UpdateintheManagementof

Sepsis
MichaelA.Gropper,MD,PhD
ProfessorandExecutiveViceChair
DepartmentofAnesthesiaandPerioperativeCare
Director,CriticalCareMedicine
UCSF

Disclosure
IhavereceivedfundingfromtheNIHand
TheGordonandBettyMooreFoundation

 Consensuscommitteeof68internationalexperts
representing30internationalorganizations.
UsedbyCMS,TJC,othersforQIpurposes.

Changestoguidelines
Initialfluidresuscitationwithcrystalloid.The2008
guidelinesdidn'tspecifyapreferenceforcrystalloidvs.
colloidfluidresuscitation.
Norepinephrine asthefirstchoicevasopressorto
maintainmeanarterialpressure65mmHg.The2008
guidelinesdidn'tspecifyapreferencefor
norepinephrinevs.dopamine.
Avoidanceofneuromuscularblockers ifpossiblein
patientswithoutacuterespiratorydistresssyndrome
(ARDS)andashortcourse(48hours)of
neuromuscularblockersforpatientswithearlyARDS
andaPao2/Fio2 <150mmHg.The2008guidelines
suggestedblanketavoidanceofneuromuscular
blockersifpossible.
SurvivingSepsisGuidelines2012

Changestoguidelines
Aprotocolized approachtobloodglucose managementthat
startsinsulindosingwhentwoconsecutivebloodglucose
levelsare>180mg/dL andtargetsanupperbloodglucose
180mg/dL.The2008guidelinessuggestedtargetingablood
glucose<150mg/dL afterinitialstabilization.
Oralorenteral(ifnecessary)feedings,astolerated,rather
thaneithercompletefastingorprovisionofonlyintravenous
glucosewithinthefirst48hoursafteradiagnosisofsevere
sepsis/septicshock.The2008guidelinesdidn'tdiscuss
feedings.
Addressinggoalsofcare,suchastreatmentplansandendof
lifeplanningasappropriate,asearlyaspossible,butwithin
72hoursofICUadmission.The2008guidelinesdidn'tspecify
atimeperiodforadvancecareplanning.
SurvivingSepsisGuidelines2012

DiagnosticCriteria
Sepsis(documentedorsuspectedinfectionplus1ofthefollowing)
Fever(coretemperature,>38.3C)
Hypothermia(coretemperature,<36C)
Elevatedheartrate(>90beatsperminor>2SDabovetheupperlimitofthe
normalrangeforage)
Tachypnea
Alteredmentalstatus
Substantialedemaorpositivefluidbalance(>20ml/kgofbodyweightovera24
hrperiod)
Hyperglycemia(plasmaglucose,>120mg/dl[6.7mmol/liter])intheabsenceof
diabetes
Inflammatoryvariables
Leukocytosis(whitecellcount,>12,000/mm3)
Leukopenia(whitecellcount,<4000/mm3)
Normalwhitecellcountwith>10%immatureforms
ElevatedplasmaCreactiveprotein(>2SDabovetheupperlimitofthenormal
range)
Elevatedplasmaprocalcitonin (>2SDabovetheupperlimitofthenormalrange)

SurvivingSepsisGuidelines2012

DiagnosticCriteria
Hemodynamicvariables
Arterialhypotension(systolicpressure,<90mmHg;
meanarterialpressure,<70mmHg;ordecreasein
systolicpressureof>40mmHginadultsorto>2SD
belowthelowerlimitofthenormalrangeforage)
Elevatedmixedvenousoxygensaturation(>70%)
Elevatedcardiacindex(>3.5liters/min/square
meterofbodysurfacearea)
SurvivingSepsisGuidelines2012

Organdysfunctionvariables
Arterialhypoxemia(ratioofthepartialpressureofarterialoxygento
thefractionofinspiredoxygen,<300)
Acuteoliguria(urineoutput,<0.5ml/kg/hr or45ml/hr foratleast2
hr)
Increaseincreatinine levelof>0.5mg/dl(>44mol/liter)
Coagulationabnormalities(internationalnormalizedratio,>1.5;or
activatedpartialthromboplastin time,>60sec)
Paralyticileus(absenceofbowelsounds)
Thrombocytopenia(plateletcount,<100,000/mm3)
Hyperbilirubinemia (plasmatotalbilirubin,>4mg/dl[68mol/liter])
Tissueperfusionvariables
Hyperlactatemia (lactate,>1mmol/liter)
Decreasedcapillaryrefillormottling

Severesepsis(sepsisplusorgandysfunction)
Septicshock(sepsispluseitherhypotension[refractoryto
intravenousfluids]orhyperlactatemia).

LeveragingtheEHR

LeveragingtheEHR

LeveragingtheEHR

LeveragingtheEHR

Resuscitation
Begingoaldirectedresuscitationwithcrystalloidduringfirst6hr
afterrecognition
Considertheadditionofalbumin whensubstantialamountsof
crystalloidarerequiredtomaintainadequatearterialpressure
Avoidhetastarch formulations
Begininitialfluidchallengeinpatientswithtissuehypoperfusion
andsuspectedhypovolemia,toachieve30mlofcrystalloidsper
kilogramofbodyweight
Continuefluidchallengetechniqueaslongasthereis
hemodynamicimprovement
Usenorepinephrineasthefirstchoicevasopressortomaintaina
meanarterialpressureof65mmHg
Useepinephrinewhenanadditionalagentisneededtomaintain
adequatebloodpressure
Addvasopressin(atadoseof0.03units/min)withweaningof
norepinephrine,iftolerated
SurvivingSepsisGuidelines2012

Resuscitation(cont)
Avoidtheuseofdopamineexceptincarefullyselectedpatients(e.g.,
patientswithalowriskofarrhythmiasandeitherknownmarkedleft
ventricularsystolicdysfunctionorlowheartrate)
Infusedobutamine oraddittovasopressortherapyinthepresence
ofmyocardialdysfunction(e.g.,elevatedcardiacfillingpressuresor
lowcardiacoutput)orongoinghypoperfusion despiteadequate
intravascularvolumeandmeanarterialpressure
Avoidtheuseofintravenoushydrocortisoneifadequatefluid
resuscitationandvasopressortherapyrestorehemodynamicstability;
ifhydrocortisoneisused,administeratadoseof200mg/day
Targetahemoglobinlevelof7to9g/dlinpatientswithout
hypoperfusion,criticalcoronaryarterydiseaseormyocardial
ischemia,oracutehemorrhage
SurvivingSepsisGuidelines2012

Fluids:CrystalClear
2013guidelinesrecommendinitialfluid
resuscitationwithcrystalloid.The2008
guidelinesdidn'tspecifyapreferencefor
crystalloidvs.colloidfluidresuscitation.

VascularPermeability

Which Fluid Should We Use for Resuscitation?

Randomized,prospectivetrialof4%albumin
versusnormalsalineforfluidresuscitation
6997patientsrandomized
Primaryoutcomewas28daymortality NEJM2004

AlbuminvsSaline
SAFEStudy:NEJM,2004
Prospective,randomizedstudyof6997patients
Objectiveneed(one):tachycardia,hypotension,lowPCWP,low
UrineOutput
Normalsalinevs4%albuminforresuscitation
Allothermanagementthesame
Primaryoutcome:28dmortality
Secondaryoutcomes:Survivaltime,neworganfailures,duration
ofmechanicalventilation,ICULOS

AlbuminvsSaline
SAFEStudy:NEJM,2004

AlbuminvsSaline
SAFEStudy:NEJM,2004

Crit CareMed2011:39

DoesColloidResuscitationImproveOutcomes?

Crit CareMed2011:39

Nostarch,please.

CrystalloidvsColloidResuscitation

Randomized, 2x2 trial of IIT and Pentastarch Resuscitation

Stopped at interim analysis because of increased mortality in
IIT group
Brunkhorst etal,NEJM2008

CrystalloidvsColloidResuscitation

Brunkhorst etal,NEJM2008

Multicenter,parallelgroup,randomizedblindedtrial
804patientswithseveresepsis
Randomizedto6%HES130/0.42orRingersacetate
Primaryoutcomewasdeathorendstagekidneyfailure
(RIFLEE)at90d
NEngl JMed2012;367:12434.

NEngl JMed2012;367:12434.

Crystalloidvs Colloid

NEngl JMed2012;367:12434.

Norepinephrine
Norepinephrineasthefirstchoice
vasopressortomaintainmeanarterial
pressure65mm.The2008guidelines
didn'tspecifyapreferencefor
norepinephrinevs.dopamine.

 Multicenter,randomizedtrialincluding1679patientsinseptic
shock
Randomizedtodopamineornorepinephrine
Ifstillhypotensiveafter20mcg/kg/mindopamineor0.19
mcg/kg/minnorepi,openlabelnorepi,epi,orvasopressincouldbe
added.
Primaryendpointwas28daymortality

Dopaminevs Norepinephrine

NEngl JMed2010;362:77989.

Dopaminevs Norepinephrine

NEngl JMed2010;362:77989.

AdverseEvents
Dopamine

Norepi

NEngl JMed2010;362:77989.

 Openlabel,randomizedtrialofheartratecontrolin
patientswithsepticshock
154patientsrandomizedtoHRcontrol(8094bpm)
withesmolol vs usualcare
PrimaryoutcomewasHRcontrol
Secondaryoutcomeshemodynamic,organfunction
measures,norepinephrinedose,mortality
Morelli etal,JAMA2013

StudyProtocol
24hoursofhemodynamicoptimization
PAOP> 12mmHgandCVP> 8mmHg
SvO2> 65%
MAP> 65mmHg

Patientsenrolledifstillrequiringnorepinephrine
andHRremains> 95bpm
Allpatientsgivenhydrocortisone300mg/d
Levosimendan (noradrenergicCa sensitizer)given
ifSvO2remainedlowinspiteoftransfusion
Morelli etal,JAMA2013

Morelli etal,JAMA2013

Morelli etal,JAMA2013

Survival

Morelli etal,JAMA2013

SteroidMetaanalysis

JAMA2009

Steroids:28dayMortality

Steroids:ShockReversal

Respiratorysupport
Usealowtidalvolumeandlimitationofinspiratoryplateau
pressurestrategyforARDS
Applyaminimalamountofpositiveendexpiratorypressurein
ARDS
Administerhigherratherthanlowerpositiveendexpiratory
pressureforpatientswithsepsisinducedARDS
Userecruitmentmaneuversinpatientswithsevererefractory
hypoxemiaduetoARDS
UsepronepositioninginpatientswithsepsisinducedARDSand
aratioofthepartialpressureofarterialoxygen(mmHg)tothe
fractionofinspiredoxygenof<100,infacilitiesthathave
experiencewithsuchpractice
Elevatetheheadofthebedinpatientsundergoingmechanical
ventilation,unlesscontraindicated
Useaconservativefluidstrategyforestablishedacutelunginjury
orARDSwithnoevidenceoftissuehypoperfusion
Useweaningprotocols

AvoidLateUseofNeuromuscular
Blockers
Avoidance ofneuromuscularblockersif
possibleinpatientswithoutacute
respiratorydistresssyndrome(ARDS)anda
shortcourse (48hours)ofneuromuscular
blockersforpatientswithearlyARDSanda
Pao2/Fio2 <150mmHg.The2008
guidelinessuggestedblanketavoidanceof
neuromuscularblockersifpossible.

 Multicenter, double-blind trial of 340 patients with early-onset,

severe ARDS
Randomized to cisatracurium or placebo
All other management identical
Primary outcome was 90-day mortality
NEnglJMed2010;363:110716.

Cisatracurium
(N=177)

Placebo
(N=162)

RRwithCisatracurium
(95%CI)

PValue

42%
52%
57%

54%
63%
67%

0.71(0.511.00)
0.76(0.561.02)
0.78(0.591.03)

0.05
0.06
0.08

VentFree Days
(D1D90)

53.1+35.8

44.6+37.5

0.03

Days withoutany
organfailure

15.8+ 9.9

12.2+ 11.1

0.01

9(5.1[2.79.4])

19(11.7[7.617.6])

0.43(0.200.93)

0.03

7(4.0[2.08.0])

19(11.7[7.617.6])

0.34(0.150.78)

0.01

72/112
(64.3[55.172.6])

61/89
(68.5[58.377.3])

Outcome

Mortality
28D
ICU
Hospital

Barotrauma
N(%[RR})

Pneumothorax
N(%[RR})

Days withoutICU
acquiredparesis
N(%[RR})

0.51
NEngl JMed2010;363:110716.

NEngl JMed2010;363:110716.

PronePositioning

Prone Positioning

Supine

Prone

PronePositioning:Metaanalysis

Abroug etal,Crit Care.2011

PROSEVATrial

PROSEVA:Protocol
474pts randomized
Doseofproning:
Within55minutesof
randomization
PPdailydurationof17+
3hours

Allpatientsventilated
withlungprotective
strategy

Criteriaforcessationof
PP:

P/F> 150
PEEP< 10
FiO2< 0.6
Allcriteriapersistat
least4hoursinsupine
position

Guerinetal,NEJM2013

Survival

Guerinet
al,NEJM
2013

PronePositioning:Recommendation
PROSEVAmoreeffectivethanpreviousstudies
Morecomplicationsthanexpectedinsupine
group(13%incidencecardiacarrest)
Highlyexperiencedcenters:noadverseevents
withproning
WatchvideoatNEJM.org

MostpatientsreceivedNMBs

Guerinetal,NEJM2013

 Multicenter,randomized,controlledtrial
548patients39ICUsin5countries
HFOVvs PCV(48ml/kg)
Fergusonetal,NEJM.2013

HFOV
(N=275)

Control
N=273

RelativeRisk
(95%CI)

PValue

Deathin
hospital

129(47%)

96(35%)

1.33(1.091.64)

0.005

DeathinICU

123(45%)

84(31%)

1.45(1.171.81)

0.001

Barotrauma

46/256(18%)

34/259(13%)

1.37(0.912.06)

0.13

Refractory
hypoxemia

19(7%)

38 (14%)

0.50(0.290.84)

0.007

Refractory
acidosis

9(3%)

8(3%)

1.12(0.442.85)

0.82

ICULOS(D)

15

14

0.93

0.93

Hosp LOS(D)

30

25

0.74

0.74

Outcome

Fergusonetal,NEJM.2013

 Multicenter,randomized,controlledtrialcomparing
HFOVtousualventilatorcare
800Patientsrandomizedin29hospitals

Youngetal,NEJM.2013

OSCARTrial

OSCARvs OSCILLATE
Differentoscillators
Differentalgorithmsforadjustment:
Meanairwaypressureinoscillatorarm:
OSCILLATE:31+ 2.6cmH2O
OSCAR::27+ 6.2cmH2O

Differentventilationincontrolgroups
Controlmortality:
35%inOSCILLATE
41%inOSCAR

WaveringonOscillation?
Takentogether,nobenefit,potentialharm
withHFOVinARDS
Negativeeffectsmaybedueto:
Ventilatorassociatedlunginjury
?Highervasopressor,fluid,sedatives

ControlarmnotARDSnet protocol

Centralnervoussystemsupport
Generalsupportivecare
Usesedationprotocols,targetingspecificdoseescalationendpoints
AvoidneuromuscularblockersifpossibleinpatientswithoutARDS
Administerashortcourseofaneuromuscularblocker(<48hr)forpatients
withearly,severeARDS
Useaprotocolspecifiedapproachtobloodglucosemanagement,withthe
initiationofinsulinaftertwoconsecutivebloodglucoselevelsof>180
mg/dl(10mmol/liter),targetingabloodglucoselevelof<180mg/dl
Usetheequivalentofcontinuousvenovenous hemofiltrationor
intermittenthemodialysisasneededforrenalfailureorfluidoverload
Administerprophylaxisfordeepveinthrombosis
Administerstressulcerprophylaxistopreventuppergastrointestinal
bleeding
Administeroralorenteralfeedings,astolerated,ratherthaneither
completefastingorprovisionofonlyintravenousglucosewithinthefirst
48hr afteradiagnosisofseveresepsisorsepticshock
Addressgoalsofcare,includingtreatmentplansandendoflifeplanningas
appropriate

EnteralNutrition
Oralorenteral(ifnecessary)feedings,as
tolerated,ratherthaneithercomplete
fastingorprovisionofonlyintravenous
glucosewithinthefirst48hoursaftera
diagnosisofseveresepsis/septicshock.
The2008guidelinesdidn'tdiscuss
feedings.

 Randomized,openlabel,multicentertrialoftrophicvs fullenteral
feedingsforthefirst6days,startedwithin48hoursofintubation
andmechanicalventilation
Afterday6,receivedfullenteralfeedings
Primaryoutcomewasventilatorfreedays
JAMA2012

Trophicvs FullFeeding

JAMA2012

Trophicvs FullFeeding

JAMA2012

 821MedicalandSurgicalICUpatientsinobservational
study
Inhospitaldeliriumassessment,globalcognition,and
executivefunctiontesting
Reassessedat3and12months
Pandharipande etal,
74%hadinhospitaldelirium
NEJM2013

BRAINICU

Pandharipande etal,
NEJM2013

GlobalCognitionat12months

Pandharipande etal,
NEJM2013

ChangingICUCulture:Getoutofbed!
EarlyMobilization
Criticallyillpatientsrapidlydevelop
weakness
Diaphragmatrophy
Proteincaloriemalnutrition
Difficultyweaningfrommechanical
ventilation
Pressureulcers
Deepvenousthrombosis

Longtermfunctionalstatusimplications
Lipshutz and Gropper, Anesthesiology, 2012

RiskFactors

Lipshutz and Gropper, Anesthesiology, 2012

CriticalIllnessMyopathy

Puthucheary etal,JAMA2013

CriticalIllnessMyopathy

Puthucheary etal,JAMA2013

Functional Status One Year Later

Sacanella etal.Crit Care.2011

RandomizedControlTrial:104patientson
mechanicalventilation
InterventionGroup:PTmedianof1.5dayspostintubation
ControlGroup:PTmedianof7.4dayspostintubation

Schweickert etal,Lancet2009

ImplementingEarlyMobilization
Earlydefinedasinitialphysiologic
stabilization,continuingthroughoutICUstay
Initiatingpatientmobilizationwithin48hoursof
patientadmissiontotheICUthrough:
ICUculturalshift,mobilityasnecessity
PracticepatternsofICUpersonnelacross
disciplines
OptimizingtheICUenvironment
Equipment
Sleep
Sedation
EngelH,Needham,DM,MorrisPE,
Gropper,MA.Crit CareMed,2013

StaffingandEquipment
UCSF:OnefulltimePT
added
NoadditionalRNorRT
staff
ICUplatformwalker,
earplugs,eyemasks,
seatingcushions
PTsmobilizepatients
tohigherlevelthanRNs

Conclusions
ThenewSurvivingSepsisGuidelinesinclude
significantchanges:
Usecrystalloidforresuscitation
Norepinephrineforbloodpressuresupport
Avoidlateuseofneuromuscularblockers
Considerrecruitmentmaneuversandprone
positioninginrefractoryhypoxemia
Oralfeedingsastolerated
Targetglucose< 180mg/dl

Instituteearlyambulation
Considerlongtermeffectsofcriticalillness