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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 The Problem of Sepsis in Children 42,000 pediatric sepsis cases/year Annual cost > $2 billion Increased mortality 5.49.5/100,000 Pediatric sepsis mortality rate in US: 10.3% - Watson RS, Carcillo JA, AJRCCM 2003 2 World Sepsis Day Thursday, September 13, 2012 3 3 Sepsis: A Global Problem With Much To Be Done Join. www.world-sepsis-day.org Pediatric Sepsis Mortality Overall pediatric mortality lower than adults (~10% vs. 2060%) Respiratory Failure < 5 % Single organ failure rarely leads to mortality CV Failure < 5 % Immunologic Failure < 5 % Hematologic Failure < 5 % Renal Failure < 5 % 5 The MODS/Sepsis Patient Respiratory Failure Immunologic Failure Cardiovascular Failure HIGH MORTALITY 50-90% Hematologic Failure 6 Renal Failure -Courtesy of Matt Paden 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) 7 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 8 Direct Effect?: Removing The Evil Humours 9 Blood Phlegm Yellow Bile Black Bile Peak Concentration Model of Sepsis Pro-inflammatory Mediators Anti-inflammatory Mediators Immunohomeostasis IL-10 CRRT/Plasma Exchange TNF PAF IL-1 SIRS CARS SIRS CARS Time Immunohomeostasis CRRT/Plasma Exchange SIRS/CARS Time 10 Adapted from Ronco et al. Artificial Organs 27(9) 792-801, 2003 Experimental Support for CRRT in Sepsis Multiple animal studies suggest physiologic and survival benefit 11 -McMaster et al. Ped CCM, 2003 CVVH – Restoration of Immune Homeostasis 12 -Paden ML, et al. Ped Neph 2006 24 Hours off CVVH End of CVVH 48 Hours 24 Hours 12 Hours Pre-CVVH Reduction of cytokines, chemokines, modulators of apoptosis • Convective removal • Membrane adsorption 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 13 Solute Molecular Weight and Clearance Solute (MW) Urea (60) 1.01 ± 0.05 1.01 ± 0.07 Creatinine (113) 1.00 ± 0.09 1.01 ± 0.06 Uric Acid (168) 1.01 ± 0.04 0.97 ± 0.04 Vancomycin (1448) 0.84 ± 0.10 0.74 ± 0.04 Cytokines (medium) cleared minimal clearance adsorbed minimal clearance Cytokines (large) 14 Convective Coefficient Diffusion Coefficient Impact of Early High Dose CRRT on Cytokines in Adult Sepsis: RCT Results IL-6 IL-10 15 IL-8 TNF-a -Cole et al., Crit Care Med 2002 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 16 Indirect Benefit?: Fluid Balance in Sepsis 17 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 18 -Boyd et al., Crit Care Med, 2011 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 (1.0-1.1; p = 0.001) 19 19 -Vincent et al., Crit Care Med 2006 Effect of Fluid Overload on Outcome in CRRT N=113 20 *p=0.02; **p=0.01 - Foland, Fortenberry et al., CCM 2004 Theory: The Fluid/Outcome Balance Fluid Balance SIRS Mortality, Vent LOS Immunohomeostasis CARS Stimulus 21 21 Time Does therapy change the late phase outcome in sepsis? 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? 22 Effect of Filtration Rate on Outcome in Septic Adults with CVVH: Is More Better? 425 patients Endpoint = survival 15 days after D/C HF 146 UF rate 20ml/kg/hr 41 % survival 139 UF rate 35ml/kg/hr 57 % survival p=0.0007 140 UF rate 45ml/kg/hr 58 % survival p=0.0013 At last, an answer! 23 - Ronco et al. Lancet 2000; 351: 26-30 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 24 -N Engl J Med. 2009 Meta-Analysis: No Benefit of High Dose CRRT in Adult Sepsis 25 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) 26 -Payen et al., Crit Care Med, 2009 Early CRRT in Sepsis: RCT 27 -Payen et al., Crit Care Med, 2009 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 28 -Boussekey et al. Intensive Care Med. 2008 Focusing on the most important outcomes 29 29 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 30 CRRT Use and Diagnosis: ppCRRT Registry 31 -Symons et al. Clin J Am Soc Nephrol 2007 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 32 -Goldstein et al., Kidney International, 2005 Can Combination Therapies Help in Sepsis? Addition of plasma filtration coupled with adsorption, followed by dialysis or filtration (CPFA) Polymyxin impregnated fibers 33 Hemoperfusion: Endotoxin Adsorption Polymyxin B: high affinity for endotoxin Charcoal hemoperfusion device: adsorption column Significant experience in Japan, Europe 34 EUPHAS Trial: Survival 23/34 (68%) 14/30 (47%) Hazard Ratio 0.43 (0.21-0.90) 35 -Cruz et al., JAMA, 2009 Is it all in how we measure? 36 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 37 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….” 38 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 39 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 40 Everything will be all right in the end. So if it is not all right, then it is not yet the end. 41