A Strategy to Enable Rapid Healing and Prevent Recurrence of Venous Ulcers

The optimal treatment strategy for lower extremity varicose veins with venous ulcers is currently under debate, despite the publication in 2014 of the Society for Vascular Surgery (SVS) guidelines for the optimal management of venous leg ulcers (VLUs).¹ According to the Clinical-Etiology-Anatomy-Pathophysiology (CEAP) classification system for chronic venous disorders, active ulcers are the most severe: class C6.² A combination of endovenous ablation and compression therapy has become the standard of care for the management of C6 chronic venous insufficiency, mainly in developed countries. A randomized clinical trial in the United Kingdom found that early treatment of saphenous vein reflux using endovenous ablation as an adjunct to compression therapy shortened the ulcer healing time and increased both the ulcer healing rate and the length of time free from ulcers.³ Nevertheless, a survey by the Japanese Society of Phlebology found variations among institutions regarding the methods used for ulcer treatment. Although the SVS guidelines recommend using moist dressings for wound care, in 2016, the rate of dressing use excluding gauze was less than 10% in Japan. Additionally, previous research reported that the ulcer healing rate during the follow-up period of 3 months to 1 year and 3 months was 78.7% in Japan.⁴

At Okamura Memorial Hospital, treatment of venous ulcers consists of endovenous ablation and adequate varicectomy (including stab avulsion of incompetent perforating veins [IPVs]), compression therapy, moist wound healing, and skin care for stasis dermatitis. The aim of this retrospective study was to evaluate the effectiveness of such treatment. The hypothesis was that moist wound healing, which maximizes autologous tissue regeneration, has an important role in wound repair. Moist wound healing in the management of venous ulcers is controversial, however. Preliminary findings were previously reported.⁵ In the current study, the authors expanded the investigation and confirmed the previously reported results by examining a larger study sample.

This retrospective study examined data from 28 patients with active VLUs (CEAP class C6) who were treated with radiofrequency ablation at the authors’ hospital between December 2014 and August 2020. The inclusion criterion was a diagnosis of primary varicose veins with ulcers requiring a correction of the venous reflux. The exclusion criteria consisted of secondary varicose veins with ulcers, such as after deep vein thrombosis (DVT) and pressure or arterial ulcers. To exclude peripheral artery disease (PAD), the authors routinely query patients about smoking history and check skin color, skin temperature, and arterial pulse of the lower extremities. Additionally, the ankle-brachial index is measured if PAD is suspected. This study was performed in accordance with the principles of the Declaration of Helsinki. The institutional review board approved the experimental protocol. Additionally, informed consent and publication consent were obtained as applicable.

Treatment strategy

Per the policy of the authors’ institution, patients were admitted overnight, and in all cases, treatment was performed on 1 leg at a time under local anesthesia.⁶ During the overnight hospital stay, the patient was permitted to continue walking under observation by the medical staff and was advised to watch for postoperative bleeding. In patients in whom it was necessary to treat both lower extremities, the contralateral limb was treated approximately 1 month after the first. A radiofrequency catheter (ClosureFast; Covidien) was used, following standard treatment methods according to published guidelines.⁷ Current smokers underwent the procedure after having not smoked for at least 2 months.⁸ If patients were undergoing anticoagulant or antiplatelet therapy and these drugs could not be withdrawn, stab avulsion was not performed. Prophylactic antibiotics (intravenous cefazolin 1 g) were administered. Prophylactic antibiotics were not used in standard varicose vein surgery from November 2019 through the end of the study period. However, they are used in the presence of implant materials and cases of advanced skin lesions, such as ulcers and atopic dermatitis, as well as in the setting of uncontrolled diabetes because of the high risk of infection in general.

Varicectomy, including of IPVs, was performed using the stab avulsion method without ligation and sutures. In approximately 1 in 10 patients to 1 in 20 patients, there may be oozing to the outer sides of the elastic stockings postoperatively; in such cases, gauze may be applied from the outside for greater pressure.⁶ Measures to prevent DVT complied with the standard guidelines for the endovenous treatment of varicose veins.⁷ Intraoperative pain was objectively assessed using the 5-point Okamura pain scale for preventing nerve injury (0, calm expression; 1, grimace; 2, body movement; 3, complaints of pain; 4, repeated complaints of pain; 5, continuation of the procedure is difficult or inhaled/intravenous anesthesia is added).⁶ The 10-point numerical rating scale score was used to assess pain postoperatively and was compared with the objective pain rating. Under observation, active walking (100 m–200 m inside the ward approximately 3–5 times per hour) was encouraged. Knee-length elastic stockings (moderate pressure, 30 mm Hg–40 mm Hg) or elastic bandages were worn constantly for 1 week postoperatively, after which they were worn during the daytime until the ulcer healed. Patients were assessed on clinical examination and by venous duplex ultrasonography preoperatively, as well as at 1 to 5 days, 1 month, and 3 months postoperatively. The wound was assessed at the time of ultrasonography, with subsequent assessments conducted 2 weeks postoperatively and monthly thereafter until the ulcer healed.

Treatment was standardized to the extent possible. Twice daily, the ulcer site was washed in the shower and then semi-closed using an irreversible membrane (IRM; Plus Moist; Zuiko Medical) dressing; in the later stages of treatment, a composite absorbent pad (Zuikopad; Zuiko Medical) was used (Figure 1). Bathing was permitted at this stage, but soap was not used. Topical agents such as povidone-iodine, antibiotic ointments, trafermin, and silver sulfadiazine were never used on the ulcer site. Debridement was usually unnecessary. Patients were instructed to visit the hospital immediately if they noticed any signs of infection, such as spontaneous pain or an unpleasant smell.

Healing was achieved when the ulcer was covered with epidermis and no exudate adhered to the dressings. If patients with active ulcers had IPVs, these were identified and marked using ultrasonography guidance immediately preoperatively, and varicose veins communicating with these IPVs were removed to the extent possible by means of stab avulsion. CEAP class C4b (lipodermatosclerosis or atrophie blanche) lesions or more severe lesions with adhesions to the surrounding tissue and fragile vascular walls that were impossible to strip were managed by breaking down the vascular bed using a Varady hook and scraping spatula, after which compression hemostasis was performed. The use of moisturizers and bath additives rich in white petroleum jelly was recommended to prevent itching resulting from stasis dermatitis.

Statistical analysis

Numbers are expressed as mean ± standard deviation (minimum–maximum). Medians were calculated using Microsoft Excel 2019 (Microsoft Corporation).

At the first visit, 36 patients were diagnosed with CEAP class C6 venous ulcers. In 7 of these patients, the ulcers had healed by the day of surgery after patients followed the instructions for moist wound healing, compression therapy, and skin care provided at their first appointment; time to healing was 3 months for 2 patients, 4 months for 2 patients, and 1 week, 2 weeks, and 5 months for 1 patient each. One patient was unable to quit smoking; thus, was unable to undergo surgery. After excluding these 8 patients, 28 patients remained for evaluation (eTable [see article PDF]). The mean patient age was 70.1 years ± 11.4 (range, 46–89 years). The disease duration from ulcer onset to the first outpatient visit was 2 weeks to 20 years; for 3 patients, disease duration was unknown. Thirteen patients (46.4%) had IPVs, and the mean surgical time was 38.9 minutes ± 23.2 (range, 12–96 minutes). The mean number of stab avulsion sites per patient was 9.7 ± 11.0 (range, 0–43). Two patients were undergoing antiplatelet drug therapy, which could not be withdrawn; thus, stab avulsion was not performed in these patients. The mean ablation length was 32.0 cm ± 11.3 (range, 10 cm–51 cm), and the mean tumescent local anesthesia solution volume was 584.8 mL ± 204.4 (220 mL–1060 mL). The mean age of the patients included in the current study were older than the mean age of the total sample of 1334 patients who underwent endovenous ablation using radiofrequency ablation in the same period, and the surgical time tended to be longer in the current study. All patients in the current study were ambulatory immediately after the procedure and did not require additional sclerotherapy. There were no cases of DVT, pulmonary embolism, or nerve injury; moreover, no patient required hospitalization beyond 1 night. The median time from surgery to ulcer healing was 55.5 days (range, 13–365 days). Generally, the larger the ulcer, the longer the time to healing.

The typical course of ulcer healing is shown in Figure 2 (case 4). In 4 patients (cases 6, 11, 13, and 23), erosion persisted for longer than 6 months postoperatively but eventually healed with the use of topical steroids. In case 11, erosion persisted for almost 1 year postoperatively; however, after steroid ointment was applied for 1 week, ulcer healing was achieved (Figure 3). In case 12, a surgical site infection developed, which was managed using antibiotics during postoperative outpatient appointments. Skin incisions measuring 1 mm to 3 mm healed within approximately 1 week, even in patients with CEAP class C4b varicose veins. Two patients experienced small ulcers or erosions during outpatient follow-up: case 16 experienced small ulcers on the lateral side of the leg contralateral to the treated area, and case 17 (mitral regurgitation grade 3) experienced erosions on the ipsilateral dorsal foot with severe edema. None of the cases in this study experienced a problem in the treated area. No ulceration recurred as of the final follow-up (median, 24.5 months [range, 3–66 months]), and ulcer healing was achieved by 1-year follow-up in all 28 patients.

Ulcer healing was achieved within a median of 55.5 days (range, 13–365 days) after radiofrequency ablation with adequate varicectomy (stab avulsion [maximum number of sites per patient, 43]), compression therapy, moist wound healing, and skin care. Ulcer healing was achieved by 1-year follow-up in all 28 patients. No ulcers had recurred by approximately 2-year follow-up. Early use of topical steroids was effective in recent cases with residual erosions, and further shortening of ulcer healing time may be expected in the future. In a study by Gohel et al,³ the median time to ulcer healing in the early intervention group (compression therapy and endovenous ablation within 2 weeks) was 56 days, the 1-year healing rate was 93.8%, and the 1-year recurrence rate was 11.4%.

The findings of the current study have strong implications for the treatment of venous ulcers. Use of an appropriate treatment strategy could lead to venous ulcer healing within approximately 2 months without the need for either skin grafting or hospitalization longer than 1 night.

Lower extremity ulcers often become intractable because the lower leg bears the body’s full weight, which increases venous pressure and causes edema. When edematous skin is injured, the wound area tends to enlarge. Generally, the reported causes of intractable ulceration are larger ulcer area, longer ulcer duration, increased ulcer depth, and previous debridement.⁹ Additional, equally applicable risk factors exist. The use of antiseptics and gauze dressings desiccates the ulcerated surface, thus amplifying pain, and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) diminishes perfusion and aggravates ulceration. Severe diabetes and infection are aggravating factors for ulceration. Smoking and secondhand smoke cause impaired circulation to the lower extremities, thus delaying wound healing,¹⁰ and they are risk factors for blood clotting and embolism,¹¹ surgical site infections,¹² and secondary varicose veins.¹³ Healing venous ulcers that are associated with complex underlying causes and risk factors requires an appropriate comprehensive treatment strategy. If treatment is undertaken with residual risk factors, the ulcer may not heal as a result.

Whether IPVs require treatment is controversial, particularly when such treatment is associated with the management of varicose veins.¹⁴ A clear association has been shown between the presence of IPVs and recurrent varicose veins.¹⁵ The authors of the current study do not perform either subfascial endoscopic perforator vein surgery¹⁶ or the transluminal occlusion of perforators technique.¹⁷ For patients with active ulcers and IPVs, the latter were marked using ultrasonography immediately preoperatively, and any varicose veins communicating with these IPVs were removed to the extent possible by performing stab avulsion and compression hemostasis. Prominent varicose veins are occasionally at sites with IPVs; the authors of the current study do not believe it is necessary to avoid IPVs when performing stab avulsion.

It is challenging to recognize IPVs during extraction. Even if complete removal of the IPVs is not achieved, the original goal is met by removing contact with the surrounding varicose veins to the extent possible. The authors of the current study performed stab avulsion in up to 43 sites under local anesthesia and no additional treatments such as ­sclerotherapy.

Debridement was performed only in case 25, wherein the necrotic skin tip was resected during the surgery. Generally, most treatments performed in the patients studied herein adhered to the DIME principle of wound care: debridement, control of infection/inflammation, moisture management, and wound environment/edge assessment.¹⁸ Although the SVS guidelines recommend surgical debridement and hydrosurgical debridement,¹ little or no delay in ulcer healing occurred in the patients in this study even without the use of a high-pressure jet or anesthesia. Patients were instructed to wash the wound in the shower for 1 to 3 minutes twice daily. The study authors’ treatment method is simple and does not require special tools or medications. Active debridement not only removes necrotic tissue and biofilm but may also destroy normal tissue and even normal cells, thereby upsetting the balance of the resident flora and stripping off the sebum. Ulcers can enlarge and deepen, ­resulting in increased risk of infection. ­Worsening of ulcers by debridement is similar to the mechanism of action of soaps, creams, and disinfectants. The boundary between normal and necrotic tissue is unclear. Therefore, it is understandable that active debridement can make venous ulcers intractable.

Patients were hospitalized overnight for treatment. Wound cleansing, dressing application, and compression therapy were continued by the patient independently or with the assistance of a family member until the ulcer healed. Even after ulcer healing occurred, patients were advised to continue compression therapy to manage persistent edema. Compression therapy is also important to prevent infection, which may be caused by edema. Moreover, patients with persistent edema should elevate their legs at night, limit the use of NSAIDs, and actively move their legs while standing.

The moist wound healing technique first reported by Winter¹⁹ in 1962 has been further improved in Japan from 2012, mainly by Natsui,²⁰ who posted online more than 3000 cases undergoing treatment using moist wound healing. Wound management methods have changed dramatically in Japan over the past 10 years.^20,21 Images of an injury managed with moist wound healing are shown in Figure 4.

The SVS guidelines recommend moist wound therapy with dressings. Wounds that are disinfected and covered with a gauze dressing dry out and scar in a conventional manner; often, they do not heal completely. Moist wound treatment has several advantages over dry wound treatment—up to 50% faster wound healing rate, lower rate of infection with no need for systemic antibiotics, painless removal of the dressing without destroying the newly formed tissue, and less scarring and better cosmetic results.²⁰

The usage rate of dressings excluding gauze for venous ulcers in Japan is less than 10%.⁴ This is because conventional dressings are seldom designed to be changed twice daily, making treatment cost extremely expensive. In addition, the product instructions state that conventional dressings should not be used if an infection is suspected. However, venous ulcers with high levels of exudate are not always infected. The IRM dressings and composite absorbent pads can be used regardless of whether infection is present, and they are relatively inexpensive, even when frequent dressing changes are required. These factors are key to their widespread use. The composite absorbent pads have numerous pores in the film that are in direct contact with the wound surface, which allows the pad to absorb exudate. Similarly, the pad is designed to prevent the wound surface from drying out (Figure 1C). If each pad is cut into quarters and changed twice daily, the cost for nearly 2 months is approximately $30 USD. Composite absorbent pads are packaged in bags of 10 pads, measure 15 cm × 15 cm in size, and are sold in Japan at a fixed price of 943 yen. The IRM product is registered with the US Food and Drug Administration as a medical product, whereas the composite absorbent pads are classified as general merchandise. Additionally, the IRM dressing is sold in some countries in Asia and the Middle East. Both products can be exported from Japan to other countries by individuals. To the authors’ knowledge, the IRM dressing is a newer medical product, and there are currently few products with a similar purpose.

Various dressings are currently commercially available. Hydrocolloids are the most common dressings, but they are often unsuitable for managing large amounts of leachate, such as in venous ulcers, because of their poor water absorption properties. Silver-based antimicrobial dressings should also be avoided in the management of VLUs. Evidence exists that silver dressings are no more effective than unmedicated low-adherence dressings for managing leg ulcers.²² The IRM dressings can be cut with scissors and used for ulcers of various sizes and shapes; they were used in about two-thirds of the cases in the current study. The dressings are available in small sizes of 125 mm × 125 mm, large sizes of 200 mm × 250 mm, and currently in variations with additional functions. In addition, since the composite absorbent pads were introduced, the authors have used them in most cases to reduce costs. The use of either IRM dressings or composite absorbent pads would not affect the results of this study because of the similarities in application.

In moist wound healing, bactericidal antiseptics such as povidone-iodine and silver sulfadiazine are not used because of the potential for damaging healthy cells²³; trafermin is not used because it has been reported to cause localized pain.⁵ Similarly, soap, body wash, and standard topical creams are not used because they contain surfactants that remove oily dirt and strip out sebum (ceramide; composed of sphingosine and a fatty acid). Use of antibiotic ointments may lead to the development of bacterial resistance. Nevertheless, in the event of infection, antibiotics are administered intravenously or orally.

Sebum generally contains approximately 1000 different species of resident flora, chiefly anaerobic bacteria (and several dozen species of resident fungi).²⁴ Rather than sterilizing or disinfecting this resident flora, it is important to maintain its diversity without disrupting its balance. If this balance is disrupted, abnormal growth of Staphylococcus aureus and other aerobic bacteria occurs, leading to infection, foul odor, and pruritus. Additionally, sebum plays an important role in infection control.²⁵

At Okamura Memorial Hospital, patients who require treatment for ulcers undergo chest radiography, electrocardiography, and blood tests (including markers of inflammation and D-dimer) at the first visit. Additionally, they are carefully evaluated for comorbidities such as heart failure, impaired renal function, and poorly controlled diabetes. More than half of the patients in the current study had undergone previous wound treatment using soap, disinfection, and silver sulfadiazine at other hospitals. In these cases, pain reduction was noted on stopping disinfection and using moist wound healing products instead. It is important to note, however, that such a change may alter the balance of the resident microbiota as well, leading to infection, which can cause a sudden increase in pain; thus, an early second appointment (between 2–10 days after the first appointment) is recommended. A disinfected and dried-out ulcer base may contract, and use of moist wound healing may temporarily increase the area of ulceration; such an increase is not clinically significant (Figure 5). Occasionally, the authors encounter ulcers in the outpatient setting that are not amenable to surgery (ie, the saphenous vein does not need to be treated), and ulcer healing in these cases may be difficult even with moist wound healing and compression therapy.

The surgery should be performed as early as possible considering the surgical schedule and the patient sent home with instructions for compression therapy, moist wound healing, and skin care. As a result of this treatment strategy in the current study, 7 patients improved from CEAP class C6 to class C5 before surgery. Of those 7 patients, comprehensive treatment was successful for a 79-year-old man with heart failure who, at the first visit, reported that he had gained 10 kg. One month after quitting smoking, discontinuing NSAID use, and wearing an elastic stocking on the affected leg, the patient lost 12 kg and the heart failure was controlled.²⁶ Additionally, the ulcer, which had measured 3.5 cm × 2 cm at the first visit, was healed within approximately 4 months (Figure 6).

Skin care after ulcer healing is important. Sclerosis of the skin because of stasis dermatitis can cause dryness, leading to increased itchiness. Involuntary scratching may cause ulcer recurrence; therefore, appropriate moisturizing is required. White petroleum jelly is generally recommended for its safety and moisturizing qualities. However, patients may start to use soap to eliminate greasiness, which could lead to increased irritation. At Okamura Memorial Hospital, the authors of the current study historically recommended patients use the hypoallergenic Curél Gel-Lotion (Kao). After Mirai Kankyo Technology succeeded in emulsifying petroleum jelly using a 3-phase emulsification technology for mixing water and oil without the use of surfactants,²⁷ the authors began recommending patients use a cosmetic product (Proud Blue Sensitive Moisture Cream) developed using this technology in severe cases.⁵ This product can produce a thin coating of petroleum jelly on the surface of the skin, acting as first aid for skin conditions such as erythema, itching, and mild pain. From the authors’ observations, the product can also effectively prevent rash formation inside compression stockings.

The 4 patients in this study who experienced long-term persistent erosion over the course of treatment for venous ulcers were of advanced age (aged 75, 79, 80, and 89 years). There is an upper limit to the number of times cells can divide, and the regenerative capacity of epithelial cells may have diminished in these patients. Thus, advanced age could be a potential factor in the erosion of venous ulcers over the course of treatment. In these 4 patients, erosion was healed with short-term use of a topical steroid. The exact mechanism of action of steroid treatment is unknown, however. The rate of epithelial skin cell turnover is approximately 1 month.²⁸ If erosion does not improve for several months, as in case 11, a change in treatment strategy should be considered.

This study has a few limitations. First, a single-center study may be subject to selection bias. Thus, strict inclusion and exclusion criteria were used. Second, factors such as ulcer size and depth and disease duration were not investigated. Third, the time to healing may have been affected by factors (eg, dressing brands) other than moist wound healing. Multicenter studies are needed to validate these findings.

Ulcer healing was achieved in a median of approximately 2 months using radiofrequency ablation with adequate varicectomy (stab avulsion [maximum number of sites in 1 patient, 43]), and the vascular beds around IPVs were reduced. Compression therapy, moist wound healing, and skin care are believed to be important strategies in the management of ulcers. Ischemic factors may be implicated in venous ulcers; thus, smoking cessation is essential to successful treatment. If long-term erosion persists after ulceration has improved, short-term steroid use should be considered. Future studies should provide a detailed analysis of the number of cases, including factors that were not fully investigated in this study.