Effects of tissue-tolerable plasma on chronic
wound treatment compared to a modern
conventional liquid antiseptic
1 Charit...
Abstract
Aim: Recently, it was reported that tissue-tolerable plasma (TTP) is highly efficient in the reduction of the
bac...
Background
In the age of multi-resistant microbes and the increasing lack of efficient antibiotics, chemical antisepsis pl...
Background – what is plasma?
In order to treat living tissue, thermal damage needs to be avoided. Low temperature
plasma (...
Methods
Patient groups
Patients suffering from chronic leg ulcers were recruited from the Department of Dermatology, Vener...
Results
Antiseptic efficacy
The total colony forming units/cm2 (cfu/cm2) after the incubation
of the bacteria on the surfa...
Results Changes of the bacterial colonization before and after the antiseptic treatment
The overall bacterial counts over ...
Results
Changes of the wound volumes under
antiseptic treatment
The initial wound volume in the TTP-
treated group dropped...
Conclusion
TTP-Treatment shows similar capacities in terms of wound disinfection to established
chemical antiseptic formul...
References
1 Kramer A, Hubner NO, Weltmann KD, Lademann J, Ekkernkamp A, Hinz P, Assadian O: Polypragmasia in the therapy ...
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EWMA 2013-Ep447-EFFECTS OF TISSUE-TOLERABLE PLASMA ON CHRONIC WOUND TREATMENT COMPARED TO A MODERN CONVENTIONAL LIQUID ANTISEPTIC

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EFFECTS OF TISSUE-TOLERABLE PLASMA ON CHRONIC WOUND TREATMENT COMPARED TO A MODERN CONVENTIONAL LIQUID ANTISEPTIC

Bernhard Lange-Asschenfeldt1, Jürgen Lademann1, Christin Ulrich1,
Franziska Kluschke1, Staffan Vandersee1, Alexa Patzelt1, Viktor Czaika1, Heike Richter1, Adríenne Bob1, Johanna Von Hutten1, Axel Kramer2

1Charité Berlin, Department of Dermatology (Berlin, Germany);
2University of Greifswald, Department for Hygiene and environmental medicine (Greifswald, Germany).

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EWMA 2013-Ep447-EFFECTS OF TISSUE-TOLERABLE PLASMA ON CHRONIC WOUND TREATMENT COMPARED TO A MODERN CONVENTIONAL LIQUID ANTISEPTIC

  1. 1. Effects of tissue-tolerable plasma on chronic wound treatment compared to a modern conventional liquid antiseptic 1 Charité – Universitätsmedizin Berlin, Department of Dermatology, Allergology and Venerology (Berlin, GERMANY) 2 University of Greifswald, University Medicine, Institute of Hygiene and Environmental Medicine (Greifswald, GERMANY) Department of Dermatology Charité University Medicine Berlin Christin Ulrich1, Franziska Kluschke1, Dr. Alexa Patzelt1, Dr. Staffan Vandersee1, Dr. Viktor A. Czaika1, Heike Richter1, Dr. Adrienne Bob1, Dr. Johanna von Hutten1, Prof. Axel Kramer2, Prof. Jürgen Lademann1, Dr. Bernhard Lange-Asschenfeldt1
  2. 2. Abstract Aim: Recently, it was reported that tissue-tolerable plasma (TTP) is highly efficient in the reduction of the bacterial load of the skin surface. These studies were until now mostly performed in vitro using either cell culture assays or experimental assays with tissue harvested from animals in vitro and on intact human skin as well. We aimed to compare the effects on bacterial colonization of the wounds and the rate of wound healing in patients of our department. Methods: Sixteen patients suffering from chronic leg ulcers were treated with either tissue-tolerable plasma or octenidine dihydrochloride as a control 3 times a week over a time period of 2 weeks. The effects on bacterial colonization of the wounds and the rate of wound healing were investigated by assessing the wound´s bacterial load as well as the change of the wound´s surface-area and depth. Results: It could be shown, that wounds treated with either TTP or octenidine dihydrochloride showed comparable healing rates and similar reduction of microbes, underlining its low cytotoxicity as suggested by previous in vivo studies. Conclusions: Our study could demonstrate, that TTP is a new and innovative antiseptic approach for the treatment of chronic leg ulcers with an antiseptic efficiency compared to one of the most efficient and biocompatible liquid antiseptic.
  3. 3. Background In the age of multi-resistant microbes and the increasing lack of efficient antibiotics, chemical antisepsis plays a major role in the prevention of infections. It is thus a crucial part of modern wound management. The ideal antiseptic substance would hereby efficiently eliminate microbes without impairing the process of tissue repair. In order to promote the healing process of acute and chronic wounds, the wound bed needs to be prepared according to modern rules after thorough wound assessment. Modern wound bed preparation translates into treatment algorithms entailing cleansing, debridement, antisepsis, elimination of wound healing inhibiting factors as well as stimulation of healing factors and the concept of moist wound healing [1]. The efficacy and safety of chemical antiseptics contributing to tissue repair has, in this respect, been proven in numerous studies [2, 3] Physical antiseptic treatments may present an interesting alternative to chemical antiseptics, since they exert their antimicrobial effects independently of chemical and biological mechanisms responsible for the resistance in microbes. Tissue tolerable plasma (TTP) represents a novel therapeutic method with promising capabilities in the field of dermatological interventions, in particular disinfection but also wound antisepsis and regeneration. The energy- transfer by plasma into living tissue is not easily educible, as a variety of features such as the medium´s actual molecule-stream, the ions, electrons and free radicals involved, as well as the emission of ultraviolet, visible and infrared light contribute to its increasingly well characterized effects[4]. Our goal was to investigate whether TTP can be safely used for wound antisepsis.
  4. 4. Background – what is plasma? In order to treat living tissue, thermal damage needs to be avoided. Low temperature plasma (tissue-tolerable plasma) is now available to minimize potential damage to the skin. The Plasma Jet Pen ( plasma jet kinpen 09), developed by the Leibniz Institute for Plasma Science and Technology, Greifswald, Germany, in cooperation with Neoplas GmbH, Greifswald, Germany, is generating a low-temperature plasma. A detailed description of the plasma jet is given by Hubner et al. [5]. The plasma jet consists of a base station including the power supply and the control unit, together with a handpiece containing the gas flow and the electrical discharge system. The discharge system was operated with argon, applied in the pulsed mode, with the pulses being generated at a frequency of 1.82 MHz. The plasma stream had a length of approximately 10 mm. The plasma-tissue interaction zone was approximately 1 mm in diameter. The plasma stream had a length of approximately 10 mm; the plasma- tissue interaction zone was approximately 1 mm in diameter. Plasma is partially ionized gas (4th state of aggregation) solid liquid gas plasma There are plenty of mainly hot plasma sources surrounding us! Source of figures: Leibniz-Institut für Plasmaforschung und Technologie e.V., Greifswald, Germany
  5. 5. Methods Patient groups Patients suffering from chronic leg ulcers were recruited from the Department of Dermatology, Venereology and Allergology, Charité Universitätsmedizin, Berlin, Germany. None of the patients showed clinical signs of wound infections and patients undergoing antibiotic treatment were excluded from the study. Patients included in the study (n= 16; 6 male and 10 female patients) suffered from chronic leg ulcers (n= 11; Widmer stage III), ulcus cruris arteriosum (n=1), ulcus cruris mixtum (n= 4). Median ulcer persistence was 12 months (minimal duration 4 weeks and longest 15 years). Median age was 75 years (33 to 90). Wound extent ranged from 1 to 36 cm2 and 4 mm in depth. The wounds were graded by the extent of exudation (none, mild and moderate). Wound dressings were chosen according to the extent of exudation. The study was approved by the Ethical Committee of Charité, Universitätsmedizin, Berlin, Germany, before start of the experiments (EA1/010/10). Treatment Arms Patients were assigned to either treatment arm A (tissue tolerable plasma, TTP) or arm B (antiseptic). The plasma treatment of the wounds was thoroughly performed in order to avoid islands of untreated wound areas because of the small beam exiting the plasma pen (1.5mm diameter). For this reason mainly smaller ulcers were assigned to the study group A. Roughly 1 cm2 of wound surface was treated for 1 min, including a 1 cm wide margin of the skin adjacent to the wound edge. Patients included in arm B were treated with an antiseptic containing 0.1% octenidine dihydrochloride (ODC) and 2% 2- phenoxyethanol as active ingredients (Octenisept®, Schuelke & Mayr GmbH, Norderstedt, Germany). ODC was applied in the same manner as in the operating room for antiseptic treatment of the skin, an amount of 0.2 ml/cm2 proved sufficient to ensure complete coverage of the wound surface. After 2 min, when the solution had completely evaporated and (like in arm A after treatment) the bacterial colonization of the treated wound surface was investigated. Patients of both study groups were treated 3 times a week over a time period of 2 weeks. Wound assessment Assessment of the wound surface and volume The wound surface was traced on a transparency (day 1) before the start of the experiments and at the end (day 14) and the depths of the wound were measured using the following formula:2/3π x lenght/2 x width/2 x depth Assessment of the bacterial load After initial debridement, nitrocellulose filters (diameter: 50 mm, pore size 0.45 µm) were gently pressed onto the wound bed and after 30 seconds subjected to further incubation and analysis. After each treatment the procedure was repeated. Filters were then placed on Columbia blood agar plates for 30 seconds, which afterwards were incubated for 18 h at 37 ºC. After 18 h the colony-forming units (CFU)/cm2 were assessed. CFUs were subjected to further microbiological analysis in order to identify the exact species of bacteria. Staphylococcus (S.) aureus and Pseudomonas (P.) aeruginosa were cultured on CASO- agar plates and identified using the 3%-hydrogenperoxide-test, and commercial test kits. These bacterial nitrocellulose-swabs were taken at each day of examination from day 1 to the end of the study on day 14. Between the days of antiseptic treatment, the wound dressings were changed using the none-touch technique in order to avoid contamination.
  6. 6. Results Antiseptic efficacy The total colony forming units/cm2 (cfu/cm2) after the incubation of the bacteria on the surface of the agar plates were counted prior to the antiseptic treatment with either TTP or octenidine. Wounds of the TTP-treated study group were more colonized (117.6 cfu/cm2) compared to the octenidine-treated group (43.7 cfu/cm2) before the antiseptic treatment (Fig. a). In order to evaluate the acute antiseptic properties of TTP and octenidine the bacterial colonization at the first two visits before and after each antiseptic treatment was determined and the median calculated. Both antiseptic treatment options lead to a significant reduction of the total bacterial count within their study group (Fig. a). Fig. b shows the total reduction of the bacterial count after the treatment with either TTP or octenidine. In the TTP-treated wounds a slight but significantly higher total reduction of the bacteria (-48.1 cfu/cm2) was observed compared to the octenidine-treated wounds (-17.1 cfu/cm2). However, the relative microbial reduction compared to the initial colonization was slightly less in the TTP-treated group (47%) compared to the octenidine-treated group (64%) (Fig. c).
  7. 7. Results Changes of the bacterial colonization before and after the antiseptic treatment The overall bacterial counts over the study period of 14 days were not significantly changing in both study groups compared to the initial colonization (Fig. a). The bacterial counts in the octenidine group were slighltly but not significantly increasing from 43.7 cfu/cm2 at visit 1 to 51.3 cfu/cm2 at visit 6 while the bacterial count in the TTP-treated group was slightly increasing from 98.0 cfu/cm2 at visit 1 to 127.8 cfu/cm2 at visit 6 (Fig. b). This translates to a total decrease of - 14.9 cfu/cm2 in the octenidine-treated group and an increase of 14.83 cfu/cm2 in the TTP- treated group over the study period of 14 days (Fig. b). In relation to the original bacterial count 35% decrease within the octenidine-treated group and an increase of 12% in the TTP-treated group was observed (Fig. c). General composition of bacterial wound colonization Within both treatment arms, the two largest groups of bacteria colonizing the wounds were identified as S. aureus (41.2%) and P. aeruginosa (17.6%). 60% of the TTP-treated wounds compared to 40% of the OCD-treated wounds were colonized by S. aureus. While no P. aeruginosa colonization was found within the TTP-treated wounds, 30% of the octenidine- treated wounds were colonized. Relation of exudation and bacterial colonization The average of all wounds included in the study were graded mild exudating (mean: 1.2) with a comparable degree in both groups. Exudation in the TTP-treated wounds was reduced by 30% and remained unchanged in the other group. Moderate exudating wounds were slightly more colonized (2.2 cfu/cm2) than mild or non- exudating wounds (1.85 cfu/cm2). Moreover, moderate exudating wounds were more commonly colonized by S. aureus and P. aeruginosa (80%) than with mild exudating wounds or wounds with no signs of exudation (50%). Relation of wound depths/sizes and bacterial colonization Deeper wounds (3-4 mm depth) compared to more superficial wounds (0-3 mm) showed a more diverse bacterial colonization spectrum (1.69 different colonies in superficial wounds compared to 2.29 different colonies in deep wounds). The depths of the TTP-treated and octenidine-treated wounds (0.21 and 0.20 respectively) were similar in our experiments. However, the diversity of colonization was also related to the original wound area. Wounds sized < 8.6 cm2 showed an average of 1.67 different bacterial species compared to wounds > 8.6 cm2 showing an average of 2.6 different bacteria species. Since the wounds in the octenidine-treated group (13.1 cm2) were bigger than the TTP-treated group (7.1 cm2) more different bacteria species were found in the octenidine-treated wounds (2.6) compared to the TTP-treated group (1.67).
  8. 8. Results Changes of the wound volumes under antiseptic treatment The initial wound volume in the TTP- treated group dropped from 0.69 cm3 to 0.30 cm3 (median) while the wound volume of the octenidine-treated group dropped from 2.7 cm3 to 1.6 cm3 (median) (Fig. a). The initial volume of the TTP-treated wounds was significantly smaller than in the octenidine-treated group at the beginning of the study as already pointed out in the method section (Fig. 3a). The wound area volume was decreasing over the study period of 2 weeks by 0.39 cm3 (median) in the TTP-treated group and by 0.89 cm3 (median) in the octenidine-treated group (Fig. b). These measurements translate to a relative wound volume change of 56 % (median) in the TTP- treated and 19% (median) in the octenidine-treated group (Fig. c).
  9. 9. Conclusion TTP-Treatment shows similar capacities in terms of wound disinfection to established chemical antiseptic formulations. It is well tolerated when used on chronic wounds. It does not impair wound regeneration, although in this study we observed a bias untowards smaller wounds in the TTP-treated arm, which must be considered to heal faster. TTP-treatment and octenidine-treatment of chronic wounds lead to a significant reduction of the bacterial load. Due to the low cytotoxicity TTP-treatment might present an alternative treatment option for antisepsis. Extended investigations on a larger study population are needed in order to identify the wound conditions that benefit most of this innovative treatment. Especially the role of TTP in the elimination of multiresistant bacteria will have to be studied in vivo.
  10. 10. References 1 Kramer A, Hubner NO, Weltmann KD, Lademann J, Ekkernkamp A, Hinz P, Assadian O: Polypragmasia in the therapy of infected wounds - conclusions drawn from the perspectives of low temperature plasma technology for plasma wound therapy. GMS Krankenhaushygiene interdisziplinar 2008;3:Doc13. 2 Daeschlein G, Assadian O, Bruck JC, Meinl C, Kramer A, Koch S: Feasibility and clinical applicability of polihexanide for treatment of second-degree burn wounds. Skin Pharmacol Physiol 2007;20:292-296. 3 Muller G, Kramer A: Biocompatibility index of antiseptic agents by parallel assessment of antimicrobial activity and cellular cytotoxicity. The Journal of antimicrobial chemotherapy 2008;61:1281-1287. 4 Weltmann KD, Kindel E, Brandenburg R, Meyer C, Bussiahn R, Wilke C, Woedtke T. Atmospheric Pressure Plasma Jet for Medical Therapy: Plasma Parameters and Risk Estimation. Contrib Plasma Phys. 49, No. 2009; 9: 631 – 640 5 Hubner NO, Matthes R, Koban I, Randler C, Muller G, Bender C, Kindel E, Kocher T, Kramer A: Efficacy of chlorhexidine, polihexanide and tissue-tolerable plasma against pseudomonas aeruginosa biofilms grown on polystyrene and silicone materials. Skin Pharmacol Physiol 2010;23 Suppl:28-34. 6 Hubner NO, Matthes R, Koban I, Randler C, Muller G, Bender C, Kindel E, Kocher T, Kramer A: Efficacy of chlorhexidine, polihexanide and tissue-tolerable plasma against pseudomonas aeruginosa biofilms grown on polystyrene and silicone materials. Skin Pharmacol Physiol 2010;23 Suppl:28-34.

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