Avoiding Anticoagulation in CRRT

(1)

2.- When Should we Use Those ? 4.- 1.-Rationale of Using Those Membranes 4.-Comparison with Other Strtegies

AVOIDING ANTICOAGULATION in CRRT: An update on EMERGING MEMBRANES Available in 2012

P.M. Honoré,Intensivist-Internist-Nephrologist Head of Clinics ICU,UZ-VUB University,Jette (Bxl,Bel) 17 th Annual CRRT Congress

Hilton San Diego Bayfront,California,Feb 2012

3.- Recent Data on

Emerging Membranes 6.- Conclusions-_Perspectives

5.- Remaining Problems & Hox To Fix it-

(2)

(3)

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 decide to accept poor filter life if it means avoiding

anticoagulation or over anticoagulation.

 In a patient with consistently short filter life who has had no bleeding complications on the initial starting protocol, where no access or other problems are identified, one may chose to aim for a higher APTT.

(4)

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 first instance

(5)

Site of Action of Anticoagulants



(6)

Mehta,RL. Regional Citrate anticoagulation for CAVHD in critically ill patients . Kidney Int, 38; 976-978, 1990.

Filter Life (hours)

Citrate Heparin

Saline Flushes

(7)

oXiris membrane -

material

Free « amine groups » of PEI → endotoxins adsorption CH₂ CH C

-

CH₂ CH₂ CH₃ CN SO₃Na

-

+ bioactivity AN69 N NH N NH NH₂ NH NH Polyethylene-imine - - - - heparin

(8)

oXiris: Unique Membrane Technology

with a 3-Fold Mode of Action

 Pre-coating w/heparin  reduces membrane thrombogenicity heparin **PEI=PolyEthylene Imine  Surface treatment  provides ability to adsorb endotoxins*

 AN69 core membrane

 efficient renal

support by diffusion & convection, as well as cytokine & toxin

adsorption

Heparin at surface remains active for Inibition of Thrombin

by formation of Thrombin – Anti –Thrombin (TAT) complex

Absorbed on PEI**: the

molecules that are negatively charged like Endotoxins & Heparin

Selectively absorbed into the membrane bulk: all molecules

which can access the membrane pores (MW<35kDa) and have a physico-chemical affinity w/ membrane (ionic binding for the positively charged molecules or hydrophilic interaction)

(9)

Comparison of AN69ST membrane

& oXiris membrane



Membrane core material: AN69 for both



_{Surface treatment: PEI bound to AN69 for}

both but 3 times more PEI for oXiris vs ST



_{Heparin coating:}



During priming with heparinized saline

for AN69ST: 600UI/m² adsorbed heparin



During manufacturing process for oXiris:

(10)

Heparin molecules are bound to PEI

1. The active site of the heparin molecule binds to antithrombin (AT).

2. Antithrombin binds to thrombin (T)—a neutral AT-T complex is formed

3. Thrombin loses its ability to catalyze the conversion of fibrinogen into fibrin 4. Neutral T-AT complex detaches from the heparin molecule.

Heparin binding sites are available again to bind antithrombin, which is specific to the oXiris membrane.

Steps 1–3 are identical to the usual process of systemic heparinization in the bloodstream.

(11)

oXiris use in CRRT – filter survival time

when used without anticoagulation

 Pilot study

25 patients , CVVH without heparin in extracorporeal circuit

Hemofiltration dose: 35 ml/kg/h, 50% pre-dilution 50% post-dilution

Blood flow rate: adjusted to reach a filtration fraction in postdilution < 15%

Ref: O.Martin et Al – Journal de la Société de réanimation de langue française, Jan 2009 Vol.18 – Suppl.1

(12)

oXiris use in CRRT without

anticoagulation

O.Martin et Al – Journal de la Société de réanimation de langue française, Jan 2009 Vol.18 – Suppl.1

(translated

from French)

―Blood was returned to the patient in 66% of cases.

No serious adverse event related to the product

was observed.‖

Conclusion: ―The use of this pre-heparinized

membrane could be a simple and safe alternative

not only to circuit heparinization for high bleeding

risk patients but also to citrate anticoagulation if

the latter is contraindicated.‖

(13)

AN69 ST and CRRT

Improvement of the

non-thrombogenicity

(14)

Clinical studies results

poster - SRLF, January 2007:

Prospective ST100 without heparin compared to retrospective M100 *

 Prospective data on Prisma, ST100 pre without heparin in ECC

45 sets, 33.33% censored data,

Median lifespan: 20h05 - 0.42h to 69.67h

 Retrospective data, on Prisma M100 pre with or without heparin in

ECC

45 sets, 22.22% censored data

Median lifespan: 16h35 - 0.67h to 66.75 h

Even if “median lifespan” is superior for ST, no significant difference was evidenced: a study including more patients is necessary to demonstrate a significant lifespan increase (see next slide).

* Hopital de La Croix-Rousse, Lyon - Pr Guerin

(15)

Survival curves for selected

Retrospective vs Prospective sets

* Hopital de La Croix-Rousse, Lyon - Pr Guerin

Gambro Clinical study report, December 2006 - Study 1434.

Lifetime Study for prospective and retrospective filters - EFFI-STAT - F. MARTEAU - MFIG1 - 24MAR06

0,00 0,10 0,20 0,30 0,40 0,50 0,60 0,70 0,80 0,90 1,00 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 Sets Su rv iv al

Group: Retrospective group treated with AN69 Prospective group treated with AN69 ST

M100 ST100

(16)

Reported average filter life with

AN69 ST sets in CRRT

The average filter

life was :

 75.3

3.2 hrs in

prismaflex ST150,

 61.3 ± 13.6 hrs in

Multifiltrate

&AV1000S

 17 ± 11.3 hrs in

Prisma M100.

(17)

Relative ultrafiltration rates and corresponding mean filter life times are:

1056.4 +/- 164 ml/hr/m² and 51.2 hrs in AV1000S, 1168 +/- 127 ml/hr/m² and 47.1 hrs in Prismaflex ST150 (AN69ST) 1916.7 +/- 314 ml/hr/m² and 16.8 hrs in M 100 (AN69).

Reported average filter life – AN69 ST

in CRRT

(18)

AN69ST compatibility of use with citrate

Regional Citrate Anticoagulation for PrismaFlex CRRT

Lisa D Burry, David D Tung, David Hallett, Toni Bailie, Virginia Carvalhana, David Lee, Steve Ramganesh, Robert Richardson, Sangeeta Mehta, and Stephen

E Lapinsky

The Annals of Pharmacotherapy 2009 September, Vol. 43

• 819 adults admitted to this ICU during the 12-month observation period; 48 (5.9%) patients received CRRT with Prismaflex and citrate. • CRRT performed with the

Prismaflex ST150 set

 Mean filter life was 38.4 ± 25.9

(19)

Lifespan of AN69 ST in CRRT

(Prismaflex ST150 set)

UFH No antico citrate

Int J Artif Organs 2010;33 (3); 139-146 - GR. Kleger, E.Fässler, Switzerland Can circuit lifetime be a quality indicator in continuous renal replacement therapy in the critically ill?

Comparison of effect of different anticoagulation methods on circuit lifetime

(20)

0,0 5,0 10,0 15,0 20,0 25,0 30,0 35,0 40,0 45,0 50,0 0 20 40 60 80 100 120 Tim e m in E n d o to x in E U /m l 0 UI/m ² 5000 UI/m ² 7000 UI/m ² 14000 UI/m ²

Impact of the pre-heparinization

Bovine blood

Does the surface coating with heparin reduce

the ability of the oXiris membrane to adsorb

endotoxins?

Quantity of heparin grafted per

m²

In-vitro test: the heparin coating does not limit the ability of the membrane to adsorb endotoxins

(21)

oXiris - No contact phase activation

(22)

Clots in deaeration chamber



_{Likely to occur in pre-filter}

replacement with heparin or

no anticoagulation



_{Blood/air interface in this}

chamber

Resolution:



Post-filter replacement



_{Pre+Post-filter replacement}



Citrate anticoagulant

blood air

(23)

Clots in deaeration chamber



_{Post dilution}

replacement prevents

clot formation in the

deaeration chamber



_{Blood/fluid/air interface}

is created rather than an

air/blood interface

blood fluid

(24)

(25)

 Modified Membrane such as oXiris is well designed for patients in AKI+sepsis as it combines cytokine adsorption, endotoxin adsorption together with low a thrombogenic CRRT membrane. A randomized

controlled trial is still needed to demonstrate the beneficial use of this membrane for AKI+sepsis patients

 OXIRIS Membrane may offer Endotoxin Adsorption with a CRRT device

 Use of Oxiris® sets in CRRT without addition of heparin in the ECC is feasible and may provide adequate filter lifespan

 The use of this pre-heparinized membrane could be a simple and safe alternative not only to circuit heparinization for high bleeding risk patients but also to citrate anticoagulation if the latter is contra-indicated