Transcript L’Evidence based medicine les atouts, les limites en

ESICM 20th congress- Berlin– October 6th
Evidence based medicine
in severe sepsis
Jean-François TIMSIT MD PhD
Medical ICU
University hospital Grenoble
INSERM U823
I have no conflict of interest to declare..
Pertinence
Definition
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Evidence-based medicine is the
conscientious, explicit and judicious use
of current best evidence in making
decisions about the care of individual
patients while considering patient
values.
Preference
Experience
Sackett DL, et al. BMJ 1996 ; 312 : 71-72.
Meta-analysis of original data
Systematic revue of RCTs
RCT
Cohort
Case-control
Analyses using computer databases
Series with literature control
Cases series case reports
Expert opinion
Animal research / in vitro studies
Evidence pyramid
Olkin – J Clin Epidemiol; 48:133 1995
Random allocation is the only way to
equilibrate groups on confounding
factors..known AND UNKNOWN +++
Concealement and blinding is the only way
to equilibrate on other treatment given to
the patient
Limitations of EBM
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Lack of evidence
Funding sources
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External validity
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limit the type and scope of research projects
Should influence the diffusion of the information
We are far from the « real world »
Lack of skills to use available informations
should lead to erroneous interpretations
EBM and treatment of septic
shock
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No RCT
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RCT but not in sepsis
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Antimicrobials
Vasoactive drugs
Fluid loading (SAFE)
Tight glycemic control
ARDS care
Red pack cells
RCT but…many controversies and no definite answers
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DrotAA
Steroids
All the articles are biased by 4 (5)
actors
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Author
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Editor
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Proven subjectivity, affectivity
Owner
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Innovative, equilibrium between different topic (publication
biais)
Expert
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Want to be PUBLISHED (the message could be sligtly
modified)
Bond with scientific societies, with firms
Reader
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Read only the final version, he has the right not to read, not
to accept
Maisonneuve H - EBM J 1996
RCT and socio-economic impact
Weight of money, of ambition
 Weight of national agency approval
capital for the firms
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Drug approval = 500 millions $ investment
Considerable economic impact for
Journals
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Impact factor, publicity, supplements,
actionnariat….
Dreyfuss D – ICM 2005; 31:345
EBM anchors
 Patient
or problem
 Intervention, test of exposure
 Comparator
 Outcomes
What patients are we talking
about???
Severe sepsis…what is it? (case-mix
infection etc…)
wes
s
Pro
Len
ers
ep
I
t
Septic shock
Severe sepsis
TFP
70
60
50
40
30
20
10
0
EGD
T
CS2
000
Cor
ticu
s
CAT
S
Kyb
ers
e pt
Ant
i E5
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Definition not precise enough
PIRO
 Only a concept…
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Steroids and Drotrecogin Alfa (Activated) for Immunocompetent Adults < 45 y
with Shock and DIC due to Early Pneumococcal Pneumonia
The“splitter” approach may be preferable to the “clumper” approach to sepsis trials
until the entire septic process can be better integrated. (Opal S Pediatr Crit Care 2005)
Severe sepsis is a world not a word
Definition and therapy are complex by essence
National or international groups working together with a
large amount of patients, the same definitions, the same
bacteriological samples, antimicrobials, symptomatic
treatment…etc
EORTC ou IASLC like
One member of the group in each ICUs
Precise studies with specific targets
Outcome= Judgment criteria
Precise
Reproducible
Sensitive to change
Related to what we wanted to measure.
..This choice is a very important issue
« Surrogate end-points »
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Closely linked to clinical end-point?
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 Surrogate <->  clinical end-point
Good calibration of the surrogate end point
and more sensitive to change
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Improvement of organ deficiencies
Caution!!!.
Bucher HG – JAMA 1999; 282:771
Surrogate end-points…example of failure
Blood pressure    DC
 LNMA   BP
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Lopez A et al – Crit Care Med 2004;32:21-30
Corticus study
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Low dose steroids vs PB in septic shock
(7days)
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Time to shock reversal (3.1 vs 5.7 dys, p=0.003)
Mortality CS:33.3 % vs Placebo 31%, p>0.5
Increase of shock and septic shock in the steroids group in the
follow up…
Sprung C et al- abstract ESICM sept 2006 and ATS2007
Which mortality is the optimal clinical endpoint?
Underlying illnesses
Acute disease
Day 14
Day 28
Day 90
1y
time
Drot AA
Placebo
p
% Lost of
Follow up
Hospital
70.3%
65.1%
0.03
0%
3-month
66.1%
62.4%
0.11
6%
1-year
58.9%
57.2%
0.49
7%
Angus D et al - Crit Care Med 2004; 32:2199 –2206)
What is the best???
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Day 14  more related to the disease
itself…low noise (death due to other cause)
Day 28  compromise?
Day 90  competing events?, probably more
important at the patient’s point of view
1 year   competing events, more important
for patient and at the societal point of view
All of the end-points  YES!!BUT
Multiple comparisons ( type I error,  Nb of
patients)
100 RCT  5 will be positive+++
Validity
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Internal validity: the study was well done
and show a true decrease in
« appropriate mortality »?
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External validity: the results are
applicable to my patients
Conflict internal and external validity
Spironolactone improve the prognosis of cardiac insufficiency (30% of the risk of death:RALES study)
Juurlink et al – NEJM 2004; 351:543
Representativity of the enroled
population: Prowess example
1690 pts/ 11 countries/ 164 sites!!!!
 A very few % of the severe sepsis
admited
 The overal treatment are not
standardized…
 External validity..?
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The control group…
« is an exagerate real life »
Finney – JAMA 2003
Preiser JC et al – ESICM2006
…Could no longer be used because physician
behaviour changed
Prowess – a learning curve?
Macias et al – Crit care med 2004;32:2385
« CONCLUSIONS: A learning curve appeared to be present
within the PROWESS trial … efficacy improved with
increasing site experience... Investigational sites may need to
require a minimum level of protocol-specific experience to
appropriately implement a given trial. …This experience
should be an important consideration in designing trials and
analysis plans. … »
COULD WE USE THIS DRUG IN GENERAL ICUs??
Macias et al – Crit care med 2004;32:2385
Cohort studies is key
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Use it ++++
To formulate hypothesis
 To confirm the external validity of RCTs
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To conclude
There is a long way from bench to bedside…
The most evident way to treat patients is
early antimicrobials and surgery if needed
early treatment of organ hypoperfusion
(Mechanical ventilation, fluids, inotropes..)
New little things change slowly (sugar/insulin,
nutrition, NI prevention, etc)
EBM is a challenge…many contradictions in the
results (DocAA, steroids, norepinephrine…)
It only shows the potential routes for improvement…
Interpret the results with some
distance…