Focus on Sepsis - SEIFEM

FocusonSepsis

LivioPaganoIstitutodiEmatologia-PolodiOnco-Ematologia

FondazionePoliclinicoAgostinoGemelliUniversitàCattolicaS.Cuore

Roma

SurvivingSepsisandSepticShock

v  Mortality rates associated with sepsis

v  30-50% for severe sepsis

v  50-60% for septic shock

v  Severe sepsis is the leading cause of death in the non-coronary ICU

v  Sepsis kills approximately 1,400 people worldwide every day

v  2013 NYS DOH issues a mandate for all hospitals to produce clinical care guidelines

for evidence-based recognition and treatment of sepsis.

v  Adult and Pediatric treatment protocols for both ED and inpatient.

v  Education of hospital staff: Physician/Resident, RN, Pharm, Laboratory.

v  Data submission for public reporting of outcomes.

•  Sepsiscanleadtoshockandorganfailure,andisaleadingcauseofdeathintheUnitedStateswithamortalityrateofapproximately30%,almostdoublethemortalityrateofacutemyocardialinfarction,orheartattack.1

•  Sepsisisthemostexpensivehospital-treatedconditionintheUnitedStates–representingover$20.3billioninhealthcarecosts.2Over1.6millionpatientsintheUSalonearediagnosedwithsepsiseachyearandapproximately500,000diefromthisillness.3

•  Thehighcostoftreatingsepsisisprimarilydrivenbytheextendedhospitalizationofpatientswhichtypicallyincludesover7daysintheIntensiveCareUnit.4

CostofSepsis

1.JAntimicrobChemother2011;66Suppl2:ii11–ii23doi:10.1093/jac/dkq5152.HCUPStatisticalBrief#160.August2013.AgencyforHealthcareResearchandQuality,Rockville,MD.3.HCUPStatisticalBrief#122.October2011.AgencyforHealthcareResearchandQuality,Rockville,MD.4.Martin,J.B.,Wheeler,A.P.(2009).Approachtothepatientwithsepsis.Clin.ChestMed.,30(1),1-16.

v Definitionv Epidemiologyv PathogeneticMechanismsv SignsandSymptomsv  Laboratoryv Outcomeandtreatment


Acontinuumofseveritydescribingthehostsystemicinflammatoryresponse

SIRS

²  SIRS–systemicinflammatoryresponsesyndrome²  Musthaveatleast2ofthefollowing:

²  Temperature>38.5ºCor<36ºC²  Heartrate>90beats/min²  Respiratoryrate>20breaths/minorPaCO2<32mmHg²  WBC>12,000cells/mm3,<4000cells/mm3,or>10%immature(band)forms

²  SIRSisthebody’sresponsetoinfection,inflammation,stress

SepsisandSevereSepsis

v  Sepsis–SIRS+suspectedorconfirmedinfection(documentedviaculturesorvisualizedviaphysicalexam/imaging)

v  SevereSepsis–Sepsis+atleastonesignoforganhypo-perfusionordysfunction

Areas of mottled skin Disseminated intravascular coagulation Capillary refill > 3 secs AKI UOP < 0.5cc/kg /hr ARDS or acute lung injury (ALI) Lactate > 2mmol /L Cardiac dysfunction on echo Altered mental status Plt < 100 Abnormal EEG Troponin Leak

SepticShock

²  SepticShock-Severesepsisplusoneofthefollowingconditions:–  MAP<60mmHg(<80mmHgifprevioushypertension)afteradequatefluidresuscitation

–  NeedforpressorstomaintainBPafterfluidresuscitation

–  Adequatefluidresuscitation=40to60mL/kgsalinesolution(NS5L-10L)

–  Lactate>4mmol/L

15

SevereSepsis

RelationshipBetweenSIRS,SepsisandSevereSepsis

BoneRCetal.Chest.1992;101:1644-55.

Trauma

Infection

SepsisOther

Pancreatitis

Burns

SIRS


PredisposingUnderlyingDiseases

²  Heartdisease-rheumaticorcongenital²  Splenectomy²  Intraabdominalsepsis²  Septicabortionorpelvicinfection²  Intravenousdrugabuse²  Immunocompromised

OrganismsResponsibleforSepticShockinRelationtoHostFactors

Asplenia EncapsulatedorganismsPneumococcusspp.,Haemophilusinfluenzae,Neisseriameningtidis,CapnocytophagiacanimorsusBabesiosis

Cirrhosis Vibrio,Yersinia,andSalmonellaspp.,otherGram-negativerods(GNRs),encapsulatedorganisms

Alcoholism Klebsiellaspp.,pnemococcus

Diabetes MucormycosisandPseudomonasssp.malignantexternalotitis,Escherichiacoli

Steroids Tuberculosis,fungi,herpesvirusNeutropenia EntericGNR,Pseudomonas,Aspergillus,

Candida,andMucorspp.,Staphylococcusaureus

T-cellabnortmalities

Listeria,Salmonella,andMycobacteriaspp.,herpesvirusgroup(herpessimplexvirus,cytomegalovirus,varicellazostervirus)

TheEpidemiologyofSepsisintheUnitedStatesNumberofcasesofsepsisintheUnitedStates,accordingtothecausativeorganism,1979-2000

NEnglJMed2003;348:1546-1554

EmergenceofGram-NegativeOrganisms

²  Antibioticpressureonnormalflora²  Useofinvasivedevices²  Immunesuppression

Resistancetothird-generationcephalosporinsEurope,2014K. pneumoniae E. coli

EARS-NET

History

²  Communityversushospital-acquired²  Priororcurrentmedications²  Recentmanipulationsorsurgery²  Underlyingdiseases²  Travelhistory

Sourcesofsepsis

v  Respiratory 38%v  Urinarytract 21%v  Intra-abdominal16.5%v  CRBSI 2.3%v  Device 1.3%v  CNS 0.8%v  Others 11.3%

Non tunneled CVC extraluminal colonization intraluminal contamination

Tunneled CVC

intraluminal infection

Candida Staphylococcus

Themainproblemarenosocomialinfections!!

GI tractGI tract

insult

injury

translocation

infection

antibiotics

selection

Normalcommensalflora

Disease

Centralvenouscatheter

Candidaandbacterialspecies


SepsisPathogenesis

Unbalanced Immune Reaction

Tissue Factor

Procoagulant State

Microvascular Thrombosis

Mediators of Inflammation

ROS

Vasodilation Capillary Leak

DIC

BacterialcomponentsinthepathogenesisofSepticShock

BacterialcomponentsSourceEndotoxin(LPS,lipidA) Allgram-bacteriaPeptidoglycan Allbacteria

Lipoteichoicacid Gram+bacteriaPore-formingExotoxins S.aureus,S.pyogenes

E.coliSuperantigens S.aureus,S.pyogenesEnzymes S.pyogenes,C.perfringens


ClinicalManifestations

²  Fever,chills,hypotension²  Hypothermia,especiallyintheelderly²  Hyperventilation-respiratoryalkalosis²  Diaphoresis,apprehension,changeinmentalstatus

Skin

v Furuncles,cellulitis,bullouslesionsv  Intravenoussites,phlebitisv Erythemamultiformev Ecchymoticorpurpuriclesionsv DIC,petechiaev Ecthymagangrenosumv Purpurafulminans

CardiovascularSigns

v “Warmshock”-↑CO,↓SVRv “Coldshock”-↓CO,↑SVRv Anaerobicmetabolism-lacticacidemia

PulmonarySigns

v  Tachypneav  Hyperventilation,respiratoryalkalosisv  ARDS,respiratoryfailurev  Ventilation-perfusionmismatchv  Widenedalveolar-arterialoxygengradientv  Reducedlungcompliance

RenalandGastrointestinalSigns

v  Acutetubularnecrosis,oliguria,anuriav  UpperGIbleedingv  Cholestaticjaundicev  Increasedtransaminaselevelsv  Hypoglycemia


Sepsisiscurrentlydiagnosedusingclinicaldefinitionscombinedwith

cultureresults

Timeisacrucialpoint!!

DiagnosticstrategiesforrapididentificationofBSIs

AutomatedinstrumentsBloodcultures

Detectionofmicrobialgrowth

Time

ID/AST

Culture-basedmethods

Gramstaining

MALDI-TOFMS MolecularmethodstointegrateMALDIandto

detectresistancedeterminants

AST

Infectiousdiseaseconsultant

BSI,bloodstreaminfection;ID,identification;AST,antimicrobialsusceptibilitytesting;MALDI-TOFMS,matrix-assistedlaserdesorptionionizationtime-of-flightmassspectrometry

Infectiousdisease

consultant

RoleofProcalcitonininsepsis²  Alternative(cytokine-like)pathwayduringsepsis:‘Hormokine’²  Bacterialtoxins(gran+/gram-)andcytokinesstimulateproductionof

Procalcitonininallparenchymaltissues²  Thisprocesscanbeattenuatedorblockedduringviralinfectionbyinterferones.²  NonendocrinetissueieLiver,Lung,Brainetc.donothaveendocrinegranules

wherecalcitonincanbestored.²  PCTisimmediatelyreleasedintothebloodstream

PCT

²  Hasbactericidalproperties²  Presentinallmammalstested²  Probablywasanearlyhostdefenseagainstinfection

²  Replacedbymorerobustdefensessuchasantibodysystemandenhancedleukocytedefenses

²  Mostimportant,perhaps,indefendingthebodyagainstinvasionofbacteriaduringfeeding.

•  Howcanweusethiscellularsignalofinfectioninthemanagementofbothsepticandnonsepticpatients

•  Goals

–  Provideantibiotictherapytoptswhoneeditassoonaspossible–  Avoidantibioticprescriptiontothosewithoutinfection–  Dobothwithastronglikelihoodofbeingcorrect,atleastasgoodasothermarkerssuchasWBC,bands,fever,CRP

PCTkineticsprovideimportantinformationonprognosisofsepsispatients

•  Clinical symptoms alone are often insufficient for early and accurate diagnosis •  PCT levels, can be observed within 3-6 hours after an infectious challenge with a

peak - up to 1000 ng/ml - after 6-12 hrs. Half-life: ~24hrs •  Specific to bacterial origin of infection and reflects the severity of the infection

Brunkhorst FM et al., Intens. Care Med (1998) 24: 888-892

Harbarth S et.al. AM J Resp Crit Care Med. 2001; 164:396-402

WhenPCTisusedasareference,thesensitivityandspecificityofsepsisdiagnosiscanbesignificantlyincreasedcomparedwithconventionalclinicalparameters.

Sensitivity:94%Specificity:77%

Adding PCT results to clinical assessment improves the accuracy of the early clinical diagnosis of sepsis

C-ReactiveProtein(CRP)

v  Anadditionalinflammatorymarkeravailableforsepsisscreening

v  AriseintheplasmaconcentartionofCRPinabsenceofothernon-infectiouscausesofinflammation(i.e.trauma,surgery,etc)maybesuggestiveofinfection

v  SevereliverdiseasemayreducethelevationofCRP.Intheseindivuduals,diagnosisofsepsisshouldnotbeexcludedbasedonlowerCRP

Lactate

•  Thebody’senergyneedsmainlymetbyaerobicmetabolism,whichrequiredoxygen

•  Ifthereisalackofoxygenitreverttoanerobicmetabolismwhichlacticacidisproduct

•  ThismayleadtoacidosiswithadecreaseofpH

•  EvidenceisclearthatLactatelevelsarepredictiveofdeathandMODS

•  Clearanceoflactateisassociatedwithimprovedsurvival•  Algorithmsofcarebasedonlactateclearanceappearto

workaswellorbetterthanotherapproaches.

Simon L. et al. Clin Infect Dis. 2004; 39:206-217.

AddingPCTresultstoclinicalassessmentimprovestheaccuracyoftheearlyclinicaldiagnosisofsepsis

•  PCTlevelsaccuratelydifferentiatesepsisfromnoninfectiousinflammation*•  PCThasbeendemonstratedtobethebestmarkerfordifferentiatingpatientswithsepsisfromthosewith

systemicinflammatoryreactionnotrelatedtoinfectiouscause

Sensitivity:89%Specificity:94%

NPV:90%PPV:94%

TCI, time to culture-based identification results ; TDI, time to direct identification results.

Timetoidentification

v  Themediantimetopositivitywas12.2hours(IQR:8.2-17.5),rangingfrom10.4h(IQR:7-15.1)forGram-negativebacteria,to15.2h(IQR:10.3-18.5)forGram-positiveisolates.Itwas16.4h(IQR:10.3-28)foryeastsand10.5h(IQR:6-16)forpolymicrobialcultures.

v  Themediantimetoidentificationforthedirectmethodwas19.5hours(IQRs:14.3-26.5h)(range:17.2hforGram-negativesto21.5hforgram-positivesandyeasts)andthatforthecomparisonculture-basedmethodwas41.7h(IQRs,35.5-53h)

020

40

60

80

100

hours

Gram-negative Gram-positive Yeast mixed

TCI TDI

Using our IPF% reference normal range [IPF% 2.39% (0.8-5.1)], a significantly (p<0.0001) higher level of IPF% in samples with positive BC [IPF% 4.86% (2.4-15.8)] than in negative

samples [IPF% 1.79% (0.5-4.7)] was found Increased IPF% significantly correlates with BCs positivity.


FactorsAssociatedwithHighestMortality

v Respiratory>abdominal>urinaryv Nosocomialinfectionv Hypotension,anuriav  Isolationofenterococciorfungiv Gram-negativebacteremia,polymicrobialv Bodytemperaturelowerthan38°Cv Agegreaterthan40v Underlyinghematologicalmalignancy

SevereSepsisRecommendations

AdultandPediatricEvidence-basedStudies

1.   EarlyDetection2.   EarlyTreatment

•  SepsisResuscitationBundle

3. Monitorreliabilityandoutcomes

Earlyantibioticsaregood

Author N Setting Mediantime(mins)

Oddsratiofordeath

GaieskiCCM2010;38;1045-53

261 ED,USA(shock)

119 0.30(1sthourvsalltimes)

DanielsEmergMedJ2010;doi:10.1136

567 Wholehospital,UK

121 0.62(1sthourvsalltimes)

KumarCCM2006;34(6):1589-1596

2154 ED,Canada(shock)

360 0.59(1st3hoursvsdelayed)

AppelboamCCM2010;14(Suppl1):50

375 Wholehospital,UK

240 0.74(1st3hoursvsdelayed)

LevyCCM2010;38(2):1-8

15022 Multi-centre 0.86(1st3hoursvsdelayed)

Rapiddetectionofsepsishaveagreat

impactonthesurvivalofpatients

FungalinfectionsMorrelletal.,AAC,2005

BacterialsepsisKumaretal.,Clin.CareMed.,2006

VariablesindependentlyassociatedwithmortalityofBSIs.Logisticregressionanalysis

v  inadequateinitialantimicrobialtherapy(OR,6.28;95%CI,3.18to12.42;P<0.001)

v  unidentifiedprimaryinfectionsite(OR,2.69;95%CI,1.38to5.27;P=0.004).

Tumbarelloetal.AntimicrobAgentsChemother2007

InappropriateAntimicrobialTherapy:ImpactonMortality

Kollefetal:Chest2002

0

100

200

300

400

500

600

No.In

fected

Pa

tients

42.0%mortality

17.7%mortality

RelativeRisk=2.37(95%C.I.1.83-3.08;P<.001)

#Deaths

#Survivors

InappropriateTherapy

AppropriateTherapy

N Engl J Med, Vol. 347, No. 13·September 26, 2002

Mortality

Septic Shock Outcomes for Patients on Hospital Wards versus

ICU’s •  Wardpatients: DelaysinICUtransfer(67mins.) IVfluidboluses(27vs15mins.) Inotropicagents(310vs22.5mins)

•  Mortality: Wards(70%)vsICUs(39%) ApacheIIscores(18.5vs24) Candidemia

JSLunberg,Crit.CareMed.1998

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Focus on Sepsis - SEIFEM