High-Frequency Ultrasound Speeds

The efficacy of noninvasive MHz high-frequency (HF) or kHz low-frequency (LF) ultrasound treatment to heal chronic wounds remains controversial.^1-4   Low-quality evidence supports potentially faster healing in the first 5 months of LF ultrasound stimulation of venous ulcers or Wagner grade 1-3 diabetic foot ulcers, but these effects remain to be verified in rigorous placebo-controlled randomized clinical trials (RCTs). Chronic wound responses to HF ultrasound are equally confusing. Treatment parameters vary widely in the literature making it difficult to find studies that all used the same HF ultrasound intensity and duty cycle applied at similar intervals to treat chronic ulcers. A large placebo-controlled RCT with significant heterogeneity among study centers reported that once-per-week venous ulcer treatment with 1 MHz HF ultrasound applied at a peak intensity of 0.5 W/cm² was reportedly ineffective in stimulating 12-month healing of large, long-duration venous ulcers.⁵ Here we review 2 recent small studies reporting significant healing benefits of applying HF ultrasound stimulation 3 to 5 times per week to venous⁶ or pressure⁷ ulcers. Though they share many limitations with prior literature, these RCTs may help clarify our understanding of HF ultrasound effects on chronic wound healing.

Reference. 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(8):14-20.

  Rationale. Various topical treatments reportedly enhance healing of venous ulcers, which pose a frequent, persistent challenge to health care. Among these are 2 forms of ultrasound treatment: high-frequency (HF) ultrasound and noncontact (NC) low- frequency (LF) ultrasound.

  Objective. This randomized clinical trial (RCT) compared healing efficacy and safety of standardized venous ulcer compression with or without HF ultrasound or NCLF ultrasound.

  Methods. An Iranian hospital-based vascular and radiation clinic enrolled subjects without arthritis, diabetes or arterial disease, confirmed by a Doppler ankle-to-brachial index of at least 0.8, who had a venous ulcer of at least 4 weeks duration without clinical improvement during 2 weeks of good standard of care (SOC) including standardized compression. Exclusion criteria were ankle or knee prosthesis, pregnancy, malignancy, neuropathy, infection, cellulitis, antibiotic use, or allergy to the ultrasound water-based contact gel. By opening a sealed opaque envelope, 30 subjects who signed informed consent were randomly assigned to standardized ulcer treatment 3 times per week for 3 months with each intervention: HF ultrasound (1-3 MHz, 0.5-1 W/cm², 1 minute per cm²) or NCLF ultrasound (40 kHz, 0.1-0.8 W/cm² 1 minute per cm²) or SOC consisting of debridement as needed, nonadherent dressing, plus graduated multilayer compression 40 mm Hg at the ankle, descending proximally. Wound area, pain, and surrounding edema were measured at baseline as well as 2 and 4 months after enrollment. Healing was assessed by monthly follow-up until completely healed. Statistical tests that were significant at P < 0.05 included Student’s t test, chi square, analysis of variance, and Fisher’s exact test.

  Results. Subjects and ulcers were comparable at baseline, with ulcer area averaging 9.5 to 10.1 cm² for all groups. All 90 subjects in the 3 groups completed the study with no side effects and significantly more reduction in ulcer area, edema, and pain for both HF ultrasound and NCLF ultrasound groups compared to SOC. Patients were followed for an average of 7.5 months. Standard of care control ulcers healed in a mean of 8.5 months, at least 5 weeks longer healing time compared to 6.86 months for the HF ultrasound group, or 6.65 months for the NCLF ultrasound groups (P = 0.001). The 2 ultrasound groups had comparable healing times.

  Authors’ Conclusions. Complete wound healing was faster, with earlier reduction in ulcer area, pain, and edema in the 2 ultrasound groups compared to SOC. No significant difference was observed between the NCLF ultrasound and HF ultrasound groups on any wound or patient outcome.

Reference. Polak A, Franek A, Blaszczak E, et al. A prospective, randomized, controlled, clinical study to evaluate the efficacy of high-frequency ultrasound in the treatment of stage II and stage III pressure ulcers in geriatric patients. Ostomy Wound Manage. 2014;60(8):16-28.

  Rationale. International pressure ulcer guidelines recommend treating nonhealing stage III and IV pressure ulcers with NCLF ultrasound to debride necrotic soft tissue and HF ultrasound as an adjunct in treating infected pressure ulcers. Available evidence makes it difficult to draw conclusions about the healing effects of HF ultrasound on pressure ulcers.

  Objective. A prospective RCT tested the hypothesis that HF ultrasound can improve stage II and III pressure ulcer healing when used within an interdisciplinary wound care program on geriatric patients at high risk of developing a pressure ulcer.

  Methods. With appropriate consent and ethics board approval in 4 nursing and care centers in Silesia, Poland, the authors recruited residents older than 70 years of age who were at high risk for pressure ulcers, as determined by the Norton and Braden Scales. Subjects were enrolled if they had 1 or 2 stage II-III pressure ulcers on the trunk, hip, or buttock region measuring more than 1 cm² in area and persisting for at least 4 weeks. Patients were excluded from participation if they had more than 2 qualifying pressure ulcers or deep tunneling necrotic ulcers likely to require surgical intervention, or if they had neoplasm, diseases of the lymphatic or central nervous system, demyelinating disease, or liver cirrhosis. Patient demographics and ulcer characteristics, including NPUAP/EPUAP staging,⁸ were recorded on enrollment, using standardized interviews and reporting forms. Each patient, by opening a sealed envelope, was randomly assigned to receive either good SOC alone or SOC with added HF ultrasound delivered at 1 MHz in a 20% duty cycle with a spatial average temporal peak intensity of 0.5 W/cm². High-frequency ultrasound was delivered 5 days per week for 1 minute per cm² of ulcer area in the first week, 2 minutes/cm² the second week, and 3 minutes/cm² the third week for a minimum of 4 weeks or until the end of treatment. Healing progress was monitored by researchers blinded to the treatment group by duplicate wound tracings at baseline and at the end of week 6 following the first treatment. If the ulcer closed before week 6, the date of closure was recorded. The primary healing outcomes were absolute and percent reduction in wound surface area from baseline. Secondary outcomes included time to complete wound closure and percent of ulcers achieving at least 50% area reduction during 6 weeks, as well as safety of the treatment, reported as adverse events. Differences between groups were tested using Fisher’s exact test for proportion differences, Mann-Whitney U-test for differences in percent change in ulcer area, and the Wilcoxen signed rank test for pre- and post-treatment healing differences between groups, with P < 0.05 considered statistically significant.

  Results. Patients and ulcers in the 2 groups were comparable at baseline with 22 evaluable patients with 23 ulcers with a mean area of 11.1 cm² in the SOC group, and 20 patients with 21 pressure ulcers with a mean area 15.4 cm² in the HF ultrasound group completing the minimum 4 weeks of treatment. At 6 weeks, both groups decreased in ulcer area, with the HF ultrasound group decreasing more than SOC controls (P = 0.047). In subset analysis, this result was statistically significant only for stage II pressure ulcers. Seven of the 14 HF ultrasound stage II pressure ulcers (50%) healed in 6 weeks compared to 17% of the 18 SOC stage II control ulcers (P = 0.062). Percent of subjects achieving 50% healing at 6 weeks paralleled the healing results, also with inadequate sample size to support statistical significance.

  Authors’ Conclusions. Standard of care plus HF ultrasound of 1 MHz at an intensity of 0.5 W/cm², delivered 1-3 minutes/cm² 5 days per week at a 20% duty cycle, reduced stage II pressure ulcer area significantly more than SOC alone. Further research is needed to determine the effects of HF ultrasound on stage III or IV pressure ulcers.

These RCTs,^5,6 one of them evaluated blinded to treatment, reported clinically important healing benefits for nonhealing venous or pressure ulcers treated with 1-3 MHz HF ultrasound delivered 3 or more times per week, with duty cycles adjusted to avoid heating artifacts. The effective dose at a spatial average temporal peak intensity range of 0.5 to 1 W/cm² was administered from 1 to 3 minutes/cm² of ulcer area, or about 5 to 30 minutes for these large chronic ulcers. There is insufficient information to define the mechanism of action for these clinically important effects on venous ulcers, similar to those obtained with NC LF ultrasound.⁵ For the pressure ulcer RCT,⁶ could the healing benefits have resulted from the extra 5 to 30 minutes of pressure ulcer offloading 5 days a week during HF ultrasound application? A double-blind placebo-controlled study could answer this question. Reviewing the literature, Polak et al⁷ noted HF ultrasound improved pressure ulcer healing only in studies where it was administered 3 or more times per week. The only exception was an 11-center, 88-subject, placebo-controlled study of considerably smaller area stage II-IV pressure ulcers reporting no effect of HF ultrasound on percent of ulcers closed 12 weeks after enrollment or risk-adjusted closure rate.⁹ It is unclear whether the discrepancy in results arose from differences in outcomes studied, baseline ulcer area, SOC variables, or placebo effects associated with the placebo-HF ultrasound control. If the latter, is there an opportunity to identify the source of such a clinically important placebo effect and harness it cost effectively to benefit patients? These 2 recent studies suggest the merit of carefully examining HF ultrasound healing efficacy in adequately powered placebo-controlled RCTs with a rigorously controlled SOC, including patients with ulcers unlikely to heal. Future HF ultrasound research should pay special attention to HF ultrasound scheduling and dosage parameters and blind-evaluated 6- to 12-week outcomes.

Laura Bolton, PhD
Adjunct Associate Professor
Department of Surgery,
Rutgers Robert Wood Johnson Medical School,
New Brunswick, NJ

This article was not subject to the WOUNDS peer-review process.