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Evidence based medicine in severe sepsis 

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. Definition. Pertinence.

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Evidence based medicine in severe sepsis 

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  1. 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..

  2. Definition Pertinence • 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. Experience Preference Sackett DL, et al. BMJ 1996 ; 312 : 71-72.

  3. 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

  4. 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

  5. Limitations of EBM • Lack of evidence • Funding sources • limit the type and scope of research projects • Should influence the diffusion of the information • External validity • We are far from the « real world » • Lack of skills to use available informationsshould lead to erroneous interpretations

  6. EBM and treatment of septic shock • No RCT • Antimicrobials • Vasoactive drugs • RCT but not in sepsis • Fluid loading (SAFE) • Tight glycemic control • ARDS care • Red pack cells • RCT but…many controversies and no definite answers • DrotAA • Steroids

  7. All the articles are biased by 4 (5) actors • Author • Want to be PUBLISHED (the message could be sligtly modified) • Editor • Innovative, equilibrium between different topic (publication biais) • Expert • Proven subjectivity, affectivity • Owner • Bond with scientific societies, with firms • Reader • Read only the final version, he has the right not to read, not to accept Maisonneuve H - EBM J 1996

  8. RCT and socio-economic impact • Weight of money, of ambition • Weight of national agency approval capital for the firms • Drug approval = 500 millions $ investment • Considerable economic impact for Journals • Impact factor, publicity, supplements, actionnariat…. Dreyfuss D – ICM 2005; 31:345

  9. EBM anchors • Patient or problem • Intervention, test of exposure • Comparator • Outcomes

  10. What patients are we talking about??? • Severe sepsis…what is it? (case-mix infection etc…)

  11. Definition not precise enough • PIRO • Only a concept…

  12. 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)

  13. 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

  14. Outcome= Judgment criteria Precise Reproducible Sensitive to change Related to what we wanted to measure. ..This choice is a very important issue

  15. « Surrogate end-points » • Closely linked to clinical end-point? •  Surrogate <->  clinical end-point • Good calibration of the surrogate end point and more sensitive to change • Improvement of organ deficiencies Caution!!!. Bucher HG – JAMA 1999; 282:771

  16. Surrogate end-points…example of failure • Blood pressure    DC • LNMA   BP Lopez A et al – Crit Care Med 2004;32:21-30

  17. Corticus study • Low dose steroids vs PB in septic shock (7days) • 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

  18. Which mortality is the optimal clinical end-point? Underlying illnesses Acute disease Day 14 Day 28 Day 90 1y time

  19. Angus D et al - Crit Care Med 2004; 32:2199 –2206)

  20. What is the best??? • 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)

  21. 100 RCT  5 will be positive+++

  22. Validity • Internal validity: the study was well done and show a true decrease in « appropriate mortality »? • External validity: the results are applicable to my patients

  23. 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

  24. 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..?

  25. Control group in the Vandenberghe study (2006) The control group…« is an exagerate real life » Finney – JAMA 2003

  26. …Could no longer be used because physician behaviour changed Preiser JC et al – ESICM2006

  27. Prowess – a learning curve?Macias et al – Crit care med 2004;32:2385

  28. « 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

  29. Cohort studies is key • Use it ++++ • To formulate hypothesis • To confirm the external validity of RCTs

  30. 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…

  31. Interpret the results with some distance…

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