Hybrid Therapies: P.M. Honoré,Intensivist-Internist-Nephrologist. 16 th Annual CRRT Congress Hilton San Diego Bayfront,California,Feb 2011

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1 Clin Studies for HVHF,HPHF&Hybrid Hybrid Therapies: Chaired Worshop with Pr P Olivier Joannes-Boyau 1.-Rationale of New Modified Membranes 2.-How to Increase Removal: «The Active Transportation Theory» 3.- Recent Data on Large Bore Membranes 4.-Most Recent Data on Hyper-Adsoptive Membranes 5.- Recently Completed Trials on Hybrid Techniques 6.- Conclusions- Perspectives P.M. Honoré,Intensivist-Internist-Nephrologist Head of Clinics,VUB University,Bxl(Bel) 16 th Annual CRRT Congress Hilton San Diego Bayfront,California,Feb 2011

2 I) Rationale:Where to Remove? The «Multiple Compartments Hypothesis» 30 Sq Meter 300 Sq Meter 1)Honore PM et al, Blood Purif 2009;27: :1-11

3 II) Rationale:How to Increase Removal? The «Active Transportation Hypothesis» 40 % 30 Sq Meter Exchange Volume of 3-4 Liters/H 4 % 300 Sq Meter Active Transportation 80 Fold 2)Di Carlo J,Alexander S. IJAO 2005

4 II) Rationale:How to Increase Removal? The «Active Transportation Hypothesis»:How To Measure? Nuclear Imaging of Mediators Through Lymphatic Thoracic Duct Ponction of Mediators Tissular Apoptosis Oxidative Stress Liver Biopsy NF-Kappa-B Pro-Mediators 3)Honore PM et al, Blood Purif 2009;28: :

5 III) Should We Target SIRS,Immunoparalysis or Both? Anti-LPS Anti-TNF Anti-IL-1 Anti-IL-10 Blood Purif. IL-10 Immunologic Support INSULT TNF IL-1 IL-6 RECOVERY Time Hyperinflammation - Immunparalysis

6 III) Should We Target SIRS,Immunoparalysis or Both? Age Charlson >0 Race, white Sex, female IL-6/IL-10 pattern Low/medium Medium/low Low/high High/low Medium/medium Medium/high High/medium High/high Hazard ratio 4) Cox Model in GenMS Study Kellum et al, Arch Intern Med 2007

7 Solute Classes by Molecular Weight Daltons Inflammatory Mediators (1,200-50,000) large middle small

8 Hybrid Systems : A Possible Threat? Proteins with molecular weight 1 M Daltons have a sieving coefficient near 1 Global decrease of proteins Immunoglobulins Inflammation Proteins TNF decrease of about 60% Ag Removal is Feasible (Ag HBs)

9 septex TM clinical safety- data SepteX clinical safety data

10 Stable albumin plasma levels during septex treatment N=24 pts CVVH/ CVVHD Am J Kidney Dis. 2004, 43: SepteX clinical safety data

11 Coagulation Status During High Cut-Off Hemofiltration N=16 pts CVVH SepteX clinical safety data Intensive Care Med 2003;29:

12 HCO treatment reduces significantly inflammatory mediator plasma levels SepteX - HCO treatment reduces significantly inflammatory mediator plasma levels

13 Substantial Reduction of Plasma IL-6 Levels Course of IL-6 plasma level during treatment with septex/hco N=24 pts CVVH Intensive Care Med 2003;29: SepteX - HCO treatment reduces significantly inflammatory mediator plasma levels

14 Interleukin-6 plasma values N=20 pts CVVH N=10 pts CVVH Crit Care Med. 2006;34: SepteX - HCO treatment reduces significantly inflammatory mediator plasma levels

15 Cellular immunomodulation through HCO treatment SepteX - Cellular immunomodulation

16 Human sepsis studies: T-Lymhocyte Proliferation is Reduced in Sepsis Muret et al Shock 2000 Hoffmann et al Kidney Int Heidecke et al Am J Surg Monocyte phagocytosis is elevated in Sepsis Simms HH, D'Amico R. Blood. 1994;83: Spark JI, Scott DJ. Br J Surg. 2001;88: SepteX - Cellular immunomodulation

17 HCO/septeX treatment restores lymphocyte proliferation in septic patients N=28 pts CVVH healthy volunteer standard HCO healthy volunteer standard HCO NDT, 2003;18: SepteX - Cellular immunomodulation

18 HCO/septeX treatment reduces monocyte phagocytosis rate of septic patients CVVH Nephron Clin Pract. 2003;94:75-80 SepteX - Cellular immunomodulation

19 SepteX TM Clinical benefits through HCO treatment SepteX clinical benefits

20 Norepinephrine requirement is reduced with septx/hco P= MAP [mmhg] P= MAP [mmhg] N=20 pts CVVH N=10 pts CVVH SepteX clinical benefits Crit Care Med. 2006;34:

21 Improvement in Simplified Acute Physiology Score (SAPS) II N=20 pts CVVH N=10 pts CVVH SepteX clinical benefits Crit Care Med. 2006;34:

22 Recent HPHF Studies in Sepsis: ml / min IL-6 Clearance CVVH UF-rate 2.5L/h Sieving coefficient: Morgera S,Bellomo R et al.crit Care Med. 2006;34:

23 Recent HPHF Studies in Sepsis: HICOSS (High Cut-Off Sepsis Study) Multicenter study with septex / HCO in septic AKI PI Dr. Morgera (Berlin), Prof. Joannidis (Innsbruck), Prof. Risler (Tübingen), Prof. Max (Marburg), Prof. Schindler (Berlin) Primary objective: Reduction of catecholamine requirements by High Cut off-cvvhd Secondary objectives: clinical improvements and Safety (albumin levels), SOFA Study design: Prospective, randomized, double-blinded multicenter study Two parallel study-arms: High Cut Off (HCO/Septex 1.1m2) compared to high flux (Polyflux 1.1m2) 120 pts, powered to show a 50% reduction in catecholamine use (at interims analysis: 81 patients enrolled, 7 drop outs) Stratification for disease severity (APACHE score 19 to 30) and age 5 days treatment period (CVVHD) and follow up of catecholamine use 28 days follow-up period Honore PM et al. 10th Congress of WFSICCM.Florence 2009 In preparation for publication

24 VI)Hybrid Systems Recent HPHF Studies in Sepsis HCO versus standard high flux HICOSS Study Results Day 28 _ Days on Norephrinine (10,0 ±9 vs 11,3 ±9) N= 81 pts CVVHD _ Days on Ventilation (13,9 ±11 vs 16,1 ±11) _ Need for RRT (9,1 ±8 vs 9,5 ±8) HCO High-Flux 19) Honore PM et al. 10th Congress of WFSICCM.Florence 2009 In preparation for publication

25 HCO vs standard high flux Recent HPHF Studies in Sepsis: _ mortality (31 vs 33%) both groups lower than predicted by APACHE score HICOSS study results day 28 N= 81 pts CVVHD _ days in ICU (19±12 12 vs 19±11) 11) HCO High-Flux In preparation for publication Honore PM et al. 10th Congress of WFSICCM.Florence 2009

26 Recent HPHF Studies in Sepsis: Safety: Stable plasma albumin levels with septex/ HCO compared to standard high flux -CVVHD N= 81 pts CVVHD Membrane High Flux Membrane HCO In preparation for publication Honore PM et al. 10th Congress of WFSICCM.Florence 2009

27 Recent HPHF Studies in Sepsis: Synergy with HVHF? CVVH + HPHF= 1l/h = 16.6 ml/kg/h HVHF+HPHF = 6 l/h = 80 ml/kg/h Uchino el al, Int Care Med 2002; 28:

28 AN69 ST* and Heparin Adsorption Hep. Hep. Hep. Polyethyleneimine heparin Hep.

29 Effect of Surface Modification on Membrane Properties of AN69ST Permeability ml/(h.m_.mmhg) Adsorption TNF (ng/m_) Adsorption kinetics of IL-6 in plasma AN69 AN69ST AN69 AN69ST

30 oxiris: Grafting Mechanism (Heparin) Unfractionated heparin without chemical modification CH 2 CH CH 2 C SO 3 Na - CN CH CH 2 + NH 2 NH N NH N NH heparin Available active sites for AT link NH Free amine groups

31 oxiris: Adsorption of Low-Molecular Weight Proteins AN69 membrane: symetrical / dense microstructure homogeneous distribution of sulphonate groups high sieving coefficient for low molecular weight proteins (< Da) Adsorption mechanism based on ionic binding in bulk Selective part 600 nm

32 _2M Adsorption Isotherms Porous AN69 Non-porous AN69 Clark et al, Kidney Int 1994

33 oxiris: Action Mode Low molecular weight protein adsorption properties LMW protein Basic AA residues AN69 polymer chain polymeric chain interaction Adsorption of low molecular weigt proteins to hemodialysis membranes: experimental results and simulations - P. Valette, M. Thomas, P. Déjardin Biomaterials, 20, 1999, 1621 Influence of the charge of low molecular weight proteins on their efficiency of filtration and / or adsorption on dialysis membranes with different intrinsic properties - N. Moachon, M. Thomas, G. Quash Biomaterials, 23, 2002, 651

34 oxiris: Action Mode Endotoxin adsorption Endotoxin: large MW molecule ( to 5M) major component of gram bacteria chemical composition: polysaccharide, carbohydrate and lipid A (LPS) Lipid A (active part of endotoxin) O O P - O O Ionic bonding with free amine groups of PEI ** S. Morimoto et al, Polymer journal, vol.27, 8, 1995, 831 S. Mitzner et al, Artificial organs, 17 (9), 1993, 775

35 oxiris: membrane adsorption capacity Rimmele T et al., NDT 2009;24: Strong irreversible bonds in-between sulfonic groups of membrane hydro-gel and basic amino acid groups of proteins: No desorption during therapy.

36 Endotoxin Removal - oxiris Endotoxin plasma concentration endotoxin plasma concentration 12 LAL response EU/mL AN69 oxiris Rimmele T et al., NDT 2009;24: time of CVVH hour

37 Endotoxin Removal - oxiris Endotoxin plasma concentration endotoxin plasma concentration 12 LAL response EU/mL AN69 oxiris Rimmele T et al., NDT 2009;24: time of CVVH hour

38 Ongoing PRT s: The IVOIRE Study GFR Criteria* Urine Output Criteria Risk Increased creatinine x1.5 or GFR decrease > 25% UO <.5ml/kg/h x 6 hr High Sensitivity Injury Increased creatinine x2 or GFR decrease > 50% UO <.5ml/kg/h x 12 hr Failure Increased creatinine x3 or GFR dec >75% or creatinine 4mg/dl (Acute rise of 0.5 mg/dl) UO <.3ml/kg/h x 24 hr or Anuria x 12 hrs High Specificity Loss ESRD Persistent ARF** = complete loss of renal function > 4 weeks End Stage Renal Disease Joannes-Boyau O, Honore PM.

39 VII)The Future: Delivered Dose vs Prescribed Dose The DO-RE-MI Study ICU length of stay and ventilation days by RRT dose Total CRRT < 35 ml/kg/hour 35 ml/kg/hour P Length of ICU stay (days) 15 (9 to 28) 8 (4 to 18) < Patients who survived 19.5 (12 to 33.5) 15 (8 to 26) Patients who died 12 (6 to 20) 4.5 (3 to 9.5) < Duration of MV (days) 12 (5 to 21) 5 (2.5 to 13) < Patients who survived 14 (5 to 24) 7 (4 to 17) Patients who died 10 (5 to 18) 4 (2 to 9.5) < )Vesconi S et al.crit Care 2009 :EAD

40 DoReMi Database (N=865) Median delivered = 27 ml/kg/h Ronco et al, 2009 Median prescribed = 34 ml/kg/h Patients (%) < >=75 Dose of CRRT (ml/kg/hr) Dose of CRRT (ml/kg/h) Delivered dose Prescribed dose

41 Conclusions & Perspectives Classical Techniques with Standard Cut-off may not target most of the mediators seen during Sepsis & SIRS Timing of Intervention Regarding SIRS or CARS shows that Intervention on both Sides might be Beneficial.. Recent Hyperpermeable (Septex) Studies are showing that the Technique is safe concerning Albumin losses Modified Membranes such as oxiris may improve cytokine adsorption, endotoxin adsorption and may promote regional anticoagulation.. Results of Studies like IVOIRE & Beyond are Awaited with Eagerness..and do carrying for the time being a Very Low Global Mortality Rate.. OXIRIS Membrane may offer Endotoxin Absorption with A CRRT device.. Synergy between HVHF & Hyperpermeable membrane should be investigated 35 ml/kg/h + septex vs 35 ml/kg/h + classical membrane maybe a possibility..