Шайдаков Евгений  Владимирович - доктор медицинских наук,
заместитель директора НИИнститута
Экспериментальной медицины СЗО РАМН
руководитель клиники института,
профессор кафедры ХУВ-1 ВМА
 XVI Европейский Венозный Форум 2015
 
                      Новости и блог          Биография          Библиография          Запись на приём          Публикации          Контакты      
 ФГБНУ «Институт экспериментальной медицины»  Санкт-Петербургская Ассоциация Флебологов (Saint-Petersburg Society of Phlebology, SPSP)  10-й Санкт-Петербургский Венозный Форум (Рождественские встречи) 30 ноября - 10 декабря 2017
Оригинал опубликован в журнале International Angiology, 2014 April;33(2):87-208
Публикуется с разрешения ЕВФ
Перевод на русский язык: © 2016 М.Е. Шайдаков, О.Я. Порембская
Копирование, цитирование - только с разрешения Е.В. Шайдакова

Лечение хронических заболеваний вен нижних конечностей

Клинические рекомендации

Nicolaides A., Kakkos S., Eklof B., Perrin M., Nelzen O., Neglen P., Partsch H., Rybak Z.

ГЛАВА 9.
Топическая терапия в лечении трофических язв

<<< ГЛАВА 8 Веноактивные препараты ГЛАВА 10 Лечение несостоятельных поверхностных и перфорантных вен >>>

Топические агенты и повязки, способствующие скорейшему отторжению некротических тканей, появлению грануляций и эпителизации венозных язв голени, приобрели за последнее время широкое распространение в клинической практике. Гидрогели, альгинатные повязки, гидроколлиоды, ферментные агенты, ростовые факторы, гели с аминокислотами и тромбоцитами, пленки с фибрином составляют арсенал возможностей для лечения трофических язв. 1 - 50 Эквиваленты кожи с культурами кератиноцитов и фибробластов, как было показано, также ускоряют заживление язв. 51 - 64 Однако до сих пор не существует I уровня доказательности, что подобная терапия имеет преимущество перед простыми раневыми повязками и компрессионной терапией.

Использование местных антибактериальных препаратов у больных с трофическими язвами считается нецелесообразным из-за появления в зоне их воздействия резистентных микроорганизмов и повышения риска контактного дерматита. 11, 65 В настоящее время нет также данных в поддержку рутинного системного введения антибиотиков для ускорения заживления язвы. Показанием для применения антибактериальной терапии является развитие инфекции мягких тканей на фоне трофических нарушений. В свете существующей проблемы появления резистентной микрофлоры назначение этих препаратов в соответствии с современными рекомендациями производится при появлении клинических признаков развития бактериальной инфекции. Обнаружение колонизации микрофлоры в данной зоне без клинических проявлений не является показанием.

Существует ряд доказательств в пользу использования повидон йодина, октенидина, фенотиона, кристацида, сукральфата, этакридин лактата, мупироцина и хлоргексидина, веществ на основе пероксида, кислорода в лечении венозных язв. 66 - 74 Местные антисептики обладают токсическим эффектом на клетки, что обусловливает их антибактериальный эффект, но, вместе с тем, нарушают эпителизацию раны. 75

Существуют доказательства, что гиалуроновая кислота и амниотическая мембрана обладают положительным эффектом на заживление язв. 76 - 80

В течение последних нескольких лет физические методы лечения с использованием отрицательного давления в области трофической язвы приобретают все большее распространение, собирая доказательства о положительном эффекте подобного лечения. 81 - 86

Электростимулирующая терапия, электромагнитная терапия, ультразвуковое воздействие низкой и высокой частоты, лазерное и инфракрасное излучение также способствуют заживлению язв, особенно длительно не заживающих, рефрактерных к рутинной терапии. 87 - 101 Экстракорпоральное ударно волновое воздействие стимулирует, как было показано в исследованиях, заживление язв. Однако все данные об эффективности данных методов лечения основаны на оценке случаев из практики или малых выборках больных.

В купированнии болевого синдрома при лечении трофических язв помогает, как было показано, применение ибупрофена медленного высвобождения. 104 - 107

Некоторые авторы отстаивают применение личинок для очищения язв. 108 - 111 Встречаются даже предложения по использованию меда для местного лечения. 112 - 115

Хотя существует огромное количество различных публикаций о лечении язв доказательства не очевидны в отношении эффективности и стоимости лечения. Для получения неопровержимых доказательств необходимо продолжить подобные исследования.

<<< ГЛАВА 8 Веноактивные препараты ГЛАВА 10 Лечение несостоятельных поверхностных и перфорантных вен >>>

Ссылки

  1. Guarnera G, De Rosa A, Camerini R. Thymosin beta-4 and venous ulcers: clinical remarks on a European prospective, randomized study on safety, tolerability, and enhancement on healing. Ann N Y Acad Sci 2007;1112:407-12. 

  2. Jorgensen B, Gottrup F, Karlsmark T, Bech-Thomsen N, Sibbald RG. Combined use of an ibuprofen-releasing foam dressing and silver dressing on infected leg ulcers. J Wound Care 2008;17(5):210-4. 

  3. Romanelli M, Dini V, Vowden P, Agren MS. Amelogenin, an extracellular matrix protein, in the treatment of venous leg ulcers and other hard-to-heal wounds: experimental and clinical evidence. Clin Interv Aging 2008;3(2):263-72. 

  4. Margolis DJ, Morris LM, Papadopoulos M, Weinberg L, Filip JC, Lang SA et al. Phase I study of H5.020CMV. PDGF-beta to treat venous leg ulcer disease. Mol Ther 2009;17(10):1822-9. 

  5. Michaels JA, Campbell WB, King BM, Macintyre J, Palfreyman SJ, Shackley P et al. A prospective randomised controlled trial and economic modelling of antimicrobial silver dressings versus non-adherent control dressings for venous leg ulcers: the VULCAN trial. Health Technol Assess 2009;13(56):1-114, iii. 

  6. Cassino R, Ricci E. Effectiveness of topical application of amino acids to chronic wounds: a prospective obser- vational study. J Wound Care 2010;19(1):29-34. 

  7. Beele H, Meuleneire F, Nahuys M, Percival SL. A prospective randomised open label study to evaluate the potential of a new silver alginate/carboxymethylcellulose antimicrobial wound dressing to promote wound healing. Int Wound J 2010;7(4):262-70. 

  8. Guarnera G, DeRosa A, Camerini R. The effect of thymosin treatment of venous ulcers. Ann N Y Acad Sci 2010;1194:207-12. 

  9. Hampton S, Coulborn A, Tadej M, Bree-Aslan C. Using a superabsorbent dressing and antimicrobial for a venous ulcer. Br J Nurs 2011;20(15):S38, S40-3. 

  10. Gupta A, McCarthy S. Pelvic varices as a cause for pelvic pain: MRI appearance. Magn Reson Imaging 1994;12(4):679-81. 

  11. Valencia IC, Falabella A, Kirsner RS, Eaglstein WH. Chronic venous insufficiency and venous leg ulceration. J Am Acad Dermatol 2001;44(3):401-21; quiz 422-4. 

  12. Fowler E, van Rijswijk L. Using wound debridement to help achieve the goals of care. Ostomy Wound Manage 1995;41(7A Suppl):23S-35S; discussion 36S. 

  13. Fowler E. Instrument/sharp debridement of non-viable tissue in wounds. Ostomy Wound Manage 1992;38(8):26, 28-30, 32-3. 

  14. Berger MM. Enzymatic debriding preparations. Ostomy Wound Manage 1993;39(5):61-2, 66-9. 

  15. Alvarez O. Moist environment for healing: matching the dressing to the wound. Ostomy Wound Manage 1988;21:64-83. 

  16. Mertz PM, Marshall DA, Eaglstein WH. Occlusive wound dressings to prevent bacterial invasion and wound infection. J Am Acad Dermatol 1985;12(4):662-8. 

  17. Friedman SJ, Su WP. Management of leg ulcers with hydrocolloid occlusive dressing. Arch Dermatol 1984;120(10):1329-36. 

  18. Nathan P, Law EJ, Ogle JD, MacMillan BG. Proteolytic enzyme activity in the granulation tissue of the human burn wound. J Trauma 1976;16(11):912-8. 

  19. Suomalainen O. Evaluation of two enzyme preparations-Trypure and Varidase in traumatic ulcers. Ann Chir Gynaecol 1983;72(2):62-5. 

  20. Phillips TJ. Successful methods of treating leg ulcers. 
The tried and true, plus the novel and new. Postgrad Med 1999;105(5):159-61, 165-6, 173-4 passim.
21.
  21. Falabella AF, Carson P, Eaglstein WH, Falanga V. The safety and efficacy of a proteolytic ointment in the treatment of chronic ulcers of the lower extremity. J Am Acad Dermatol 1998;39(5 Pt 1):737-40.
22.
  22. Geronemus RG, Robins P. The effect of two new dressings on epidermal wound healing. J Dermatol Surg Oncol 1982;8(10):850-2.
23.
  23. Helfman T, Ovington L, Falanga V. Occlusive dressings and wound healing. Clin Dermatol 1994;12(1):121-7. 24.
  24. Westerhof W, vanGinkel CJ, Cohen EB, Mekkes JR. Prospective randomized study comparing the debriding effect of krill enzymes and a non-enzymatic treatment in venous leg ulcers. Dermatologica 1990;181(4):293-7. 25.
  25. McGrath MH. Peptide growth factors and wound healing. Clin Plast Surg 1990;17(3):421-32.
26.
  26. Falanga V, Eaglstein WH, Bucalo B, Katz MH, Harris B, Carson P. Topical use of human recombinant epider- mal growth factor (h-EGF) in venous ulcers. J Dermatol Surg Oncol 1992;18(7):604-6.
  27. Robson MC, Phillips TJ, Falanga V, Odenheimer DJ, Parish LC, Jensen JL et al. Randomized trial of topically applied repifermin (recombinant human keratinocyte growth factor-2) to accelerate wound healing in venous ulcers. Wound Repair Regen 2001;9(5):347-52.
  28. Jaschke E, Zabernigg A, Gattringer C. Recombinant human granulocyte-macrophage colony-stimulating factor applied locally in low doses enhances healing and prevents recurrence of chronic venous ulcers. Int J Dermatol 1999;38(5):380-6.
  29. Senet P, Bon FX, Benbunan M, Bussel A, Traineau R, Calvo F et al. Randomized trial and local biological effect of autologous platelets used as adjuvant therapy for chronic venous leg ulcers. J Vasc Surg 2003;38(6):1342- 8.
  30. Stacey MC, Mata SD, Trengove NJ, Mather CA. Randomised double-blind placebo controlled trial of topical autologous platelet lysate in venous ulcer healing. Eur J Vasc Endovasc Surg 2000;20(3):296-301.
  31. Hillstrom L. Iodosorb compared to standard treatment in chronic venous leg ulcers a multicenter study. Acta Chir Scand Suppl 1988;544:53-6.
  32. Holloway GA, Jr., Johansen KH, Barnes RW, Pierce GE. Multicenter trial of cadexomer iodine to treat venous stasis ulcer. West J Med 1989;151(1):35-8.
  33. Bouza C, Munoz A, Amate JM. Efficacy of modern dressings in the treatment of leg ulcers: a systematic review. Wound Repair Regen 2005;13(3):218-29.
  34. Meaume S, Gemmen E. Cost-effectiveness of wound management in France: pressure ulcers and venous leg ulcers. J Wound Care 2002;11(6):219-24.
  35. Harding K, Gottrup F, Jawien A, Mikosinski J, Twardowska-Saucha K, Kaczmarek S et al. A prospective, multi-centre, randomised, open label, parallel, comparative study to evaluate effects of AQUACEL(R) Ag and Urgotul(R) Silver dressing on healing of chronic venous leg ulcers. Int Wound J 2012;9(3):285-94.
  36. Upton Z, Wallace HJ, Shooter GK, van Lonkhuyzen DR, Yeoh-Ellerton S, Rayment EA et al. Human pilot studies reveal the potential of a vitronectin: growth factor complex as a treatment for chronic wounds. Int Wound J 2011;8(5):522-32.
  37. Kelechi TJ, Mueller M, Hankin CS, Bronstone A, Samies J, Bonham PA. A randomized, investigator-blinded, con- trolled pilot study to evaluate the safety and efficacy of a poly-N-acetyl glucosamine-derived membrane material in patients with venous leg ulcers. J Am Acad Dermatol 2012;66(6):e209-15.
  38. Lantis JC, 2nd, Gendics C. In vivo effect of sustained release silver sulphadiazine foam on bioburden and wound closure in infected venous leg ulcers. J Wound Care 2011;20(2):90-6.
  39. Skorkowska-Telichowska K, Zuk M, Kulma A, Bugajska- Prusak A, Ratajczak K, Gasiorowski K et al. New dressing materials derived from transgenic flax products to treat long-standing venous ulcers--a pilot study. Wound Repair Regen 2010;18(2):168-79. 

  40. Trial C, Darbas H, Lavigne JP, Sotto A, Simoneau G, Til- let Y et al. Assessment of the antimicrobial effectiveness of a new silver alginate wound dressing: a RCT. J Wound Care 2010;19(1):20-6. 

  41. Michaels JA, Campbell B, King B, Palfreyman SJ, Shackley P, Stevenson M. Randomized controlled trial and cost-effectiveness analysis of silver-donating antimicrobial dressings for venous leg ulcers (VULCAN trial). Br J Surg 2009;96(10):1147-56. 

  42. O’Connell SM, Impeduglia T, Hessler K, Wang XJ, Carroll RJ, Dardik H. Autologous platelet-rich fibrin matrix as cell therapy in the healing of chronic lower-extremity ulcers. Wound Repair Regen 2008;16(6):749-56. 

  43. Ficarelli E, Bernuzzi G, Tognetti E, Bussolati O, Zucchi A, Adorni D et al. Treatment of chronic venous leg ulcers by platelet gel. Dermatol Ther 2008;21 Suppl 1:S13-7. 

  44. Schmutz JL, Meaume S, Fays S, Ourabah Z, Guillot B, Thirion V et al. Evaluation of the nano-oligosaccharide factor lipido-colloid matrix in the local management of venous leg ulcers: results of a randomised, controlled trial. Int Wound J 2008;5(2):172-82. 

  45. Palfreyman S, Nelson EA, Michaels JA. Dressings for venous leg ulcers: systematic review and meta-analysis. Br Med J 2007;335(7613):244. 

  46. Vowden P, Romanelli M, Price P. Effect of amelogenin extracellular matrix protein and compression on hard- to-heal venous leg ulcers. J Wound Care 2007;16(5):189- 95. 

  47. Vanscheidt W, Ukat A, Horak V, Bruning H, Hunyadi J, Pavlicek R et al. Treatment of recalcitrant venous leg ulcers with autologous keratinocytes in fibrin sealant: a multinational randomized controlled clinical trial. Wound Repair Regen 2007;15(3):308-15. 

  48. Lazareth I, Ourabah Z, Senet P, Cartier H, Sauvadet A, Bohbot S. Evaluation of a new silver foam dressing in patients with critically colonised venous ulcer.
 Wound Care 2007;16(3):129-32. 

  49. Franks PJ, Moody M, Moffatt CJ, Hiskett G, Gatto P, Davies C et al. Randomized trial of two foam dressings in the management of chronic venous ulceration. Wound Repair Regen 2007;15(2):197-202.
  50. Taddeucci P, Pianigiani E, Colletta V, Torasso F, Andreassi L, Andreassi A. An evaluation of Hyalofill-F plus compression bandaging in the treatment of chronic venous ulcers. J Wound Care 2004;13(5):202-4. 

  51. Yonezawa M, Tanizaki H, Inoguchi N, Ishida M, Katoh M, Tachibana T et al. Clinical study with allogeneic cultured dermal substitutes for chronic leg ulcers. Int J Dermatol 2007;46(1):36-42. 

  52. Hartmann A, Quist J, Hamm H, Brocker EB, Friedl P. Transplantation of autologous keratinocyte suspension in fibrin matrix to chronic venous leg ulcers: improved long-term healing after removal of the fibrin carrier. Dermatol Surg 2008;34(7):922-9. 

  53. Goedkoop R, Juliet R, You PH, Daroczy J, de Roos KP, Lijnen R et al. Wound stimulation by growth-arrested human keratinocytes and fibroblasts: HP802-247, a new-generation allogeneic tissue engineering product. Dermatology 2010;220(2):114-20. 

  54. Brem H, Balledux J, Sukkarieh T, Carson P, Falanga V. Healing of venous ulcers of long duration with a bilayered living skin substitute: results from a general 
surgery and dermatology department. Dermatol Surg 2001;27(11):915-9.
55.
  55. Curran MP, Plosker GL. Bilayered bioengineered skin substitute (Apligraf): a review of its use in the treatment of venous leg ulcers and diabetic foot ulcers. BioDrugs 2002;16(6):439-55.
  56. Karr JC. Retrospective comparison of diabetic foot ulcer and venous stasis ulcer healing outcome between a dermal repair scaffold (PriMatrix) and a bilayered living cell therapy (Apligraf). Adv Skin Wound Care 2011;24(3):119-25.
  57. Manizate F, Fuller A, Gendics C, Lantis JC, 2nd. A prospective, single-center, nonblinded, comparative, post- market clinical evaluation of a bovine-derived collagen with ionic silver dressing versus a carboxymethylcellulose and ionic silver dressing for the reduction of bi- oburden in variable-etiology, bilateral lower-extremity wounds. Adv Skin Wound Care 2012;25(5):220-5.
  58. Kirsner RS, Marston WA, Snyder RJ, Lee TD, Cargill DI, Slade HB. Spray-applied cell therapy with human allogeneic fibroblasts and keratinocytes for the treatment of chronic venous leg ulcers: a phase 2, multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2012;380(9846):977-85.
  59. Sano H, Ichioka S, Kouraba S, Minamimura A, Sato T, Sekiya N et al. Treatment of venous ulcers with bone marrow-impregnated collagen matrix. J Plast Surg Hand Surg 2012;46(1):37-44.
  60. Landsman AS, Cook J, Cook E, Landsman AR, Garrett P, Yoon J et al. A retrospective clinical study of 188 consecutive patients to examine the effectiveness of a biologically active cryopreserved human skin allograft (TheraSkin(R)) on the treatment of diabetic foot ulcers and venous leg ulcers. Foot Ankle Spec 2011;4(1):29-41.
  61. Ortega-Zilic N, Hunziker T, Lauchli S, Mayer DO, Huber C, Baumann Conzett K et al. EpiDex(R) Swiss field trial 2004-2008. Dermatology 2010;221(4):365-72.
  62. Falanga V, Sabolinski M. A bilayered living skin construct (APLIGRAF) accelerates complete closure of hard-to-heal venous ulcers. Wound Repair Regen 1999;7(4):201-7.
  63. Hasegawa T, Suga Y, Mizoguchi M, Muramatsu S, Mizuno Y, Haruna K et al. Intractable venous leg ulcer treated successfully with allogeneic cultured dermal substitute. Scand J Plast Reconstr Surg Hand Surg 2007;41(6):326- 8.
  64. Seidman C, Raffetto JD, Overman KC, Menzoian JO. Venous ulcer fibroblasts respond to basic fibroblast growth factor at the cell cycle protein level. Ann Vasc Surg 2006;20(3):376-80.
  65. Lineaweaver W, Howard R, Soucy D, McMorris S, Freeman J, Crain C et al. Topical antimicrobial toxicity. Arch Surg 1985;120(3):267-70.
  66. Tawfick W, Sultan S. Does topical wound oxygen (TWO2) offer an improved outcome over conventional compression dressings (CCD) in the management of refractory venous ulcers (RVU)? A parallel observational comparative study. Eur J Vasc Endovasc Surg 2009;38(1):125-32.
  67. Tumino G, Masuelli L, Bei R, Simonelli L, Santoro A, Francipane S. Topical treatment of chronic venous ulcers with sucralfate: a placebo controlled randomized study. Int J Mol Med 2008;22(1):17-23.
  68. Vanscheidt W, Harding K, Teot L, Siebert J. Effectiveness and tissue compatibility of a 12-week treatment of chronic venous leg ulcers with an octenidine based anti- septic-a randomized, double-blind controlled study. Int Wound J 2012;9(3):316-23.
  69. Mackelfresh J, Soon S, Arbiser JL. Combination therapy of doxycycline and topical tacrolimus for venous ulcers. Arch Dermatol 2005;141(11):1476-7.
  70. Sadler GM, Wallace HJ, Stacey MC. Oral doxycycline for the treatment of chronic leg ulceration. Arch Dermatol Res 2012;304(6):487-93. 

  71. O’Meara S, Al-Kurdi D, Ologun Y, Ovington LG. Antibiotics and antiseptics for venous leg ulcers. Cochrane Database Syst Rev 2010(1):CD003557. 

  72. Hokkam E, El-Labban G, Shams M, Rifaat S, El-Mezaien M. The use of topical phenytoin for healing of chron- ic venous ulcerations. Int J Surg 2011;9(4):335-8. 

  73. Cesarone MR, Belcaro G, Errichi BM, Ricci A, Bavera P, Ippolito E et al. Faster healing of venous ulcers with crystacide: a clinical and microcirculatory 8-week registry study. Panminerva Med 2010;52(2 Suppl 1):11-4. 

  74. Dharap SB, Ghag GS, Kulkarni KP, Venkatesh V. Efficacy and safety of oxum in treatment of the venous ulcer. J Indian Med Assoc 2008;106(5):326, 328-30. 

  75. Geronemus RG, Mertz PM, Eaglstein WH. Wound healing. The effects of topical antimicrobial agents. Arch Dermatol 1979;115(11):1311-4. 

  76. Mermet I, Pottier N, Sainthillier JM, Malugani C, Cairey-Remonnay S, Maddens S et al. Use of amniotic membrane transplantation in the treatment of venous leg ulcers. Wound Repair Regen 2007;15(4):459-64. 

  77. Meaume S, Ourabah Z, Romanelli M, Manopulo R, De Vathaire F, Salomon D et al. Efficacy and tolerance of a hydrocolloid dressing containing hyaluronic acid for the treatment of leg ulcers of venous or mixed origin. Curr Med Res Opin 2008;24(10):2729-39. 

  78. Humbert P, Mikosinki J, Benchikhi H, Allaert FA. Efficacy and safety of a gauze pad containing hyaluronic acid in treatment of leg ulcers of venous or mixed origin: a double-blind, randomised, controlled trial. Int Wound J 2012;10(2):159-66. 

  79. Dereure O, Czubek M, Combemale P. Efficacy and safety of hyaluronic acid in treatment of leg ulcers: a double- blind RCT. J Wound Care 2012;21(3):131-2, 134-6, 138-9. 

  80. Tauzin H, Humbert P, Viennet C, Saas P, Muret P. Human amniotic membrane in the management of chronic venous leg ulcers. Ann Dermatol Venereol 2011;138(8- 9):572-9. 

  81. Kieser DC, Roake JA, Hammond C, Lewis DR. Negative pressure wound therapy as an adjunct to compression for healing chronic venous ulcers. J Wound Care 2011;20(1):35-7. 

  82. Ross RE, Aflaki P, Gendics C, Lantis Ii JC. Complex lower extremity wounds treated with skin grafts and NPWT: a retrospective review. J Wound Care 2011;20(10):490, 492-5. 

  83. Armstrong DG, Marston WA, Reyzelman AM, Kirsner RS. Comparative effectiveness of mechanically and electrically powered negative pressure wound therapy devices: a multicenter randomized controlled trial. Wound Repair Regen 2012;20(3):332-41. 

  84. Vig S, Dowsett C, Berg L, Caravaggi C, Rome P, Birke-Sorensen H et al. Evidence-based recommendations for the use of negative pressure wound therapy in chronic wounds: steps towards an international consensus. J Tissue Viability 2011;20 Suppl 1:S1-18. 

  85. Egemen O, Ozkaya O, Ozturk MB, Aksan T, Orman C, Akan M. Effective use of negative pressure wound therapy provides quick wound-bed preparation and complete graft take in the management of chronic venous ulcers. Int Wound J 2012;9(2):199-205. 

  86. Raad W, Lantis JC, 2nd, Tyrie L, Gendics C, Todd G. Vacuum-assisted closure instill as a method of sterilizing massive venous stasis wounds prior to split thickness skin graft placement. Int Wound J 2010;7(2):81-5. 

  87. Sobanko JF, Alster TS. Efficacy of low-level laser therapy for chronic cutaneous ulceration in humans: a review and discussion. Dermatol Surg 2008;34(8):991-1000. 

  88. Junger M, Arnold A, Zuder D, Stahl HW, Heising S. Local therapy and treatment costs of chronic, venous leg ulcers with electrical stimulation (Dermapulse): a prospective, placebo controlled, double blind trial. Wound Repair Regen 2008;16(4):480-7.
  89. Caetano KS, Frade MA, Minatel DG, Santana LA, Enwemeka CS. Phototherapy improves healing of chronic venous ulcers. Photomed Laser Surg 2009;27(1):111-8.
  90. Cullum NA, Al-Kurdi D, Bell-Syer SE. Therapeutic ultrasound for venous leg ulcers. Cochrane Database Syst Rev 2010(6):CD001180.
  91. Aziz Z, Cullum N, Flemming K. Electromagnetic therapy for treating venous leg ulcers. Cochrane Database Syst Rev 2011;2:CD002933.
  92. Young S, Hampton S, Tadej M. Study to evaluate the effect of low-intensity pulsed electrical currents on levels of oedema in chronic non-healing wounds. J Wound Care 2011;20(8):368, 370-3.
  93. Taylor RR, Sladkevicius E, Guest JF. Modelling the cost- effectiveness of electric stimulation therapy in non-healing venous leg ulcers. J Wound Care 2011;20(10):464, 466, 468-72.
  94. Rawe IM, Vlahovic TC. The use of a portable, wearable form of pulsed radio frequency electromagnetic energy device for the healing of recalcitrant ulcers: a case report. Int Wound J 2012;9(3):253-8.
  95. Schumann H, Calow T, Weckesser S, Muller ML, Hoffmann G. Water-filtered infrared A for the treatment of chronic venous stasis ulcers of the lower legs at home: a randomized controlled blinded study. Br J Dermatol 2011;165(3):541-51.
  96. Watson JM, Kang’ombe AR, Soares MO, Chuang LH, Worthy G, Bland JM et al. Use of weekly, low dose, high frequency ultrasound for hard to heal venous leg ulcers: the VenUS III randomised controlled trial. Br Med J 2011;342:d1092.
  97. Watson JM, Kang’ombe AR, Soares MO, Chuang LH, Worthy G, Bland JM et al. VenUS III: a randomised controlled trial of therapeutic ultrasound in the management of venous leg ulcers. Health Technol Assess 2011;15(13):1-192.
  98. Blum K, Chen AL, Chen TJ, Downs BW, Braverman ER, Kerner M et al. Healing enhancement of chronic venous stasis ulcers utilizing H-WAVE(R) device therapy: a case series. Cases J 2010;3:54.
  99. Taradaj J, Franek A, Brzezinska-Wcislo L, Cierpka L, Dolibog P, Chmielewska D et al. The use of therapeutic ultrasound in venous leg ulcers: a randomized, control- led clinical trial. Phlebology 2008;23(4):178-83.
  100. Saltmarche AE. Low level laser therapy for healing acute and chronic wounds - the extendicare experience. Int Wound J 2008;5(2):351-60.
  101. Mercer JB, Nielsen SP, Hoffmann G. Improvement of wound healing by water-filtered infrared-A (wIRA) in patients with chronic venous stasis ulcers of the lower legs including evaluation using infrared thermography. Ger Med Sci 2008;6:Doc11.
  102. Fioramonti P, Onesti MG, Fino P, Fallico N, Scuderi N. Extracorporeal shock wave therapy for the treatment of venous ulcers in the lower limbs. Ann Ital Chir 2012;83(1):41-4.
  103. Saggini R, Figus A, Troccola A, Cocco V, Saggini A, Scuderi N. Extracorporeal shock wave therapy for management of chronic ulcers in the lower extremities. Ultra- sound Med Biol 2008;34(8):1261-71.
  104. Gottrup F, Jorgensen B, Karlsmark T, Sibbald RG, Rimdeika R, Harding K et al. Less pain with Biatain-Ibu: initial findings from a randomised, controlled, double- blind clinical investigation on painful venous leg ulcers. Int Wound J 2007;4 Suppl 1:24-34.
  105. Gottrup F, Jorgensen B, Karlsmark T, Sibbald RG, Rim- deika R, Harding K et al. Reducing wound pain in venous leg ulcers with Biatain Ibu: a randomized, controlled double-blind clinical investigation on the performance and safety. Wound Repair Regen 2008;16(5):615-25. 

  106. Hessler I, Panfil EM. Ulcus curis venosum: topical drugs and dressings in evaluation. How effective are the measures in terms of pain management? Pflege Z 2011;64(10):616-7. 

  107. Romanelli M, Dini V, Polignano R, Bonadeo P, Maggio G. Ibuprofen slow-release foam dressing reduces wound pain in painful exuding wounds: preliminary findings from an international real-life study. J Dermatolog Treat 2009;20(1):19-26. 

  108. Dumville JC, Worthy G, Soares MO, Bland JM, Cullum N, Dowson C et al. VenUS II: a randomised controlled trial of larval therapy in the management of leg ulcers. Health Technol Assess 2009;13(55):1-182, iii-iv. 

  109. Dumville JC, Worthy G, Bland JM, Cullum N, Dowson C, Iglesias C et al. Larval therapy for leg ulcers (VenUS II): randomised controlled trial. Br Med J 2009;338:b773. 

  110. Spilsbury K, Cullum N, Dumville J, O’Meara S, Petherick E, Thompson C. Exploring patient perceptions of larval therapy as a potential treatment for venous leg ulceration. Health Expect 2008;11(2):148-59.
  111. Chan DC, Fong DH, Leung JY, Patil NG, Leung GK. Maggot debridement therapy in chronic wound care. Hong Kong Med J 2007;13(5):382-6.
  112. Gethin G, Cowman S. Manuka honey vs. hydrogel-a prospective, open label, multicentre, randomised controlled trial to compare desloughing efficacy and healing out- comes in venous ulcers. J Clin Nurs 2009;18(3):466-74.
  113. Smith T, Legel K, Hanft JR. Topical Leptospermum honey (Medihoney) in recalcitrant venous leg wounds: a preliminary case series. Adv Skin Wound Care 2009;22(2):68-71.
  114. Jull AB, Rodgers A, Walker N. Honey as a topical treatment for wounds. Cochrane Database Syst Rev 2008(4):CD005083.
  115. Jull A, Walker N, Parag V, Molan P, Rodgers A. Randomized clinical trial of honey-impregnated dressings for venous leg ulcers. Br J Surg 2008;95(2):175-82.