Levy

TheManagementofSepsis:WhatsNewin2013

MitchellM.LevyMD,FCCMProfessorofMedicine

Chief,DivisionofPulmonary,Sleep,andCriticalCareWarrenAlpertMedicalSchoolofBrownUniversity

Providence,RI

Disclosures

Personal: Financial:

None SSC

Financial: None No industry support since 2006

ProjectedIncidenceofSevereSepsisintheUS:20012050

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Angus DC, et al. JAMA 2000;284:2762-70.Angus DC, et al. Crit Care Med 2001. In Press.

Pathophysiology

SepsisasCytokineStorm

Sepsispresentation Fever,shock,respiratoryfailure

ProinflammatorycytokinesTNF,IL1,IL6 Allincreased insepsis

Encouragingresultsinanimalmodelspretreated withtherapeuticsthatblockedproinflammatorycytokines

(Hotchkiss and Karl N Engl J Med 2003;348:138)

Virulent pathogens (pneumococci, meningococcus, Group A strep, S. aureus, Clostrida spp.)

Pro-inflammatory markers-cytokines, chemokines C

C, ROS RNS kinins, procoagulants

Early onset septic shock, MODS

Virulent pathogens: pneumococcus, S. aureus, Group A strep, Clostridia, meningococci

Proinflammatory mediators-cytokines, chemokines, procoagulants, kinins, ROI, RNI, C

Young, previously healthy patients with rapid onset septic shock - fits our animal models

Traditional view of sepsis and its pathophysiology

TLRs are the major pattern recognition receptors of innate immunity

/8

Microorganisms

Immune cells

Host-derived mediators

5 PRRs

PAMPs DAMPs HSPHeparanHyaluronateFibrinogenBiglycanSurfactant AHMGB-1HemeMRP8/14Histone

Caspase-1 & 5ASCNALP1 & 3Pyrin

ASCNF-B

TLRsNLRs

RLHs

Cinel and Opal CCM 2009:291

CLRs CDRs

GenomicStorm

Xiao et al. Jour Exp Med 2011. 208(13):2581-2590

CARS

CompensatoryAntiinflammatoryResponseSyndromecharacteristics:

PredominanceofTh2andTregresponsesoverTh1andT17responses

CD4lymphopeniaandBlymphocytedysfunction

MonocytesstimulatedbyPAMPsfailtoproduceadequatecytokines

DecreasedexpressionofHLADRonmonocytes

Impairedneutrophilsphagocytosis

Immunosuppression

EndStagesepticpatients: Apoptosisinducedlossofcellsofinnateandadaptiveimmunesystem

CD4,CD8,T,B,dendriticcells Occurringwhenclonalexpansionoflymphocytesshouldbeoccurring

Severedepletionofimmuneeffectorcellsisuniversalfindinginsepsis

Hotchkiss et al. Lancet ID 2013. 13:260-268

Immunosuppressiontheory Initialhyperactivationofinnateimmuneresponse Proinflammatorycytokineproduction

Persistsforavariableperiod Patientsage Comorbidities Organismvirulence Otherfactors

Followedbydefectiveinnateandadaptiveimmunity

Hotchkiss et al. Lancet ID 2013. 13:260-268

Virulent pathogens (pneumococci, meningococcus, Group A strep, S. aureus, Clostrida spp.)

Pro-inflammatory markers-cytokines, chemokines C

C, ROS RNS kinins, procoagulants

Early onset septic shock, MODS

Less virulent pathogens: Stenotrophomonas, enterococci, Acinetobacter, CMV, Candida

Anti-inflammatory state-cytokines, apoptosis, LPS reprogramming, Decreased HLA DR, TNFR, TLR4, expanded Treg cells, MDSCs

gradual deterioration and progressive organ failure-fits most of our patients

Realistic view of sepsis and its pathophysiology

Sepsis-induced immunosuppression


Innate immunity

Adaptive immunity

Swelling

Fluid shifts

NO

O2-

PAF, IL-6, IL-8 MCP-1, E-,P-selectins

Mitochondrial injury

apoptosis

Oxidant stress

PMN elastase

Vasodilationexudation

Microcirculation: Pro-inflammatory, procoagulant state

Capillary lumen

Interstitial space

Fibrin

DiagnosisofSepsis

HowDoWeIdentifySepticPatients? HeartAttack

EKG CardiacEnzymes

CPK MB

Troponin CRP BNP Echocardiogram CardiacCatheterization

Sepsis Signsandsymptoms

Fever,chills,elevatedWBC,difficultybreathing

Looksick Objectivemeasurements

SSCInteractiveDatabase

SepsisManagement

SurvivingSepsisCampaign:Internationalguidelinesformanagementofseveresepsis

andsepticshock:2012

R Phillip Delllinger MD1; Mitchell M. Levy MD2, Andrew Rhodes MD BS3; Djillali Annane MD4; Herwig Gerlach MD PhD5; Steven M. Opal MD6; Jonathan E.

Sevransky MD7; Charles L. Sprung MD8; Ivor S. Douglas MD9; Roman Jaeschke MD10; Tiffany M. Osborn MD MPH11; Mark E. Nunnally MD12; Sean R. Townsend MD13; Konrad Reinhart MD14; Ruth M. Kleinpell PhD RN-CS15; Derek C. Angus

MD MPH16, Clifford S. Deutschman MD MS17; Flavia R. Machado MD PhD18, Gordon Dr. Rubenfeld MD19; Steven A. Webb MB BS PhD20; Richard J. Beale

MB BS21; Jean-Louis Vincent MD PhD22; Rui Moreno MD PhD23; and the Surviving Sepsis Campaign Guidelines Committee including the Pediatric

Subgroup*

Critical Care Med. 2013 Feb;41(2):580-637Intensive Care Med. 2013 Feb;39(2):165-228

CurrentSurvivingSepsisCampaignGuidelinesSponsors

AmericanAssociationofCriticalCareNurses AmericanCollegeofChestPhysicians AmericanCollegeofEmergencyPhysicians AustralianandNewZealandIntensiveCare

Society

AsiaPacificAssociationofCriticalCareMedicine

AmericanThoracicSociety BrazilianSocietyofCriticalCare(AIMB) CanadianCriticalCareSociety ChineseSocietyofCriticalCareMedicine ChineseSocietyofCriticalCareMedicineof

ChineseMedicalAssociation

EuropeanRespiratorySociety EuropeanSocietyofClinicalMicrobiology

andInfectiousDiseases

EuropeanSocietyofIntensiveCareMedicine EuropeanSocietyofPediatricandNeonatalIntensive

Care

GermanSepsisSociety InfectiousDiseasesSocietyofAmerica IndianSocietyofCriticalCareMedicine JapaneseAssociationforAcuteMedicine JapaneseSocietyofIntensiveCareMedicine LatinAmericanSepsisInstitute PanArabCriticalCareMedicineSociety PediatricAcuteLungInjuryandSepsisInvestigators SocietyAcademicEmergencyMedicine SocietyofCriticalCareMedicine SocietyofHospitalMedicine SurgicalInfectionSociety WorldFederationofCriticalCareNurses WorldFederationofSocietiesofIntensiveandCritical

CareMedicine

Diagnosis

1. To optimize identification of causative organisms, werecommend at least two blood cultures be obtainedbefore antimicrobial therapy is administered as long assuch cultures do not cause significant delay (>45minutes) in antimicrobial administration, with at leastone drawn percutaneously and one drawn through eachvascular access device, unless the device was recently(

InitialResuscitation1. We recommend the protocolized resuscitation of a patient

with sepsisinduced shock, defined as tissue hypoperfusion(hypotension persisting after initial fluid challenge or bloodlactate concentration 4 mmol/L). This protocol should beinitiated as soon as hypoperfusion is recognized and shouldnot be delayed pending ICU admission. During the first 6 hrsof resuscitation, the goals of initial resuscitation of sepsisinduced hypoperfusion should include all of the following asone part of a treatment protocol:

Central venous pressure (CVP): 812mm Hg Mean arterial pressure (MAP) 65mm Hg Urine output 0.5mL.kg1.hr 1 Centralvenous(superiorvenacava)ormixedvenousoxygensaturation

70%or65%,respectively

(Grade1C)

InitialResuscitation

2. In patients with elevated lactate levels as a marker of tissuehypoperfusion we suggest targeting resuscitation tonormalize lactate as rapidly as possible (grade 2C).

3. We suggest that during the first 6 hrs of resuscitation ofsevere sepsis or septic shock, if ScvO2

Antibiotictherapy

1. We recommend that intravenousantimicrobial therapy be started as early aspossible and within the first hour ofrecognition of septic shock (1B) and severesepsis without septic shock (grade1C).

RelationshipbetweenShock,AnitiboticTiming,andMortality

Kumar A. et al. Critical Care Medicine. 2006 Jun. 34(6):1589-96

Each hours of delay: survival 7.6%

HospitalMortalitybyTimetoAntibiotics

Time to Antibiotics: Wards vs. ED

Antibiotictherapy

4. We suggest the use of lowprocalcitonin levels to assist theclinician in the discontinuation ofempiric antibiotics when no evidenceof infection is found (grade 2C).

Fluidtherapy1. We recommend crystalloids be used as the initialfluid of choice in the resuscitation of severe sepsisand septic shock (grade 1B).

2. We recommend against the use of hydroxy ethylstarches for fluid resuscitation of severe sepsis andseptic shock (grade 1B).

3. We suggest the use of albumin in the fluidresuscitation of severe sepsis and septic shockwhen patients require repeated boluses ofcrystalloids (grade 2C).

Fluidtherapy4. We recommend that initial fluid challenge in patients with

sepsisinduced tissue hypoperfusion with suspicion ofhypovolemnic be started with 1000 mL of crystalloids (toachieve a minimum of 30ml/kg of crystalloids in the first 4 to6 hours). More rapid administration and greater amounts offluid, may be needed in some patients (see InitialResuscitation recommendations) (Grade 1B).

5. We recommend that a fluid challenge technique usingincremental fluid boluses be applied wherein fluidadministration is continued as long as the hemodynamicimprovement either based on dynamic (e.g. delta pulsepressure, stroke volume variation) or static (eg, arterialpressure, heart rate) variables continues (Grade 1C).

Vasopressors1. We recommend that vasopressor therapy initially target a mean

arterial pressure (MAP) of 65 mm Hg (grade 1C).

2. We recommend norepinephrine as the first choice vasopressor(Grade 1 B).

3. We recommend epinephrine (added or substituted) when anadditional agent is needed to maintain adequate blood pressure(Grade 2B).

4. We suggest vasopressin 0.03 units/minute can be added to andsubsequently potentially substituted for norepinephrine (Grade2A).

5. We suggest dopamine as an alternative vasopressor agent tonorepinephrine in highly selected patients at very low risk ofarrhythmias and with low cardiac output and/or low heart rate.(Grade 2C).

Corticosteroids1. We suggest not using intravenous corticosteroids in adult

septic shock patients if adequate fluid resuscitation andvasopressor therapy is able to restore hemodynamic stability.In case this is not achievable we recommend a daily dose of200 mg intravenous hydrocortisone given by continuousintravenous infusion (Grade 2C).

2. We suggest not using the ACTH stimulation test to identifythe subset of adults with septic shock who should receivehydrocortisone (Grade 2B).

3. We suggest that patients with septic shock receivehydrocortisone rather than other steroids (Grade 2B).Further we recommend that hydrocortisone alone be usedinstead of hydrocortisone plus fludrocortisone (Grade 1B).

LicensedTherapeuticAgentsforSepsis

Antibiotics

RecentFailedClinicalTrialsinSepsis

TNF ActivatedProteinC TLR4inhibitor Talectoferrin TissueFactorPathwayInhibitor 25Failedclinicaltrialsforimmunomudulation

19) PMX-b-conjugants20) PMX-b-columns ?

21) E556422) Anti-CD14 Mab

23) IL-1ra24) PAF inhibitors

25) IVIG ?26) PAF-AH

27) Ibuprofen28) Anti-2 integrin

29) Albumin hemoperfusion30) NO synthase inhibitors

31) Growth Hormone32) Tight insulin control

33) Stress dose steroids ?34) Bradykinin inhibitors

35) TAK 24236) Talactoferrin

1) High Dose Steroids2) J5 antisera3) TNF Mab

4) Chimeric TNF Mab5) Humanized TNFMab

6) TNF-Fab7) sTNFR1:Fc8) sTNFR2:Fc

9) Anti-lipid A E510) Anti-lipid A HA1A

11) BPI12) Heparin

13) Antithrombin 14) C1H inhibitor

15) TFPI16) APC

17) NAPc218) rHDL

Clinical Research with anti-inflammatory or anti-coagulant agents for sepsis: Good ideas and preclinical data

36 novel agents for sepsis tested in

clinical trials: 32 no clear benefit; 3

worsened outcome; 1 +/- success (rhAPC), now

withdrawn

Anti-TNF immunoadhesin

0

10

20

30

40

50

60

placebo Low dose Mid dose High dose

placebo Low dose Mid dose High dose

P

FutureImmunomodulatoryApproaches

Blockinflammatorycytokinesbrieflyandearly Biomarkerdirected

Augmenthost(adaptive)immunitylate IL7

InducesproliferationofTcells IncreaseCD4andCD8Tcells Reverseslymphopenia Increasescelladhesionmolecules Decreasedsepsisinducedapoptosis

Newapproachestoimmunotherapy

Individualization Genome,proteometargetedtherapy

Focusedtargetingofimmuneresponse Biomarkers Timing Predominanceofinflammationorimmunesuppression


1) Treat very early and try to abort the process before immune suppression develops

2) Reverse immune depression after initial resuscitation and promote recovery

3) Tissue hibernation, mitochondrial sparing, repair pro-resolution and regeneration strategies

Can we rapidly determine the immune status of the patient and intervene appropriately?

Glucosecontrol

1. We recommend a protocolized approach to bloodglucose management in ICU patients with severesepsis, commencing insulin dosing when twoconsecutive blood glucose levels are >180 mg/dL.This protocolized approach should target an upperblood glucose < 180 mg/dL rather than an uppertarget blood glucose < 110 mg/dL (Grade 1A).

TheSurvivingSepsisCampaign

APerformanceImprovementInitiativeinSepsisUsingSepsisBundlestoImprove

Care

SSC Methodology: Multifaceted Intervention

National/regional/network launch meetings Identify local champions Introduce sepsis bundles Educational tools

SSC manual SSC slides

Staff support for coordinating sites Regular conference calls

Website SSC and IHI website Sepsis list-serve

Interactive database Automated uploading to SSC server Technical support Local audit and feedback capabilities

Change in Compliance Over Time

Levy MM et al. CCM 38(2):367-374, February 2010.

Change in Mortality Over Time

Levy MM et al. CCM 38(2):367-374, February 2010.

Surviving Sepsis Campaign:Data Analysis January 2005-

December 2009 First analysis:

2 years 15,000 pts January 2005-December 2006

Current analysis: 4 years 28,150 pts January 2005-December 2008

SSC: Demographics

Mortality: Site Quarter

Mortality over 4 year study period 36.7% to 27.5%

ARR: 9.2% RRR: 25.0%

P=0.005

SSC: Association between compliance

and Mortality

SEPSIS MORTALITY ON THE WARDS

IMPROVED MORTALITY WITH HIGHER COMPLIANCE

Whats Next?

The Surviving Sepsis Campaign:Government involvement

Sepsis metrics (from SSC) now approved by National Quality Forum (US)

New York State department of health programs CMS

Multiple sepsis projects

Conclusions: Complex,redundantmechanismsofinflammationandimmunesuppression Likelybalancebetweenhyperimmuneresponseand

prolongedimmunesuppression

Earlyidentificationofsepsisiskeytotherapy

Rapidadministrationofappropriateantibiotics Early,aggressiveresuscitation Alltrialsforimmunotherapyhavefailed Therearenonewagentsforsepsis Increasedcompliancewithperformancemetricsisassociatedwithimprovedsurvival

The Management of Sepsis: Whats New in 2013 DisclosuresProjected Incidence of Severe Sepsis in the US: 2001-2050PathophysiologySepsis as Cytokine StormSlide Number 6Slide Number 7Slide Number 8Genomic StormCARSImmunosuppressionImmunosuppression theorySlide Number 13Slide Number 14Slide Number 15Diagnosis of SepsisHow Do We Identify Septic Patients?SSC Interactive DatabaseSepsis ManagementSurviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2012Current Surviving Sepsis Campaign Guidelines SponsorsDiagnosisInitial ResuscitationInitial ResuscitationAntibiotic therapyRelationship between Shock, Anitibotic Timing, and MortalityHospital Mortality by Time to AntibioticsTime to Antibiotics: Wards vs. EDAntibiotic therapyFluid therapyFluid therapyVasopressorsCorticosteroidsLicensed Therapeutic Agents for SepsisRecent Failed Clinical Trials in SepsisClinical Research with anti-inflammatory or anti-coagulant agents for sepsis: Good ideas and preclinical dataFuture Immunomodulatory ApproachesNew approaches to immunotherapySlide Number 39Glucose controlThe Surviving Sepsis CampaignA Performance Improvement Initiative in Sepsis Using Sepsis Bundles to Improve Care SSC Methodology: Multifaceted InterventionChange in Compliance Over TimeChange in Mortality Over TimeSurviving Sepsis Campaign:Data Analysis January 2005-December 2009SSC: DemographicsMortality: Site QuarterSSC: Association between compliance and MortalitySEPSIS MORTALITY ON THE WARDSIMPROVED MORTALITY WITH HIGHER COMPLIANCEWhats Next?The Surviving Sepsis Campaign:Government involvementConclusions:

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