Biocompatibility Assessment of Edwards Vantex Central Venous Catheter

with Oligon Material vs. Chlorhexidine and Silver Sulfadiazine

(Antiseptic) Coated Central Venous Catheter

Vantex CVC Whitepaper 03Vantex CVC vs. Antiseptic CVC

Written by:

Jeffrey M. Lohre, M.A.Edwards Lifesciences LLC

John W. Sagartz, D.V.M.,Diplomate, A.C.V.P.

IntroductionCentral venous catheters (CVC) are integral to the care ofcritically ill patients. Nosocomial infections associated withCVC’s are a serious medical complication. To address thisproblem, numerous methods have been developed to modify the surface of catheters to reduce bacterial adherence and biofilmformation. Two such products commercially available today arethe Edwards Vantex CVC with Oligon material (with or withoutheparin coating*) and a chlorhexidine/silver sulfadiazine coatedCVC from Arrow International, Inc. (antiseptic-coated CVC).

The Vantex CVC utilizes an antimicrobial material called Oligonthat is extruded from polyurethane combined with natural silverand platinum metals and carbon black. Since the antimicrobialproperties are integral to the Oligon material, antimicrobialprotection is inherent to both the inner and outer surfaces of thecatheter. The antiseptic-coated CVC is comprised of silversulfadiazine and chlorhexidine, which is only (at the time this testwas conducted) applied to the outer surface of the catheter.While both CVC devices have been shown to be efficacious atreducing bacterial growth in limited studies, the potential forallergic or sensitivity response of patients exposed to thesecatheters has not been thoroughly researched. The aim of thisstudy was to examine the biocompatibility of both of theseantimicrobial catheters.

Body fluids interact withsilver and platinum particles in the material,

causing a release of silver ions.

SilverIon

PlatinumParticle

SilverParticle

Electrolyte Electron

LEGEND

Test MethodThe biocompatibility of the Vantex CVC with Oligon material(with or without heparin coating) and the chlorhexidine/silversulfadiazine coated CVC (antiseptic-coated CVC) wereevaluated as suggested in the International StandardsOrganization (ISO) 10993-1-1994 Biological Evaluation ofMedical Devices – Part 1: Guidance on Selection of Tests andthe FDA General Program Memorandum No. G95-1. Thespecific test procedures performed were:

In Vivo Tests

• USP Mouse Systemic Injection – Normal Saline and Vegetable Oil Extracts.

• USP Rabbit Intracutaneous Irritation – Normal Saline andVegetable Oil Extracts.

• Guinea Pig Maximization Test – Normal Saline andVegetable Oil Extracts.

• USP Rabbit Intramuscular Implantation with HistologicalEvaluation – Approximately 7-and 30-Day Implant Duration(considered to be Sub-Chronic Evaluation).

• Genotoxicity: Mouse Micronucleus Test – Normal Saline and5% Ethanol in Normal Saline Extracts.

In Vitro Tests

• Agar Overlay – Solid Sample.

• Medium Eluate Method (MEM).

• Blood Compatibility.

• Genotoxicity: Ames Plate Incorporation Test – Normal Salineand 5% Ethanol in Normal Saline Extracts.

• Genotoxicity: Sister Chromatid Exchange Test – DistilledWater and 1% Ethanol in Normal Saline Extracts.

• Genotoxicity: Mouse Lymphoma Assay – Normal Saline andEthanol Extracts.

The test articles for this study were treated portions of therepresentative test samples. This comprised both the internaland external surfaces of the Vantex CVC with Oligon materialsample, and only the external treated surface area of theantiseptic-coated CVC. Extracts were prepared at a ratio of 6cm2 of surface area of each test article per milliliter extractionmedium (120 cm2/20 mL) as recommended by both theInternational Standards Organization (ISO) 10993-12: SamplePreparation and Reference Materials and the United StatePharmacopoeia 23 for material of ≤ 0.5 mm thickness.

Exceptions to the test sample size were the heparin coatedOligon Sister Chromatid Exchange Test samples, which wasevaluated at 1.0 cm2/mL as part of a whole device evaluation.Blood Compatibility testing of the non-heparin coated Oligonbody tubing was performed at 6 cm2/mL but was reduced to 3 cm2/mL due to slight hemolysis noted at the elevatedconcentration in the static testing of both the material andextract thereof. The reduction in sample to extractconcentrations was considered acceptable based on industrystandards for materials evaluation for the Blood CompatibilityTest and was required due to the known cytotoxic nature of thetest article in the Sister Chromatid Exchange Test.

All extracts were prepared at 70 ± 2°C for 24 ± 1 hours asacceptable in the same two guidelines (more elevatedtemperatures were considered inappropriate given the nature ofthe base materials and the presence of coatings; whereas,reduced temperatures were not selected as the product wasexposed to temperatures similar to the 70°C extractiontemperature during the sterilization of the product). Theexception to the 70°C extraction which uses a 37 ± 2°Ctemperature for 24 ± 2 hours per the industry standard testmethodology. All studies were conducted in accordance withGLP regulations, in that strict compliance to standardoperating procedures was maintained; however, the studiesmust be considered non-GLP as the protocol, final report,QAU audits and record storage were not in strict complianceto Federal Register 21 CFR Part 58.

Test Results and Discussion†

Vantex CVC with Oligon Material ResultsThe Vantex CVC with Oligon material (non-heparin coated)demonstrated biocompatibility in all test procedures at themaximum concentration evaluated in all procedures except theBlood Compatibility static evaluation of the solid and extractsamples. In all other tests, there was no evidence of systemictoxicity, intracutaneous or intramuscular irritation, cytotoxicity,hemolysis (in the dynamic environment more representative ofthe clinical application), effect on clotting time, or genotoxicpotential. The exception to these results was the BloodCompatibility Test on the static samples. Both the solid sampleand extracts were all found to be non-hemolytic at levels inexcess of the clinical application of the material with theexception of the solid and extract samples in the staticenvironment. When reduced to a sample to extractconcentration of 3 cm2/mL, the extract was determined to benon-hemolytic. This solid sample was still determined to beminimally hemolytic (11.6% hemolysis with a non-hemolyticacceptance criteria of < 5% hemolysis) at the reducedconcentration. This minimal hemolysis was not consideredsignificant due to the dynamic environment present in theclinical application and the recognized slightly toxic and anti-microbial properties of this Oligon material.

Similarly, the Vantex CVC with Oligon material (treated withheparin) was determined to show no evidence of systemictoxicity in the Mouse Micronucleus Test, sensitization potential,or genotoxic potential. The heparin-treated catheter diddemonstrate cytotoxicity in the Sister Chromatid Exchange(SCE) procedure at the elevated concentrations evaluated,therefore requiring testing at the reduced concentrations. Theheparin-treated catheter also demonstrated a host response ofmild cytotoxicity intramuscularly at the 7-day duration, with nohost response noted at the 30-day explant. These results wereanticipated due to the presence of the surfactant used as abinding agent for the heparin, and were evidenced in theseprocedures due to the sensitivity of the procedures and theirstatic nature, which does not provide a system similar to theclinical application.

Chlorhexidine/Silver Sulfadiazine(Antiseptic) Coated CVC ResultsThe antiseptic-coated CVC was found to have a heightenedresponse in six of the eight procedures as compared to theVantex CVC with Oligon material (non-heparin coated) at themaximum concentration evaluated. While there was noevidence of intracutaneous irritation or sensitization potential,there was evidence of the antiseptic-coated CVC being morecytotoxic and systemically toxic than would be expected from aprocedural response to a surfactant treatment. The antiseptic-coated CVC, at the elevated concentration, was significantlymore cytoxic in cell culture (100% cytotoxic) and morehemolytic (100% hemolysis). It also produced greatermammalian cellular lysis (complete lysis) in the genotoxicityprocedures; a reduction in the test sample size (concentration)was required to demonstrate no genotoxic potential. Asmentioned previously, these procedures are sensitive and staticin nature, offering a significant challenge to any antimicrobialtreatments. However, even in the in vivo mouse systemicinjection, using both normal saline and 5% ethanol in normalsaline extraction mediums, a severely toxic host response wasobserved in the form of death and convulsions. These extremein vivo toxic responses were observed in a test procedure mostclosely mimicking the clinical application of the catheter. Whenretested at the reduced temperature of 37°C, the test article wasfound to be acceptable; however, the test sample clearlydemonstrated cytotoxicity when directly assessed according toISO and USP guidelines at the same parameters as the VantexCVC with Oligon material (with or without heparin coating).

Additionally, the host response in an intramuscular implantwith a 7-day duration was classified as cytotoxic as compared tothe negative control material. In comparing the 7-day findingsof the Vantex CVC with Oligon material (non-heparin coated)to the antiseptic-coated CVC, the cytotoxic response to theantiseptic-coated CVC was clearly more intense; the meanseverity for myofiber necrosis was approximately 67% greater for the antiseptic-coated CVC (mean necrosis score of 1.5 vs.

2.5 for the antiseptic-coated CVC). Although the differencesmay not prove to be statistically significant, they do, in theopinion of the pathologist reviewing these results, havebiological significance which shows within the scope of thesestudies: the cytotoxic effect of the antiseptic-coated CVC issubstantially more severe than that of the Vantex CVC withOligon material.

While the guinea pig maximization assay did not demonstratepotential sensitization, the potential for patient sensitivity to thechlorhexidine component of the antiseptic-coated CVC may beof concern in some countries, due to reports of anaphylacticshock after exposure to chlorhexidine agents. While heparinmay also hold the potential for adverse reactions such asheparin-induced thrombocytopenia, the methods of detectingadverse reactions, coupled with the slower onset and the lowlevel of heparin present on the Vantex CVC, make this aminimal risk.

100 90 80 70 60 50 40 30 20 10

06.0cm2/mL 3.0cm2/mL 1.5cm2/mL 0.3cm2/mL

Catheter Segment Size

Vantex CVC with Oligon material (non-heparin coated) Chlorhexidine/silver sulfadiazine (antiseptic) coated

100% 100% 100%

20%

4.8% 0% 0% 0%

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0 6.0cm2/mL 3.0cm2/mL 1.0cm2/mL

Concentration with 100% Cell Survival

Vantex CVC with Oligon material (non-heparin coated) Chlorhexidine/silver sulfadiazine (antiseptic) coated

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0% 0%

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Figure 2 Cytotoxicity of CVCs Tested

Figure 1 Hemolysis of CVC Extracts Tested

Survival Rate of Mice Exposed to CVC Extracts during the USP Mouse Systemic Test (extracted 70ºC/24 hours)

Vantex CVC with Oligon material (non-heparin coated)

Chlorhexidine/silver sulfadiazine (antiseptic) coated

Edwards Lifesciences LLC · One Edwards Way · Irvine, CA 92614 · Phone: 949.250.2500 · 800.424.3278 · www.edwards.comEdwards Lifesciences (Canada) Inc. · 4 Robert Speck Parkway, Suite 900 · Mississauga, Ontario · Canada L4Z 1S1 · 905.566.4220 · 800-268-3993

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Antimicrobial activity on the Oligon surface and inner lumensof the catheter during handling and placement has beendemonstrated through in vitro testing against organismscommonly associated with nosocomial infections. Theactivity of the antimicrobial agents is localized at the cathetersurfaces and is not intended for treatment of systemicinfections.

In vitro testing demonstrated that the Oligon materialprovided broad spectrum effectiveness (≥ 3 log reductionfrom initial concentration within 48 hours) against theorganisms tested: Staphylococcus aureus, Staphylococcusepidermidis, Klebsiella pneumoniae, Enterococcus faecalis,Candida albicans, Escherichia coli, Serratia marcescens,Acinetobacter calcoaceticus, Corynebacterium diptheriae,Enterobacter aerogenes, GMRSa and Pseudomanasaeruginosa. The impact of Oligon material on infection rateshas not been demonstrated.

*Contact inhibition of microbial growth on surface ofcatheters. Effective against organisms commonly associatedwith nosocomial infection, e.g., S. epidermidis.

Antimicrobial activity associated with AMC THROMBOSHIELD(an Antimicrobial Heparin Coating) has been demonstratedusing in vitro agar diffusion assays against the followingorganisms: Staphylococcus epidermidis, Staphylococcusaureus, Enterococcus faecalis, Candida albicans, Escherichiacoli, Serratia marcescens and Acinetobacter calcoaceticus.

†Data on file.

Edwards Lifesciences, Edwards, the stylized E logo and AMCTHROMBOSHIELD are trademarks of Edwards LifesciencesCorporation. Vantex is a trademark of Edwards LifesciencesCorporation and registered in the U.S. Patent and TrademarkOffice. Oligon is a trademark of Implemed, Inc.

See instructions for use for full prescribing information.

©2002 Edwards Lifesciences LLC. All rights reserved. 3127-10/01-CC

References1 Torricelli R, Wuthrich B. Life-threatening anaphylactic shock due to skin application of chlorhexidine.

Clin Exp Allergy. 1996;26:1122 Gabler WL, Roberts D, Harold W. The effect of chlorhexidine on blood cells. J Periodontal Res.

1987;22:150-155.3 Butler WH, Iswarah TJ. Chlorhexidine: Safety Evaluation. Royal Society of Medicine, International

Congress and Symposium. Series Number 23.4 Center for Devices and Radiological Health. FDA Public Health Notice, Potential Hypersensitivity

Reactions to Chlorhexidine-Impregnated Medical Devices. March 1998.

ConclusionAs observed in the testing, the Vantex CVC with Oligon materialprovides a biocompatible central venous catheter with lesspotential risk for allergic response than a chlorhexidine/ silversulfadiazine (antiseptic) coated CVC. The potential for improveddevice compatibility plus the potential to reduce bacterial growthdemonstrates that the Vantex CVC with Oligon material is anexcellent alternative over an antiseptic-coated CVC.