ORIGINAL INVESTIGATION
Treatment Options for Venous Leg Ulcers: Effectiveness of Vascular Surgery, Bioengineered Tissue, and Electrical Stimulation Gaurav Thakral, MD; Javier La Fontaine, DPM, MS; Paul Kim, DPM; Bijan Najafi, PhD; Adam Nichols, DPM; and Lawrence A. Lavery, DPM, MPH
ABSTRACT OBJECTIVE: To evaluate the peer-reviewed literature that compares advanced venous leg ulcer therapies to standard of care with compression dressings. METHODS: A MEDLINE search for venous ulcer treatment with electrical stimulation, surgical vein correction, and bioengineered tissues was conducted. Randomized clinical trials comparing advanced treatment with standard of care using compression dressing were included. A total of 7 bioengineered tissue, 4 surgical treatment, and 4 electrical stimulation randomized clinical trials were identified. RESULTS: Compared with nonstandard treatments, electrical stimulation demonstrated improved wound healing, fewer adverse events, and shorter duration of healing. Healing rates at the end of the study were greater for surgical intervention, followed by similar outcomes for electrical stimulation and bioengineered tissues. Studies involving bioengineered tissues and surgical venous ablation demonstrated inconsistent/inconclusive results. CONCLUSIONS: Utilization of electrical stimulation in venous ulcer management has not been fully explored. Further studies of dosing electrical stimulation therapy may reveal therapeutic and preventive benefits for managing venous ulcers not yet elucidated. KEYWORDS: venous leg ulcer, surgery, bioengineered tissue, electrical stimulation, wound healing, edema ADV SKIN WOUND CARE 2015;28:164Y72
INTRODUCTION Venous leg ulcers (VLUs) are a common and costly disease process, estimated to consume 1% of the total healthcare costs in the United States. Statistics indicate that VLUs occur in about 0.3% of the adult population1 and are associated with obesity, history of pregnancy, and deep vein thrombosis.2 The incidence of VLUs is
higher in women and increases with age for both sexes,3 and the prevalence of VLUs on admission at long-term-care facilities is reported to be as high as 2.5%.4 Furthermore, as obesity and obesityrelated health risks continue to rise,5,6 an increased incidence of venous stasis and VLUs can be expected. Chronic venous disease commonly arises from a combination of calf muscle failure and venous pathology. These factors contribute to the leakage of macromolecules into the interstitial tissues, causing lower-extremity edema and perpetuating the underlying pathology. Contraction of the calf muscle generates pressure to propel venous blood toward the heart. Muscle strength has been shown to be significantly lower in patients with recently healed VLUs compared with that in control subjects.7 Skeletal muscle atrophy from immobility is considered a primary cause for failure for the muscle pump mechanism.8 Moreover, active and passive movement of the ankle joint has been shown to significantly increase venous return velocities in both healthy subjects and those with venous disease.9,10 There are 2 underlying etiologies of venous pathology. First of these is venous microangiopathy; it is thought to evolve from distension of the capillary walls with subsequent leakage of macromolecules, such as fibrinogen, into the dermis and subcutaneous tissue of the lower leg.11 Once in the extravascular space, fibrinogen polymerizes to form a pericapillary fibrin cuff that prevents exchange of oxygen and nutrients leading to cell death and ulceration.12,13 The abnormal diffusion of macromolecules into the extracellular space traps growth factors and blood cells. The resulting vessel growth and deformity are associated with elongation, dilation, and tortuosity of capillary beds; endothelial damage with widening interendothelial spaces; and increased pericapillary edema.14 The other pathological process is incompetent valves within the veins themselves. When valves are incompetent, blood is allowed to flow in a retrograde fashion leading to disruption of Starling equilibrium, with a
Gaurav Thakral, MD, is Research Staff, and Javier La Fontaine, DPM, MS, is Associate Professor; both at the Department of Plastic Surgery, The University of Texas Southwestern Medical Center, Dallas, Texas. Paul Kim, DPM, is Associate Professor, Department of Plastic Surgery, Georgetown University School of Medicine, Washington, District of Columbia. Bijan Najafi, PhD, is Associate Professor of Surgery and Engineering, Department of Surgery, University of Arizona School of Medicine, Phoenix, Arizona. Adam Nichols, DPM, is a Fellow, and Lawrence A. Lavery, DPM, MPH, is Professor, Department of Plastic Surgery, and is Codirector of Research and Medical Director of the Comprehensive Wound Care Center; The University of Texas Southwestern Medical Center, Dallas, Texas. Dr Najafi has disclosed that the University of Arizona School of Medicine received research grant funding from the Qatar National Research Fund, NPRP 5-117-3-028. Dr Lavery has disclosed that he has a patent-pending project with Diabetica Solutions; receives payment from Healthpoint Biotherapeutics for the development of educational presentations; and receives stock options from Prizm Medical. The other coauthors have disclosed that they have no financial relationships related to this article. Submitted September 9, 2013: accepted in revised form February 4, 2014. ADVANCES IN SKIN & WOUND CARE & VOL. 28 NO. 4
164
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
WWW.WOUNDCAREJOURNAL.COM
ORIGINAL INVESTIGATION
net loss of fluids into surrounding tissue.8 The accumulated fluid inactivates the fatty acid of dermal sebum, leaving the skin vulnerable to breakdown and subsequent infection from common dermal pathogensVstreptococci and staphylococci.15 Compression therapy is the criterion standard treatment for VLUs.13Y15 A review of 16 studies that applied multilayered high compression for VLUs showed healing rates of 34% to 79% (average, 60.9%) at 12 weeks. As a result, many ulcers remain unhealed.16,17 One of the advanced therapies recommended for VLUs is electrical stimulation. According to some researchers, electrical stimulation has a much more pronounced accelerating effect on tissue regeneration processes than other types of electrotherapy.18 Cellular and growth factor deficiencies are present in the chronic wound environment. In VLUs, venous hypertension may cause blood proteins to leak in the extravascular space, trapping growth factors and cytokines needed for tissue repair. As a consequence, the conditions of the VLU wound environment may not efficiently support the epidermal migration, attachment, and proliferation of regenerating cells needed for healing. Based on these premises, bioengineered tissues have become an area of research in VLUs. The purpose of this review is to describe randomized clinical trials (RCTs) in which bioengineered tissue, surgery, and electrical stimulation were compared with standard of care, regardless if treatment group was combined with compression.
METHODS Many therapeutic agents have been suggested for use as adjunctive therapy for VLU healing. The authors searched for Englishlanguage studies in MEDLINE for clinical trials in VLU treatment using the following keywords: electrical stimulation, surgical vein correction, and bioengineered tissues. Because compression therapy is the criterion standard, the studies reviewed often compared compression and advanced therapies with compression alone. The authors did not exclude these studies. Studies were excluded for not comparing treatment with standard of care,19Y26 populations of mixed wound pathology,27 and uncontrolled studies.28Y31 All identified abstracts were reviewed as a primary filter. Selected studies were reviewed in their entirety. A comparison of the selected treatments highlights the need to consider cost and reduction in ulcer recurrence in selecting a treatment modality.
Compression Therapy Compression stockings are the criterion standard treatment for venous and lymphatic disorders.32 Compression aims to reduce or control venous reflux and peripheral edema. Venous compression may achieve narrowing of veins, restoration of valvular competence, or acceleration of venous flow.33 As venous incompetence leads to secondary complications, the use of compression alone may not be sufficient. A review of 11 studies suggested that WWW.WOUNDCAREJOURNAL.COM
combined modalities using intermittent pneumatic leg compression with pharmacological prophylaxis are more effective than single modalities in preventing venous thromboembolism.34 Similarly, for treatment of venous ulcers, compression therapy is combined with other modalities involving surgical intervention, electrical stimulation, and bioengineered tissues.
Bioengineered Tissue Seven studies compared bioengineered tissue with the standard of care involving compression therapy (Table 1). These tissues are intended to act as a ‘‘booster’’ in the host chronic wound. Indications for their use usually include noninfected, chronic, and partialand full-thickness chronic VLUs.35 Bioengineered tissues consist of a single or bilayer matrix that provides a scaffold, as well as cells to promote healing. Only 2 of the 7 studies reported positive results. One of the positive studies was the largest RCT (n = 275), and the other positive study was the one with the smallest sample size (n = 18) (Table 1). The most recently published RCT included 266 subjects; however, there was no difference in patients treated with bioengineered tissue and control subjects treated with compression therapy.36 Five of the 7 studies were very small and certainly underpowered. The size of the study groups in the negative studies ranged from 8 to 22 patients per treatment group (Table 1). These small studies would have needed extraordinary results in order to have statistical significance; most of them did not even report a strong trend that would indicate that bioengineered tissue improved VLU healing. One of 2 positive studies was a larger, multicenter study in which allogeneic tissue (Apligraf; Organogenesis, Canton, Massachusetts) was applied 5 times in 3 weeks; a higher proportion of wounds healed with the addition of cultured allogeneic human skin equivalent compared with standard of care alone (63% vs 49%; P = .02). Patients received an average of 3.3 applications. All applications of bioengineered tissue occurred in the initial 3 weeks, yet the healing efficiency was measured 21 weeks after the last possible application.37 Multiple studies have been conducted using human fibroblastdermal substitutes (HDFSs) (Dermagraft; Organogenesis). The largest of which, by Harding et al36 compared HDFS (Dermagraft) with 4-layer compression with compression alone over a 12-week course of treatment and secondarily at 24 weeks at a follow-up end point. Up to 4 applications of the HDFS were performed; these were done at weeks 0, 1, 4, and 8. Patients who were morbidly obese or had a greater than 50% wound area reduction to compression over a 2-week screening period were excluded. The primary outcome was defined as complete epithelialization for 2 consecutive visits. When compared overall, there was no difference in wound healing, with 31.5% of the control group healed at 12 weeks compared with 34.4% who received HDFS. In a subgroup of patients with ulcers present less than 1 year, 37.1% of the control group achieved
165
ADVANCES IN SKIN & WOUND CARE & APRIL 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
ORIGINAL INVESTIGATION
Table 1.
BIOENGINEERED TISSUE FOR HEALING AND PREVENTATION OF VLU Author
Treatment
Study Design
Duration of Study and Follow-up
Population
Falanga et al,37 1998
Allogeneic cultured human skin equivalent (Apligraf; Organogenesis)
Maximum of 5 times in first 3 wk
Healing: 6 mo Follow-up: 12 mo
Treatment n = 146 Compression n = 129
Goedkoop et al,68 2010
Allogeneic growth-arrested, human keratinocytes and fibroblasts spray (DFB Pharmaceuticals Inc, Fort Worth, Texas)
Weekly for 12 wk
Healing: 3 mo Follow-up: 6 mo
Harding et al,36 2013
Human allogeneic fibroblast-derived dermal tissue (Dermagraft)
4 applications over 12 wk
Healing: 3 mo Follow-up: 6 mo
2.5/1:9a n = 14 5/1:9a n = 17 10/1:9a n = 15 2.5/1:1a n = 17 5/1:1a n = 16 10/1:1a n = 16 Compression n = 15 Treatment n = 186 Compression n = 180
Krishnamoorthy et al,39 2003
Allogeneic fibroblast-derived dermal sheet (Dermagraft)
Span of 12 wk
Healing: 3 mo
Lindgren et al,40 1998
Allogeneic keratinocyte sheets
Weekly for 12 wk
Healing: 2 mo
Omar et al,38 2004
Allogeneic fibroblast-derived dermal sheet (Dermagraft)
4 applications in 12 wk
Healing: 3 mo
Treatment n = 10 Compression n = 8
Teepe et al,41 1993
Allograft cultured epidermal
Weekly for 6 wk
Healing: 6 wk Recurrence: 6 mo
Treatment n = 22 Compression n = 21
Group 1 (n = 13): 12 applications Group 2 (n = 13): 4 applications Group 3 (n = 14): 1 application Compression (n = 13) Treatment n = 15 Compression n = 12
a Cell concentration (106 cell/mL)/cell ratio (keratinocyte:fibroblast) Abbreviation: NS, not significant
healing, whereas 52.1% of the HDFS healed (P = .029). There was an inverse relationship in those with wounds present for more than 1 year (21.4% vs 16.3%) (P G .05). Ulcers involving less than 10 cm2 healed in 39.2% of control subjects and 47% within the treatment group (P G .05). Again, there was an inverse response in ulcers larger than 10 cm2 (15% vs 13%) (P G .05). Those patients treated with compression alone had a higher recurrence rate over the 24-week followup (23%) than did those who received HDFS (15%) (P G .05). Adverse events, most commonly infection, were similar between the groups.34 ADVANCES IN SKIN & WOUND CARE & VOL. 28 NO. 4
Omar et al38 conducted a small RCT and compared 4 applications of Dermagraft to a 4-layer compression bandage (ProFore; Smith & Nephew, St Petersburg, Florida). A trend of improved healing was shown when Dermagraft was applied 4 times over 12 weeks (50%, n = 10) compared with standard of care (13%, n = 8) (P = .15).38 Capillary density in histological sections did not show significant changes for either group. In a similar study, Krishnamoorthy et al39 evaluated 3 treatment schedules of Dermagraft compared with compression with Profore. Healing rates for a single application
166
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
WWW.WOUNDCAREJOURNAL.COM
ORIGINAL INVESTIGATION
In addition, the active treatment group had dermatitis in an unspecified number of study subjects that was overcome by trimming the edges of the allograft so it barely touched the skin.40 A 6-week randomized trial by Teepe et al41 noted (n = 43) no difference in healing between 24 patients treated with cultured epidermal allografts and 23 patients treated with hydrocolloid dressing (25% vs 22%, P 9 .05). Four active and 3 control subjects were dropped because of infection.41
Table 1.
CONTINUED Outcome Wound healing: bioengineered tissue (63%) vs compression (49%) (P = .02) Wound area reduction: NS Recurrence: bioengineered tissue (12%) vs compression (16%) (P 9 .05) Adverse events: death (5 bioengineered tissue and 4 control), adverse experience (3 bioengineered tissue and 7 control), wound infection (2 bioengeneered tissue), and cellulitis (12 bioengineered tissue and 10 control) Wound healing: bioengineered tissue (40%) vs compression (33%) (P 9 .05) Wound area reduction: NS Recurrence: bioengineered tissue (61%) vs compression (50%) (P 9 .05) Adverse events: NS
Surgery Surgical intervention for venous ulceration focuses on ablating the pathologic veins. Surgical treatment addresses the underlying venous pathology of VLU. Four RCTs that evaluated healing rates between surgical vein correction and compression therapy were found (Table 2). Guest et al42 reported healing rates of 68% at 26 weeks for VLUs treated with surgery compared with the control group’s healing rates of 64% (P = .75). One active treatment and 2 control patients received antibiotics for cellulitis.42 Zamboni et al43 compared surgical correction of venous reflux with control subjects in 47 patients. There was no statistical difference in the healing rateVsurgical treatment group (100%) and control subjects (96%, P 9 .05). The recurrence rate, however, was significantly lower in the surgery group (9% vs 38%, P G .05).43 Two large multicenter studies (n = 500, 200) demonstrated no significant difference in healing rates among surgical and standardof-care treatment.44,45 In 1 study, van Gent et al44 found no difference in healing rates when comparing surgical (83%) treatment with compression therapy (73%); nor did they find a difference in recurrence rates (22% surgical, 23% compression) (P 9 .05).44 However, Gohel et al45 reported the results of a multicenter study with 500 patients and demonstrated similar healing rates between the treatment groups (93% surgery, 89% control, P = .73). However, there were significantly lower ulcer recurrence rates for surgical patients (31%) compared with control patients (56%, P G .01).45 Two other studies demonstrated significantly lower recurrence rates at 3 and 4 years.43,45 After an ulcer heals through standard of care, the underlying pathology remains and requires constant compression therapy to minimize recurrence. Thus, although there is little evidence as to the efficacy of surgical intervention compared with compression, there are studies with results that support its use in preventing recurrence of VLUs.
Wound healing: bioengineered tissue (34%) vs compression (31%) (P = .2) Wound area reduction: bioengineered tissue (83.7%) vs compression (73.0%) (P 9 .05) Recurrence: bioengineered tissue (15%) vs compression (23%) (P 9 .05) Adverse events: wound infection (43 bioengineered tissue and 46 control), cellulitis (12 bioengineered tissue and 18 control), peripheral edema (13 bioengineered tissue and 5 control) Wound healing: group 1 (38%), group 2 (38%), group 3 (7%) vs compression (15%) (P 9 .05) Wound area reduction: NS Recurrence: NS Adverse events: NS
Wound healing: bioengineered tissue (13%) vs compression (17%) (P 9 .05) Wound area reduction: bioengineered tissue (35%) vs compression (15%) (P 9 .05) Recurrence: NS Adverse events: NS Wound healing: bioengineered tissue (50%) vs compression (13%) (P 9 .05.) Wound area reduction: bioengineered tissue (84%) vs compression (16%) (P = .002) Recurrence: NS Adverse events: Wound infection (4 bioengineered tissue and 3 control), reatment failure (1 bioengineered tissue), and noncompliance (1 control) Wound healing: bioengineered tissue (41%) vs compression (33%) (P 9 .05.) Wound area reduction: NS Recurrence: 13% bioengineered tissue vs 14% compression P 9 .05 Adverse events: NS
of Dermagraft were half that of standard of care (7% vs 15%, respectively). Also, similar results were seen for 4 applications over 12 weeks (38%) and once-weekly application over the same time period (38%, P 9 .05) and the control. The authors concluded 4 applications of Dermagraft were the optimal dosing regimen39 (Table 1). Lindgren et al40 showed no difference in the proportion of wounds that healed when comparing 12 patients treated with compression to 15 patients treated with cryopreserved split-thickness allografts and compression (compression 17% vs 13%) after 8 weeks. WWW.WOUNDCAREJOURNAL.COM
Electrical Stimulation Electrical stimulation has been used for more than 100 years for various ailments and may offer a unique treatment option to heal venous stasis ulcers. Electrical stimulation shows evidence of bactericidal and bacteriostatic effects on organisms that commonly colonize and infect leg wounds.46Y54 Bacterial load and infection are thought to be important factors in chronic wounds and delayed healing.55Y59 Bacterial colonization of more than 105 organisms per gram of tissue is associated with infection and
167
ADVANCES IN SKIN & WOUND CARE & APRIL 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
ORIGINAL INVESTIGATION
Table 2.
SURGICAL TREATMENT FOR HEALING AND PREVENTATION OF VLUs Duration of Study and Follow-up
Population
Outcome
Saphenofemoral junction disconnection, stripping of the long saphenous vein to below the knee, and calf varicosity avulsions
Healing rates at 3 y Recurrence rates at 4 y
Treatment n = 258 Compression n = 242
Guest et al,42 2003
Superficial venous surgery
18 mo
Treatment n = 37 Compression n= 39
van Gent et al,44 2006
Subfascial endoscopic perforating vein surgery combined with superficial vein ligation
3y
Treatment n = 97 Compression n = 103
Zamboni et al,43 2003
Minimally invasive surgical hemodynamic correction of reflux
3y
Treatment n = 21 Compression n = 24
Wound healing: surgery (93%) vs compression (89%) (P = .73) Wound area reduction: NS Reoccurrence: surgery (31%) vs compression (56%) (P G .01) Adverse events: 2 compression patients admitted for cellulitis, 8 postoperative complications (1 deep vein thrombosis, 5 wound infections, 1 hematoma, 1 phlebitis) Wound healing: surgery (68%) vs compression (64%) (P = .75) Wound area reduction: NS Recurrence: NS Adverse events: 2 compression and 1 surgery patients were treated for cellulitis Wound healing: surgery (72%) vs compression (53%) (P = .11) Wound area reduction: NS Recurrence: surgery (22%) vs compression (23%) (P 9 .05) Adverse events: NS Wound healing: surgery (100%) vs compression (96%) (P 9 .05) Wound area reduction: NS Reoccurrence: surgery (9%) vs compression (38%) (P G .05) Adverse events: NS
Author
Treatment of Interest
Gohel et al,45 2007
Abbreviation: NS, not significant
delayed wound healing in chronic wounds.56,58Y60 Halbert et al56 took bacterial cultures from 83 limbs and showed an association between delayed wound healing and higher bacterial counts in leg ulcers. When compared with noncolonized ulcers, colonized ulcers had longer duration at presentation and larger size at presentation and took longer to heal (P G .01).56,61 Routine use of antibiotics in uncomplicated ulcers does not improve healing rates or decrease bacterial colonization.62,63 Therefore, electrical stimulation may act to reduce bacterial colonization, while simultaneously improving venous return and accelerate wound healing in VLU treatment. In addition to increased skin perfusion, electrical stimulation therapy has been shown to improve venous flow.1Y4 Transcutaneous electrical nerve stimulation was evaluated in 24 healthy individuals and was shown to increase the activity of the calf muscle pump. There was a 19-fold increase in the ejection volume of the popliteal vein at 2 pulses per second compared with 120 pulses per second.7 Increased venous return with electrical stimulation may help to explain observations of improved edema, as well as better cutaneous circulation with electrical stimulation. One device setting facilitates velocity, while the other facilitates ejected volume. Lower stimuli per minute that increase peak sysADVANCES IN SKIN & WOUND CARE & VOL. 28 NO. 4
tolic velocity may be able to eject blood against gravity to pass incompetent valves while standing or ambulating. An increase in stimuli per minute may permit edema reduction after prolonged activity or during supine rest. No studies were identified that addressed venous stasis while standing and resting. A dual-setting therapy may have additional benefits over single setting. The authors identified 4 RCTs using electrical stimulation in patients with VLUs (Table 3). Three of these showed positive results and minimal to no adverse events. Franek et al64 compared high-voltage stimulation, a topically applied pharmaceutical compound, and standard of care using Unna boot. The topical pharmaceutical compound consisted of potassium permanganate, rivanol, and 0.1% copper sulphate. In this study, subjects with diabetes had their blood sugar stabilized for 6 months prior to enrollment; cohorts consisted of 30 patients (electrical stimulation), 32 patients (topical pharmaceutical), and 14 patients (control). Most ulcers in the electrical stimulation group were nearly devoid of a suppurative wound layer after 2 weeks of treatment. Disappearance of this layer favored granulation tissue formation from week 2 to week 3 between groups (P G .003).64 Despite having one of the shorter durations of all studies included in this review, high-voltage stimulation
168
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
WWW.WOUNDCAREJOURNAL.COM
ORIGINAL INVESTIGATION
Table 3.
ELECTRICAL STIMULATION FOR HEALING AND PREVENTION OF VLUs Franek et al,64 2000
Venous ulcers using FREMS
50 min, daily, 6 d a week for 3 wk
100 V, 0.1 ms, 100 Hz
Stiller et al,65 1992
Venous ulcers using PEMF
3 hours, daily, 7 d a week for 2 mo
Ogrin et al,66 2009
Venous ulcers using transcutaneous electrical nerve stimulation
5 min, twice a day for 3 mo
0.06 mV/cm. The signal is 3-part pulse (+, j, +) of 3.5-ms width 4 mA, 5Hz
Lundberg et al,67 1992
VLUs in diabetics using alternating current
20 min, twice a day for 3 mo
80 Hz, pulse width 1 ms
Treatment n = 33 Ointment n = 32 Control n = 14 Treatment n = 18 placebo n = 13 Treatment n = 14 placebo n = 15 Treatment n = 32 placebo n = 32
Wound healing: NS Wound area reduction: ES 59%, ointment 35% vs control 25% (P G .05) Adverse events: no events
Wound healing: NS Wound area reduction ES 48% vs control increase of 42% (P G .0002) Adverse event: no events Wound healing: ES 57% vs placebo 67% (P 9 .05) Wound area reduction: ES 0.8 T 0.2 vs placebo 0.7 T 0.2 cm2 per week (P 9 .05) Adverse event: NS Wound healing: ES 42% vs 15% placebo (P G .05) Wound area reduction: 59 T 11% ES vs 39 T 14% placebo (P G .05) Adverse event: allergy (2 ES and 1 placebo), pain (3 ES, and 2 placebos), and refusal/ nonattendance (3 ES and 2 placebos)
Abbreviations: NS, not significant; PEMF, pulsed electromagnetic field; FREMS, frequency-modulated electromagnetic neural stimulation
reduced wound area significantly more than did compression alone. These results suggest that high-voltage stimulation may be a useful nonsurgical method for eliminating hard-to-remove suppurative formation in patients unable to tolerate mechanical debridement. Stiller et al65 applied an elastic compression wrap at approximately 20 mm Hg as standard of care and excluded patients unable to elevate their feet for 3 hours a day. They noted granulation tissue increased in the electrical stimulation group (68%Y83%), whereas there was no change for the compression group (67%Y67%) (P G .04). In a global assessment, 50% of active treatment patients healed or had markedly improved wounds, whereas there was no improvement in the compression group (P G .001). Also, patients receiving active treatment had pain reduction of 0.61 compared with 0.15 in those receiving placebo therapy and a scale from -3 to 4 (P G .04).65 Ogrin et al66 applied electrical stimulation of 5 minutes twice daily for a total of 14 hours over 12 weeks, and they identified no differences in wound healing compared with control treatment. The authors noted no improvement in oxygen tension in the electrical stimulation group. The maximum hours of electrical stimulation used by Franek et al,64 Stiller et al,65 and Lundberg et al67 were far greater at 168, 50, and 56 hours, respectively. Laboratory studies have shown that under direct current, endothelial cell orientation was seen as early as 4 hours after the onset of an electrical field. Electrical stimulation up to 3 days accelerated the orientation and WWW.WOUNDCAREJOURNAL.COM
elongation of endothelial cells compared with the control.20 No clinical study has yet investigated the dose-related benefit to electrical stimulation.
CONCLUSIONS Although compression therapy may be the criterion standard in the treatment of VLUs, the results are less than ideal. The rate of healing is low, and the rate of recurrence is high. As demonstrated by this review, there is little evidence to support the use of adjunctive therapies to heal VLUs at this time. Most of the electrical stimulation and bioengineered tissue studies were very small. The surgical treatment studies reported produced a higher percentage of healed wounds, as well as the lowest recurrence rates, probably because of the selection process. Surgery patients are probably healthier patients with venous disease that is amenable to surgical repair. High-risk patients and patients with severe venous disease were appropriately excluded. One of the key benefits of surgical treatment is the apparent reduction in ulcer recurrence, although this was not documented in all studies.43,45 Despite the small sample size, electrical stimulation showed positive results and promise as an option for adjunctive treatment.
&
REFERENCES
169
1. Barwell JR, Davies CE, Deacon J, et al. Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised controlled trial. Lancet 2004;363:1854-9. ADVANCES IN SKIN & WOUND CARE & APRIL 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
ORIGINAL INVESTIGATION
2. Fowkes FG, Evans CJ, Lee AJ. Prevalence and risk factors of chronic venous insufficiency. Angiology 2001;52(Suppl 1):S5-15. 3. Heit JA, Rooke TW, Silverstein MD, et al. Trends in the incidence of venous stasis syndrome and venous ulcer: a 25-year population-based study. J Vasc Surg 2001;33:1022-7. 4. Wipke-Tevis DD, Rantz MJ, et al. Prevalence, incidence, management, and predictors of venous ulcers in the long-term-care population using the MDS. Adv Skin Wound Care 2000; 13:218-24. 5. Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003;289:76-9. 6. Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP. The continuing epidemics of obesity and diabetes in the United States. JAMA 2001;286:1195-200. 7. Yang D, Vandongen YK, Stacey MC. Changes in calf muscle function in chronic venous disease. Cardiovasc Surg 1999;7:451-6. 8. Clarke-Moloney M, Lyons GM, Burke PE, O’Keeffe D, Grace PA. A review of technological approaches to venous ulceration. Crit Rev Biomed Eng 2005;33:511-56. 9. Staubesand J, Heisterkamp T, Stege H. Use of duplex sonography to investigate the effect of active and passive movement at the ankle joint for promoting venous return. Clin Anat 1995;8:96-101. 10. Sochart DH, Hardinge K. The relationship of foot and ankle movements to venous return in the lower limb. J Bone Joint Surg Br 1999;81:700-4. 11. Browse NL, Burnand KG. The cause of venous ulceration. Lancet 1982;2:243-5. 12. Falanga V. Venous ulceration. J Dermatol Surg Oncol 1993;19:764-71. 13. Valencia IC, Falabella A, Kirsner RS, Eaglstein WH. Chronic venous insufficiency and venous leg ulceration. J Am Acad Dermatol 2001;44:401-21. 14. Eberhardt RT, Raffetto JD. Chronic venous insufficiency. Circulation 2005;111:2398-409. 15. Robson MC, Cooper DM, Aslam R, et al. Guidelines for the treatment of venous ulcers. Wound Repair Regen 2006;14:649-62. 16. Ju¨nger M, Wollina U, Kohnen R, Rabe E. Efficacy and tolerability of an ulcer compression stocking for therapy of chronic venous ulcer compared with a below-knee compression bandage: results from a prospective, randomized, multicentre trial. Curr Med Res Opin 2004; 20:1613-23. 17. Kurz X, Kahn SR, Abenhaim L, et al. Chronic venous disorders of the leg: epidemiology, outcomes, diagnosis and management. Summary of an evidence-based report of the VEINES task force. Venous Insufficiency Epidemiologic and Economic Studies. Angiology 1999;18:83-102. 18. Zhao M, Bai H, Wang E, Forrester JV, McCaig CD. Electrical stimulation directly induces pre-angiogenic responses in vascular endothelial cells by signaling through VEGF receptors. J Cell Sci 2004;117(Pt 3):397-405. 19. Ieran M, Zaffuto S, Bagnacani M, Annovi M, Moratti A, Cadossi R. Effect of low frequency pulsing electromagnetic fields on skin ulcers of venous origin in humans: a double-blind study. J Orthop Res 1990;8:276-82. 20. Jankovic A, Binic I. Frequency rhythmic electrical modulation system in the treatment of chronic painful leg ulcers. Arch Dermatol Res 2008;300:377-83. 21. Kenkre JE, Hobbs FD, Carter YH, Holder RL, Holmes EP. A randomized controlled trial of electromagnetic therapy in the primary care management of venous leg ulceration. Fam Pract 1996;13:236-41. 22. Santamato A, Panza F, Fortunato F, et al. Effectiveness of the frequency rhythmic electrical modulation system for the treatment of chronic and painful venous leg ulcers in older adults. Rejuvenation Res 2012;15:281-7. 23. Chang DW, Sanchez LA, Veith FJ, Wain RA, Okhi T, Suggs WD. Can a tissue-engineered skin graft improve healing of lower extremity foot wounds after revascularization? Ann Vasc Surg 2000;14:44-9. 24. Poskitt KR, James AH, Lloyd-Davies ER, Walton J, McCollum C. Pinch skin grafting or porcine dermis in venous ulcers: a randomised clinical trial. Br Med J (Clin Res Ed) 1987;294:674-6. 25. Tausche AK, Skaria M, Bo¨hlen L, et al. An autologous epidermal equivalent tissue-engineered from follicular outer root sheath keratinocytes is as effective as split-thickness skin autograft in recalcitrant vascular leg ulcers. Wound Repair Regen 2003;11:248-52. 26. van den Hoogenband HM. Treatment of leg ulcers with split-thickness skin grafts. J Dermatol Surg Oncol 1984;10:605-8. 27. Houghton PE, Kincaid CB, Lovell M, et al. Effect of electrical stimulation on chronic leg ulcer size and appearance. Phys Ther 2003;83:17-28. 28. Clancy JM, Shehade SA, Blight AE, Young KE, Levick PL. Treatment of leg ulcers with cultured epithelial grafts. J Am Acad Dermatol 1988;18:1356-7. 29. Liu JY, Hafner J, Dragieva G, Seifert B, Burg G. Autologous cultured keratinocytes on porcine gelatin microbeads effectively heal chronic venous leg ulcers. Wound Repair Regen 2004;12: 148-56. 30. Mol MA, Nanninga PB, van Eendenburg JP, Westerhof W, Mekkes JR, van Ginkel CJ. Grafting WWW.WOUNDCAREJOURNAL.COM
31.
32. 33. 34.
35. 36.
37.
38. 39. 40. 41.
42.
43.
44.
45.
46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58.
171
of venous leg ulcers. An intraindividual comparison between cultured skin equivalents and full-thickness skin punch grafts. J Am Acad Dermatol 1991;24:77-82. Navra´tilova´ Z, Slonkova´ V, Semra´dova´ V, Adler J. Cryopreserved and lyophilized cultured epidermal allografts in the treatment of leg ulcers: a pilot study. J Eur Acad Dermatol Venereol 2004;18:173-9. O’Meara S, Cullum N, Nelson EA, Dumville JC. Compression for venous leg ulcers. Cochrane Database Syst Rev 2012;11:CD000265. Ramelet AA. Phlebectomy. Technique, indications and complications. Int Angiol 2002; 21(2 Suppl 1):46-51. Review. Kakkos SK, Caprini JA, Geroulakos G, Nicolaides AN, Stansby GP, Reddy DJ. Combined intermittent pneumatic leg compression and pharmacological prophylaxis for prevention of venous thromboembolism in high-risk patients. Cochrane Database Syst Rev 2008; 8(4):Review. Fivenson D, Scherschun L. Clinical and economic impact of Apligraf for the treatment of nonhealing venous leg ulcers. Int J Dermatol 2003;42:960-5. Harding K, Sumner M, Cardinal M. A prospective, multicentre, randomised controlled study of human fibroblast-derived dermal substitute (Dermagraft) in patients with venous leg ulcers. Int Wound J 2013;10:132-7. Falanga V, Margolis D, Alvarez O, et al. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Human Skin Equivalent Investigators Group. Arch Dermatol 1998;134:293-300. Omar AA, Mavor AI, Jones AM, Homer-Vanniasinkam S. Treatment of venous leg ulcers with Dermagraft. Eur J Vasc Endovasc Surg 2004;27:666-72. Krishnamoorthy L, Harding K, Griffiths D, et al. The clinical and histological effects of Dermagraft\ in the healing of chronic venous leg ulcers. Phlebology 2003;18:12-22. Lindgren C, Marcusson JA, Toftga˚rd R. Treatment of venous leg ulcers with cryopreserved cultured allogeneic keratinocytes: a prospective open controlled study. Br J Dermatol 1998;139:271-5. Teepe RG, Roseeuw DI, Hermans J, et al. Randomized trial comparing cryopreserved cultured epidermal allografts with hydrocolloid dressings in healing chronic venous ulcers. J Am Acad Dermatol 1993;29:982-8. Guest M, Smith J, Tripuraneni G, et al. Randomized clinical trial of varicose vein surgery with compression versus compression alone for the treatment of venous ulceration. Phlebology 2003;18:130-6. Zamboni P, Cisno C, Marchetti F, et al. Minimally invasive surgical management of primary venous ulcers vs. compression treatment: a randomized clinical trial. Eur J Vascular Endovasc Surg 2003;25:313-8. van Gent WB, Hop WC, van Praag MC, Mackaay AJ, de Boer EM, Wittens CH. Conservative versus surgical treatment of venous leg ulcers: a prospective, randomized, multicenter trial. J Vasc Surg 2006;44:563-71. Gohel MS, Barwell JR, Taylor M, Chant T, Foy C, Earnshaw JJ, et al. Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial. BMJ 2007;335:83. Laatsch L, Ong P, Kloth L. In vitro effects of two silver electrodes on select wound pathogens. J Clin Electrophysiol 1995;7:10-5. Ong PC, Laatsch LJ, Kloth LC. Antibacterial effects of a silver electrode carrying micro-amperage direct current in-vitro. J Clin Electrophysiol 1994;6:14 Rowley BA. Electrical current effects on E. coli growth rates. Proc Soc Exp Biol Med 1972; 139:929-34. Rowley BA, McKenna JM, Chase GR, Wolcott LE. The influence of electrical current on an infecting microorganism in wounds. Ann N Y Acad Sci 1974;238:543-51. Szuminsky NJ, Albers AC, Unger P, Eddy JG. Effect of narrow, pulsed high voltages on bacterial viability. Phys Ther 1994;74:660-7. Thibodeau EA, Handelman SL, Marquis RE. Inhibition and killing of oral bacteria by silver ions generated with low intensity direct current. J Dent Res 1978;57:922-6. Barranco SD, Spadaro JA, Berger TJ, Becker RO. In vitro effect of weak direct current on Staphylococcus aureus. Clin Orthop Relat Res 1974;100:250-5. Kincaid CB, Lavoie KH. Inhibition of bacterial growth in vitro following stimulation with high voltage, monophasic, pulsed current. Phys Ther 1989;69:651-5. Kloth LC. Electrical stimulation for wound healing: a review of evidence from in vitro studies, animal experiments, and clinical trials. Int J Low Extrem Wounds 2005;4:23-44. Edwards R, Harding KG. Bacteria and wound healing. Curr Opin Infect Dis 2004;17:91-6. Halbert AR, Stacey MC, Rohr JB, Jopp-McKay A. The effect of bacterial colonization on venous ulcer healing. Australas J Dermatol 1992;33:75-80. Madsen SM, Westh H, Danielsen L, Rosdahl VT. Bacterial colonization and healing of venous leg ulcers. Acta Pathol Microbiol Immunol Scand 1996;104:895-9. Robson MC, Heggers JP. Bacterial quantification of open wounds. Mil Med 1969;134:19-24. ADVANCES IN SKIN & WOUND CARE & APRIL 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
ORIGINAL INVESTIGATION
59. Bendy RH, Jr, Nuccio PA, Wolfe E, et al. Relationship of quantitative wound bacterial counts to healing of decubiti: effect of topical gentamicin. Antimicrob Agents Chemother (Bethesda) 1964;10:147-55. 60. Thomsen TR, Aasholm MS, RudkjLbing VB, et al. The bacteriology of chronic venous leg ulcer examined by culture-independent molecular methods. Wound Repair Regen 2010;18(1):38-49. 61. Lookingbill DP, Miller SH, Knowles RC. Bacteriology of chronic leg ulcers. Arch Dermatol 1978;114:1765-8. 62. Huovinen S, Kotilainen P, Ja¨rvinen H, et al. Comparison of ciprofloxacin or trimethoprim therapy for venous leg ulcers: results of a pilot study. J Am Acad Dermatol 1994;31(2 Pt 1):279-81. 63. Alinovi A, Bassissi P, Pini M. Systemic administration of antibiotics in the management of venous ulcers. A randomized clinical trial. J Am Acad Dermatol 1986;15(2 Pt 1):186-91. 64. Franek A, Polak A, Kucharzewski M. Modern application of high voltage stimulation for
enhanced healing of venous crural ulceration. Med Eng Phys 2000;22:647-55. 65. Stiller MJ, Pak GH, Shupack JL, Thaler S, Kenny C, Jondreau L. A portable pulsed electromagnetic field (PEMF) device to enhance healing of recalcitrant venous ulcers: a double-blind, placebo-controlled clinical trial. Br J Dermatol 1992;127:147-54. 66. Ogrin R, Darzins P, Khalil Z. The use of sensory nerve stimulation and compression bandaging to improve sensory nerve function and healing of chronic venous leg ulcers. Curr Aging Sci 2009;2:72-80. 67. Lundberg TC, Eriksson SV, Malm M. Electrical nerve stimulation improves healing of diabetic ulcers. Ann Plast Surg 1992;29:328-31. 68. Goedkoop R, Juliet R, You PHK, et al. Wound stimulation by growth-arrested human keratinocytes and fibroblasts: HP802-247, a new-generation allogeneic tissue engineering product. Dermatology 2010;220:114-20.
Get fast news updates on the latest developments in the skin and wound care field.
Advances in
SKIN&WOUND CARE
®
eNEWS
Sign up for our free monthly eNews and we’ll send you cutting edge information on what’s new in skin and wound care, plus we’ll include free links to Bonus Content and CME articles.
It’s easy and it’s free. To register, visit http://www.nursingcenter.com/aswcenews
ADVANCES IN SKIN & WOUND CARE & VOL. 28 NO. 4
172
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
WWW.WOUNDCAREJOURNAL.COM
Treatment Options for Venous Leg Ulcers: Effectiveness of Vascular Surgery, Bioengineered Tissue, and Electrical Stimulation Gaurav Thakral, MD; Javier La Fontaine, DPM, MS; Paul Kim, DPM; Bijan Najafi, PhD; Adam Nichols, DPM; and Lawrence A. Lavery, DPM, MPH
ABSTRACT OBJECTIVE: To evaluate the peer-reviewed literature that compares advanced venous leg ulcer therapies to standard of care with compression dressings. METHODS: A MEDLINE search for venous ulcer treatment with electrical stimulation, surgical vein correction, and bioengineered tissues was conducted. Randomized clinical trials comparing advanced treatment with standard of care using compression dressing were included. A total of 7 bioengineered tissue, 4 surgical treatment, and 4 electrical stimulation randomized clinical trials were identified. RESULTS: Compared with nonstandard treatments, electrical stimulation demonstrated improved wound healing, fewer adverse events, and shorter duration of healing. Healing rates at the end of the study were greater for surgical intervention, followed by similar outcomes for electrical stimulation and bioengineered tissues. Studies involving bioengineered tissues and surgical venous ablation demonstrated inconsistent/inconclusive results. CONCLUSIONS: Utilization of electrical stimulation in venous ulcer management has not been fully explored. Further studies of dosing electrical stimulation therapy may reveal therapeutic and preventive benefits for managing venous ulcers not yet elucidated. KEYWORDS: venous leg ulcer, surgery, bioengineered tissue, electrical stimulation, wound healing, edema ADV SKIN WOUND CARE 2015;28:164Y72
INTRODUCTION Venous leg ulcers (VLUs) are a common and costly disease process, estimated to consume 1% of the total healthcare costs in the United States. Statistics indicate that VLUs occur in about 0.3% of the adult population1 and are associated with obesity, history of pregnancy, and deep vein thrombosis.2 The incidence of VLUs is
higher in women and increases with age for both sexes,3 and the prevalence of VLUs on admission at long-term-care facilities is reported to be as high as 2.5%.4 Furthermore, as obesity and obesityrelated health risks continue to rise,5,6 an increased incidence of venous stasis and VLUs can be expected. Chronic venous disease commonly arises from a combination of calf muscle failure and venous pathology. These factors contribute to the leakage of macromolecules into the interstitial tissues, causing lower-extremity edema and perpetuating the underlying pathology. Contraction of the calf muscle generates pressure to propel venous blood toward the heart. Muscle strength has been shown to be significantly lower in patients with recently healed VLUs compared with that in control subjects.7 Skeletal muscle atrophy from immobility is considered a primary cause for failure for the muscle pump mechanism.8 Moreover, active and passive movement of the ankle joint has been shown to significantly increase venous return velocities in both healthy subjects and those with venous disease.9,10 There are 2 underlying etiologies of venous pathology. First of these is venous microangiopathy; it is thought to evolve from distension of the capillary walls with subsequent leakage of macromolecules, such as fibrinogen, into the dermis and subcutaneous tissue of the lower leg.11 Once in the extravascular space, fibrinogen polymerizes to form a pericapillary fibrin cuff that prevents exchange of oxygen and nutrients leading to cell death and ulceration.12,13 The abnormal diffusion of macromolecules into the extracellular space traps growth factors and blood cells. The resulting vessel growth and deformity are associated with elongation, dilation, and tortuosity of capillary beds; endothelial damage with widening interendothelial spaces; and increased pericapillary edema.14 The other pathological process is incompetent valves within the veins themselves. When valves are incompetent, blood is allowed to flow in a retrograde fashion leading to disruption of Starling equilibrium, with a
Gaurav Thakral, MD, is Research Staff, and Javier La Fontaine, DPM, MS, is Associate Professor; both at the Department of Plastic Surgery, The University of Texas Southwestern Medical Center, Dallas, Texas. Paul Kim, DPM, is Associate Professor, Department of Plastic Surgery, Georgetown University School of Medicine, Washington, District of Columbia. Bijan Najafi, PhD, is Associate Professor of Surgery and Engineering, Department of Surgery, University of Arizona School of Medicine, Phoenix, Arizona. Adam Nichols, DPM, is a Fellow, and Lawrence A. Lavery, DPM, MPH, is Professor, Department of Plastic Surgery, and is Codirector of Research and Medical Director of the Comprehensive Wound Care Center; The University of Texas Southwestern Medical Center, Dallas, Texas. Dr Najafi has disclosed that the University of Arizona School of Medicine received research grant funding from the Qatar National Research Fund, NPRP 5-117-3-028. Dr Lavery has disclosed that he has a patent-pending project with Diabetica Solutions; receives payment from Healthpoint Biotherapeutics for the development of educational presentations; and receives stock options from Prizm Medical. The other coauthors have disclosed that they have no financial relationships related to this article. Submitted September 9, 2013: accepted in revised form February 4, 2014. ADVANCES IN SKIN & WOUND CARE & VOL. 28 NO. 4
164
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
WWW.WOUNDCAREJOURNAL.COM
ORIGINAL INVESTIGATION
net loss of fluids into surrounding tissue.8 The accumulated fluid inactivates the fatty acid of dermal sebum, leaving the skin vulnerable to breakdown and subsequent infection from common dermal pathogensVstreptococci and staphylococci.15 Compression therapy is the criterion standard treatment for VLUs.13Y15 A review of 16 studies that applied multilayered high compression for VLUs showed healing rates of 34% to 79% (average, 60.9%) at 12 weeks. As a result, many ulcers remain unhealed.16,17 One of the advanced therapies recommended for VLUs is electrical stimulation. According to some researchers, electrical stimulation has a much more pronounced accelerating effect on tissue regeneration processes than other types of electrotherapy.18 Cellular and growth factor deficiencies are present in the chronic wound environment. In VLUs, venous hypertension may cause blood proteins to leak in the extravascular space, trapping growth factors and cytokines needed for tissue repair. As a consequence, the conditions of the VLU wound environment may not efficiently support the epidermal migration, attachment, and proliferation of regenerating cells needed for healing. Based on these premises, bioengineered tissues have become an area of research in VLUs. The purpose of this review is to describe randomized clinical trials (RCTs) in which bioengineered tissue, surgery, and electrical stimulation were compared with standard of care, regardless if treatment group was combined with compression.
METHODS Many therapeutic agents have been suggested for use as adjunctive therapy for VLU healing. The authors searched for Englishlanguage studies in MEDLINE for clinical trials in VLU treatment using the following keywords: electrical stimulation, surgical vein correction, and bioengineered tissues. Because compression therapy is the criterion standard, the studies reviewed often compared compression and advanced therapies with compression alone. The authors did not exclude these studies. Studies were excluded for not comparing treatment with standard of care,19Y26 populations of mixed wound pathology,27 and uncontrolled studies.28Y31 All identified abstracts were reviewed as a primary filter. Selected studies were reviewed in their entirety. A comparison of the selected treatments highlights the need to consider cost and reduction in ulcer recurrence in selecting a treatment modality.
Compression Therapy Compression stockings are the criterion standard treatment for venous and lymphatic disorders.32 Compression aims to reduce or control venous reflux and peripheral edema. Venous compression may achieve narrowing of veins, restoration of valvular competence, or acceleration of venous flow.33 As venous incompetence leads to secondary complications, the use of compression alone may not be sufficient. A review of 11 studies suggested that WWW.WOUNDCAREJOURNAL.COM
combined modalities using intermittent pneumatic leg compression with pharmacological prophylaxis are more effective than single modalities in preventing venous thromboembolism.34 Similarly, for treatment of venous ulcers, compression therapy is combined with other modalities involving surgical intervention, electrical stimulation, and bioengineered tissues.
Bioengineered Tissue Seven studies compared bioengineered tissue with the standard of care involving compression therapy (Table 1). These tissues are intended to act as a ‘‘booster’’ in the host chronic wound. Indications for their use usually include noninfected, chronic, and partialand full-thickness chronic VLUs.35 Bioengineered tissues consist of a single or bilayer matrix that provides a scaffold, as well as cells to promote healing. Only 2 of the 7 studies reported positive results. One of the positive studies was the largest RCT (n = 275), and the other positive study was the one with the smallest sample size (n = 18) (Table 1). The most recently published RCT included 266 subjects; however, there was no difference in patients treated with bioengineered tissue and control subjects treated with compression therapy.36 Five of the 7 studies were very small and certainly underpowered. The size of the study groups in the negative studies ranged from 8 to 22 patients per treatment group (Table 1). These small studies would have needed extraordinary results in order to have statistical significance; most of them did not even report a strong trend that would indicate that bioengineered tissue improved VLU healing. One of 2 positive studies was a larger, multicenter study in which allogeneic tissue (Apligraf; Organogenesis, Canton, Massachusetts) was applied 5 times in 3 weeks; a higher proportion of wounds healed with the addition of cultured allogeneic human skin equivalent compared with standard of care alone (63% vs 49%; P = .02). Patients received an average of 3.3 applications. All applications of bioengineered tissue occurred in the initial 3 weeks, yet the healing efficiency was measured 21 weeks after the last possible application.37 Multiple studies have been conducted using human fibroblastdermal substitutes (HDFSs) (Dermagraft; Organogenesis). The largest of which, by Harding et al36 compared HDFS (Dermagraft) with 4-layer compression with compression alone over a 12-week course of treatment and secondarily at 24 weeks at a follow-up end point. Up to 4 applications of the HDFS were performed; these were done at weeks 0, 1, 4, and 8. Patients who were morbidly obese or had a greater than 50% wound area reduction to compression over a 2-week screening period were excluded. The primary outcome was defined as complete epithelialization for 2 consecutive visits. When compared overall, there was no difference in wound healing, with 31.5% of the control group healed at 12 weeks compared with 34.4% who received HDFS. In a subgroup of patients with ulcers present less than 1 year, 37.1% of the control group achieved
165
ADVANCES IN SKIN & WOUND CARE & APRIL 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
ORIGINAL INVESTIGATION
Table 1.
BIOENGINEERED TISSUE FOR HEALING AND PREVENTATION OF VLU Author
Treatment
Study Design
Duration of Study and Follow-up
Population
Falanga et al,37 1998
Allogeneic cultured human skin equivalent (Apligraf; Organogenesis)
Maximum of 5 times in first 3 wk
Healing: 6 mo Follow-up: 12 mo
Treatment n = 146 Compression n = 129
Goedkoop et al,68 2010
Allogeneic growth-arrested, human keratinocytes and fibroblasts spray (DFB Pharmaceuticals Inc, Fort Worth, Texas)
Weekly for 12 wk
Healing: 3 mo Follow-up: 6 mo
Harding et al,36 2013
Human allogeneic fibroblast-derived dermal tissue (Dermagraft)
4 applications over 12 wk
Healing: 3 mo Follow-up: 6 mo
2.5/1:9a n = 14 5/1:9a n = 17 10/1:9a n = 15 2.5/1:1a n = 17 5/1:1a n = 16 10/1:1a n = 16 Compression n = 15 Treatment n = 186 Compression n = 180
Krishnamoorthy et al,39 2003
Allogeneic fibroblast-derived dermal sheet (Dermagraft)
Span of 12 wk
Healing: 3 mo
Lindgren et al,40 1998
Allogeneic keratinocyte sheets
Weekly for 12 wk
Healing: 2 mo
Omar et al,38 2004
Allogeneic fibroblast-derived dermal sheet (Dermagraft)
4 applications in 12 wk
Healing: 3 mo
Treatment n = 10 Compression n = 8
Teepe et al,41 1993
Allograft cultured epidermal
Weekly for 6 wk
Healing: 6 wk Recurrence: 6 mo
Treatment n = 22 Compression n = 21
Group 1 (n = 13): 12 applications Group 2 (n = 13): 4 applications Group 3 (n = 14): 1 application Compression (n = 13) Treatment n = 15 Compression n = 12
a Cell concentration (106 cell/mL)/cell ratio (keratinocyte:fibroblast) Abbreviation: NS, not significant
healing, whereas 52.1% of the HDFS healed (P = .029). There was an inverse relationship in those with wounds present for more than 1 year (21.4% vs 16.3%) (P G .05). Ulcers involving less than 10 cm2 healed in 39.2% of control subjects and 47% within the treatment group (P G .05). Again, there was an inverse response in ulcers larger than 10 cm2 (15% vs 13%) (P G .05). Those patients treated with compression alone had a higher recurrence rate over the 24-week followup (23%) than did those who received HDFS (15%) (P G .05). Adverse events, most commonly infection, were similar between the groups.34 ADVANCES IN SKIN & WOUND CARE & VOL. 28 NO. 4
Omar et al38 conducted a small RCT and compared 4 applications of Dermagraft to a 4-layer compression bandage (ProFore; Smith & Nephew, St Petersburg, Florida). A trend of improved healing was shown when Dermagraft was applied 4 times over 12 weeks (50%, n = 10) compared with standard of care (13%, n = 8) (P = .15).38 Capillary density in histological sections did not show significant changes for either group. In a similar study, Krishnamoorthy et al39 evaluated 3 treatment schedules of Dermagraft compared with compression with Profore. Healing rates for a single application
166
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
WWW.WOUNDCAREJOURNAL.COM
ORIGINAL INVESTIGATION
In addition, the active treatment group had dermatitis in an unspecified number of study subjects that was overcome by trimming the edges of the allograft so it barely touched the skin.40 A 6-week randomized trial by Teepe et al41 noted (n = 43) no difference in healing between 24 patients treated with cultured epidermal allografts and 23 patients treated with hydrocolloid dressing (25% vs 22%, P 9 .05). Four active and 3 control subjects were dropped because of infection.41
Table 1.
CONTINUED Outcome Wound healing: bioengineered tissue (63%) vs compression (49%) (P = .02) Wound area reduction: NS Recurrence: bioengineered tissue (12%) vs compression (16%) (P 9 .05) Adverse events: death (5 bioengineered tissue and 4 control), adverse experience (3 bioengineered tissue and 7 control), wound infection (2 bioengeneered tissue), and cellulitis (12 bioengineered tissue and 10 control) Wound healing: bioengineered tissue (40%) vs compression (33%) (P 9 .05) Wound area reduction: NS Recurrence: bioengineered tissue (61%) vs compression (50%) (P 9 .05) Adverse events: NS
Surgery Surgical intervention for venous ulceration focuses on ablating the pathologic veins. Surgical treatment addresses the underlying venous pathology of VLU. Four RCTs that evaluated healing rates between surgical vein correction and compression therapy were found (Table 2). Guest et al42 reported healing rates of 68% at 26 weeks for VLUs treated with surgery compared with the control group’s healing rates of 64% (P = .75). One active treatment and 2 control patients received antibiotics for cellulitis.42 Zamboni et al43 compared surgical correction of venous reflux with control subjects in 47 patients. There was no statistical difference in the healing rateVsurgical treatment group (100%) and control subjects (96%, P 9 .05). The recurrence rate, however, was significantly lower in the surgery group (9% vs 38%, P G .05).43 Two large multicenter studies (n = 500, 200) demonstrated no significant difference in healing rates among surgical and standardof-care treatment.44,45 In 1 study, van Gent et al44 found no difference in healing rates when comparing surgical (83%) treatment with compression therapy (73%); nor did they find a difference in recurrence rates (22% surgical, 23% compression) (P 9 .05).44 However, Gohel et al45 reported the results of a multicenter study with 500 patients and demonstrated similar healing rates between the treatment groups (93% surgery, 89% control, P = .73). However, there were significantly lower ulcer recurrence rates for surgical patients (31%) compared with control patients (56%, P G .01).45 Two other studies demonstrated significantly lower recurrence rates at 3 and 4 years.43,45 After an ulcer heals through standard of care, the underlying pathology remains and requires constant compression therapy to minimize recurrence. Thus, although there is little evidence as to the efficacy of surgical intervention compared with compression, there are studies with results that support its use in preventing recurrence of VLUs.
Wound healing: bioengineered tissue (34%) vs compression (31%) (P = .2) Wound area reduction: bioengineered tissue (83.7%) vs compression (73.0%) (P 9 .05) Recurrence: bioengineered tissue (15%) vs compression (23%) (P 9 .05) Adverse events: wound infection (43 bioengineered tissue and 46 control), cellulitis (12 bioengineered tissue and 18 control), peripheral edema (13 bioengineered tissue and 5 control) Wound healing: group 1 (38%), group 2 (38%), group 3 (7%) vs compression (15%) (P 9 .05) Wound area reduction: NS Recurrence: NS Adverse events: NS
Wound healing: bioengineered tissue (13%) vs compression (17%) (P 9 .05) Wound area reduction: bioengineered tissue (35%) vs compression (15%) (P 9 .05) Recurrence: NS Adverse events: NS Wound healing: bioengineered tissue (50%) vs compression (13%) (P 9 .05.) Wound area reduction: bioengineered tissue (84%) vs compression (16%) (P = .002) Recurrence: NS Adverse events: Wound infection (4 bioengineered tissue and 3 control), reatment failure (1 bioengineered tissue), and noncompliance (1 control) Wound healing: bioengineered tissue (41%) vs compression (33%) (P 9 .05.) Wound area reduction: NS Recurrence: 13% bioengineered tissue vs 14% compression P 9 .05 Adverse events: NS
of Dermagraft were half that of standard of care (7% vs 15%, respectively). Also, similar results were seen for 4 applications over 12 weeks (38%) and once-weekly application over the same time period (38%, P 9 .05) and the control. The authors concluded 4 applications of Dermagraft were the optimal dosing regimen39 (Table 1). Lindgren et al40 showed no difference in the proportion of wounds that healed when comparing 12 patients treated with compression to 15 patients treated with cryopreserved split-thickness allografts and compression (compression 17% vs 13%) after 8 weeks. WWW.WOUNDCAREJOURNAL.COM
Electrical Stimulation Electrical stimulation has been used for more than 100 years for various ailments and may offer a unique treatment option to heal venous stasis ulcers. Electrical stimulation shows evidence of bactericidal and bacteriostatic effects on organisms that commonly colonize and infect leg wounds.46Y54 Bacterial load and infection are thought to be important factors in chronic wounds and delayed healing.55Y59 Bacterial colonization of more than 105 organisms per gram of tissue is associated with infection and
167
ADVANCES IN SKIN & WOUND CARE & APRIL 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
ORIGINAL INVESTIGATION
Table 2.
SURGICAL TREATMENT FOR HEALING AND PREVENTATION OF VLUs Duration of Study and Follow-up
Population
Outcome
Saphenofemoral junction disconnection, stripping of the long saphenous vein to below the knee, and calf varicosity avulsions
Healing rates at 3 y Recurrence rates at 4 y
Treatment n = 258 Compression n = 242
Guest et al,42 2003
Superficial venous surgery
18 mo
Treatment n = 37 Compression n= 39
van Gent et al,44 2006
Subfascial endoscopic perforating vein surgery combined with superficial vein ligation
3y
Treatment n = 97 Compression n = 103
Zamboni et al,43 2003
Minimally invasive surgical hemodynamic correction of reflux
3y
Treatment n = 21 Compression n = 24
Wound healing: surgery (93%) vs compression (89%) (P = .73) Wound area reduction: NS Reoccurrence: surgery (31%) vs compression (56%) (P G .01) Adverse events: 2 compression patients admitted for cellulitis, 8 postoperative complications (1 deep vein thrombosis, 5 wound infections, 1 hematoma, 1 phlebitis) Wound healing: surgery (68%) vs compression (64%) (P = .75) Wound area reduction: NS Recurrence: NS Adverse events: 2 compression and 1 surgery patients were treated for cellulitis Wound healing: surgery (72%) vs compression (53%) (P = .11) Wound area reduction: NS Recurrence: surgery (22%) vs compression (23%) (P 9 .05) Adverse events: NS Wound healing: surgery (100%) vs compression (96%) (P 9 .05) Wound area reduction: NS Reoccurrence: surgery (9%) vs compression (38%) (P G .05) Adverse events: NS
Author
Treatment of Interest
Gohel et al,45 2007
Abbreviation: NS, not significant
delayed wound healing in chronic wounds.56,58Y60 Halbert et al56 took bacterial cultures from 83 limbs and showed an association between delayed wound healing and higher bacterial counts in leg ulcers. When compared with noncolonized ulcers, colonized ulcers had longer duration at presentation and larger size at presentation and took longer to heal (P G .01).56,61 Routine use of antibiotics in uncomplicated ulcers does not improve healing rates or decrease bacterial colonization.62,63 Therefore, electrical stimulation may act to reduce bacterial colonization, while simultaneously improving venous return and accelerate wound healing in VLU treatment. In addition to increased skin perfusion, electrical stimulation therapy has been shown to improve venous flow.1Y4 Transcutaneous electrical nerve stimulation was evaluated in 24 healthy individuals and was shown to increase the activity of the calf muscle pump. There was a 19-fold increase in the ejection volume of the popliteal vein at 2 pulses per second compared with 120 pulses per second.7 Increased venous return with electrical stimulation may help to explain observations of improved edema, as well as better cutaneous circulation with electrical stimulation. One device setting facilitates velocity, while the other facilitates ejected volume. Lower stimuli per minute that increase peak sysADVANCES IN SKIN & WOUND CARE & VOL. 28 NO. 4
tolic velocity may be able to eject blood against gravity to pass incompetent valves while standing or ambulating. An increase in stimuli per minute may permit edema reduction after prolonged activity or during supine rest. No studies were identified that addressed venous stasis while standing and resting. A dual-setting therapy may have additional benefits over single setting. The authors identified 4 RCTs using electrical stimulation in patients with VLUs (Table 3). Three of these showed positive results and minimal to no adverse events. Franek et al64 compared high-voltage stimulation, a topically applied pharmaceutical compound, and standard of care using Unna boot. The topical pharmaceutical compound consisted of potassium permanganate, rivanol, and 0.1% copper sulphate. In this study, subjects with diabetes had their blood sugar stabilized for 6 months prior to enrollment; cohorts consisted of 30 patients (electrical stimulation), 32 patients (topical pharmaceutical), and 14 patients (control). Most ulcers in the electrical stimulation group were nearly devoid of a suppurative wound layer after 2 weeks of treatment. Disappearance of this layer favored granulation tissue formation from week 2 to week 3 between groups (P G .003).64 Despite having one of the shorter durations of all studies included in this review, high-voltage stimulation
168
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
WWW.WOUNDCAREJOURNAL.COM
ORIGINAL INVESTIGATION
Table 3.
ELECTRICAL STIMULATION FOR HEALING AND PREVENTION OF VLUs Franek et al,64 2000
Venous ulcers using FREMS
50 min, daily, 6 d a week for 3 wk
100 V, 0.1 ms, 100 Hz
Stiller et al,65 1992
Venous ulcers using PEMF
3 hours, daily, 7 d a week for 2 mo
Ogrin et al,66 2009
Venous ulcers using transcutaneous electrical nerve stimulation
5 min, twice a day for 3 mo
0.06 mV/cm. The signal is 3-part pulse (+, j, +) of 3.5-ms width 4 mA, 5Hz
Lundberg et al,67 1992
VLUs in diabetics using alternating current
20 min, twice a day for 3 mo
80 Hz, pulse width 1 ms
Treatment n = 33 Ointment n = 32 Control n = 14 Treatment n = 18 placebo n = 13 Treatment n = 14 placebo n = 15 Treatment n = 32 placebo n = 32
Wound healing: NS Wound area reduction: ES 59%, ointment 35% vs control 25% (P G .05) Adverse events: no events
Wound healing: NS Wound area reduction ES 48% vs control increase of 42% (P G .0002) Adverse event: no events Wound healing: ES 57% vs placebo 67% (P 9 .05) Wound area reduction: ES 0.8 T 0.2 vs placebo 0.7 T 0.2 cm2 per week (P 9 .05) Adverse event: NS Wound healing: ES 42% vs 15% placebo (P G .05) Wound area reduction: 59 T 11% ES vs 39 T 14% placebo (P G .05) Adverse event: allergy (2 ES and 1 placebo), pain (3 ES, and 2 placebos), and refusal/ nonattendance (3 ES and 2 placebos)
Abbreviations: NS, not significant; PEMF, pulsed electromagnetic field; FREMS, frequency-modulated electromagnetic neural stimulation
reduced wound area significantly more than did compression alone. These results suggest that high-voltage stimulation may be a useful nonsurgical method for eliminating hard-to-remove suppurative formation in patients unable to tolerate mechanical debridement. Stiller et al65 applied an elastic compression wrap at approximately 20 mm Hg as standard of care and excluded patients unable to elevate their feet for 3 hours a day. They noted granulation tissue increased in the electrical stimulation group (68%Y83%), whereas there was no change for the compression group (67%Y67%) (P G .04). In a global assessment, 50% of active treatment patients healed or had markedly improved wounds, whereas there was no improvement in the compression group (P G .001). Also, patients receiving active treatment had pain reduction of 0.61 compared with 0.15 in those receiving placebo therapy and a scale from -3 to 4 (P G .04).65 Ogrin et al66 applied electrical stimulation of 5 minutes twice daily for a total of 14 hours over 12 weeks, and they identified no differences in wound healing compared with control treatment. The authors noted no improvement in oxygen tension in the electrical stimulation group. The maximum hours of electrical stimulation used by Franek et al,64 Stiller et al,65 and Lundberg et al67 were far greater at 168, 50, and 56 hours, respectively. Laboratory studies have shown that under direct current, endothelial cell orientation was seen as early as 4 hours after the onset of an electrical field. Electrical stimulation up to 3 days accelerated the orientation and WWW.WOUNDCAREJOURNAL.COM
elongation of endothelial cells compared with the control.20 No clinical study has yet investigated the dose-related benefit to electrical stimulation.
CONCLUSIONS Although compression therapy may be the criterion standard in the treatment of VLUs, the results are less than ideal. The rate of healing is low, and the rate of recurrence is high. As demonstrated by this review, there is little evidence to support the use of adjunctive therapies to heal VLUs at this time. Most of the electrical stimulation and bioengineered tissue studies were very small. The surgical treatment studies reported produced a higher percentage of healed wounds, as well as the lowest recurrence rates, probably because of the selection process. Surgery patients are probably healthier patients with venous disease that is amenable to surgical repair. High-risk patients and patients with severe venous disease were appropriately excluded. One of the key benefits of surgical treatment is the apparent reduction in ulcer recurrence, although this was not documented in all studies.43,45 Despite the small sample size, electrical stimulation showed positive results and promise as an option for adjunctive treatment.
&
REFERENCES
169
1. Barwell JR, Davies CE, Deacon J, et al. Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised controlled trial. Lancet 2004;363:1854-9. ADVANCES IN SKIN & WOUND CARE & APRIL 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
ORIGINAL INVESTIGATION
2. Fowkes FG, Evans CJ, Lee AJ. Prevalence and risk factors of chronic venous insufficiency. Angiology 2001;52(Suppl 1):S5-15. 3. Heit JA, Rooke TW, Silverstein MD, et al. Trends in the incidence of venous stasis syndrome and venous ulcer: a 25-year population-based study. J Vasc Surg 2001;33:1022-7. 4. Wipke-Tevis DD, Rantz MJ, et al. Prevalence, incidence, management, and predictors of venous ulcers in the long-term-care population using the MDS. Adv Skin Wound Care 2000; 13:218-24. 5. Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003;289:76-9. 6. Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP. The continuing epidemics of obesity and diabetes in the United States. JAMA 2001;286:1195-200. 7. Yang D, Vandongen YK, Stacey MC. Changes in calf muscle function in chronic venous disease. Cardiovasc Surg 1999;7:451-6. 8. Clarke-Moloney M, Lyons GM, Burke PE, O’Keeffe D, Grace PA. A review of technological approaches to venous ulceration. Crit Rev Biomed Eng 2005;33:511-56. 9. Staubesand J, Heisterkamp T, Stege H. Use of duplex sonography to investigate the effect of active and passive movement at the ankle joint for promoting venous return. Clin Anat 1995;8:96-101. 10. Sochart DH, Hardinge K. The relationship of foot and ankle movements to venous return in the lower limb. J Bone Joint Surg Br 1999;81:700-4. 11. Browse NL, Burnand KG. The cause of venous ulceration. Lancet 1982;2:243-5. 12. Falanga V. Venous ulceration. J Dermatol Surg Oncol 1993;19:764-71. 13. Valencia IC, Falabella A, Kirsner RS, Eaglstein WH. Chronic venous insufficiency and venous leg ulceration. J Am Acad Dermatol 2001;44:401-21. 14. Eberhardt RT, Raffetto JD. Chronic venous insufficiency. Circulation 2005;111:2398-409. 15. Robson MC, Cooper DM, Aslam R, et al. Guidelines for the treatment of venous ulcers. Wound Repair Regen 2006;14:649-62. 16. Ju¨nger M, Wollina U, Kohnen R, Rabe E. Efficacy and tolerability of an ulcer compression stocking for therapy of chronic venous ulcer compared with a below-knee compression bandage: results from a prospective, randomized, multicentre trial. Curr Med Res Opin 2004; 20:1613-23. 17. Kurz X, Kahn SR, Abenhaim L, et al. Chronic venous disorders of the leg: epidemiology, outcomes, diagnosis and management. Summary of an evidence-based report of the VEINES task force. Venous Insufficiency Epidemiologic and Economic Studies. Angiology 1999;18:83-102. 18. Zhao M, Bai H, Wang E, Forrester JV, McCaig CD. Electrical stimulation directly induces pre-angiogenic responses in vascular endothelial cells by signaling through VEGF receptors. J Cell Sci 2004;117(Pt 3):397-405. 19. Ieran M, Zaffuto S, Bagnacani M, Annovi M, Moratti A, Cadossi R. Effect of low frequency pulsing electromagnetic fields on skin ulcers of venous origin in humans: a double-blind study. J Orthop Res 1990;8:276-82. 20. Jankovic A, Binic I. Frequency rhythmic electrical modulation system in the treatment of chronic painful leg ulcers. Arch Dermatol Res 2008;300:377-83. 21. Kenkre JE, Hobbs FD, Carter YH, Holder RL, Holmes EP. A randomized controlled trial of electromagnetic therapy in the primary care management of venous leg ulceration. Fam Pract 1996;13:236-41. 22. Santamato A, Panza F, Fortunato F, et al. Effectiveness of the frequency rhythmic electrical modulation system for the treatment of chronic and painful venous leg ulcers in older adults. Rejuvenation Res 2012;15:281-7. 23. Chang DW, Sanchez LA, Veith FJ, Wain RA, Okhi T, Suggs WD. Can a tissue-engineered skin graft improve healing of lower extremity foot wounds after revascularization? Ann Vasc Surg 2000;14:44-9. 24. Poskitt KR, James AH, Lloyd-Davies ER, Walton J, McCollum C. Pinch skin grafting or porcine dermis in venous ulcers: a randomised clinical trial. Br Med J (Clin Res Ed) 1987;294:674-6. 25. Tausche AK, Skaria M, Bo¨hlen L, et al. An autologous epidermal equivalent tissue-engineered from follicular outer root sheath keratinocytes is as effective as split-thickness skin autograft in recalcitrant vascular leg ulcers. Wound Repair Regen 2003;11:248-52. 26. van den Hoogenband HM. Treatment of leg ulcers with split-thickness skin grafts. J Dermatol Surg Oncol 1984;10:605-8. 27. Houghton PE, Kincaid CB, Lovell M, et al. Effect of electrical stimulation on chronic leg ulcer size and appearance. Phys Ther 2003;83:17-28. 28. Clancy JM, Shehade SA, Blight AE, Young KE, Levick PL. Treatment of leg ulcers with cultured epithelial grafts. J Am Acad Dermatol 1988;18:1356-7. 29. Liu JY, Hafner J, Dragieva G, Seifert B, Burg G. Autologous cultured keratinocytes on porcine gelatin microbeads effectively heal chronic venous leg ulcers. Wound Repair Regen 2004;12: 148-56. 30. Mol MA, Nanninga PB, van Eendenburg JP, Westerhof W, Mekkes JR, van Ginkel CJ. Grafting WWW.WOUNDCAREJOURNAL.COM
31.
32. 33. 34.
35. 36.
37.
38. 39. 40. 41.
42.
43.
44.
45.
46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58.
171
of venous leg ulcers. An intraindividual comparison between cultured skin equivalents and full-thickness skin punch grafts. J Am Acad Dermatol 1991;24:77-82. Navra´tilova´ Z, Slonkova´ V, Semra´dova´ V, Adler J. Cryopreserved and lyophilized cultured epidermal allografts in the treatment of leg ulcers: a pilot study. J Eur Acad Dermatol Venereol 2004;18:173-9. O’Meara S, Cullum N, Nelson EA, Dumville JC. Compression for venous leg ulcers. Cochrane Database Syst Rev 2012;11:CD000265. Ramelet AA. Phlebectomy. Technique, indications and complications. Int Angiol 2002; 21(2 Suppl 1):46-51. Review. Kakkos SK, Caprini JA, Geroulakos G, Nicolaides AN, Stansby GP, Reddy DJ. Combined intermittent pneumatic leg compression and pharmacological prophylaxis for prevention of venous thromboembolism in high-risk patients. Cochrane Database Syst Rev 2008; 8(4):Review. Fivenson D, Scherschun L. Clinical and economic impact of Apligraf for the treatment of nonhealing venous leg ulcers. Int J Dermatol 2003;42:960-5. Harding K, Sumner M, Cardinal M. A prospective, multicentre, randomised controlled study of human fibroblast-derived dermal substitute (Dermagraft) in patients with venous leg ulcers. Int Wound J 2013;10:132-7. Falanga V, Margolis D, Alvarez O, et al. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Human Skin Equivalent Investigators Group. Arch Dermatol 1998;134:293-300. Omar AA, Mavor AI, Jones AM, Homer-Vanniasinkam S. Treatment of venous leg ulcers with Dermagraft. Eur J Vasc Endovasc Surg 2004;27:666-72. Krishnamoorthy L, Harding K, Griffiths D, et al. The clinical and histological effects of Dermagraft\ in the healing of chronic venous leg ulcers. Phlebology 2003;18:12-22. Lindgren C, Marcusson JA, Toftga˚rd R. Treatment of venous leg ulcers with cryopreserved cultured allogeneic keratinocytes: a prospective open controlled study. Br J Dermatol 1998;139:271-5. Teepe RG, Roseeuw DI, Hermans J, et al. Randomized trial comparing cryopreserved cultured epidermal allografts with hydrocolloid dressings in healing chronic venous ulcers. J Am Acad Dermatol 1993;29:982-8. Guest M, Smith J, Tripuraneni G, et al. Randomized clinical trial of varicose vein surgery with compression versus compression alone for the treatment of venous ulceration. Phlebology 2003;18:130-6. Zamboni P, Cisno C, Marchetti F, et al. Minimally invasive surgical management of primary venous ulcers vs. compression treatment: a randomized clinical trial. Eur J Vascular Endovasc Surg 2003;25:313-8. van Gent WB, Hop WC, van Praag MC, Mackaay AJ, de Boer EM, Wittens CH. Conservative versus surgical treatment of venous leg ulcers: a prospective, randomized, multicenter trial. J Vasc Surg 2006;44:563-71. Gohel MS, Barwell JR, Taylor M, Chant T, Foy C, Earnshaw JJ, et al. Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial. BMJ 2007;335:83. Laatsch L, Ong P, Kloth L. In vitro effects of two silver electrodes on select wound pathogens. J Clin Electrophysiol 1995;7:10-5. Ong PC, Laatsch LJ, Kloth LC. Antibacterial effects of a silver electrode carrying micro-amperage direct current in-vitro. J Clin Electrophysiol 1994;6:14 Rowley BA. Electrical current effects on E. coli growth rates. Proc Soc Exp Biol Med 1972; 139:929-34. Rowley BA, McKenna JM, Chase GR, Wolcott LE. The influence of electrical current on an infecting microorganism in wounds. Ann N Y Acad Sci 1974;238:543-51. Szuminsky NJ, Albers AC, Unger P, Eddy JG. Effect of narrow, pulsed high voltages on bacterial viability. Phys Ther 1994;74:660-7. Thibodeau EA, Handelman SL, Marquis RE. Inhibition and killing of oral bacteria by silver ions generated with low intensity direct current. J Dent Res 1978;57:922-6. Barranco SD, Spadaro JA, Berger TJ, Becker RO. In vitro effect of weak direct current on Staphylococcus aureus. Clin Orthop Relat Res 1974;100:250-5. Kincaid CB, Lavoie KH. Inhibition of bacterial growth in vitro following stimulation with high voltage, monophasic, pulsed current. Phys Ther 1989;69:651-5. Kloth LC. Electrical stimulation for wound healing: a review of evidence from in vitro studies, animal experiments, and clinical trials. Int J Low Extrem Wounds 2005;4:23-44. Edwards R, Harding KG. Bacteria and wound healing. Curr Opin Infect Dis 2004;17:91-6. Halbert AR, Stacey MC, Rohr JB, Jopp-McKay A. The effect of bacterial colonization on venous ulcer healing. Australas J Dermatol 1992;33:75-80. Madsen SM, Westh H, Danielsen L, Rosdahl VT. Bacterial colonization and healing of venous leg ulcers. Acta Pathol Microbiol Immunol Scand 1996;104:895-9. Robson MC, Heggers JP. Bacterial quantification of open wounds. Mil Med 1969;134:19-24. ADVANCES IN SKIN & WOUND CARE & APRIL 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
ORIGINAL INVESTIGATION
59. Bendy RH, Jr, Nuccio PA, Wolfe E, et al. Relationship of quantitative wound bacterial counts to healing of decubiti: effect of topical gentamicin. Antimicrob Agents Chemother (Bethesda) 1964;10:147-55. 60. Thomsen TR, Aasholm MS, RudkjLbing VB, et al. The bacteriology of chronic venous leg ulcer examined by culture-independent molecular methods. Wound Repair Regen 2010;18(1):38-49. 61. Lookingbill DP, Miller SH, Knowles RC. Bacteriology of chronic leg ulcers. Arch Dermatol 1978;114:1765-8. 62. Huovinen S, Kotilainen P, Ja¨rvinen H, et al. Comparison of ciprofloxacin or trimethoprim therapy for venous leg ulcers: results of a pilot study. J Am Acad Dermatol 1994;31(2 Pt 1):279-81. 63. Alinovi A, Bassissi P, Pini M. Systemic administration of antibiotics in the management of venous ulcers. A randomized clinical trial. J Am Acad Dermatol 1986;15(2 Pt 1):186-91. 64. Franek A, Polak A, Kucharzewski M. Modern application of high voltage stimulation for
enhanced healing of venous crural ulceration. Med Eng Phys 2000;22:647-55. 65. Stiller MJ, Pak GH, Shupack JL, Thaler S, Kenny C, Jondreau L. A portable pulsed electromagnetic field (PEMF) device to enhance healing of recalcitrant venous ulcers: a double-blind, placebo-controlled clinical trial. Br J Dermatol 1992;127:147-54. 66. Ogrin R, Darzins P, Khalil Z. The use of sensory nerve stimulation and compression bandaging to improve sensory nerve function and healing of chronic venous leg ulcers. Curr Aging Sci 2009;2:72-80. 67. Lundberg TC, Eriksson SV, Malm M. Electrical nerve stimulation improves healing of diabetic ulcers. Ann Plast Surg 1992;29:328-31. 68. Goedkoop R, Juliet R, You PHK, et al. Wound stimulation by growth-arrested human keratinocytes and fibroblasts: HP802-247, a new-generation allogeneic tissue engineering product. Dermatology 2010;220:114-20.
Get fast news updates on the latest developments in the skin and wound care field.
Advances in
SKIN&WOUND CARE
®
eNEWS
Sign up for our free monthly eNews and we’ll send you cutting edge information on what’s new in skin and wound care, plus we’ll include free links to Bonus Content and CME articles.
It’s easy and it’s free. To register, visit http://www.nursingcenter.com/aswcenews
ADVANCES IN SKIN & WOUND CARE & VOL. 28 NO. 4
172
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
WWW.WOUNDCAREJOURNAL.COM
