Clinicaldecision-makinginED:shock

Somefactyourepidemiologisthasnottoldyou

Kuan-FuChen,MDPhD
Thislecturewasdesignedfor
Emergencyphysicianswhowouldliketo
KnowmoreaboutuidresuscitaEon
Learnsomejargoninclinicalresearch
TrytheaudienceinteracEveresponsesystem
Avoidothersessionsatthispoint
Justsitdownandgetsomerest
6/24/12 Kuan-FuChenSEMTW2012 2
Q0.
1. (R1-2)
2. (R3-5)
3. (<V6)
4. (>V5)
5.
6/24/12 Kuan-FuChenSEMTW2012 3
Q1.Whatwouldyourelyon
dailypracEce?
1. Previousexperience
2. ScienEctheory
3. Expertopinion
4. LatestRCTs
5. Latestguidelines
6. PaEents/familyspreference
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Whydoweneedevidence?
Experiencenotbe`erthanevidence?
CumulaEvewisdom?
Evidencereallyreliable?
Dowehavecapabilitytoevaluateevidence?
ResponsibleforadapEngprematureevidence?
6/24/12 Kuan-FuChenSEMTW2012 5
Scenario
48F,visitedEDowingtodyspneafordays
Noknowpasthistory
Hashistoryofstomachuabout2wksago
Withalteredmentalstatus
Vitals@Triage
BT:39.4,HR:122,RR:32
BP:89/43,SpO2:79%
Fingersugar:HI
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Q2.
1. Pentastarch(HAES-steril)10%500mlstat
2. Pentastarch(HAES-steril)6%500mlstat
3. Albumin20%100mlstat
4. Albumin5%500mlstat
5. Dextran500mlstat
6. GelaEn500ml/btl
7. Bloodproducts:PRBCorFFP
8. Normalsaline500ccstat
9. LactateRingerssoluEon500ccstat
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Colloids
ContainparEclesnotcrosssemi-permeable
membranes
StaysalmostenErelywithinintravascularspace
(iniEally)
Stayintravascularforaprolongedperiod
comparedtocrystalloids
leakoutofintravascularspace
whenthecapillarypermeabilitysignicantlychanges
e.g.Severetraumaorsepsis
GoldstandardforIVresuscitaEonunElrecently
GelaEnousproperEes
CauseplateletdysfuncEon
InterferewithbrinolysisandcoagulaEonfactors
Cancausesignicantcoagulopathyinlargevolumes
6/24/12 Kuan-FuChenSEMTW2012 8
Colloids
Types
Albumin:e.g.4.5-5%,20-25%humanalbuminsoluEon
Dextran:e.g.6%Dextran70
GelaEn:e.g.3.5%polygeline(Haemaccel)
Hydroxyethylstarch:e.g.6%hetastarch(Elo-HAES,Hespan;Pentaspain,HAES-steril),
Uses
Maintenanceofplasmavolume
Acutereplacementofplasmavolumedecit.
Shorttermvolumeexpansion(gelaEn,dextran)
Mediumtermvolumeexpansion(albumin,pentastarch)
Longtermvolumeexpansion(hetastarch)
Sideeects
DiluEoncoagulopathy
Anaphylaxis
Interferencewithbloodcrossmatching(Dextran70)
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Crystalloids&colloids
Crystalloid Colloid
Intravascular persistance Poor Good
Haemodynamic stabilisation Transient Prolonged
Required infusion volume Large Moderate
Risk of tissue oedema Obvious Insignificant
Enhancement of capillary
perfusion
Poor Good
Risk of anaphylaxis Nil Low to moderate
Plasma colloid osmotic
pressure
Reduced Maintained
Cost Inexpensive Expensive
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Fluidshins/intakes
Intracellular
30liters
IntersEEal
9liters
IV3liters
KidneysGutsLungsSkin
Extracellularuid-12litres
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Crystalloids&colloids
30litres
9litres 3litres
2litersof
blood
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Crystalloids&colloids
30litres
9litres 5litres
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Crystalloids&colloids
30litres
9litres 3litres
2litersof
colloid
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Crystalloids&colloids
30litres
9litres 5litres
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Crystalloids&colloids
29litres
8litres 7litres
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Crystalloids&colloids
30litres
9litres 3litres
2litersof
0.9%saline
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Crystalloids&colloids
30litres
9litres 5litres
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Crystalloids&colloids
29litres
10.5litres 4.5litres
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Crystalloids&colloids
30litres
9litres 3litres
2litersof
5%dextrose
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Crystalloids&colloids
31litres
9.7litres 3.3litres
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Letdosomehomework
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^/?1/1? 1.1 l^
!
Population*
Albumin*vs.*Crystalloid* HES*vs.*Crystalloid*
Survival! Safety! Survival! Safety!
Year!&!
type!
Results! Year!&!
type!
Results! Year!&!
type!
Results! Year!&!
type!
Results!
Mixed!ICU!
patients!
1994!MA! Increased!
mortality!
2001!
pharmaco
Cvigilance!!
No!incidence!
during!1998C
2000!
2007!&!
2009!
MA!
No!
difference!
2004!SR! Anaphylactoid,!
IRR:!4.51!!
(vs.!Albumin)!
2001!MA! No!
difference!
2004!MA! RR!for!
morbidity:!
0.92!
! ! 2007!
proC
spective!
RRT!OR:!0.4!
2004!
SAFE!
study!
No!
difference!
2004!
SAFE!
study!
RRT:!similar! ! ! 2009!
MA!
RRT!OR:!1.9!
! ! 2004!SR!
LargeC
scale!
pharmaco
Cvigilance!
Incidence!rate!
AE:!!
3186!!
SAE:!!
1.3!per!10
6
!
infusions!
! ! 2010!
MA!
ARF!RR:!1.5;!
!
RRT!RR:!not!
significant!
!
Summaryoflatestevidence(I)
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Population*
Albumin*vs.*Crystalloid* HES*vs.*Crystalloid*
Survival( Safety( Survival( Safety(
Year(&(
type(
Results( Year(&(
type(
Results( Year(&(
type(
Results( Year(&(
type(
Results(
Sepsis(&(
severe(
infection(
2004(
SAFE(
study(
No(
difference(
2011(
SAFE(2
nd
(
analysis(
No(
difference(
for(RRT(
2008(
Factorial(
trial(
RR:(1.87(
stopped(
earlier(
2001(
RCT(
AKI,(RR:(1.83(
2006(MA( RR:(0.19(
(vs.(
Gelatin)(
2011(
French(
trial(
No(
difference(
for(renal(
failure((vs.(
Placebo)(
2009(
MA(
Increased(
mortality(
2008(
Factori
al(trial(
More(RBC;((
more(AKI((doseT
dependent)(
2011(
SAFE(2
nd
(
analysis(
aOR:(0.71( ( ( ( ( 2008T
2011(
3MA(
More(AKI(
2011(MA( OR:(0.82( ( ( ( ( 2009(
Retro((
AKI(or(RRT,((
OR:(1.85(
2011(
Africa(
RCT(
No(
difference((
( ( ( ( 2011(
before
/after(
AKI,(OR:(3.65(
Head(
injury(
2004(
SAFE(
study(
Increased(
mortality(
( ( 2011(
retro(
OR:(2.5( 2008(
pros(
More(blood(
transfusion(
(
Summaryoflatestevidence(II)
24
Q3.paper
1. Guidelines
2. SystemaEcReview&Meta-Analysis
3. RandomizedControlledTrials
4. ObservaEonalstudies
5. ExperiencefromTaiwan
6. Neitherofabove
7. Itdepends
6/24/12 Kuan-FuChenSEMTW2012 25
Albuminingeneral
Population*
Albumin(vs.(Crystalloid(
Survival* Safety*
Year*&*
type*
Results* Year*&*type* Results*
Mixed*ICU*
patients*
1994*MA* Increased*mortality* 2001*pharmacoDvigilance** No*incidence*during*1998D2000*
2001*MA* No*difference* 2004*MA* RR*for*morbidity:*0.92*
2004*
SAFE*
study*
No*difference* 2004*SAFE*study* RRT:*similar*
* * 2004*SR*LargeDscale*
pharmacoDvigilance*
Incidence*rate*AE:*3186**
SAE:*1.3*per*10
6
*infusions*
*
6/24/12 Kuan-FuChenSEMTW2012 26
SAFEstudy
Salinevs.4%AlbuminFluidEvaluaEon
CollaboraEonofAustralianandNewZealandIntensive
CareSocietyClinicalTrialsGroup,AustralianRedCross
BloodService,&GeorgeInsEtuteforInternaEonal
Health
BlindedRCT/c7000ptsinICUin2004
Similaroutcomesat28days
RRofdeath:0.99,95%CI0.91-1.09
daysofrenal-replacementtherapy(p=0.41)

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SAFEstudy
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SAFEstudy
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HESingeneral
Population*
HES$vs.$Crystalloid$
Survival* Safety*
Year*&*type* Results* Year*&*type* Results*
Mixed*ICU*
patients*
2007*&*2009*MA* No*difference* 2004*SR* Anaphylactoid,*IRR:*4.51**
(vs.*Albumin)*
* * 2007*prospective* RRT*OR:*0.4*
* * 2009*MA* RRT*OR:*1.9*
* * 2010*MA* RRT*RR:*not*significant;**
ARF*RR:*1.5*
*
6/24/12 Kuan-FuChenSEMTW2012 30
Q4.
1. OddsraEo(OR)
2. RiskraEo(RR)
3. Riskdierence(RD)
4. Neitherofthem
5. Itdepends
6/24/12 Kuan-FuChenSEMTW2012 31
Dierence/inconsistencebtw
eect/modelesEmates
OveresEmaEon
OR>>RR>RD
Heterogeneity(inconsistence)
RD>RROR
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Dierence/inconsistencebtw
eect/modelesEmates
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Dierence/inconsistencebtw
eect/modelesEmates
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Dierence/inconsistencebtw
eect/modelesEmates
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Summaryofeectmeasure
OR RR RD
Communica,on
Consistency
Mathema,cs3
! + ++
+ + !
++ ! !
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AlbumininspecicpopulaEon
Population*
Albumin(vs.(Crystalloid(
Survival* Safety*
Year*&*type* Results* Year*&*type* Results*
Sepsis*&*
severe*
infection*
2004*SAFE*study* No*difference* 2011*SAFE*2
nd
*analysis* No*difference*for*RRT*
2006*MA* RR:*0.19*(vs.*Gelatin)* 2011*French*trial* No*difference*for*renal*
failure*(vs.*Placebo)*
2011*SAFE*2
nd
*analysis* aOR:*0.71* * *
2011*MA* OR:*0.82* * *
2011*Africa*RCT* No*difference** * *
Head*
injury*
2004*SAFE*study* Increased*mortality* * *
*
6/24/12 Kuan-FuChenSEMTW2012 37
SAFEstudy
Predenedsubgroup
1218paEents/cseveresepsis
Trendtowardsreduced28-daymortality
0.87,albuminvs.Saline,CI0.74-1.02,p=0.06
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Q5.
1.
2.
3.
4.
5.
6/24/12 Kuan-FuChenSEMTW2012 39
Subgroupanalysis
Pre-denedvs.Post-hoc
MulEplicityissue
InaEonofTypeIerror
NASCIStrial
NaEonalAcuteSpinalCordInjuryStudies
MethyprednisoloneRxinacuteSCI
6/24/12 Kuan-FuChenSEMTW2012 40
2
nd
analysisforSAFEstudy
ITTbased
Adjustedforcompletedbaselinedataina
mulEvariatelogisEcregression
AdjustedORfordeath
Albuminversussalineof0.71(95%CI0.520.97)
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2
nd
analysisforSAFEstudy
6/24/12 Kuan-FuChenSEMTW2012 42
Q6.
1.
2.
3.
4.
5.
6/24/12 Kuan-FuChenSEMTW2012 43
IntenEontotreat?
As-treatedanalysis
Comparewhoactuallyreceivedtreatmentvs.control
IgnorerandomizaEon
Per-protocolanalysis
Comparewhocomplywithassignedtreatment
Compliersintreatmentvs.fullcontrolgroup
Inten7on-to-treatanalysis
StandardesEmate
IgnorecompliancejustuserandomizaEon
Instrumentalvariable/complieraveragecausaleect
6/24/12 44
SimpsonsParadox-confounding
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6/24/12 46
6/24/12 Kuan-FuChenSEMTW2012 47
MulEcenterRCTinAfricain2011
MortalityaneruidbolusinAfricanchildrenwith
severeinfecEon
Mostlychildrenwithouthypotensionandtreated
outsideICU
HalEngrecruitmentaner3141/3600enrolled
57%hasmalaria
RRofdeath:
salinevs.Control1.44;95%C.I.1.09to1.90;P=0.01;
albuminbolusvs.salinebolus,1.01;95%CI,0.78to1.29;P
=0.96
anybolusvs.control,1.45;95%CI,1.13to1.86;P=0.003
6/24/12 Kuan-FuChenSEMTW2012 48
MulEcenterRCTinAfricain2011
6/24/12 Kuan-FuChenSEMTW2012 49
MulEcenterRCTinAfricain2011
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MulEcenterRCTinAfricain2011
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Q7.

1.
2.
3.
4.
5.
6/24/12 Kuan-FuChenSEMTW2012 52
Generalizability
Target'
Population
Study&
population
Target'
Population
Study&
population
Target'
Population
Study&
population
6/24/12 Kuan-FuChenSEMTW2012 53
HESinspecicpopulaEon
! HES$vs.$Crystalloid$
Population! Survival! Safety!
! Year!&!type! Results! Year!&!type! Results!
Sepsis!&!
severe!
infection!
2008!Factorial!trial! RR:!1.87!stopped!earlier! 2001!RCT! AKI,!RR:!1.83!
2009!MA! Increased!mortality! 2008!Factorial!trial! More!RBC;!!
more!AKI!(doseLdependent)!
! ! 2008L2011!3MA! More!AKI!
! ! 2009!Retro!! AKI!or!RRT,!!
OR:!1.85!
! ! 2011!before/after! AKI,!OR:!3.65!
! 2011!retro! OR:!2.5! 2008!pros! More!blood!transfusion!
!
6/24/12 Kuan-FuChenSEMTW2012 54
IntensiveInsulinTherapyandPentastarch
ResuscitaEoninSevereSepsis
Factorialtrialin2008
Stoppedearlyforsafetyreasons
Highermortalitytrend
HESassociatedwithhigherratesofARR&RRT
Dosage
Highdose-increasedmortalityrateat90days
RR:1.87(58%versus31%;p<0.001)
136vs.48mL/kgover21days
notseenincrystalloidgroup
6/24/12 Kuan-FuChenSEMTW2012 55
Q8.
1.
2.
3.
4.
5.
6/24/12 Kuan-FuChenSEMTW2012 56
Interimanalysis
6/24/12 Kuan-FuChenSEMTW2012 57
^/??/1? 1'. /^
!
Population*
Albumin*vs.*Crystalloid* HES*vs.*Crystalloid*
Survival! Safety! Survival! Safety!
Year!&!
type!
Results! Year!&!
type!
Results! Year!&!
type!
Results! Year!&!
type!
Results!
Mixed!ICU!
patients!
1994!MA! Increased!
mortality?!!
(Old!study)!
2001!
pharmaco
Gvigilance!!
No!incidence!
during!1998G
2000!
2007!&!
2009!
MA!
No!
difference!
2004!SR! Anaphylactoid,!
IRR:!4.51!!
(vs.!Albumin)!
2001!MA! No!
difference!
2004!MA! RR!for!
morbidity:!
0.92!
! ! 2007!
proG
spective!
RRT!OR:!0.4!
2004!
SAFE!
study!
No!
difference!
2004!
SAFE!
study!
RRT:!similar! ! ! 2009!
MA!
RRT!OR:!1.9!
(overGestimated)!
! ! 2004!SR!
LargeG
scale!
pharmaco
Gvigilance!
Incidence!rate!
AE:!!
3186!!
SAE:!!
1.3!per!10
6
!
infusions!
! ! 2010!
MA!
ARF!RR:!1.5;!
!
RRT!RR:!not!
significant!
!
Summaryoflatestevidence(I)
6/24/12 Kuan-FuChenSEMTW2012 58
Population*
Albumin*vs.*Crystalloid* HES*vs.*Crystalloid*
Survival( Safety( Survival( Safety(
Year(&(
type(
Results( Year(&(
type(
Results( Year(&(
type(
Results( Year(&(
type(
Results(
Sepsis(&(
severe(
infection(
2004(
SAFE(
study(
No(
difference(
2011(
SAFE(2
nd
(
analysis(
No(
difference(
for(RRT(
2008(
Factorial(
trial(
RR:(1.87(
stopped(
earlier(
2001(
RCT(
AKI,(RR:(1.83(
2006(MA( RR:(0.19(
(vs.(
Gelatin)(
2011(
French(
trial(
No(
difference(
for(renal(
failure((vs.(
Placebo)(
2009(
MA(
Increased(
mortality(
2008(
Factori
al(trial(
More(RBC;((
More(AKI((doseT
dependent)(
2011(
SAFE(2
nd
(
analysis(
aOR:(0.71( ( ( ( ( 2008T
2011(
3MA(
More(AKI(
2011(MA( OR:(0.82( ( ( ( ( 2009(
Retro((
AKI(or(RRT,((
OR:(1.85(
2011(
Africa(
RCT(
No(
difference((
( ( ( ( 2011(
before
/after(
AKI,(OR:(3.65(
Head(
injury(
2004(
SAFE(
study(
Increased(
mortality(
( ( 2011(
retro(
OR:(2.5( 2008(
pros(
More(blood(
transfusion(
(
Summaryoflatestevidence(II)
59
Takehomemessage
Certaintypeofcolloidsmightbehelpfulunder
certaincircumstance
Albuminmightbehelpfulforseveresepsis
HESmightbeharmfulingeneral
BecauEousofcumulaEvedoseofcolloids
PhysiciansneedtobecapableofevaluaEng
evidencebeforeapplyingthemintodaily
pracEce.
6/24/12 Kuan-FuChenSEMTW2012 60
QUESTIONS?
kfchen@cgmh.org.tw