DEBATE: Timing of CRRT in Critical Care 9th International pCRRT Conference on Pediatric Continuous Renal Replacement Therapy August 31-September 2, 2017 DEBATE: Timing of CRRT in Critical Care “Early may not always be better” -- Jordan Symons MD, Seattle VS. “Early is what’s the need of the hour” -- Joseph Carcillo MD, Pittsburgh

Framing the Question “Early may not always be better” “Early is what’s the need of the hour” Thoughtful . . . Rational . . . Careful . . . Deliberate What hour? This hour? Are we really sure?

We’ve been thinking about this for a long time . . .

Is it possible . . . Early may not always be better? Why do we remain unsure? Is it possible . . . Early may not always be better?

“Early CRRT Just Makes Sense!” Estrogen replacement therapy for all postmenopausal women Tight glycemic control in critically ill patients BP <140/90 in older adults These all SEEMED to make sense . . .

“Early CRRT Just Makes Sense!” Higher dose of RRT in AKI ATN and RENAL trials: no benefit CVVH for sepsis Payen, Crit Care Med 2009: no benefit High-volume hemofiltration IVOIRE, Intens Care Med 2013: no benefit Early goal-directed therapy in shock Recent studies suggest: might not be better

Is it possible . . . Early may not always be better? Some things in medicine may seem to make sense at first but later we discover it’s more complicated . . . Is it possible . . . Early may not always be better?

“There must be some data . . .” Multiple studies comparing “early” vs. “late” RRT for AKI Most are single-center Most are not RCTs Most lack a control group that did not receive RRT Many used select populations (e.g. post-op) This means . . . high risk for bias

Meta-Analyses of Early RRT Seabra, 2008 (AJKD) 23 studies: early found to be better Were all studies of good quality? Karvellas, 2010 (Crit Care Med) 15 studies: early found to be better BUT The randomized sub-group analysis failed Raises doubts about superiority of early vs. late

Updated Meta-Analysis of Early RRT for AKI: 2016 36 studies 7 RCT, 10 prospective cohort trials, 19 retrospective cohort trials 9 studies (1042 patients) “high quality” No survival advantage with early RRT Did not change with sub-group analysis by reason for admit (med vs surg) or definition of “early” (time vs. biochemical) Wierstra et al. Critical Care 2016

Updated Meta-Analysis of Early RRT for AKI: 2016 Wierstra et al. Critical Care 2016

Updated Meta-Analysis of Early RRT for AKI: 2016 “The results of our meta-analysis contradict the findings reported by previous authors and we conclude that ‘early’ initiation of RRT in critically ill patients with AKI does not improve survival.” Wierstra et al. Critical Care 2016

Careful, ongoing review of the data raises significant doubts . . . Is it possible . . . Early may not always be better?

Full cohort Matched cohort “Dialysis was associated with increased survival when initiated in patients with AKI who have a more elevated creatinine level but was associated with increased mortality when initiated in patients with lower creatinine concentrations.”

100 patients; high NGAL; high SOFA; most on pressors/vent Early: RRT <12h of AKI stage 2 Late: wait for “classic indications” for RRT NO DIFFERENCE in mortality

Single center; N=231, mostly cardiac patients high NGAL Early: <8h after AKI stage 2 Late: <12h after AKI stage 3 35% lower mortality in the “Early” group

NO DIFFERENCE in mortality Multicenter, N=620 Early: RRT <6h of AKI stage 3 Late: “absolute” indications for RRT NO DIFFERENCE in mortality 60% in “Late” didn’t end up needing RRT Those without RRT: lowest mortality Those in “Late” with RRT: highest mortality

Is it possible . . . Early may not always be better? The newest RCTs have varying definitions of early vs late, study single vs. multicenter populations, with (at best) conflicting results . . . Is it possible . . . Early may not always be better?

Is this study generalizable? BUT: Single center, retrospective No objective criteria for initiation Early <5d; late >5d Is this study generalizable?

“This is confusing – are there experts who can clarify this issue?”

ADQI 17: Consensus on Initiation Not based on time Not based on a blood test result Not specifically “early” vs. “late” Ostermann et al. ADQI consensus paper. Blood Purif 2016

ADQI 17: Comment on GFR, AKI Staging and RRT Initiation “While AKI stage correlates with both hospital and 1-year mortality it is not an indication for RRT per se. In fact, many patients with even stage 3 AKI will have spontaneous recovery without RRT.” “Based on existing evidence, the decision to start acute RRT should be individualized and not be based solely on renal function or stage of AKI without considering the clinical context.” Ostermann et al. ADQI consensus paper. Blood Purif 2016

Is it possible . . . Early may not always be better? The experts from ADQI say that we should “individualize” the decision to start RRT . . . Is it possible . . . Early may not always be better?

“What about fluid overload?” N=113 *p=0.02; **p=0.01 Foland JA et al: Crit Care Med 2004 Gillespie R et al: Pediatr Nephrol 2004 Kaplan-Meier survival estimates, by percentage fluid overload category Hazard Ratio 3.02 (1.50-6.10) Goldstein SL et al: Pediatrics 2001 Sutherland et al: AJKD 2010 “Fluid Overload is the Enemy”

“What about fluid overload?” Fluid overload associated with mortality If there is a CRRT indication, do not delay! That’s what the ADQI experts tell us Could we try to PREVENT fluid overload? Perhaps a better pathway for our patients?

“Can biomarkers help?” NGAL, IGFBP7/TIMP2, etc. These predict AKI They do NOT predict need for RRT Remember – even some with AKI stage 3 won’t need RRT and may do better without it

Early vs. Late: A False Dichotomy

Early vs. Late: A False Dichotomy

“Early may not always be better” “Wait as long as possible”

Who can really tell us if CRRT is needed, in this or any hour?

(Re)Framing the Question “Early may not always be better” “Early is what’s the need of the hour”