endotoxins adsorption - CRRT Online

Exp Studies for HVHF,HPHF&Hybrid Therapies:Chaired Worshop with Pr M.Matejovic1.-Rationale of NewModified MembranesIn CRRT4.Rationale 4.- on ModifiedAN 69 Membranes withEndotoxin Adsorption2.- Rationale of ABPin SIRS post-Bypass5.- Recently CompletedTrials..3.- Rationale of HybridTherapies in Sepsis6.- Conclusions-PerspectivesP.M. Honoré,Intensivist-Internist-NephrologistHead of Clinics,VUB University ,Bxl(Bel)17 th Annual CRRT CongressHilton San Diego Bayfront,California,Feb 2012

II) Rationale:How to Increase Removal ?The «Active Transportation Hypothesis »:How To Measure ?NuclearImagingof MediatorsThroughLymphaticThoracicDuctPonctionofMediatorsTissularApoptosisOxidativeStressLiverBiopsyNF-Kappa-BPro-Mediators3)Honore PM et al, Blood Purif 2009;28:135-147

III) Should We Target SIRS,Immunoparalysis or Both ?Anti-LPSAnti-TNFAnti-IL-1Anti-IL-10Blood Purif.IL-10Immunologic SupportTNFIL-6RECOVERYIL-1TimeHyperinflammation - Immunparalysis

III) Should We Target SIRS,Immunoparalysis or Both ?AgeCharlson >0Race, whiteSex, femaleIL-6/IL-10 patternLow/mediumMedium/lowLow/highHigh/lowMedium/mediumMedium/highHigh/mediumHigh/high0.1 1 2 510 50Hazard ratio4) Cox Model in GenMS Study Kellum et al, Arch Intern Med 2007

Solute Classes by MolecularWeightDaltons• Inflammatory Mediators (1,200-50,000)“large”“middle”“small”

Recent HPHF Studies in Sepsis: New functionalmembrane with defined large pore sizeHCO membrane

Recent HPHF Studies in Sepsis:mL / minIL-6 ClearanceCVVHUF-rate 2.5L/hSieving coefficient:0.010.010.000.930.930.84Morgera S,Bellomo R et al.Crit Care Med. 2006;34:2099-04

Recent HPHF Studies in Sepsis:Safety: Stable plasma albumin levelswith septeX/ HCO compared to standard high flux -CVVHDN= 81 ptsCVVHDMembrane High FluxMembrane HCOIn preparation for publicationHonore PM et al. 10th Congress of WFSICCM.Florence 2009

VI)Hybrid Systems Recent HPHF Studies in SepsisHCO versus standard high fluxHICOSS Study Results – Day 28● Days on Norephrinine (10,0 ±9vs 11,3 ±9)N= 81 ptsCVVHD● Days on Ventilation (13,9 ±11 vs16,1 ±11)● Need for RRT (9,1 ±8 vs 9,5 ±8)HCOMembrane AHigh-FluxMembrane B19) Honore PM et al. 10th Congress of WFSICCM.Florence 2009In preparation for publication

Recent HPHF Studies in Sepsis: Synergy with HVHF ?CVVH + HPHF= 1l/h =16.6 ml/kg/hHVHF+HPHF = 6 l/h =80 ml/kg/hUchino el al , Int Care Med 2002; 28: 651-655

Hybrid Systems : The Possible Answer ?• Proteins with molecular weight ≤ 1 M Daltons have asieving coefficient near 1• Global decrease of proteins Immunoglobulins Inflammation Proteins TNF decrease of about 60% Ag Removal is Feasible (Ag HBs)

Plasmapheresis vs Plasma Exchange• Plasma Exchange(PE) centrifugation membrane• Plasmapheresis (PP) orPlasmafiltration (PF)PLASMA FILTERPLASMA FILTERPlasmaPlasmaFFP/colloid/IgGPatientHonore PM et al.Ann Intensive Care 2011PatientADSORBANTCOLUMN

Hybrid Systems : PMX Cartridges(EUPHAS)64 Post-Surgical SepsisRandomizationPMX Treatment for 2 Sess (N=34)Standard Therapy (N=30)34 PMX Treatment 30 Standard TherapySOFA Score Improved No Changes(P)Hemodynamics(MAP) Improved No Improvement(P)28 Days Mortality 32 % 55 % (P 0.43)Vasopressors Decreased No Changes(T)22) Cruz D et al JAMA 2009; 301:2445-2452

Newly AdsorptiveMembranes: All in One ?Daltons• Inflammatory Mediators (1,200-50,000)“large”“middle”“small”Honore PM et al., Ann of Intensive Care 2011;1:24

AN69 ST* and Heparin AdsorptionHep.Polyethyleneimineheparin

Effect of SurfaceModification on MembraneProperties of AN69STPermeabilitymL/(h.m².mmHg)3020Adsorption TNF(ng/m²)9060Adsorption kinetics of IL-6 in plasma1030AN69 AN69ST AN69 AN69ST

-New HyperAdsorptive Membrane(oXiris)CH 3- - - -CH 2 CH CH 2 C SO 3 NaCH 2CN+NH 2NHNNHN-NH--bioactivity-NHFree « amine groups »: endotoxins adsorptionAN69Polyethylene-imineheparin

oXiris: Unique Membrane Technologyheparinwith a 3-Fold Mode of Action**PEI=PolyEthylene Imine‣ Pre-coating w/heparin Heparin reduces at surface membraneremainsthrombogenicityactive for Inibition of Thrombinby formation of Thrombin –Anti –Thrombin (TAT) complex‣ Surface treatment provides Absorbed on ability PEI**: the toadsorb molecules endotoxins*that are negativelycharged like Endotoxins &Heparin‣ AN69 core membrane efficient renalSelectively absorbed into thesupport membrane bulk: by diffusion all molecules &convection, which can access the as membrane well ascytokine pores (MW

oXiris: Action ModeLow molecular weight proteinadsorption propertiesLMW proteinBasic AA residuesAN69 polymer chainpolymeric chaininteraction• 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. QuashBiomaterials, 23, 2002, 651

oXiris: Action ModeEndotoxin adsorptionEndotoxin:‣ large MW molecule (100 000 to 5M)‣ major component of gram – bacteria‣ chemical composition: polysaccharide, carbohydrate and lipid A (LPS)Lipid A (active part of endotoxin)OOP-OOIonic bondingwith free aminegroups of PEI** S. Morimoto et al, Polymer journal, vol.27, 8, 1995, 831S. Mitzner et al, Artificial organs, 17 (9), 1993, 775

Endotoxins adsorption – in vitroHonore PM,Clark W et al.,Proceeding of the 10 WFCCM,Florence 2009

oXiris: Adsorption of Low-MolecularWeight ProteinsAN69 membrane:‣ symetrical / dense microstructure‣ homogeneous distribution of sulphonate groups‣ high sieving coefficient for low molecular weight proteins (< 40 000Da)Adsorption mechanism based on ionic binding in bulkSelective part600 nm

Β2M Adsorption IsothermsPorous AN69Non-porous AN69Clark et al, Kidney Int 1994

oXiris: membrane adsorption capacityRimmele T et al., NDT 2009;24:354-357Strong irreversible bonds in-between sulfonic groups of membrane hydro-gel and basic aminoacid groups of proteins: No desorption during therapy.

LAL response EU/mLEndotoxin Removal - oXirisEndotoxin plasma concentrationendotoxin plasma concentration1210864AN69oXiris200 2 4 6 8time of CVVH hourRimmele T et al., NDT 2009;24:354-357

IVOIRE STUDY140patients with Septic Shock and Acute KidneyInjury35ml/kg/hRandomizationwithin 24 hours ofICU admission(! Early septicshock)70ml/kg/hAny dose ofvasopressors(Noradrenaline)Or > 5µg/kg/m ofDopamine- Oliguria < 0.5ml/kg/h- creatinine X 2MortalityRIFLE InjuryD28D9030

RIFLE CriteriaGFR CriteriaUrine Output CriteriaRiskInjuryIncreased creatininex1.5 or GFR decrease> 25%Increased creatinine x2or GFR decrease > 50%UO < .5ml/kg/hx 6 hrUO < .5ml/kg/hx 12 hrHighSensitivityFailureLossESKDIncrease creatininex3or GFR decrease> 75%UO < .3ml/kg/hx 24 hr orAnuria x 12 hrsPersistent ARF** = complete loss ofkidney function > 4 weeksEnd Stage Kidney Disease(> 3 months)HighSpecificity

Patient flow diagram167 patients assessed for eligibility27 Excluded14 Refuse participation2 Obesity > 150 kg11 Met exclusion criteria140 Randomized2 patients excluded1 Withdraw consent1 Acute leukemia1 patient excluded1 Withdraw consent66 patientsanalyzed71 patientsanalyzed

VIII) The Future: Ongoing PRT’s: The IVOIRE StudyhIgh VOlume in Intensive caRE• End of 2008 :140 patients included,Study endeed..• Mortality at Day 28 : 39 %• Mortality at Day 90 : 51 %• Expected Mortality by 3 severity scoresSOFA, SAPS II & LOD• 68 %

Hemodiafe studyATN studyRenal studyIVOIRE66/Mortality73 %60 %52 %49 %

=75Patients (%)Patients (%)DoReMi Database (N=865)605040Median delivered = 27 mL/kg/hRonco et al, 2009Median prescribed = 34 mL/kg/h3020100Dose Dose of of CRRT CRRT (mL/Kg/hr) (mL/kg/h)Delivered dose Prescribed dose

Conclusions & Perspectives‣ Classical Techniques with Standard Cut-off may not target most of themediators seen during Sepsis & SIRS…‣ Timing of Intervention Regarding SIRS or CARS shows that Intervention onboth Sides might be Beneficial..‣ Recent Hyperpermeable (Septex) Studies are showing that the Technique issafe 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 should be released during thiscongress..and do carrying for the time being a Very Low Global MortalityRate..‣ OXIRIS Membrane may offer Endotoxin Absorption with A CRRT device..‣ Synergy between HVHF & Hyperpermeable membrane should be investigated35 ml/kg/h + septeX vs 35 ml/kg/h + classical membrane maybe a possibility..