1. Sean M Bagshaw, MD, MSc Division of Critical Care Medicine Faculty of Medicine and Dentistry, University of Alberta 1 st International Symposium on AKI in Children Cincinnati, Ohio September 28, 2012 Fluid is a Drug: Late Conservative Fluid Management

2. Disclosure Summary Sean M Bagshaw, MD, MSc –Consultancy: Gambro Inc. –Speaking: Gambro Inc., Alere Inc.

3. Learning Objectives Review and Discuss: –Fluid Overload –Fluid Management –Concept of “De-Resuscitation”

4. ‘The dose makes the poison’ Paracelus

5. Brierley et al CCM 2009 Identification/diagnosis Therapeutic Monitoring –Individualized Early/Aggressive Initial Resuscitation –Hemodynamic stabilization –Shock reversal

6. 11.8% vs. 39.2% HR 3.8; 95% CI, 1.6-7.2, p=0.002 Oliveira et al ICM 2008 Fluids (mL/kg) 0-66-720-72 Crystalloid Control Active 5 28 10 0 80 90 Red Cells Control Active 15.7 45.1 43.1 31.4 58.8 68.6 Inotrope Control Active 7.8 29.4 22.4 19.6 29.4 49.0

7. Han et al Pediatrics 2003 OutcomesAppropriate Fluid Therapy (n, %) All patients (n=91)41 (45) Shock Reversed (n=24)24 (100) Persistent Shock (n=67)17 (25) Survivors (n=65)32 (49) Non-Survivors (n=26)9 (35) Shock reversal ~ >9-fold ↑ OR survival Persistent shock (per hour) ~ >2-fold ↓ OR survival

8. Percent Fluid Overload (%FO) %FO = Σ [FLUID IN – FLUID OUT] [Admission Weight (kg)] [Admission Weight (kg)] x 100 Goldstein et al Pediatrics 2001

9. Arikan et al Ped CCM 2012 74% reached peak %FO <7 days n=80

10. Goldstein et al Pediatrics 2001

11. “It is possible that in some cases CVVH/D may be a prevention, rather than a treatment, for worsening degrees of fluid overload.” “Early initiation of CVVH to allow for sufficient blood product and nutrition administration, while preventing fluid overload may improve patient survival…” Goldstein et al Pediatrics 2001

12. Michael et al Pediatr Nephrol 2004

13. %FO>10% for PICU Admission: 68.4% vs. 22.1%, p 10% for PICU Admission: 68.4% vs. 22.1%, p<0.001 Risk factors for %FO>10% ~ smaller children; AKI Indications for CRRT Initiation ~ FO in 39% %FO at CRRT Initiation ~ 10.6% vs. 13.9% (p=NS) Benoit et al Pediatr Nephrol 2007; Flores et al Pediatr Nephrol 2008

14. Foland et al CCM 2004 15.1 9.3 15.5 9.2

15. Gillespie et al Pediatr Nephrol 2004 n=77

16. n=116 Goldstein et al KI 2005

17. Sutherland et al AJKD 2010 %FO ~ adj-OR 1.03 (95% CI, 1.01-1.05) n=297

18. Akikan et al PCCM 2012 %FO stratified by Oxygen Index in first 5 days of PICU Median OI 11.5

19. Payen et al Crit Care 2008 Any ARF 36% (n=1120) Early ARF Early ARF 75% (n=842) Late ARF Late ARF 25% (n=278) CRRT 25% (n=278) Early AKI Late AKI No AKI Mean fluid balance (L/24hr) HR 1.21, 95%CI, 1.13-1.28, p<0.001

20. Fluid Overload at RRT Initiation Bouchard et al KI 2009 Adj-OR death for fluid overload at RRT initiation 2.07, 95%CI, 1.27-3.37

21. Prowle et al NRN 2010

22. Challenges… Available literature: –Small sample size –Retrospective or Registry data Few data from INTERVENTIONAL trials: –Focused specifically on children! –Fluid management AFTER initial resuscitation –Focused on strategies for fluid management: Volume: “Conservative” vs. “Liberal” (standard) Type: Crystalloid or Colloid; Isotonic or Balanced

23. Brandstrup et al Ann Surg 2003 n=172

24. Brandstrup et al Ann Surg 2003 Complication Conservative (n=69) Liberal (n=72) p Pulmonary edema (%)05.60.20 Pulmonary congestion (%)2.911.1 0.09 Pneumonia (%)4.312.50.13 Cardiac arrhythmia (%)09.70.03 Cardiopulmonary* (%)7.223.60.007 Tissue Healing (%)15.930.60.04

25. FACTT - Wiedemann et al NEJM 2006VariableCONLIBp Death (d 60) (%)25.528.40.30 Ventilator-free days (d 1-28) 14.612.10.001 ICU-free days (d 1-28) 13.411.20.001 RRT (day 60) (%)10140.06

26. Difference in fluid balance excluding initial resuscitation FACTT - Wiedemann et al NEJM 2006

27. Valentine et al CCM 2012 n=168

28. Valentine et al CCM 2012 n=168

29. Maitland et al NEJM 2011

30. 24 bags ≈ 9000 mg NaCl ≈

31. Next Steps… Body has not evolved a natural mechanism to remove excess ↑ Na+ and water “De-resuscitation” in MODS/AKI? –When can fluid be ideally removed? Triggers? –How much fluid should/must be removed? –What is the timeline for active elimination?

32. NGAL-Directed RRT Initiation Use of Neutrophil Gelatinase- Associated Lipocalin (NGAL) to Optimize Fluid Dosing, Continuous Renal Replacement Therapy (CRRT) Initiation and Discontinuation in Critically Ill Children With Acute Kidney Injury (AKI) ClinicalTrials.gov Identifier: NCT01416298 Available at: http://www.clinicaltrials.gov/ct2/show/NCT01416298?term=NCT01416298&rank=1

33. Summary (Excessive) fluid accumulation is bad Contribute to and/or worsen AKI/MODS Short/longer term injury to non-renal organs ↑ Risk morbidity/poor outcomes Need to better understand ideal strategies to (safely) mitigate and/or remove excess extravascular fluid

34. Thank You For Your Attention! Questions? bagshaw@ualberta.ca