Is There a Rationale To Use CRRT For Treating Sepsis? James D. Fortenberry MD, FCCM, FAAP Pediatrician in Chief Children’s Healthcare of Atlanta Professor of Pediatric Critical Care Emory University School of Medicine

2 The Problem of Sepsis in Children  42,000 pediatric sepsis cases/year  Annual cost > $2 billion  Increased mortality 5.4  9.5/100,000  Pediatric sepsis mortality rate in US: 10.3% - Watson RS, Carcillo JA, AJRCCM 2003

3 World Sepsis Day  Thursday, September 13,

Sepsis: A Global Problem With Much To Be Done Join.

5 Pediatric Sepsis Mortality  Overall pediatric mortality lower than adults (~10% vs %)  Single organ failure rarely leads to mortality Hematologic Failure < 5 % Immunologic Failure < 5 % CV Failure < 5 %Respiratory Failure < 5 % Renal Failure < 5 %

6 The MODS/Sepsis Patient HIGH MORTALITY 50-90% -Courtesy of Matt Paden

7 Is There a Rationale For Extracorporeal Therapies in Sepsis?  Potential benefits in severe sepsis: MOSF Management of fluid overload (CRRT) Immunohomeostasis: pro/anti-inflammatory mediators (CRRT/plasma) Mechanical support of organ perfusion during acute episode (ECMO) Improved coagulation response with decreased organ microthrombosis (plasma exchange) Clearance of circulating endotoxin (hemoperfusion)

8 Possible Benefits of CRRT in Sepsis  Direct Clearance of immune mediators Adsorption of mediators to membrane Clearance of organic acids  Indirect Improvement of fluid balance “Kinder, gentler” effect on hemodynamics in shock Opportunity for enhanced nutrition

9 Blood Black BileYellow Bile Phlegm Direct Effect?: Removing The Evil Humours

10 Peak Concentration Model of Sepsis

11 Experimental Support for CRRT in Sepsis  Multiple animal studies suggest physiologic and survival benefit -McMaster et al. Ped CCM, 2003

12 CVVH – Restoration of Immune Homeostasis Pre-CVVH12 Hours 24 Hours 48 Hours End of CVVH24 Hours off CVVH  Reduction of cytokines, chemokines, modulators of apoptosis Convective removal Membrane adsorption -Paden ML, et al. Ped Neph 2006

13 Is There A “Best” Method of CRRT In Sepsis?  No prospective data available assessing patient outcomes using diffusive (CVVHD) and convective (CVVH) therapies Retrospective data suggested benefit of CVVH in sepsis No convincing prospective data

14 Solute Molecular Weight and Clearance Solute (MW)Convective Coefficient Diffusion Coefficient Urea (60)1.01 ± ± 0.07 Creatinine (113)1.00 ± ± 0.06 Uric Acid (168)1.01 ± ± 0.04 Vancomycin (1448)0.84 ± ± 0.04 Cytokines (medium)clearedminimal clearance Cytokines (large)adsorbed minimal clearance

15 Impact of Early High Dose CRRT on Cytokines in Adult Sepsis: RCT Results IL-6 IL-8 TNF-aIL-10 -Cole et al., Crit Care Med 2002

16 Unknowns of Hemofiltration for Sepsis  Interaction of immune system with foreign surface of the circuit? Good or bad? Complement activation Bradykinin generation Leukocyte adhesion  Clearance of anti-inflammatory mediators?  Clearance of unknown good mediators?  What do plasma levels of mediators really mean? Honore concept: tissue levels

17 Indirect Benefit?: Fluid Balance in Sepsis

18 Fluid Balance in Septic Shock  Vasopressin in Septic Shock Trial (VASST) study: 778 adults  More positive fluid balance at 12 hours and at day 4 (quartiles) correlated with increased mortality 18 -Boyd et al., Crit Care Med, 2011 * *

19 Fluid Balance in Septic Shock  Sepsis Occurrence in Acutely Ill Patients (SOAP): multicenter prospective observational European trial  1177 septic adults  Multivariate analysis predictors of mortality: Cumulative fluid balance in first 72 hours (per liter increase: OR 1.1 ( ; p = 0.001) 19 -Vincent et al., Crit Care Med 2006

20 Effect of Fluid Overload on Outcome in CRRT N=113 *p=0.02; **p= Foland, Fortenberry et al., CCM 2004

21 Theory: The Fluid/Outcome Balance 21 Time Mortality, Vent LOS Fluid Balance SIRS CARS Stimulus Immunohomeostasis Does therapy change the late phase outcome in sepsis?

22 Is There a Rationale for CRRT?  Aggressive management of fluids does make a difference in ALI (FACTT trial)  Not proven in sepsis  Could higher dose of CRRT impact the sepsis outcome?

23 Effect of Filtration Rate on Outcome in Septic Adults with CVVH: Is More Better? - Ronco et al. Lancet 2000; 351: At last, an answer!

24 On Further Review: Does Dose Matter?  The RENAL Replacement Therapy Study  RCT: 1508 critically ill adults  CRRT of high (40) vs. low intensity (25 ml/kg/hr)  No difference in 90 day mortality or RRT independence -N Engl J Med. 2009

25 Meta-Analysis: No Benefit of High Dose CRRT in Adult Sepsis

26 Early Initiation of CVVH in Adult Sepsis: RCT  80 adults  Randomized: UF 25 ml/kg/hr for 96 hours Conventional treatment  All met SIRS/Sepsis criteria  Number and severity of organ dysfunction higher in CVVH (p=0.05) -Payen et al., Crit Care Med, 2009

27 Early CRRT in Sepsis: RCT -Payen et al., Crit Care Med, 2009

28 RRT in Sepsis/MODS: High Volume Hemofiltration  Pilot RCT of 20 adults with septic shock and ARF to high volume hemofiltration [HVHF 65 ml/(kg h)] vs low volume hemofiltration [LVHF 35 ml/(kg h).  HVHF: decreased vasopressor requirement trend towards increased urine output no effect on survival, LOS, RRT, mechanical ventilation -Boussekey et al. Intensive Care Med. 2008

29 Focusing on the most important outcomes 29

30 CRRT and Outcome in Pediatric MODS  Single center: 113 patients  103 patients with MODS  Diagnosis of sepsis not well delineated  70% on vasopressors  Overall survival 61%/59% in MODS  >3 organ MODS patient survival independently associated with fluid overload  Outcomes better than predicted -Foland et al., Crit Care Med 2004

31 CRRT Use and Diagnosis: ppCRRT Registry -Symons et al. Clin J Am Soc Nephrol 2007

32 MODS/Sepsis and CRRT: The PPCRRT Registry  116 patients  47 with sepsis  51.7% overall survival  Fluid overload specific risk factor independent of PRISM 2 -Goldstein et al., Kidney International, 2005

33 Can Combination Therapies Help in Sepsis?  Addition of plasma filtration coupled with adsorption, followed by dialysis or filtration (CPFA)  Polymyxin impregnated fibers

34 Hemoperfusion: Endotoxin Adsorption  Polymyxin B: high affinity for endotoxin  Charcoal hemoperfusion device: adsorption column  Significant experience in Japan, Europe

35 EUPHAS Trial: Survival -Cruz et al., JAMA, /30 (47%) 23/34 (68%) Hazard Ratio 0.43 ( )

36 Is it all in how we measure?

37 Problems with CRRT Sepsis Studies  No consistent definitions of AKI  Stratification of severity of AKI missing Fluid overload Biomarkers absent  Many studies-intervention late  No pediatric trials

38 CRRT Recommended for Use in Pediatric Sepsis  2007 ACCM guidelines (SCCM 2009)  “…after shock resusucitation…CRRT can be used to remove fluid in patients who are 10% overloaded”  “high flux CRRT (> 35 ml/kg/hr should be considered….”

39 Conclusions  There is a rationale for CRRT in sepsis  So far, data hasn’t demonstrated earlier CVVH or more intense RRT dosing improves outcome in adults  Insufficient evidence to support a role for RRT as adjuvant therapy for septic shock in adults unless severe AKI

40 What Do We Need?  Pediatric studies! We don’t really know in children yet  Use of PRIFLE/AKIN for classification/study entry  Correlation with/correction for FO  Biomarkers to identify injury earlier  Mortality is not the only outcome  In absence of RCT, continue assertive use of fluid management and CRRT to address FO and sepsis in children

41 Everything will be all right in the end. So if it is not all right, then it is not yet the end.