Sep;27(9):1807-13.Seleniumreplace-mentinpatientswithseveresystemicinflammatoryresponsesyndromeimprovesclinicaloutcome.

6AngstwurmMW,EngelmannL,ZimmermannT,LehmannC,SpesCH,AbelP,StraussR,Meier-HellmannA,InselR,RadkeJ,SchüttlerJ,GärtnerR.CritCareMed.2007Jan;35(1):118-26.SeleniuminIntensiveCare(SIC):resultsofaprospectiverandomized,placebo-controlled,multiple-centerstudyinpatientswithseveresystemicinflammatoryresponsesyndrome,sepsis,andsepticshock.

7ForcevilleX,LaviolleB,AnnaneD,VitouxD,BleichnerG,KorachJM,CantaisE,GeorgesH,SoubirouJL,Com-besA,BellissantE.CritCare.2007;11(4):R73.Effectsofhighdosesofselenium,assodiumselenite,insepticshock:aplacebo-controlled,randomized,double-blind,phaseIIstudy.

8 ValentaJ,BrodskaH,DrabekT,HendlJ,KazdaA.IntensiveCareMed.2011May;37(5):808-15.doi:10.1007/s00134-011-2153-0.High-doseseleniumsubstitutioninsepsis:aprospectiverandomizedclinicaltrial.

9ManzanaresW,BiestroA,TorreMH,GalussoF,FacchinG,HardyG.IntensiveCareMed.2011Jul;37(7):1120-7.doi:10.1007/s00134-011-2212-6.High-doseseleniumreducesventilator-associatedpneumoniaandillnessseveri-tyincriticallyillpatientswithsystemicinflammation.

10AndrewsPJ,AvenellA,NobleDW,CampbellMK,CroalBL,SimpsonWG,ValeLD,BattisonCG,Jenkins-onDJ,CookJA;ScottishIntensivecareGlutamineorseleNiumEvaluativeTrialTrialsGroup.BMJ.2011Mar17;342:d1542.doi:10.1136/bmj.d1542.Randomisedtrialofglutamine,selenium,orboth,tosupplementparenteralnutritionforcriticallyillpatients.

11HeylandD,MuscedereJ,WischmeyerPE,CookD,JonesG,AlbertM,ElkeG,BergerMM,DayAG;CanadianCriticalCareTrialsGroup.NEnglJMed.2013Apr18;368(16):1489-97.doi:10.1056/NEJMoa1212722.Erratumin:NEnglJMed.2013May9;368(19):1853.Arandomizedtrialofglutamineandantioxidantsincriticallyillpatients.

12SakrY,MaiaVP,SantosC,StrackeJ,ZeidanM,BayerO,ReinhartK.CritCare.2014Apr9;18(2):R68.doi:10.1186/cc13825.Adjuvantseleniumsupplementationintheformofsodiumseleniteinpostoperativecriticallyillpatientswithseveresepsis.
















Significantlymorecriticallyillpatientsintheinterventiongroupimpactedtheanalysisoftheretrospectivetrialonselenium supplementation in patients with severe sepsis

Inthisretrospectivestudy,overallICUmortalitywas31.3%andhospitalmortali-ty41.8%.WhereastheICUmortality didnotsignificantlydifferinthetwogroups(29.5%vs.33.9%;p=0.135), the selenium supplemented group dis-playedahigherhospitalmortality(39.15vs.46%;p=0.027).BoththeICUandhospitalstaysweresignificantlylongerintheinterventiongroup(p=0.01andp=0.001,respectively).However,amul-tivariateanalysisshowed,thatadjuvantseleniumtherapywasnotindependentlyassociatedwithworsehospitalmorta-lity(OR=1.19,95%CI=0.86-1.65;p=0.288).Themultivariateanalysisincludedage,gender,SAPSIIscore,

surgerytype,co-morbidities,focusonsepsis,SOFAsub-scoresandbloodlactatelevels.

The authors themselves point out, that thehigherhospitalmortalityandthelon-gerICUandhospitalstaysareattributab-letothesignificantlyhighernumber ofseverelyillpatientsintheselenium- supplementedgroup.Furthermore,theauthorsalsopointoutthatunlikeearlytrials,inwhichtheproportionofsurgicalpatientsfluctuatedbetween13%and40%,theirstudycontained100%surgi-calcases(Fig.21).


Fig.

21Percentageofmedicalandsurgicalsepsispatients indifferentsepsistrials.[5-8,10]

0%

20%

40%

60%

80%

10%

30%

50%

70%

90%

100%

Angstwurm(1999)

Angstwurm(2007)

Forceville(2007)

Valenta(2011)

Andrews(2011)

Heyland(2013)

Sakr(2014)

Medical sepsis Surgical sepsis


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Trial design Number of patients Intervention Result LimitationsAngstwurm et al. (1999)

controlled, randomized, prospective, open-label pilot trial (single center)

N (selenase®) = 21N (control) = 21

Intervention group (selenase®):535 µg/day selenium for 3 days, 285 µg/day selenium for 3 days, 155 µg/day selenium for 3 days and 35 µg/day selenium thereafter Placebo group: 35 µg/day selenium

Selenium level at ICU admission markedly below normalIntervention group (selenase®):Selenium level ↑ (p = 0.003)APACHE III score↓ (p = 0.041)Mortality ↓ (-19%; p = 0.135)Patients with APACHE III > 53: Mortality (at hospital discharge) ↓ (-53%; p = 0.0053)No adverse reactions from selenase®

No toxic symptoms

• trial size• no placebo group• low selenase® doses

Angstwurm et al. (2007)

Prospective, randomized, double-blind, multicenter phase III trial

N (selenase®) = 92N (placebo) = 97

Intervention group (selenase®):Bolus: 1,000 µg1,000 µg/day selenium as selenase® for 14 days Placebo group:< 100 µg/day selenium

Selenium level at ICU admission markedly below normalIntervention group (selenase®):Selenium level ↑ (p > 0.001)28-days mortality ↓ (-14%; p = 0.048)Pat. with septic shock:28-days mortality ↓ (-26%; p = 0.018)Pat. with APACHE III > 102:28-days mortality ↓ (-26%; p = 0.040)Pat. with > triple organ failure:28-days mortality ↓ (-23%; p = 0.039)No adverse reactions from selenase®

No toxic symptoms

Forceville et al. (2007)

prospective, randomized, double-blind, multicenter trial

N (sodium selenite) = 31N (placebo) = 29

Intervention group:Bolus: 4,000 µg selenium1,000 µg/day selenium for 9 days

Intervention group:Duration of mechanical ventilation = no significant differenceMortality = no significant differenceNo adverse reactions from sodium seleniteNo toxic symptoms

• trial size• Patients enrolled too late (not until after 48h)• baseline selenium value unknown• selenium value not measured

Valenta et al. (2011)

Prospective, randomized, open-label trial (single center)


Intervention group:1,000 µg selenium as selenase® on day 1500 µg/day selenium as selenase® for 14 days Control group:< 75 µg/day selenium

Selenium level at ICU admission markedly below normalIntervention group (selenase®):Selenium level ↑ (p > 0.001)28-days mortality ↓ (-7%; p = 0.367)Pat. with APACHE II < 28:28-days mortality ↓ (-19%; p = 0.100)Significant reduction in PCT vs. control group (p < 0.05)No adverse reactions from selenase®

No toxic symptoms

• no bolus

Manzanares et al. (2011)

placebo-controlled, randomized, prospective, single-blinded, phase II trial (single center)


Intervention group:Bolus: 2,000 µg selenium1,600 µg/day selenium for 10 days Placebo group:73 ± 16 µg/day selenium

Intervention group:SOFA ↓ (p = 0.0001)Early ventilator-associated pneumonia ↓ (-31%; p = 0.04)Nosocomial pneumonia ↓ (-19%, p = 0.03)No adverse reactions from sodium seleniteNo toxic symptoms

• trial size• baseline selenium value unknown• selenium value not measured

Overview of trials








-

Trial design Number of patients Intervention Result LimitationsAngstwurm et al. (1999)

controlled, randomized, prospective, open-label pilot trial (single center)


Intervention group (selenase®):535 µg/day selenium for 3 days, 285 µg/day selenium for 3 days, 155 µg/day selenium for 3 days and 35 µg/day selenium thereafter Placebo group: 35 µg/day selenium

Selenium level at ICU admission markedly below normalIntervention group (selenase®):Selenium level ↑ (p = 0.003)APACHE III score↓ (p = 0.041)Mortality ↓ (-19%; p = 0.135)Patients with APACHE III > 53: Mortality (at hospital discharge) ↓ (-53%; p = 0.0053)No adverse reactions from selenase®

No toxic symptoms

• trial size• no placebo group• low selenase® doses

Angstwurm et al. (2007)

Prospective, randomized, double-blind, multicenter phase III trial

N (selenase®) = 92N (placebo) = 97

Intervention group (selenase®):Bolus: 1,000 µg1,000 µg/day selenium as selenase® for 14 days Placebo group:< 100 µg/day selenium

Selenium level at ICU admission markedly below normalIntervention group (selenase®):Selenium level ↑ (p > 0.001)28-days mortality ↓ (-14%; p = 0.048)Pat. with septic shock:28-days mortality ↓ (-26%; p = 0.018)Pat. with APACHE III > 102:28-days mortality ↓ (-26%; p = 0.040)Pat. with > triple organ failure:28-days mortality ↓ (-23%; p = 0.039)No adverse reactions from selenase®

No toxic symptoms

Forceville et al. (2007)

prospective, randomized, double-blind, multicenter trial


Intervention group:Bolus: 4,000 µg selenium1,000 µg/day selenium for 9 days

Intervention group:Duration of mechanical ventilation = no significant differenceMortality = no significant differenceNo adverse reactions from sodium seleniteNo toxic symptoms

• trial size• Patients enrolled too late (not until after 48h)• baseline selenium value unknown• selenium value not measured

Valenta et al. (2011)

Prospective, randomized, open-label trial (single center)


Intervention group:1,000 µg selenium as selenase® on day 1500 µg/day selenium as selenase® for 14 days Control group:< 75 µg/day selenium

Selenium level at ICU admission markedly below normalIntervention group (selenase®):Selenium level ↑ (p > 0.001)28-days mortality ↓ (-7%; p = 0.367)Pat. with APACHE II < 28:28-days mortality ↓ (-19%; p = 0.100)Significant reduction in PCT vs. control group (p < 0.05)No adverse reactions from selenase®

No toxic symptoms

• no bolus

Manzanares et al. (2011)

placebo-controlled, randomized, prospective, single-blinded, phase II trial (single center)


Intervention group:Bolus: 2,000 µg selenium1,600 µg/day selenium for 10 days Placebo group:73 ± 16 µg/day selenium

Intervention group:SOFA ↓ (p = 0.0001)Early ventilator-associated pneumonia ↓ (-31%; p = 0.04)Nosocomial pneumonia ↓ (-19%, p = 0.03)No adverse reactions from sodium seleniteNo toxic symptoms

• trial size• baseline selenium value unknown• selenium value not measured








Trial design Number of patients Intervention Result Limitations

Andrews et al. (2011)

randomized, controlled, double-blind, factorial, multicenter trial

N (selenase®) = 127N (glutamine) = 126N (selenase® + glutamine) = 124N (placebo) = 125

Placebo group: Standard parenteral nutritionGlutamine group:+ 20.2 g glutamineselenase® group:+ 500 µg seleniumselenase® + glutamine group: + 500 µg selenium + 20.2 g glutamine

selenase® group: New infections ↓ (-5%, p= 0.24)New infections in patients with ≥ 5 days selenase® supplementation ↓ (-13%, p= 0.03)Mortality after 6 months = no significant difference

• Only 56% of participants were sepsis patients• baseline selenium value unknown• selenium value not measured

Heyland et al. (2013)

Randomized, controlled, blinded, 2-by-2 factorial, multicenter trial

N (antioxidants) = 308N (glutamine) = 303N (antioxidants + glutamine) = 310N (placebo) = 302

Antioxidant group:500 µg/day selenium as selenase® parenteral + 300 µg selenium, 20 mg zinc, 500 mg vita-min E, 10 mg beta-carotene, 1500 mg vitamin C enteralGlutamine group:0.5 g/kg body weight parenteral + 30 g enteral

Selenium level at ICU admission within reference rangeAntioxidant group:Selenium level ↑ (p = < 0.001)28-days mortality = no significant difference

• only 31% of participants were sepsis patients• late initiation of selenium supplementation• low selenium dose• interaction through concomitant vitamin C

Sakr et al. (2014)

Retrospective trial N (selenase®) = 413N (control) = 634

Intervention group:Bolus: 1,000 µg selenium1,000 µg/day selenium for 14 days Control group:100 µg/day selenium

selenase® group:ICU mortality = no significant differenceHospital mortality ↑ (+7%; p = 0.027)ICU stay ↑ (p = 0.01)Hospital stay ↑ (p = 0.001)Selenium supplementation not independently associated with worse out-come (OR = 1.19, p = 0.288)Selenium supplementation after a multivariate analysis not associated with hospital mortality

• retrospective trial• selenium group contains significantly more severely ill patients• no precise criteria for initiation of selenium supplementation• All patients were surgical patients with sepsis





Selenium in guidelines

Adults Infants with lowbirthweight

Children (prematureand term infants)

Burn patients

Sepsis patients

ICU patients in general

GuidelineParenteralNutrition ofDGEM2007

BiesalskiHKetal.:Wasser,Elektroly-te,VitamineundSpurenelemente.AktErnMed2007;32,Sup1:S30–S34.

× × × × ×ESPENGuidelinesonParenteralNutrition

ClinicalNutrition(2009)28,387–400.× × × ×

DeutscheSepsis-Leitlinien

Prävention, Diagnose, Therapie undNachsorgederSepsis

ReinhartK,BrunkhorstFM,AWMFonline2010.

×CanadianClinicalPractice Guidelines2013

www.criticalcarenutrition.com× ×

GuidelinesfortheProvisionandAssessmentofNutritionSupportTherapyintheAdultCriticallyIIIPatient:SCCMandA.S.P.E.N.

McClaveetal.,Jpen33(2009)3,277–316.

× ×GuidelinesonPediatric Parenteral Nutrition

JofPediatrGastroenterolNutr. 41:S39–S46,November2005ESPG-HAN

×NutritionSupportforAdults: OralNutritionSupport,EnteralTubeFeedingandParenteralNutrition

NationalInstituteforClinicalExcellen-ceFeb2006,UK

×

Summary72 Guidelines

http://www.dgem.de/material/pdfs/7%20Wasser,%20Elektrolyte,%20Vitamine,%20Spurenelementes-2006-951867.pdf

http://www.dgem.de/material/pdfs/7%20Wasser,%20Elektrolyte,%20Vitamine,%20Spurenelementes-2006-951867.pdf


http://www.awmf.org/leitlinien/detail/ll/079-001.html

http://www.awmf.org/leitlinien/detail/ll/079-001.html

http://www.criticalcarenutrition.com








73Guidelines

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Selenium for sepsis

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