1. 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

2. 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?

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

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

5. “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 . . .

6. “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

7. 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?

8. “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

9. 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

10. 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

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

12. 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

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

14. 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.”

15. 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

16. 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

17. 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

18. 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?

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

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

21. 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

22. 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

23. 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?

24. “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 ( )
Goldstein SL et al: Pediatrics 2001
Sutherland et al: AJKD 2010
“Fluid Overload is the Enemy”

25. “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?

26. “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

27. Early vs. Late: A False Dichotomy

28. Early vs. Late: A False Dichotomy

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

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

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