Major Published Clinical Trials in AKI What do
Major Published Clinical Trials in AKI: What do they Really Mean? Michael Zappitelli, MD, MSc Montreal Children's Hospital Mc. Gill University Health Centre
What does “Clinical Trials in AKI” mean? No AKI Illness – PICU Cardiac surgery Nephrotoxin AKI Reduce AKI incidence Therapeutics Preventive
What does “Clinical Trials in AKI” mean? No RRT need Patient develops AKI Reduce RRT need Therapeutics Preventive Good outcome Improve outcome Therapeutics Preventive RRT initiation timing Poor outcome
What does “Clinical Trials in AKI” mean? Good outcome Patient requires RRT Poor outcome RRT intervention evaluation Modality “Dose” Timing Intra/Post-RRT therapeutics? Survival Renal recovery Complications Cost/Morbidity
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
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
RENAL study Timing not standardized >25 ml/kg/hr no difference Modality not addressed
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
Timing and dose “Early”: within 12 hours of inclusion “Late”: when “standard” RRT criteria used “High”: ~40 ml/kg/hr for 70 kg “Low”: ~ 15 -20 ml/kg/hr for 70 kg
Timing and dose Publication Bias Only 2 RCT’s Heterogeneity – unable to account for lack of consensus on “early” definition
Diuretics: do they help once CRRT stopped? They excreted more sodium No difference in renal recovery
AKI prevention: EPO?
Extra process
AKI prevention: EPO? Biomarker selected sicker patients with worse outcomes
AKI prevention: EPO? But EPO did not alter outcome
Child Remote Ischemic Preconditioning
Child Remote Ischemic Preconditioning Plasma Creatinine Estimated GFR Plasma Cys. C No effect Plasma NGAL Too low power Urine NGAL Urine Output ? Significance of preventing 50% SCr rise?
Fenoldopam: infants, biventricular anatomy Secondary endpoints: Trend towards reduced p. RIFLE AKI Less diuretics and vasodilators in Rx group
Fenoldopam MORTALITY
ANP/BNP
ANP/BNP Peak SCr RRT Need 2009 Cochrane review: Similar findings More complications with higher dose Useful for “prevention”, not “treatment” Mortality X
Must it all be about RCT's right away? 30 day mortality 23% 43% 28% 51% Propensity score analysis “Early” = latest day after surgery “Late” = 2 days after surgery or later 90 -day mortality
Other avenues with evidence § § § Therapeutic hypothermia Off pump versus on pump (cardiac surgery) Statins Sodium bicarbonate Anti-inflammatory agents Fenoldopam, ANP/BNP
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
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
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 § pp. CRRT members § Montreal Children's Hospital AKI research team
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