oXiris membrane - CRRT Online

AVOIDING ANTICOAGULATION in CRRT: An update onEMERGING MEMBRANES Available in 20121.-Rationale of UsingThose Membranes4.-Comparison withOther Strtegies2.- When Should weUse Those ?5.- Remaining Problems& Hox To Fix it-3.- Recent Data onEmerging Membranes6.- Conclusions-PerspectivesP.M. Honoré,Intensivist-Internist-NephrologistHead of Clinics ICU,UZ-VUB University,Jette (Bxl,Bel)17 th Annual CRRT CongressHilton San Diego Bayfront,California,Feb 2012

How long should filters last• >48 hours is very good• >24 hours is acceptable• < 12 hours is problematic• < 6 hours is very poor• Depending on the patients risk of bleeding one may decideto accept poor filter life if it means avoidinganticoagulation or over anticoagulation.• In a patient with consistently short filter life who has hadno bleeding complications on the initial starting protocol,where no access or other problems are identified, one maychose to aim for a higher APTT.

Patient at high risk of bleeding• With problems such as –• 1.Within 48 hours of surgery 4. Platelets < 50• 2. INR > 2 5. Recent active bleeding• 3. APTT > 50 6. Urea > 45 or ureamic complication• Generally it is worth trying anticoagulant free RRT in the firstinstance

Site of Action of Anticoagulants•

Heparin or CitrateSaline FlushesHeparinFilter Life (hours)CitrateMehta,RL. Regional Citrate anticoagulation for CAVHD incritically ill patients . Kidney Int, 38; 976-978, 1990.

-oXiris membrane - materialCH 3- - - -CH 2 CH CH 2 C SO 3 NaCH 2CN+NH 2NHNNHN-NH---bioactivityNHFree « amine groups » of PEI → 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

Comparison of AN69ST membrane& oXiris membrane• Membrane core material: AN69 for both• Surface treatment: PEI bound to AN69 forboth but 3 times more PEI for oXiris vs ST• Heparin coating:During priming with heparinized salinefor AN69ST: 600UI/m² adsorbed heparinDuring manufacturing process for oXiris:4500UI/m² adsorbed heparin for oXiris

‗Bio-activity‘ of the Grafted HeparinHeparin molecules are bound to PEI1. The active site of the heparin molecule binds to antithrombin (AT).2. Antithrombin binds to thrombin (T)—a neutral AT-T complex is formed3. Thrombin loses its ability to catalyze the conversion of fibrinogen into fibrin4. Neutral T-AT complex detaches from the heparin molecule.Heparin binding sites are available again to bind antithrombin, which is specific tothe oXiris membrane.Steps 1–3 are identical to the usual process of systemic heparinization in thebloodstream.

AN69 ST and CRRTImprovement of the nonthrombogenicity

Clinical studies resultsposter - SRLF, January 2007:Prospective ST100 without heparin compared to retrospectiveM100 *Prospective data on Prisma, ST100 pre without heparin in ECC45 sets, 33.33% censored data,Median lifespan: 20h05 - 0.42h to 69.67hRetrospective data, on Prisma M100 pre with or without heparin inECC45 sets, 22.22% censored dataMedian lifespan: 16h35 - 0.67h to 66.75 hEven if “median lifespan” is superior for ST, no significant difference wasevidenced: a study including more patients is necessary to demonstrate asignificant lifespan increase (see next slide).* Hopital de La Croix-Rousse, Lyon - Pr GuerinGambro Clinical study report, December 2006 - Study 1434.

Sets SurvivalSurvival curves for selectedRetrospective vs Prospective sets1,000,900,800,70M100ST1000,600,500,400,300,200,100,00Group:0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69Retrospective group treated with AN69Prospective group treated with AN69 STTime (hours)Lifetime Study for prospective and retrospective filters - EFFI-STAT - F. MARTEAU - MFIG1 - 24MAR06* Hopital de La Croix-Rousse, Lyon - Pr GuerinGambro Clinical study report, December 2006 - Study 1434.

Reported average filter life withAN69 ST sets in CRRTThe average filterlife was :‣ 75.3 3.2 hrs inprismaflex ST150,‣ 61.3 ± 13.6 hrs inMultifiltrate&AV1000S‣ 17 ± 11.3 hrs inPrisma M100.

Reported average filter life – AN69 STin CRRTRelative ultrafiltration ratesand corresponding mean filterlife times are:‣1056.4 +/- 164 ml/hr/m²and 51.2 hrs in AV1000S,‣1168 +/- 127 ml/hr/m² and47.1 hrs in Prismaflex ST150(AN69ST)‣1916.7 +/- 314 ml/hr/m²and 16.8 hrs in M 100(AN69).

AN69ST compatibility of use with citrateRegional Citrate Anticoagulation for PrismaFlex CRRTLisa D Burry, David D Tung, David Hallett, Toni Bailie, Virginia Carvalhana,David Lee, Steve Ramganesh, Robert Richardson, Sangeeta Mehta, and StephenE LapinskyThe Annals of Pharmacotherapy 2009 September, Vol. 43• 819 adults admitted to this ICUduring the 12-month observationperiod; 48 (5.9%) patients receivedCRRT with Prismaflex and citrate.• CRRT performed with thePrismaflex ST150 set‣ Mean filter life was 38.4 ± 25.9hours.

Lifespan of AN69 ST in CRRT(Prismaflex ST150 set)UFHcitrateNo anticoComparison ofeffect ofdifferentanticoagulationmethods oncircuit lifetimeInt J Artif Organs 2010;33 (3); 139-146 - GR. Kleger, E.Fässler, SwitzerlandCan circuit lifetime be a quality indicator in continuous renal replacementtherapy in the critically ill?

EndotoxinEU/mlDoes the surface coating with heparin reducethe ability of the oXiris membrane to adsorbendotoxins?Impact of the pre-heparinization50,045,040,035,030,025,020,015,010,05,00,00 20 40 60 80 100 120Tim e m inBovine blood0 UI/m²5000 UI/m²7000 UI/m²14000 UI/m²Quantity ofheparingrafted perm²In-vitro test: the heparin coating does not limit the ability of the membrane toadsorb endotoxins

oXiris - No contact phase activationin-vitro data

Clots in deaeration chamber• Likely to occur in pre-filterreplacement with heparin orno anticoagulation• Blood/air interface in thischamberResolution:• Post-filter replacement• Pre+Post-filter replacement• Citrate anticoagulantairblood

Clots in deaeration chamber• Post dilutionreplacement preventsclot formation in thedeaeration chamber• Blood/fluid/air interfaceis created rather than anair/blood interfaceairfluidblood

Conclusions & Perspectives‣ Modified Membrane such as oXiris is well designed for patients inAKI+sepsis as it combines cytokine adsorption, endotoxin adsorptiontogether with low a thrombogenic CRRT membrane. A randomizedcontrolled trial is still needed to demonstrate the beneficial use ofthis membrane for AKI+sepsis patients‣ OXIRIS Membrane may offer Endotoxin Adsorption with a CRRTdevice‣ Use of Oxiris® sets in CRRT without addition of heparin in the ECCis feasible and may provide adequate filter lifespan‣ The use of this pre-heparinized membrane could be a simple and safealternative not only to circuit heparinization for high bleeding riskpatients but also to citrate anticoagulation if the latter is contraindicated