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Similarly, the Vantex CVC with Oligon material (treated with heparin) was determined to show no evidence of systemic toxicity in the Mouse Micronucleus Test, sensitization potential, or genotoxic potential. The heparin-treated catheter did demonstrate cytotoxicity in the Sister Chromatid Exchange (SCE) procedure at the elevated concentrations evaluated, therefore requiring testing at the reduced concentrations. The heparin-treated catheter also demonstrated a host response of mild cytotoxicity intramuscularly at the 7-day duration, with no host response noted at the 30-day explant. These results were anticipated due to the presence of the surfactant used as a binding agent for the heparin, and were evidenced in these procedures due to the sensitivity of the procedures and their static nature, which does not provide a system similar to the clinical application.

Chlorhexidine/Silver Sulfadiazine (Antiseptic) Coated CVC Results

The antiseptic-coated CVC was found to have a heightened response in six of the eight procedures as compared to the Vantex CVC with Oligon material (non-heparin coated) at the maximum concentration evaluated. While there was no evidence of intracutaneous irritation or sensitization potential, there was evidence of the antiseptic-coated CVC being more cytotoxic and systemically toxic than would be expected from a procedural response to a surfactant treatment. The antiseptic- coated CVC, at the elevated concentration, was significantly more cytoxic in cell culture (100% cytotoxic) and more hemolytic (100% hemolysis). It also produced greater mammalian cellular lysis (complete lysis) in the genotoxicity procedures; a reduction in the test sample size (concentration) was required to demonstrate no genotoxic potential. As mentioned previously, these procedures are sensitive and static in nature, offering a significant challenge to any antimicrobial treatments. However, even in the in vivo mouse systemic injection, using both normal saline and 5% ethanol in normal saline extraction mediums, a severely toxic host response was observed in the form of death and convulsions. These extreme in vivo toxic responses were observed in a test procedure most closely mimicking the clinical application of the catheter. When retested at the reduced temperature of 37°C, the test article was found to be acceptable; however, the test sample clearly demonstrated cytotoxicity when directly assessed according to ISO and USP guidelines at the same parameters as the Vantex CVC with Oligon material (with or without heparin coating).

Additionally, the host response in an intramuscular implant with a 7-day duration was classified as cytotoxic as compared to the negative control material. In comparing the 7-day findings of the Vantex CVC with Oligon material (non-heparin coated) to the antiseptic-coated CVC, the cytotoxic response to the antiseptic-coated CVC was clearly more intense; the mean severity 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 differences may not prove to be statistically significant, they do, in the opinion of the pathologist reviewing these results, have biological significance which shows within the scope of these studies: the cytotoxic effect of the antiseptic-coated CVC is substantially more severe than that of the Vantex CVC with Oligon material.

While the guinea pig maximization assay did not demonstrate potential sensitization, the potential for patient sensitivity to the chlorhexidine component of the antiseptic-coated CVC may be of concern in some countries, due to reports of anaphylactic shock after exposure to chlorhexidine agents. While heparin may also hold the potential for adverse reactions such as heparin-induced thrombocytopenia, the methods of detecting adverse reactions, coupled with the slower onset and the low level of heparin present on the Vantex CVC, make this a minimal risk.

Figure 1 Hemolysis of CVC Extracts Tested

Percent Hemolysis

50 40 30 20

20%

10 0

6.0cm2/mL

100 90 80 70 60

100%

100%

100%

4 8% 0%

3.0cm2/mL 1.5cm2/mL Catheter Segment Size

0% 0% 0.3cm2/mL

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

Figure 2 Cytotoxicity of CVCs Tested

Percent Hemolysis

0

0%

0%

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

100 90 80 70 60

50 40 30 20

10

100%

100%

100%

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

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