Ultrasound is among the most frequently used imaging modalities in clinical practice.1,2 Modern ultrasound technology was developed during World War I, when French physicist Paul Langevin created a device capable of detecting underwater submarines using high-frequency sonar.3 Over the next few decades, many experimented with military, scientific, and industrial applications of ultrasound technology. Ultrasound as a diagnostic medical tool emerged in the early 1940s after neurologist and psychiatrist Karl Dussik of the University of Vienna and his physicist brother Friedrich used an ultrasound beam to search for brain tumors and locate the cerebral ventricles in the brain containing cerebrospinal fluid.4 Since then, ultrasound has been used for diagnostic and therapeutic purposes in many specialties of medicine, including as an adjunctive therapy for wounds that fail to heal following standard of care (SOC).5,6
Globally, 202 million individuals have peripheral vascular disease, also referred to as peripheral arterial disease (PAD).7 The disorder includes both arterial and venous insufficiency, with the latter being more prevalent. It is estimated that approximately 38 million Americans suffer from venous insufficiency, and 19.5 million have PAD.8 The end-stage manifestation of venous and arterial insufficiency includes nonhealing wounds whose progression may lead to limb-salvage procedures, including limb loss through necessary surgical amputation. Lower-extremity ulceration is a debilitating occurrence that not only affects the patient directly but also has a great impact on the health system and the economy. Up to 1.8% of adults in industrialized nations have leg ulcers.9,10 Chronic ulcers cost the United States $25 billion each year.11 Venous disease is the most common causative factor for leg ulcers (contributing to up to 84% of all ulcerations),12 and 1 of 5 people with leg ulcers have arterial disease.13 Although most venous ulcers can heal within a year following standard compression therapy,14 up to 70% recur, and many of them do so within 3 months of healing.15
For more than 4 decades, researchers, beginning with the in vivo work of Samuels et al,16 Dyson et al,17 and Young and Dyson,18 have investigated the effects of ultrasound therapy on venous ulcers, noting its beneficial effects on promoting the different stages of wound healing. Today, duplex ultrasonography (DUS) is considered the first line of diagnostic assessment in venous ulcers, evaluating for both venous reflux and obstruction.19 Early reviews of the therapeutic effects of ultrasound as applied to venous ulcers suggested a beneficial effect. However, methodological inconsistencies among the studies impeded generalizability and conclusions.20,21 In 2010, Kloth and Niezgoda6 reviewed the effect of ultrasound on wound healing, including venous ulcers. This article provides an updated review of the diagnostic and therapeutic use of ultrasound on venous and arterial ulcers, with a focus on the use of low-frequency ultrasound (LFUS), the current accepted therapeutic ultrasound modality for wound treatment.6
The authors conducted an online search on PubMed for English-language peer-reviewed journal articles dated January 1, 2010 and later using the search terms “ultrasound for venous ulcers” and “ultrasound for arterial ulcers.” The search yielded 282 articles on ultrasound treatment for venous ulcers and 455 articles for ultrasound treatment on arterial ulcers. Articles were then selected based on their relevance for ultrasound mechanism of action in wounds, diagnostic assessments for venous/arterial disease, and treatment approaches and outcomes in venous/arterial ulcers. In addition, reference lists were reviewed to ensure that all relevant evidence was included.
Data from 36 recent articles were included after review. These included 9 systematic reviews, 5 randomized controlled trials (RCTs, including 4 that evaluated the direct therapeutic effect of ultrasound), and 10 prospective studies. No articles addressed the application of ultrasound therapy to arterial ulcers.
Ultrasound Mechanism of Action
An ultrasound transducer applies mechanical energy via acoustic compression waves transmitted above the limit of human hearing that cause wound tissue molecules to vibrate.5,6,22 Ultrasound dosage is based on frequency (kHz or MHz), power (in terms of intensity; W/cm2), pulsed or continuous modes, and treatment duration.6,9 Frequency is a key ultrasound variable. High frequencies of ultrasound have shorter wavelengths and are absorbed more easily.6 Therefore, they are not as penetrating and are used on superficial body structures and for Doppler vascular assessment. Therapeutic-range high-frequency ultrasound (HFUS) is transmitted at a frequency of 1 to 3 MHz and is applied to wounds via direct or periwound application or by subaqueous immersion. Low frequencies penetrate deeper and are used to treat open wounds.6 In contrast, LFUS is transmitted at a frequency of 20 to 120 kHz and is applied to wounds using a subaqueous noncontact method or light contact with saline.5
Acoustic cavitation and microstreaming are the 2 principal mechanisms of action of ultrasound that are crucial to the wound healing process.5,6,22,23 Cavitation is when vibrating ultrasonic energy forms microbubbles from the dissolved gas that accumulates in its field. As the microbubbles move and compress, they cause cellular changes in wound tissue. Ultrasonic sound waves emit physical forces that displace small ions and molecules, creating microstreaming, which in turn moves fluids around and along cellular membranes. Together, cavitation and microstreaming affect cellular activity and are postulated to facilitate wound healing by reducing inflammation; promoting cellular proliferation, stimulation, and recruitment; increasing collagen synthesis and tensile strength; and promoting angiogenesis, wound contraction, and fibrinolysis.16,22,24
These physical energy occurrences are observed more frequently at lower kilohertz frequencies.6,23 Transient cavitation occurs in saline with LFUS and emits energy that results in fibrinolysis and decreases bioburden, effectively debriding the wound.5,6,25 The antimicrobial effects of LFUS in reducing bacteria and destroying biofilm have been reported by multiple in vitro studies.5,24,26–31 In addition, some in vivo human and animal studies and clinical studies have demonstrated that LFUS destroys bacteria in the cell wall and improves healing rates in recalcitrant wounds.5,27,30,32–35 When transmitted at 22.5, 25, or 35 kHz, the removal of necrotic tissue and reduction of bioburden in the wound bed by LFUS are as effective as surgical and mechanical debridement and are less painful, making it an optimal debridement method.6
In chronic venous ulcers, microcirculation is inhibited during the inflammatory phase, with increased blood flow observed during stasis.36–40 Thermal HFUS is applied to warm tissues and stimulate perfusion.5,6 Recent findings support the role of ultrasound in stimulating angiogenesis, collagen formation, and microcirculation during the wound healing process.36,39 Low-intensity (30 mW/cm) pulsed ultrasound applied 3 times per week to venous ulcers resulted in a significantly higher positive labeling of collagen fibers and vascular endothelial growth factor and more CD68(+) protein cells (P < .05) compared with biopsied tissues of venous ulcers treated daily with 1% silver sulfadiazine.39 In a pilot study,36 a microlight-guide spectrophotometer evaluated the effects of LFUS applied at 34 kHz to 14 chronic venous leg ulcers (VLUs) and found that hemoglobin oxygen saturation values significantly increased for at least 30 minutes after only 1 ultrasound application (P = .031), indicating that LFUS resulted in improved blood oxygenation, albeit with temporary effect.
Diagnostic Ultrasound in Venous and Arterial Disease
As previously mentioned, ultrasound is the most accessible and noninvasive diagnostic imaging tool for patients with PAD and should be the first diagnostic assessment for suspected chronic venous disease.19,41–43 The Society for Vascular Surgery and the American Venous Forum recommend that patients with risk factors and/or suspected compromised circulation undergo an arterial and venous evaluation using DUS to assess both the deep and superficial venous system for lower-extremity varicose veins, edema, or venous skin changes (Clinical, Etiology, Anatomy, Physiology clinical stage 2–6)44 to determine the pattern(s) of incompetence prior to making treatment recommendations.41 Unfortunately, diagnostic ultrasound is underutilized for PAD, because of clinicians’ lack of training, expertise, and confidence in the technology.45 Primary care providers sometimes do not recognize the signs and symptoms of venous insufficiency, which when left untreated result in chronic venous ulcers with high rates of ulcer recurrence.46 The underlying pathophysiology of venous insufficiency is consequent venous hypertension.41 It is important for physicians to attempt to rule out venous disease by asking patients about the classic symptoms of venous reflux: leg heaviness, leg fatigue, and a dull, aching discomfort that is exacerbated by prolonged leg dependence and improves with leg elevation. This is particularly important in patients with chronic venous ulcers who may not necessarily report these symptoms.
When evaluating a patient with open wounds, it is recommended that a highly experienced vascular ultrasound technician perform the examination at an outpatient wound center,6,42,46,47 because this technology is operator dependent. Hospital radiology departments may not be the optimal DUS setting for wound care patients because of a potential lack of advanced dressing supplies or nursing staff on site to redress wounds, which can result in a limited study.
The equipment required to perform the venous ultrasound examination is simple by current standards, and the assessment is performed readily using a handheld ultrasonography probe. Gray-scale imaging, pulsed-wave Doppler, and a linear 7.0- to 15-MHz transducer are necessary elements that are found on most portable DUS units available today.41,42,48 Color Doppler can expedite the evaluation, but it is not required, because pulsed-wave Doppler is a much more reliable and reproducible means of documenting reflux (although color flow provides superior guidance when delivering treatment such as sclerotherapy).43,47,49 Spectral Doppler ultrasonography and color-flow vascular imaging supplement gray-scale ultrasound in identifying blood vessels, confirming the direction of blood flow, and detecting vascular stenosis or occlusion.
In general, the goals of the diagnostic ultrasound examination are to identify all incompetent truncal veins and to determine whether they are responsible for the patient’s clinical problem.41,47 When evaluating patients for reflux, the examination should be performed in the pathophysiologically appropriate standing position. Generally, the examination begins at the saphenofemoral junction.42 The common femoral vein is evaluated for obstruction and reflux. Next, the great saphenous vein (GSV) is followed from its junction down beyond the level of any visible varicose veins. The relationship of the GSV to any abnormal veins is assessed by tracing its course and the course of any tributaries that might lead to the abnormal veins. Clinicians should be aware of the standard tributary anatomy of the GSV and able to recognize its frequent variations.43 The anterior accessory GSV originates from the GSV just below the saphenofemoral junction and then courses obliquely down the anterior thigh, where it is often responsible for varicose veins.
Typically, DUS is used to evaluate the GSV and the small saphenous veins and their primary tributaries found within the saphenous fascia.41,43 During axial or cross-sectional imaging, these veins resemble an “Egyptian” eye.42 The majority of the tributaries of the GSV and small saphenous veins are unnamed and are found using imaging in the subcutaneous tissue outside the superficial fascia.43
Diagnosing Peripheral Arterial Disease
The ankle-brachial index (ABI) compares the brachial systolic pressure with the ankle systolic pressure and is measured to determine PAD.50 An ABI should be obtained on patients older than 70 years, patients 50 years or older with cardiovascular risk factors, or any patient with symptoms of PAD or an abnormal lower-limb vascular examination. Patients with a normal ABI but a high suspicion for intermittent claudication should have the measurement repeated after exercise. An ABI of 1.3 or greater is attributable to incompressible vessel walls at the ankle and is nondiagnostic. Patients with an elevated ABI will need additional testing, such as Doppler waveform analysis.49 A change in waveform from one level to the next is indicative of PAD and is highly operator dependent.
Therapeutic Use of Ultrasound on Venous Ulcers
Although the Society for Vascular Surgery, American Venous Forum, and American College of Phlebology recommend venous ultrasonography in addition to standard compressive therapy and local wound care to help improve ulcer healing and to reduce the risk of recurrence,41,48 recent systematic reviews, including a 2017 Cochrane review that analyzed 11 RCTs, have not found reliable evidence to support the treatment of venous ulcers and prevention of ulcer recurrence rates with either LFUS or HFUS.12,51,52 The main issue behind the low-quality evidence has been poor trial design, including small heterogeneous samples, problems with bias, imprecision, and limited data. Older but small RCTs suggest that noncontact LFUS (NLFUS) has a beneficial effect on healing ischemic, neuropathic, and venous wounds, but the strength of evidence is also very limited.21,53
High-frequency Versus Low-frequency Ultrasound Therapy
In the past, HFUS was targeted by clinical research,6,17,54–61 with some studies suggesting a beneficial effect on venous ulcers6,17,54,55,58–60 and others demonstrating no significant difference in outcomes between HFUS and sham ultrasound.6,56,57 Complications resulting from HFUS, including burns and endothelial injury, led to its limited use in clinical practice.61 Further, studies demonstrated that LFUS promotes wound healing better than HFUS.6,58,61,62 A recent, large RCT conducted by Watson et al9 investigated the weekly application of pulsed, low-dose HFUS (0.5 W/cm2, 1 MHz) and SOC (n = 168 patients) compared with SOC alone (n = 169 patients) for up to 12 weeks on patients with at least 1 chronic VLU (>6 months’ duration) greater than 5 cm2 and without moderate to severe arterial disease (Table). Before and after adjusting for wound variables, use of compression bandaging, and the study center, there was no significant difference in time to heal between the intervention and control group, nor was there any difference between the proportion of patients with VLUs healed by 12 months, change in ulcer size at 4 weeks, recurrence rates, or quality of life. However, the HFUS group had significantly more adverse events (P = .30) than the SOC group. In a follow-up economic evaluation, the authors found that the HFUS group actually took 14.7 days longer to heal than the SOC group, had 0.009 fewer quality-adjusted life-years, and had higher treatment costs.63 The authors did not find any therapeutic benefit of applying HFUs to recalcitrant VLUs, nor was this modality cost-effective.9,63
In 2004, the US Food and Drug Administration (FDA) approved NLFUS (40 kHz) therapy for use on wounds.23,61,64,65 Older retrospective analyses demonstrated that LFUS reduced pain related to venous wounds6,66,67 and improved healing rates in VLUs and other chronic wounds.6,68,69 Prospective studies6,21,23,53,70,71 including 2 VLU RCTs and 1 RCT involving ischemic wounds52,70,71 also found that LFUS led to improved healing rates. A 2008 systematic review by Ramundo and Gray72 did not find sufficient evidence to confirm the beneficial effect of LFUS as a debridement method, but as discussed in the section on mechanisms of action, more recent literature supports the use of LFUS in reducing bioburden, destroying biofilm, and debriding wounds.6,24–27,32,33 In 2012, Escandon et al33 published a small pilot study of the effect of NLFUS on venous wound healing, pain, bacterial counts, and the expression of inflammatory cytokines. After 4 weeks of treatment, there was a significant reduction in wound area (P = .0039), and decreases in pain, bacterial counts, and inflammatory cytokines were also observed, further supporting the use of LFUS for wound debridement and for facilitating the transition of the VLU from stasis, preparing the wound for the next step of the wound management process.
Previously, there were no trials that compared the effect of HFUS and LFUS on VLUs.64 Two recent RCTs evaluated adjunctive HFUS and LFUS therapy applied 3 times weekly to VLUs with SOC alone (Table).61,64 Both RCTs were small, with 90 participants randomized and distributed evenly across the 3 groups. Both trials included VLUs with a duration of at least 4 weeks that failed to heal after only 2 weeks of standard compression therapy.
Olyaie et al64 compared the effectiveness of HFUS, NLFUS, and SOC (defined as multilayered compression bandaging and nonadherent dressing applied 3 times per week and sharp debridement performed twice weekly for 3 months; Table). Patients with arterial disease were excluded. The SOC group had an initial mean area of 9.60 cm2, which decreased to 4.28 cm2 at 4 months, a 44.6% reduction. The mean wound areas at the beginning of the study for the HFUS and NLFUS groups were 9.86 and 10.01 cm2, respectively, which decreased to 3.23 and 2.72 cm2 at 4 months (a reduction of 32.8% and 27.2%, respectively). These differences in wound sizes were significant (P = .04). For the SOC, HFUS, and NLFUS groups, all wounds were healed after a respective mean 8.50, 6.86, and 6.65 months (P = .001). The ultrasound groups had significant decreases in edema and pain reported at 4 months (P < .05). Although the ultrasound groups had better outcomes than the SOC group, there were no significant differences in outcomes among the patients treated with HFUS versus LFUS, although the treatment response appeared better in the LFUS group.
Beheshti et al61 applied HFUS, LFUS, or SOC to the 3 respective study groups until the VLUs healed (Table). Patients with neuropathy, infections, PAD, and diabetes were excluded. No patient or wound characteristics were provided, but the authors noted they were well balanced among study groups. The mean time to heal was 8.13 months for the SOC group, and the HFUS and LFUS groups had significantly lower mean times to heal of 6.10 and 5.70 months, respectively (P < .001). Both ultrasound groups also had a significant reduction in wound area (P = .01), pain (P < .001), and edema (P < .0001) at 4 months, compared with the SOC group. Six months after complete wound healing, there were no significant differences in recurring VLUs among all groups. While both ultrasound groups demonstrated better wound healing outcomes compared with SOC alone, there were no significant differences between HFUS and LFUS, similar to what was observed in the study by Olyaie et al,64 although (again) LFUS appeared to have a better response to treatment.
Other Low-frequency Ultrasound Clinical Studies
The 2 RCTs comparing LFUS with HFUS and SOC demonstrated that ultrasound therapy was more effective than SOC in healing VLUs, but did not find that LFUS was significantly more beneficial than HFUS.61,64 A systematic review with meta-analysis and a second meta-analysis that evaluated the use of LFUS on chronic wound healing rates were published in 2011.73,74 The systematic review included 8 RCTs that evaluated different doses of LFUS on venous and diabetic foot ulcers, suggesting a beneficial effect, especially within 5 months of application, when LFUS was applied, but the authors noted significant biases that might affect the trial data.73 The meta-analysis included 8 studies of NLFUS and concluded that the modality consistently reduced wound area and improved healing rates.74
A more recent RCT by Gibbons et al75 in 2015 evaluated NLFUS applied 3 times per week for 4 weeks versus SOC in 81 patients with demonstrated arterial flow and with VLUs with a duration greater than 30 days and an area of 4 to 50 cm2 (Table). At 4 weeks, the mean wound area reduced by 61.6% in the NLFUS group compared with 45% in the SOC group (P = .02). The NLFUS group had significantly reduced median and absolute wound areas (P = .02 and P = .003) and pain scores (P = .01) compared with the SOC group. Therefore, a more favorable treatment response was observed with NLFUS therapy.
A small pilot study evaluated the effect of low-intensity (<100 mW/cm2) LFUS on 20 subjects who were randomized to receive either 20 kHz for either 15 or 45 minutes per session, 100 kHz for 14 minutes, or a sham for 15 minutes over 4 sessions.16 Eight of the 15 ulcers (53.3%) treated with LFUS healed within 4 treatment sessions compared with 2 of the 5 (40%) in the sham group. Participants undergoing 20 kHz of LFUS for 15 minutes showed the most favorable healing rates, with a significantly faster rate of wound closure (P < .03), and all 5 healed by the fourth treatment session, suggesting that shorter sessions of low-dose LFUS may be more effective. Another small study compared the effect of low-dose, pulsed LFUS applied 3 times per week for 3 months with daily treatment of 1% silver sulfadiazine. The ultrasound group had mean percentage area reduction of 41% on day 90, whereas the silver sulfadiazine group did not have a decrease in area (P < .05). Larger RCTs are needed to confirm the findings from these small prospective studies.
Ultrasound is also used to guide the application of other advanced treatments to the wound. For example, ultrasound is currently used to direct endovenous ablation of deeper superficial veins and incompetent perforating veins.41
Ultrasound-guided foam sclerotherapy (UGFS) is an increasingly utilized endovenous ablation technique. Ultrasound-guided foam sclerotherapy combines the principles of sclerotherapy with the advantages of image guidance and is the most minimally invasive ablation technique for the elimination of superficial venous reflux and alleviation of venous hypertension41,42,47 compared with the surgical method of flush saphenofemoral ligation with stripping (also known as high ligation and stripping [HL/S]).76–78 For nearly 100 years, sclerotherapy has injected chemicals into the veins to obstruct them and cause endoluminal fibrosis.41,79 Accurate identification of incompetent vein segments and their distinction from adjoining normal veins and arteries improve the success and minimize the risk associated with sclerotherapy of deeper and larger veins. The target vein can be punctured with real-time ultrasound guidance, leading to a more precise and elegant delivery of the sclerosant.41
Ultrasound-guided foam sclerotherapy has also been studied for its effect on healing venous wounds, although the evidence has been limited by small sample sizes and short follow-up times.40 Nevertheless, multiple observational studies conducted in recent years support the use of UGFS on superficial venous reflux and chronic venous insufficiency to improve the healing outcomes of chronic venous ulcers, noting that this technique appears to be as effective as surgery, with similar recurrence rates.40,80–83 These recent studies reported high healing rates, with 96% of venous ulcers healed at 3 months80 and at least 79.4% healed at 6 months.40,82 Recurrence rates at 1 and 2 years ranged from 2.3% to 8.1% and 4.9% to 14.9%, repectively.40,80,83 However, high recanalization rates with UGFS have impacted its clinical use. Howard et al83 recently reported recanalization rates of 39% at 1 year and 24% at 2 years.
Recently, treatment for vascular disease has relied more on endovenous thermal ablation (EVTA), which is done using radiofrequency or laser technology applied to major culprit refluxing truncal vessels and performed under local tumescent anesthesia.41,42,47 To identify refluxing venous segments, DUS is used in patient selection for this procedure.41 Laser and radiofrequency EVTA of the saphenous veins and their primary tributaries utilize catheters peripherally inserted into the abnormal vein and carefully advanced to the level of reflux (but far enough from the deep venous system), based on safety parameters under the guidance of ultrasound.41 These catheters are then activated and withdrawn across the treatment segment, resulting in the permanent occlusion of the incompetent vein segments.
Ultrasound can also be used to reduce pain during these procedures by guiding tumescent anesthesia,84,85 and ultrasound-guided femoral and sciatic nerve blocks may also considerably reduce pain during endovenous laser ablation.86,87 As with UGFS, Cochrane systematic reviews have found laser and radiofrequency EVTA to be as effective as HL/S on varicose veins,76,77,88 and the most recent systematic review and meta-analysis published in 2016 touts EVTA superiority over surgery and UGFS because of higher anatomical success rates (98.5% for endovenous laser ablation, 97.1% for radiofrequency ablation, 63.6% for UGFS, and 58.0% for HL/S).89 This was further supported by an RCT published in 2016 by Venermo78 that compared HL/S, endovenous laser ablation, and UGFS and demonstrated that 49% of patients treated with UGFS had recurrent GSV reflux at 1 year, compared with 3% treated with surgery or endovenous laser ablation. Further, although UGFS is less costly than EVTA,90 EVTA is more cost-effective.91 Researchers have only just begun to explore the effect of EVTA on venous ulcers.92 Alden et al92 studied the effect of UGFS and EVTA versus compression therapy on healing and recurrence rates in 86 patients with 95 venous ulcers. Ulcers treated with UGFS or EVTA had significantly improved healing rates (9.7% vs 4.2% per week; P = .001) and significantly fewer recurrences after 1 year (27.1% vs 48.9%; P < .015) than ulcers treated with compression therapy alone. More research is needed, however, on the effect of EVTA techniques on venous ulcers to better understand the treatment effect.
Low-frequency Ultrasound Treatment Protocol for Wounds
Low-frequency ultrasound is indicated for the debridement, irrigation, and topical treatment of venous ulcers with infection and impaired circulation and results in reduced bioburden, pain, antibiotic usage, and healing rates.6 Wounds with systematic, advancing cellulitis; metal components; associations with electronic devices; and uncontrolled pain should be treated cautiously with LFUS. There are currently 4 LFUS devices that have been cleared by the FDA for their use on acute and chronic wounds, most notably for their debridement role.6
Standardized treatment parameters for LFUS in wound care are still lacking.5 The manufacturers’ recommendations for use and the FDA-cleared indications should guide facility-based LFUS protocols.5 Ultrasound has been applied 1 to 3 times weekly in research protocols.8 Treatment algorithms recommended by the manufacturers are generally based on longer treatment times for larger wound sizes, so that each session length is determined by the wound area.61,64 Generally, lower doses of LFUS have been more effective in wound healing; 15 minutes of 20 kHz LFUS (633 J/cm2) at 1-Hz pulse repetition frequency has been recommended.16
The role of ultrasound in diagnosing venous and arterial disease is well established. In terms of therapeutic function, in the past, HFUS was frequently studied,6,17,54–61 but today, LFUS (NLFUS in particular) is utilized more in the wound care setting for its superior role in debriding the wound and preparing it for treatment.61 However, inconsistent and limited evidence hinders the more widespread adoption of ultrasound therapy in clinical practice. Although LFUS appears to have a better treatment response than HFUS, recent RCTs found that, in terms of statistical significance, LFUS is no more effective than HFUS in healing venous ulcers.61,64 However, these trials did not evaluate the safety of these modalities; adverse event and complication rates are a known issue with HFUS, hindering its clinical use.61 Watson et al9 found that HFUS caused significantly more adverse events than SOC, but there are no data to compare HFUS and LFUS.
Clinical practice guidelines recommend ultrasound as adjunctive therapy for chronic venous ulcers, but recent systematic reviews and meta-analyses found that the quality of evidence was lowered by limitations in trial design, including small heterogeneous trial populations, significant bias, imprecision, and limited data.12,51,52,73 Generally, these issues continue to weaken the evidence obtained from more recent trials (Table). Among the 4 most recent therapeutic ultrasound RCTs,9,61,64,75 although the study groups were more homogeneous, 3 had small samples. (However, the trial by Watson et al9 is considered the largest trial evaluating therapeutic ultrasound on venous ulcers to date, with 337 patients enrolled.) Safety data continue to be very limited, with the Watson et al9 trial, as mentioned previously, being the only one to evaluate adverse events.
The strength of evidence for ultrasound therapy is further complicated by the makeup of the patient population with venous and arterial disease. For example, when comparing UGFS with HL/S, randomization is not realistic and may not be ethical, considering the advanced age and frailty of the targeted patient populations.40,80 Clinical research is only beginning to evaluate EVTA techniques on venous ulcers,92 and the reality is most patients would never choose surgery over a minimally invasive procedure.40 Therefore, one has to rethink the appropriate evidence base for these modalities.
The limitations of this literature review are that it is a generalized, high-level review that summarizes updated information published on the diagnostic and therapeutic use of ultrasound on venous and arterial ulcers since 2010. This article is not intended to be a comprehensive, detailed systematic review. The search for articles was limited to PubMed because it is the largest online database of peer-reviewed medical articles. Because abstracts were first scanned for relevant content information, some articles with relevant information may not have been captured by the literature search.
Based on the search results, it would appear that this is the first review that attempted to cover the effect of ultrasound on arterial ulcers. A clear omission from recent literature is that, although diagnostic ultrasound is widely used to assess venous and arterial disease, no recent evidence was found for the therapeutic effect of ultrasound on arterial ulcers. This is not surprising when considering that arterial disease is often excluded from clinical trials.61,64,75
Although the question of appropriateness of RCTs is controversial in terms of the future directions of ultrasound research on venous and arterial wounds, what can be addressed by further study are the data and sample limitations currently weakening the evidence base. Broader study samples with more complete patient and wound data and a stronger study design that can comprehensively analyze the efficacy, effectiveness, and safety of ultrasound therapy on wounds would help to strengthen clinical findings. It is hoped that more clinicians will follow clinical practice guidelines that recommend diagnostic ultrasound for venous and arterial disease and the application of ultrasound therapy to venous ulcers so that adequate wound management can begin as soon as possible for the patient. However, standardized treatment protocols are still needed, which require a stronger evidence base. To better support the debridement and adjunctive wound healing role of LFUS, standardized parameters are also needed that better measure and report the effects of ultrasound on bioburden.5,23
Diagnostic ultrasound is used to assess venous and arterial disease and guide the appropriate treatment, including for venous and arterial ulcers. Therapeutic LFUS can effectively debride the wound bed and jumpstart the stalled healing process in a chronic wound; it is also used as an adjunctive topical wound treatment with SOC and helps guide the application of other advanced therapies in venous ulcers. Because of poor trial design and inconsistent and limited data, stronger evidence is still needed to support the effectiveness of ultrasound therapy on venous and arterial ulcers.
- Duplex ultrasound is the first line of diagnostic assessment for venous and arterial disease.
- Low-frequency ultrasound therapy is indicated for the debridement and treatment of impaired venous ulcers.
- Low-frequency ultrasound is used as adjunctive therapy to prepare the wound bed for treatment by reducing bioburden, destroying biofilm, and promoting microcirculation to transition the wound healing process from stasis.
- Ultrasound is also used to guide the application of other advanced therapies, such as sclerotherapy, to the wound.
- Standardized treatment protocols are still needed for the application of therapeutic ultrasound to the wound.
1. Kiessling F, Fokong S, Bzyl J, Lederle W, Palmowski M, Lammers T. Recent advances in molecular, multimodal and theranostic ultrasound imaging. Adv Drug Deliv Rev 2014;72:15–27.
2. Shung KK. Diagnostic ultrasound: past, present, and future. J Med Biol Eng 2011;31:371–4.
3. Arshadi R, Cobbold RS. A pioneer in the development of modern ultrasound: Robert William Boyle (1883-1955). Ultrasound Med Biol 2007;33(1):3–14.
4. Shampo MA, Kyle RA. Karl Theodore Dussik—pioneer in ultrasound. Mayo Clin Proc 1995;70(12):1136.
5. Korzendorfer H, Hettrick H. Biophysical technologies for management of wound bioburden. Adv Wound Care (New Rochelle) 2014;3:733–41.
6. Kloth L, Niezgoda JA. Ultrasound for wound debridement and healing. In: Wound Healing: Evidence-Based Management. Kloth L, McCulloch J, eds. Philadelphia, PA: FA Davis; 2010.
7. Fowkes FG, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013;382:1329–40.
9. Watson JM, Kang’ombe AR, Soares MO, et al. Use of weekly, low dose, high frequency ultrasound for hard to heal venous leg ulcers: the VenUS III randomised controlled trial. BMJ 2011;342:d1092.
10. Graham ID, Harrison MB, Nelson EA, Lorimer K, Fisher A. Prevalence of lower-limb leg ulceration: a systematic review of prevalence studies. Adv Skin Wound Care 2003;16:305–16.
11. Sen CK, Gordillo GM, Roy S, et al. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen 2009;17:763–71.
12. Dale JJ, Callam MJ, Ruckley CV, Harper DR, Berrey PN. Chronic ulcers of the leg: a study of prevalence in a Scottish community. Health Bull (Edin) 1983;41:311–4.
13. Nelson EA. Venous leg ulcers. BMJ Clin Evid 2011;2011:1902.
14. Iglesias C, Nelson EA, Cullum NA, Torgerson DJ; VenUS Team. VenUS I: a randomised controlled trial of two types of bandage for treating venous leg ulcers. Health Technol Assess 2004;8(29):iii,1–105.
15. Vowden KR, Vowden P. Preventing venous ulcer recurrence: a review. Int Wound J 2006;3:11–21.
16. Samuels JA, Weingarten MS, Margolis DJ, et al. Low-frequency (<100 kHz), low-intensity (<100 mW/cm2
) ultrasound to treat venous ulcers: a human study and in vitro experiments. J Acoust Soc Am 2013;134(2):1541–7.
17. Dyson M, Franks C, Suckling J. Stimulation of healing of varicose ulcers by ultrasound. Ultrasonics 1976;14:232–6.
18. Young SR, Dyson M. Effect of therapeutic ultrasound on the healing of full-thickness excised skin lesions. Ultrasonics 1990;28:175–80.
19. Kokkosis AA, Labropoulos N, Gasparis AP. Investigation of venous ulcers. Semin Vasc Surg 2015;28(1):15–20.
20. Flemming K, Cullum N. Therapeutic ultrasound for venous leg ulcers. Cochrane Database Syst Rev 2000;4:CD001180.
21. Cullum N, Nelson EA, Flemming K, Sheldon T. Systematic reviews of wound care management: (5) beds; (6) compression; (7) laser therapy, therapeutic ultrasound, electrotherapy and electromagnetic therapy. Health Technol Assess 2001;5(9):1–221.
22. Lai J, Pittelkow MR. Physiological effects of ultrasound mist on fibroblasts. Int J Dermatol 2007;46:587–93.
23. Ennis WJ, Valdes W, Gainer M, Meneses P. Evaluation of clinical effectiveness of MIST ultrasound therapy for the healing of chronic wounds. Adv Skin Wound Care 2006;19:437–46.
24. Karau MJ, Piper KE, Steckelberg JM, Kavros SJ, Patel R. In vitro activity of the Qoustic Wound Therapy System against planktonic and biofilm bacteria. Adv Skin Wound Care 2010;23:316–20.
25. Wollina U, Heinig B, Kloth K. The use of biophysical technologies in chronic wound management. In: Measurements in Wound Healing. Mani R, Romanelli M, Shukla V, eds. London: Springer-Verlag; 2012.
26. Conner-Kerr T, Alston G, Stovall A, et al. The effects of low frequency ultrasound (35 kHz) on methicillin-resistant Staphylococcus aureus
(MRSA) in vitro. Ostomy Wound Manage 2010;56:32–43.
27. Serena T, Lee K, Lam K, Attar P, Meneses P, Ennis W. The impact of noncontact, nonthermal, low-frequency ultrasound on bacterial counts in experimental and chronic wounds. Ostomy Wound Manage 2009;55:22–30.
28. Ensing GT, Neut D, van Horn JR, van der Mei HC, Busscher HJ. The combination of ultrasound with antibiotics released from bone cement decreases the viability of planktonic and biofilm bacteria: an in vitro study with clinical strains. J Antimicrob Chemother 2006;58:1287–90.
29. Qian Z, Sagers RD, Pitt WG. The effect of ultrasound frequency upon enhanced killing of Pseudomonas aeuroginosa
biofilm. Ann Biomed Eng 1997;25:69–76.
30. Scherba G, Weigel RM, O’Brien WD Jr. Quantitative assessment of the germicidal efficacy of ultrasonic energy. Appl Environ Microbiol 1991;57:2079–84.
31. Pitt WG, McBride MO, Lunceford JK, Roper RJ, Sagers RD. Ultrasonic enhancement of antibiotic action on gram-negative bacteria. Antimicrob Agents Chemother 1994;38:2577–82.
32. Kavros SJ, Schenk EC. Use of noncontact low frequency ultrasound in the treatment of chronic foot and leg ulcerations: a 51-patient analysis. J Am Podiatr Med Assoc 2007;97:95–101.
33. Escandon J, Vivas AC, Perez R, Kirsner R, Davis S. A prospective pilot study of ultrasound therapy effectiveness in refractory venous leg ulcers. Int Wound J 2012;9:570–8.
34. Schoenbach SF, Song IC. Ultrasonic debridement: a new approach in the treatment of burn wounds. Plast Reconstr Surg 1980;66:34–7.
35. Carmen JC, Roeder BL, Nelson JL, et al. Ultrasonically enhanced vancomycin activity against Staphylococcus epidermidis
biofilms in vivo. J Biomater Appl 2004;18(4):237–45.
36. Wollina U, Heinig B, Naumann G, Scheibe A, Schmidt WD, Neugebauer R. Effects of low-frequency ultrasound on microcirculation in venous leg ulcers. Indian J Dermatol 2011;56:174–9.
37. Smith PC. The causes of skin damage and leg ulceration in chronic venous disease. Int Low Extrem Wounds 2006;5:160–8.
38. Pascarella L, Schönbein GW, Bergan JJ. Microcirculation and venous ulcers: a review. Ann Vasc Surg 2005;19:921–7.
39. de Ávila Santana L, Alves JM, Andrade TA, et al. Clinical and immunohistopathological aspects of venous ulcers treatment by low-intensity pulsed ultrasound (LIPUS). Ultrasonics 2013;53:870–9.
40. Pang KH, Bate GR, Darvall KA, Adam DJ, Bradbury AW. Healing and recurrence rates following ultrasound-guided foam sclerotherapy of superficial venous reflux in patients with chronic venous ulceration. Eur J Vasc Endovasc Surg 2010;40:790–5.
41. Gloviczki P, Comerota AJ, Dalsing MC, et al. The care of patients with varicose veins and associated chronic venous diseases: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg 2011;53(5 Suppl):2S–48S.
42. Coleridge-Smith P, Labropoulos N, Partsch H, Myers K, Nicolaides A, Cavezzi A. Duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs—UIP consensus document. Part I. Basic principles. Eur J Vasc Endovasc Surg 2006;31(1):83–92.
43. Cavezzi A, Labropoulos N, Partsch H, et al. Duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs—UIP consensus document. Part II. Anatomy. Eur J Vasc Endovasc Surg 2006;31(3):288–99.
44. Eklöf B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg 2004;40:1248–52.
45. Fish JH, Klein-Weigel P, Fraedrich G. Overview of the role of duplex ultrasound for treatment and surveillance of peripheral arterial disease. J Patient-Centered Res Rev 2015;2:104–11.
46. Coronado R. Venous insufficiency: the changing paradigm in vascular disease. Vasc Dis Manage 2015;12:E126–E130.
48. Meissner MH, Moneta G, Burnand K, et al. The hemodynamics and diagnosis of venous disease. J Vasc Surg 2007;46(Suppl S):4S–24S.
49. Yamaki T, Nozaki M, Sasaki K. Color duplex-guided sclerotherapy for the treatment of venous malformations. Dermatol Surg 2000;26:323–328.
50. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report. Circulation 2006;113:e463–654.
51. Cullum NA, Al-Kurdi D, Bell-Syer SE. Therapeutic ultrasound for venous leg ulcers. Cochrane Database Syst Rev 2010;6:CD001180.
52. Cullum N, Liu Z. Therapeutic ultrasound for venous leg ulcers. Cochrane Database Syst Rev 2017;5:CD001180.
53. Kavros SJ, Miller JL, Hanna SW. Treatment of ischemic wounds with noncontact, low-frequency ultrasound: the Mayo Clinic experience, 2004-2006. Adv Skin Wound Care 2007;20:221–6.
54. Roche C, West J. A controlled trial investigating the effect of ultrasound on venous ulcers referred from general practitioners. Physiotherapy 1984;70:475–82.
55. Callam MJ, Harper DR, Dale JJ, Ruckley CV, Prescott RJ. A controlled trial of weekly ultrasound therapy in chronic leg ulceration. Lancet 1987;2:204–6.
56. Lundeberg T, Nordström F, Brodda-Jansen G, Eriksson SV, Kjartansson J, Samuelson UE. Pulsed ultrasound does not improve healing of venous ulcers. Scand J Rehabil Med 1990;22:195–7.
57. Eriksson SV, Lundeberg T, Malm M. A placebo controlled trial of ultrasound therapy in chronic leg ulceration. Scand J Rehabil Med 1991;23:211–3.
58. Johannsen F, Gam AN, Karlsmark T. Ultrasound therapy in chronic leg ulceration: a meta-analysis. Wound Repair Regen 1998;6:121–6.
59. Swist-Chmielewska D, Franek A, Brzezińska-Wcisło L, Błaszczak E, Polak A, Król P. Experimental selection of best physical and application parameters of ultrasound in the treatment of venous crural ulceration. Pol Merkur Lekarski 2002;12(72):500–5.
60. Dolibog P, Franek A, Taradaj J, Blaszczak E, Cierpka L. Efficiency of therapeutic ultrasound for healing venous leg ulcers in surgically-treated patients. Wounds 2008;20:334–40.
61. Beheshti A, Shafigh Y, Parsa H, Zangivand AA. Comparison of high-frequency and MIST ultrasound therapy for the healing of venous leg ulcers. Adv Clin Exp Med 2014;23:969–75.
62. Ernst E. Ultrasound for cutaneous wound healing. Phlebology 1995;10:2–4.
63. Chuang LH, Soares MO, Watson JM, et al. Economic evaluation of a randomized controlled trial of ultrasound therapy for hard-to-heal venous leg ulcers. Br J Surg 2011;98:1099–106.
64. Olyaie M, Rad FS, Elahifar MA, Garkaz A, Mahsa G. High-frequency and noncontact low-frequency ultrasound therapy for venous leg ulcer treatment: a randomized, controlled study. Ostomy Wound Manage 2013;59:14–20.
65. Unger PG. Low-frequency, noncontact, nonthermal ultrasound therapy: a review of the literature. Ostomy Wound Manage 2008;54:57–60.
66. Gehling ML, Samies JH. The effect of noncontact, low-intensity, low-frequency therapeutic ultrasound on lower-extremity chronic wound pain: a retrospective chart review. Ostomy Wound Manage 2007;53:44–50.
67. Bell AL, Cavorsi J. Noncontact ultrasound therapy for adjunctive treatment of nonhealing wounds: retrospective analysis. Phys Ther 2008;88:1517–24.
68. Haan J, Lucich S. A retrospective analysis of acoustic pressure wound therapy: effects on the healing progression of chronic wounds. J Am Col Certif Wound Spec 2009;1:28–34.
69. Kavros SJ, Liedl DA, Boon AJ, Miller JL, Hobbs JA, Andrews KL. Expedited wound healing with noncontact, low-frequency ultrasound therapy in chronic wounds: a retrospective analysis. Adv Skin Wound Care 2008;21:416–23.
70. Weichenthal M, Mohr P, Stegmann W, Breitbart EW. Low-frequency ultrasound treatment of chronic venous ulcers. Wound Repair Regen 1997;5:18–22.
71. Peschen M, Weichenthal M, Schöpf E, Vanscheidt W. Low-frequency ultrasound treatment of chronic venous leg ulcers in an outpatient therapy. Acta Derm Venereol 1997;77:311–4.
72. Ramundo J, Gray M. Is ultrasonic mist therapy effective for debriding chronic wounds? J Wound Ostomy Continence Nurs 2008;35:579–83.
73. Voigt J, Wendelken M, Driver V, Alvarez OM. Low-frequency ultrasound (20-40 kHz) as an adjunctive therapy for chronic wound healing: a systematic review of the literature and meta-analysis of eight randomized controlled trials. Int J Low Extrem Wounds 2011;10:190–9.
74. Driver VR, Yao M, Miller CJ. Noncontact low-frequency ultrasound therapy in the treatment of chronic wounds: a meta-analysis. Wound Repair Regen 2011;19:475–80.
75. Gibbons GW, Orgill DP, Serena TE, et al. A prospective, randomized, controlled trial comparing the effects of noncontact, low-frequency ultrasound to standard care in healing venous leg ulcers. Ostomy Wound Manage 2015;61:16–29.
76. Nesbitt C, Eifell RK, Coyne P, Badri H, Bhattacharya V, Stansby G. Endovenous ablation (radiofrequency and laser) and foam sclerotherapy versus conventional surgery for great saphenous vein varices. Cochrane Database Syst Rev 2011;10:CD005624.
77. Nesbitt C, Bedenis R, Bhattacharya V, Stansby G. Endovenous ablation (radiofrequency and laser) and foam sclerotherapy versus open surgery for great saphenous vein varices. Cochrane Database Syst Rev 2014;7:CD005624.
78. Venermo M, Saarinen J, Eskelinen E, et al. Randomized clinical trial comparing surgery, endovenous laser ablation and ultrasound-guided foam sclerotherapy for the treatment of great saphenous varicose veins. Br J Surg 2016;103:1438–44.
79. McPheeters HO. Treatment of varicose veins; a twenty-five year reflection. Minn Med 1956;39:271–5.
80. Darvall KA, Bate GR, Adam DJ, Silverman SH, Bradbury AW. Ultrasound-guided foam sclerotherapy for the treatment of chronic venous ulceration: a preliminary study. Eur J Vasc Endovasc Surg 2009;38:764–9.
81. Neto FC, de Araújo GR, Kessler IM, de Amorim RF, Falcão DP. Treatment of severe chronic venous insufficiency with ultrasound-guided foam sclerotherapy: a two-year series in a single center in Brazil. Phlebology 2015;30:113–8.
82. Lloret P, Redondo P, Cabrera J, Sierra A. Treatment of venous leg ulcers with ultrasound-guided foam sclerotherapy: healing, long-term recurrence and quality of life evaluation. Wound Repair Regen 2015;23:369–78.
83. Howard JK, Slim FJ, Wakely MC, et al. Recanalisation and ulcer recurrence rates following ultrasound-guided foam sclerotherapy. Phlebology 2016;31:506–13.
84. Toonder IM, Lawson JA, Wittens CH. Tumescent, how do I do it? Phlebology 2013;28 Suppl 1:15–20.
85. Chen JQ, Xie H, Deng HY, et al. Endovenous laser ablation of great saphenous vein with ultrasound-guided perivenous tumescence: early and midterm results. Chin Med J (Engl) 2013;126:421–5.
86. Yilmaz S, Ceken K, Alimoglu E, Sindel T. US-guided femoral and sciatic nerve blocks for analgesia during endovenous laser ablation. Cardiovasc Intervent Radiol 2013;36:150–7.
87. Dzieciuchowicz L, Espinosa G, Grochowicz L. Evaluation of ultrasound-guided femoral nerve block in endoluminal laser ablation of the greater saphenous vein. Ann Vasc Surg 2010;24:930–4.
88. Siribumrungwong B, Noorit P, Wilasrusmee C, Attia J, Thakkinstian A. A systematic review and meta-analysis of randomised controlled trials comparing endovenous ablation and surgical intervention in patients with varicose vein. Eur J Vasc Endovasc Surg 2012;44:214–23.
89. Boersma D, Kornmann VN, van Eekeren RR, et al. Treatment modalities for small saphenous vein insufficiency: systematic review and meta-analysis. J Endovasc Ther 2016;23:199–211.
90. Davies HO, Popplewell M, Darvall K, Bate G, Bradbury AW. A review of randomized controlled trials comparing ultrasound-guided foam sclerotherapy with endothermal ablation for the treatment of great saphenous varicose veins. Phlebology 2016;31:234–40.
91. Marsden G, Perry M, Bradbury A, et al. A cost-effectiveness analysis of surgery, endothermal ablation, ultrasound-guided foam sclerotherapy and compression stockings for symptomatic varicose veins. Eur J Vasc Endovasc Surg 2015;50:794–801.
92. Alden PB, Lips EM, Zimmerman KP, et al. Chronic venous ulcer: minimally invasive treatment of superficial axial and perforator vein reflux speeds healing and reduces recurrence. Ann Vasc Surg 2013;27:75–83.