from outreach team to treatment in the icu - frontpage sepsis for anesthesiologists.pdf · • my...

Surviving SepsisSurviving SepsisFrom outreach team to treatment in the ICUFrom outreach team to treatment in the ICU

Armand R.J. GirbesArmand R.J. GirbesProfessor in Intensive Care MedicineProfessor in Intensive Care Medicine

Clinical PharmacologistClinical PharmacologistVU medical centerVU medical center

Amsterdam, NLAmsterdam, NL

Surviving SepsisSurviving SepsisFrom outreach team to treatment in the ICUFrom outreach team to treatment in the ICU

•• What you (probably) expectWhat you (probably) expect

–– Clear explication of SSCClear explication of SSC–– Know all the factsKnow all the facts–– Practical informationPractical information

Surviving sepsis campaignSurviving sepsis campaign

•• My presentationMy presentation

–– Basics IC treatment sepsisBasics IC treatment sepsis–– Key points SSCKey points SSC–– Key points I disagree with Key points I disagree with –– Key trials in sepsis treatment (disappointingKey trials in sepsis treatment (disappointing……))

–– But also But also ““Towards a higher level of confusionTowards a higher level of confusion””

Presentation available at: Presentation available at: www.ArmandGirbes.comwww.ArmandGirbes.com

Sepsis Sepsis -- definitiondefinition

SepsisSepsis

•• EpidemiologyEpidemiology–– 5050--95 cases per 100,000 per year95 cases per 100,000 per year

•• 9% increase per year !9% increase per year !–– 2% hospital admissions2% hospital admissions

•• 9% severe sepsis & septic shock9% severe sepsis & septic shock= 10% of all ICU admissions= 10% of all ICU admissions

–– peak in 6th decade of lifepeak in 6th decade of life–– No 3 in death cause No 3 in death cause –– underestimated !!underestimated !!

Epidemiology of sepsis in GermanyEpidemiology of sepsis in Germany

•• Main pointsMain points–– ProspectiveProspective--observational cross sectional 1observational cross sectional 1--day point prevalence day point prevalence

studystudy–– 454 ICU454 ICU’’s in 310 stratified representative hospitalss in 310 stratified representative hospitals–– Screened patients: N = 3877Screened patients: N = 3877

•• 12.4% sepsis 12.4% sepsis –– 11% severe sepsis11% severe sepsis•• Hospital mortality of severe sepsis = 55%Hospital mortality of severe sepsis = 55%

–– EstimatedEstimated•• Incidence: 85 Incidence: 85 –– 76 cases per 100,000 per year76 cases per 100,000 per year

–– Data from longitudinal survey in 371 patients: incidence 110 casData from longitudinal survey in 371 patients: incidence 110 caseses

SepsisSepsis

•• Epidemiology Epidemiology -- CausesCauses–– chestchest–– abdomenabdomen–– genitourinary systemgenitourinary system–– primary bloodstreamprimary bloodstream

–– rate pneumonia/rate pneumonia/bacteraemiabacteraemia/multiple site infection /multiple site infection

80% of all causes80% of all causes

Main pathogens in sepsisMain pathogens in sepsis

Increased knowledge of mechanismIncreased knowledge of mechanism

SepsisSepsis

•• Key elementsKey elements

–– diffuse endovascular injurydiffuse endovascular injury–– aberrant release of proaberrant release of pro--inflammatory cytokinesinflammatory cytokines–– procoagulantprocoagulant response / response / dysregulateddysregulated coagulationcoagulation

–– apoptosisapoptosis

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• PracticalPractical–– Patient 63 years, 75 kgPatient 63 years, 75 kg

•• Urgent admission Urgent admission –– peritonitisperitonitis•• BP 90/60 mm HgBP 90/60 mm Hg HR 118/minHR 118/min•• RR 30 breaths/min, mask 100% OxygenRR 30 breaths/min, mask 100% Oxygen•• Sick, cardiac murmur grade II 2RSick, cardiac murmur grade II 2R•• Laboratory Na 142; K 4.9; Urea 14Laboratory Na 142; K 4.9; Urea 14 ↑↑; ; CreatCreat 170 170 ↑↑; ; HbHb 9 9 mmol/lmmol/l; ;

TransaminasesTransaminases: N; WBC : N; WBC ↑↑↑↑, Platelets , Platelets ↓↓•• Chest XChest X--ray: ray: ……....•• Other?Other? BGABGA

ClottingClotting

LactateLactate

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• What to do?What to do?–– Fluid resuscitationFluid resuscitation–– IntubationIntubation–– InotropesInotropes –– which ones? (Hemodynamic) goals?which ones? (Hemodynamic) goals?–– Steroids? Steroids? –– Antibiotics? Which ones?Antibiotics? Which ones?

–– SOURCE CONTROLSOURCE CONTROL•• SurgeonSurgeon

PatientPatient

•• Sigmoid perforationSigmoid perforation with fecal disseminationwith fecal dissemination

–– Sigmoid resection, A.P.Sigmoid resection, A.P.–– Abdominal rinsingAbdominal rinsing

•• Treatment Treatment startsstarts in ER and is in ER and is continuedcontinued in ORin OR–– And And then continuedthen continued in the intensive care unit !!in the intensive care unit !!

QuestionQuestion

•• What is the evidence?What is the evidence?–– FluidsFluids–– InotropesInotropes–– Pulmonary Artery catheterPulmonary Artery catheter–– SteroidsSteroids–– Activated Protein CActivated Protein C

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• Surviving Sepsis CampaignSurviving Sepsis Campaign–– WWW.survivingsepsis.orgWWW.survivingsepsis.org

–– Effort to reduce mortality due to sepsisEffort to reduce mortality due to sepsis•• EBM approachEBM approach

–– Not totally successful Not totally successful ……–– Good & helpful effortGood & helpful effort

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• Importance of BASICSImportance of BASICS–– Recognize sepsisRecognize sepsis–– Do appropriate diagnosticsDo appropriate diagnostics–– Start early treatment Start early treatment –– do not waitdo not wait–– Treat first what kills firstTreat first what kills first–– Source controlSource control–– Do not harmDo not harm–– Better is the enemy of goodBetter is the enemy of good

•• Enough is what is needed, which is enoughEnough is what is needed, which is enough

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• Recognition of sepsisRecognition of sepsis•• You see only what you look for and recognize only what you knowYou see only what you look for and recognize only what you know

–– HypothermiaHypothermia–– Delirium / confusionDelirium / confusion–– OliguriaOliguria

–– LasixLasix signsign–– Haloperidol signHaloperidol sign

Can be a (early) sign of sepsisCan be a (early) sign of sepsis

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• Sepsis resuscitation bundleSepsis resuscitation bundle–– Measure serum lactateMeasure serum lactate–– Obtain Obtain bloodculturesbloodcultures prior to AB treatmentprior to AB treatment–– Administer AB within 1 hour (ASAP)Administer AB within 1 hour (ASAP)–– In case of hypotension In case of hypotension [or signs of organ [or signs of organ hypoperfusionhypoperfusion]]

•• Fluid administrationFluid administration•• VasopressorsVasopressors

–– ScvOScvO22 > 70%> 70%

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• Amazing !Amazing !–– It is better to start early treatment in case of severe illnessIt is better to start early treatment in case of severe illness

•• Problem !Problem !–– Design:Design:

•• Different group of doctors for both groupsDifferent group of doctors for both groups

•• ProblemProblem–– Only 1 study in 1 center by 1 investigator with a patentOnly 1 study in 1 center by 1 investigator with a patent

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• Correct early antibiotics do matter!!Correct early antibiotics do matter!!

P<0.001P<0.001

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• Fluid resuscitationFluid resuscitation–– No difference for crystalloids versus colloidsNo difference for crystalloids versus colloids–– No advantage for HESNo advantage for HES

•• Evidence for induction of renal failureEvidence for induction of renal failure•• ItchItch

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• VasopressorsVasopressors

–– No evidence for No evidence for ““best best inotropeinotrope in sepsisin sepsis””–– No good RCT No good RCT –– will never be there !will never be there !–– Norepinephrine + dobutamine good combinationNorepinephrine + dobutamine good combination

•• Rationale Rationale –– based on based on ““soft endpointssoft endpoints””

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• VasopressorsVasopressors–– How to use?How to use?

•• Goal directedGoal directed•• Sufficient is enoughSufficient is enough•• Knowledge of hemodynamic diagnosisKnowledge of hemodynamic diagnosis•• Knowledge of pharmacological propertiesKnowledge of pharmacological properties

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• SteroidsSteroids–– Discussion / debate continuesDiscussion / debate continues–– Reduces need for vasoactive drugsReduces need for vasoactive drugs–– Population with benefit: not well defined yetPopulation with benefit: not well defined yet–– SSC: steroids SSC: steroids -- yesyes–– Published positive studiesPublished positive studies

•• Single group (Single group (AnnaneAnnane))•• Publication biasPublication bias

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• Blood transfusionBlood transfusion–– If If HbHb < 6 < 6 mmol/lmmol/l

•• Low Low HbHb not goodnot good•• High High HbHb not goodnot good

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• Glucose regulationGlucose regulation–– Treat high glucoseTreat high glucose–– Optimum not known Optimum not known –– strict & risk for hypoglycemiastrict & risk for hypoglycemia–– Studies vd Studies vd BergheBerghe (NEJM) (NEJM) 4.44.4--6.1 versus > 12 6.1 versus > 12 mmol/lmmol/l

•• Not confirmed by other studiesNot confirmed by other studies

–– SSC: glucose 4.4 SSC: glucose 4.4 -- 8.3 8.3 mmol/lmmol/l

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• Stress ulcer prophylaxisStress ulcer prophylaxis–– Advised by SSC.Advised by SSC.

•• Not based on recent studiesNot based on recent studies•• Ranitidine increases risk on VAPRanitidine increases risk on VAP

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• SDDSDD–– Not advised in SSC despite many RCTNot advised in SSC despite many RCT–– Unjustified considering the dataUnjustified considering the data

•• and amazing !and amazing !

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• Drotrecogin alpha [aPC, Drotrecogin alpha [aPC, XigrisXigris®®]]–– Advised by SSCAdvised by SSC–– Dutch guidelines on aPCDutch guidelines on aPC–– Proven effective in RCTProven effective in RCT

•• But only 1 trialBut only 1 trial

Drug intervention trials in Drug intervention trials in (severe) Sepsis(severe) Sepsis

•• Since 1980sSince 1980s–– Drug intervention trialsDrug intervention trials

•• modify endotoxin releasemodify endotoxin release•• inhibition of inhibition of proinflammatoryproinflammatory cytokinescytokines

•• > 80 trials> 80 trials

Phase III trials in severe sepsisPhase III trials in severe sepsis

•• PatternPattern–– Positive phase II studiesPositive phase II studies–– No dose finding studiesNo dose finding studies–– (Relative) large phase III studies(Relative) large phase III studies

Negative findingsNegative findings

Phase III trials in severe sepsisPhase III trials in severe sepsis

•• Modification of endotoxin releaseModification of endotoxin release

•• Inhibition of Inhibition of proinflammatoryproinflammatory cytokinescytokines

•• Inhibition of plateletInhibition of platelet--activatingactivating--factor factor inflammatory pathwayinflammatory pathway

FailureFailure

FailureFailure

FailureFailure

Phase III trials in severe sepsisPhase III trials in severe sepsis

•• Explanation for failuresExplanation for failures–– Misconception & limitation of underlying modelsMisconception & limitation of underlying models

•• Targeting single steps is inappropriateTargeting single steps is inappropriate•• OversimplificationOversimplification•• Animal model incorrect Animal model incorrect [e.g. wrong animal; single exposure [e.g. wrong animal; single exposure i.oi.o. continuous]. continuous]

–– Difference in timing in experimental modelsDifference in timing in experimental models•• Too late administrationToo late administration

–– Inappropriate modelsInappropriate models•• E.g. infusion of endotoxinE.g. infusion of endotoxin

–– Inappropriate doseInappropriate dose•• Dose finding studies in general lackingDose finding studies in general lacking

–– Insufficient attention to role of concomitant treatmentInsufficient attention to role of concomitant treatment

Phase III trials in severe sepsisPhase III trials in severe sepsis

Polderman & Girbes, Lancet 2004

Phase III trials in severe sepsisPhase III trials in severe sepsis

DIC important in sepsisDIC important in sepsis•• Natural anticoagulant proteinsNatural anticoagulant proteins

•• AT IIIAT III•• Protein CProtein C•• Tissue Factor Pathway InhibitorTissue Factor Pathway Inhibitor

–– Levels decrease during sepsisLevels decrease during sepsis–– Tempting target for interventionTempting target for intervention

•• Highly promising preliminary resultsHighly promising preliminary results•• Only aPC positive resultOnly aPC positive result

Phase III trials in severe sepsisPhase III trials in severe sepsis

Phase III trials in severe sepsisPhase III trials in severe sepsis

Activated protein C Activated protein C vs. placebo in phase III vs. placebo in phase III study on mortality and bleeding study on mortality and bleeding

Mortality Severe bleeding

rhAPC 210/850 (24.7%) 30/850 (3.5%)Placebo 259/840 (30.8%) 17/840 (2%)

RR 80.6% RR 175%RRR 19.4% RRR -75%ARR 6.1% ARR -1.5%NNT 16 NNT 66

ENHANCE DrotA(a)EVAD DrotA(a)EVAD Placebo

Sur

viva

l (%

)

60

70

80

90

100

Days After the Start of the Infusion0 7 14 21 28

PROWESS & ENHANCEPROWESS & ENHANCE

PROWESS DrotAA(24.7% mortality)

ENHANCE DrotAA(25.3% mortality)

PROWESS Placebo (30.8% mortality)

APC longAPC long--term effectterm effect

LongLong--term effectterm effect

aPC trialaPC trial

•• ProblemsProblems–– Changed protocol halfwayChanged protocol halfway

•• Inclusion criteriaInclusion criteria•• Change of drug Change of drug ““vehiculumvehiculum””

–– Possible interaction with heparinPossible interaction with heparin–– Effect ONLY in 2Effect ONLY in 2ndnd part of the studypart of the study–– Inclusion prematurely stopped Inclusion prematurely stopped (because of efficacy)(because of efficacy)

–– Only one study; No confirmatory study doneOnly one study; No confirmatory study done

Effects of heparin in Sepsis trialsEffects of heparin in Sepsis trials

Polderman & Girbes, Lancet 2004

Problems in aPC trialProblems in aPC trial

16901690970970480480490490720720360360360360

TotalTotal

P=0.0012P=0.0012150 (31)150 (31)PlaceboPlacebo108 (22)108 (22)rhAPCrhAPCAmendedAmended

P=0.5665P=0.5665109 (30)109 (30)Placebo Placebo 102 (28)102 (28)rhAPCrhAPCOriginalOriginal

Died by Day Died by Day 2828

TherapyTherapyStrataStrata

aPC in less severe sepsisaPC in less severe sepsis

aPC in less severe sepsisaPC in less severe sepsis

N=2613

Severe sepsis trial designSevere sepsis trial design

•• Like in myocardial infarction?Like in myocardial infarction?•• Like in cancer trials?Like in cancer trials?•• Like in hypertension trials?Like in hypertension trials?•• Like in osteoporosis trials?Like in osteoporosis trials?

ICU trials require different approach ICU trials require different approach

ICUICU

•• Mortality depends onMortality depends on

–– ICU organization ICU organization •• intensivist drivenintensivist driven•• 24/24 and 7/7 presence24/24 and 7/7 presence•• nurse density [fte per ICU bed]nurse density [fte per ICU bed]•• size / volume size / volume -- experienceexperience

Effect of ICUEffect of ICU

Sepsis trials in the ICUSepsis trials in the ICU

•• Centers include only 1 or 2 patientsCenters include only 1 or 2 patients•• No attention paid to No attention paid to ““concomitant treatmentconcomitant treatment””

–– ICU organizationICU organization–– different SMR different SMR (mortality corrected for severity of disease)(mortality corrected for severity of disease)

–– antibiotics and infectionantibiotics and infection•• timingtiming•• correct?correct?•• source controlsource control

–– early goal directed therapyearly goal directed therapy–– etc etc etcetc

Sepsis trials in the ICUSepsis trials in the ICU

Sepsis trials in the ICUSepsis trials in the ICU

Sepsis drug intervention trials in the ICUSepsis drug intervention trials in the ICU

•• Ongoing trialsOngoing trials–– EritoranEritoran (TLR 4 Lipid A antagonist)(TLR 4 Lipid A antagonist)–– Recombinant Human Antithrombin (+DIC)Recombinant Human Antithrombin (+DIC)–– GR270773 (proteinGR270773 (protein--free free phospholipidphospholipid emulsion binding endotoxinemulsion binding endotoxin–– TAKTAK--242242

Drug trials in sepsisDrug trials in sepsisCONCLUSIONS TRIALSCONCLUSIONS TRIALS

•• Sepsis is a complicated syndromeSepsis is a complicated syndrome•• All drug intervention trials negative, but oneAll drug intervention trials negative, but one

–– Is the model appropriate?Is the model appropriate?–– Do we jump to phase III too quicklyDo we jump to phase III too quickly

•• Trial designTrial design–– RCTRCT–– Patient inclusion criteriaPatient inclusion criteria

•• Source control YES or NO; antibioticsSource control YES or NO; antibiotics

Participating ICU inclusion criteria missingParticipating ICU inclusion criteria missing

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• ConclusionsConclusions–– Basics most importantBasics most important

•• Do simple things first and wellDo simple things first and well•• Early recognition, early Early recognition, early –– ““correctcorrect”” –– treatmenttreatment•• Source controlSource control

–– Organization of ICU importantOrganization of ICU important•• Quality directed organizationQuality directed organization•• Sufficient nursesSufficient nurses•• Sufficient intensivistsSufficient intensivists

SurvivingSurviving SepsisSepsisFromFrom outreachoutreach team to team to treatmenttreatment in the ICUin the ICU

•• Questions?Questions?

•• Presentation available at:Presentation available at:

www.ArmandGirbes.comwww.ArmandGirbes.com•• Document with links to several complete Document with links to several complete

papers for 3 weeks:papers for 3 weeks:Password: NVAPassword: NVA