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Major Published Clinical Trials in AKI: What do they Really Mean?

Major Published Clinical Trials in AKI: What do they Really Mean?. Michael Zappitelli, MD, MSc Montreal Children's Hospital McGill University Health Centre. What does “Clinical Trials in AKI” mean?. No AKI. Illness – PICU Cardiac surgery Nephrotoxin. AKI. Reduce AKI incidence

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Major Published Clinical Trials in AKI: What do they Really Mean?

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  1. Major Published Clinical Trials in AKI: What do they Really Mean? Michael Zappitelli, MD, MSc Montreal Children's Hospital McGill University Health Centre

  2. What does “Clinical Trials in AKI” mean? No AKI Illness – PICU Cardiac surgery Nephrotoxin AKI Reduce AKI incidence Therapeutics Preventive

  3. What does “Clinical Trials in AKI” mean? No RRT need RRT need Reduce RRT need Therapeutics Preventive Patient develops AKI Good outcome Poor outcome Improve outcome Therapeutics Preventive RRT initiation timing

  4. What does “Clinical Trials in AKI” mean? Good outcome Patient requires RRT Poor outcome Survival Renal recovery Complications Cost/Morbidity RRT intervention evaluation Modality “Dose” Timing Intra/Post-RRT therapeutics?

  5. Overview Major trials on dose and timing Brief meta-analyses review Selected adult and pediatric trials Brief review of meta-analyses Context of pediatric AKI and future directions

  6. ATN Study Timing not standardized Did it really answer the dose question? Allowed for different modalities No benefit to increase HD dose > 3/week + Kt/V >1.2-1.4 OR CRRT > 20 ml/kg/hr

  7. RENAL study Timing not standardized >25 ml/kg/hr no difference Modality not addressed

  8. Meta-analyses: similar findings Several meta-analyses: intensity and/or renal recovery Casey et al, Renal Failure, 2010 Zhang et al, J of Critical Care, 2010 Jun et al, CJASN, 2010 Negash et al, Cochrane review, updated 2011 Modality - several meta-analyses: IHD vs CRRT Tonelli et al, AJKD, 2002 Rabindranath, Cochrane review, 2008 Bagshaw et al, Crit Care Med, 2008 Highlight: Poor quality evidence, heterogeneity

  9. Timing and dose “Early”: within 12 hours of inclusion “Late”: when “standard” RRT criteria used “High”: ~40 ml/kg/hr for 70kg “Low”: ~ 15-20 ml/kg/hr for 70 kg

  10. Timing and dose Publication Bias Heterogeneity – unable to account for lack of consensus on “early” definition Only 2 RCT’s

  11. Diuretics: do they help once CRRT stopped? They excreted more sodium No difference in renal recovery

  12. AKI prevention: EPO?

  13. Extra process

  14. AKI prevention: EPO? Biomarker selected sicker patients with worse outcomes

  15. AKI prevention: EPO? But EPO did not alter outcome

  16. Child Remote Ischemic Preconditioning

  17. Child Remote Ischemic Preconditioning Estimated GFR Plasma CysC Plasma Creatinine No effect Too low power ?Significance of preventing 50% SCr rise? Urine Output Plasma NGAL Urine NGAL

  18. Fenoldopam: infants, biventricular anatomy Secondary endpoints: Trend towards reduced pRIFLE AKI Less diuretics and vasodilators in Rx group

  19. Fenoldopam MORTALITY

  20. ANP/BNP

  21. ANP/BNP Peak SCr 2009 Cochrane review: Similar findings More complications with higher dose Useful for “prevention”, not “treatment” RRT Need Mortality X

  22. Must it all be about RCT's right away? 30 day mortality 23% 43% Propensity score analysis 28% 51% “Early” = latest day after surgery “Late” = 2 days after surgery or later 90-day mortality

  23. Other avenues with evidence • Therapeutic hypothermia • Off pump versus on pump (cardiac surgery) • Statins • Sodium bicarbonate • Anti-inflammatory agents • Fenoldopam, ANP/BNP

  24. Summary & Conclusion • Dose/Intensity of RRT: • ATN/RENAL study suggest intensity above ~ 20-25 ml/kg/hr will not improve outcomes • No pediatric data, but: • Should we be more aware of the dose we provide? • Are we actually delivering what we think we are? • Modality based on clinical factors • Use of diuretics to enhance water clearance unlikely to improve outcome or prevent RRT need • Does not mean they do not play important role • “Earlier” RRT initiation may be beneficial • Need to standardize definition • Pediatrics: different epidemiology, fluid overload – future trials

  25. Summary & Conclusion • Clinical trials in pediatrics ARE feasible • We have: • Definition (s) • Biomarkers • Demonstrated importance • Need to sort out: • Existing practice • Best outcome to study • Best population to study • Balance risk of Rx vs potential benefit • Demonstrate clinical equipoise

  26. THANK YOU • Composium organizers: • Stuart Goldstein • Timothy Bunchman • KIDMO colleagues: • David Askenazi • Geoffrey Fleming • Matthew Paden • David Selewski • Brian Bridges • David Cooper • Cincinnati Children's Hospital Medical Centre • ppCRRT members • Montreal Children's Hospital AKI research team

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