Ultrasound (US) delivers mechanical vibration above the upper threshold of human hearing (>20 kHz). US in the megahertz range (1-3 MHz) has been used to treat musculoskeletal disorders, often by physical therapists. Although the exact mechanism underlying its clinical effects is not known, therapeutic US has been shown to have a variety of effects at a cellular level, including angiogenesis, leukocyte adhesion, growth factor, collagen production, and increases in macrophage responsiveness, fibrinolysis, and nitric oxide levels. The therapeutic effects of US energy in the kilohertz range have also been examined. Although the precise effects are not known, the low-frequency US in this range may improve wound healing via the production, vibration, and movement of micron-sized bubbles in the coupling medium and tissue.

The mechanical energy from the USis typically transmitted to the tissue through a coupling gel. Several high-intensity US devices with contact probes are currently available for wound débridement. Low-intensity US devices have been developed that do not require coupling gel or other direct contact. The MIST Therapy System delivers a saline mist to the wound with low-frequency US (40 KHz). A second device, the Qoustic Wound Therapy System, also uses sterile saline to deliver US energy (35 KHz) for wound débridement and irrigation.

US is intended as an adjunct to standard wound care. Therefore, the evidence is needed that demonstrates US plus standard wound care provides superior wound closure outcomes compared with standard wound care alone.

The primary endpoints of interest for trials of wound closure are as follows, consistent with 2006 guidance from the U.S. Food and Drug Administration for the industry in developing products for the treatment of chronic cutaneous ulcer and burn wounds^1,:

1.     Incidence of complete wound closure.

2.     Time to complete wound closure (reflecting accelerated wound closure).

3.     Incidence of complete wound closure following surgical wound closure.

4.     Pain control.

Regulatory Status

In 2005, the MIST Therapy® device (Celleration) was cleared for marketing by the Food an Drug Administration through the 510(k) process “to promote wound healing through wound cleansing and maintenance débridement by the removal of yellow slough, fibrin, tissue exudates, and bacteria.”² In February 2015, Celleration was acquired by Alliqua Biomedical (Langhorne, PA).

In 2007, the AR1000 Ultrasonic Wound Therapy System (Arobella Medical, Minnetonka, MN) was cleared for marketing by the Food and Drug Administration through the 510(k) process, listing the MIST Therapy® system and several other ultrasonic wound débridement and hydrosurgery systems as predicate devices. The AR1000 system probe uses “contact or noncontact techniques to achieve intended wound therapy modalities to promote wound healing.”^3,Indications in the 510(k) summary are listed as “Selective and non-selective dissection and fragmentation of soft and or hard tissue” and “Surgical, excisional or sharp-edge wound debridement (acute and chronic wounds, bums) for the removal of nonviable tissue including but not limited to diseased tissue, necrotic tissue, slough and eschar, fibrin, tissue exudates, bacteria and other matter.”^3, This device is now known as the Qoustic Wound Therapy System™.

Several other devices have been approved as being substantially equivalent to the earlier devices. Food and Drug Administration product code: NRB.

Related Policies

• Negative-Pressure Wound Therapy (Policy #013 in the Treatment Section)
• Electrostimulation and Electromagnetic Therapy for Treating Wounds (Policy #069 in the Treatment Section)

· Wounds and ulcers which are too painful for sharp or excisional debridement and have failed conventional debridement with documentation supporting the same.
· Wounds and ulcers meeting Medicare coverage for debridement but with documented contraindications to sharp or excisional debridement.
· Wounds and ulcers meeting Medicare coverage for debridement but with documented evidence of no signs of improvement after 30 days of standard wound care.

FIDE-SNP Coverage:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in December 2007 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through November 1, 2018.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function¾including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

This literature review focuses on evidence evaluating whether the addition of noncontact low-frequency ultrasound (NLFU) improves wound healing compared with standard treatment alone. Observational studies may be considered if they provide additional information on adverse events or durability.

Noncontact Low-Frequency Ultrasound

Systematic Reviews

Tricco et al (2015) published an overview of systematic reviews on treatments for complex wounds, which reviewed multiple therapies including ultrasound.^4, The review by Voigt et al (2011) was included. Conclusions related to ultrasound therapy are summarized in Table 1.

Table 1. Overview and Summary Conclusions of Systematic Reviews

Disorder	Intervention	Outcomes	Type of Review	QOE	Conclusion
Venous ulcer	US	Time to healing/rate of healing	SR w/o MA	Low/moderate	No difference
Venous ulcer	HFUS, LFUS, US	Proportion of patients with healed wounds	SR with MA	High	No difference
Mixed arterial/ venous ulcer	US	Wound area/size reduction	SR with MA	Low/moderate	Effective
Diabetic ulcer	US	Ulcer healing	SR w/o MA	Low/moderate	No difference
Pressure ulcer	US	Wound area/size reduction, time to healing/rate of healing	SR w/o MA	Low/moderate	No difference
Pressure ulcer	US	Proportion of patients with healed wounds	SR with MA	High and low/moderate	No difference
Pressure ulcer	US	Proportion of patients with healed wounds	SR w/o MA	Low/moderate	Uncertain (conflicting evidence or indeterminate)

Adapted from Trico et al (2015).^4,
HFUS: high-frequency ultrasound; LFUS: low-frequency ultrasound; MA: meta-analysis; QOE: quality of evidence; SR: systematic review; US: ultrasound; w/o: without.

Tables 2 and 3 summarize systematic reviews that compare results from NLFU with standard care. The Voigt et al (2011) systematic review only included RCTs; studies used contact or noncontact ultrasound for treating chronic lower-limb wounds.^5, Five RCTs on NLFU were identified, one of which was unpublished. A pooled analysis of 2 sham-controlled trials found a significantly smaller proportion of nonhealed wounds at 3 months in the NLFU group than in the control group (relative risk, 0.74; 95% confidence interval, 0.58 to 0.95; p=0.02). The 2 NLFU studies were those by Ennis et al (2005), described in the following section,^6, and by Peschen et al (1997),⁷ which delivered ultrasound therapy with a dated device during foot bathing. A systematic review by Chang et al (2017)^8, included all study types; however, only 2 of the RCTs (Ennis et al [2005]^6, and Kavros et al [2007]^9,) were included. Chang et al (2017) did not include meta-analyses, and the narrative synthesis did not provide complete information on the range of comparative effects; therefore, it is not included in the tables below.

Table 2. Systematic Review Characteristics

Study (Year)	Dates	Studies	Participants	N (Range)	Design	Duration, mo
Voight et al (2011)5,	Up to Mar 2011	2	Patients with chronic lower-limb wounds	22-55	RCTs	2-3

RCT: randomized controlled trial.


Table 3. Systematic Review Results

Study (Year)	Time to Complete Wound Healing	% Nonhealed Wounds at 3 mo	Pain Outcomes	Safety Outcomes
Voight et al (2011)5,
Total N	NR	77	NR	NR
Pooled effect (95% CI)		RR=0.74 (0.58 to 0.95), p=0.02
I2, %		0

CI: confidence interval; NR: not reported; RR, relative risk.

Randomized Controlled Trials

One double-blind, multicenter, sham-controlled trial and a number of unblinded RCTs comparing NLFU with standard wound care alone have been performed. Trials including at least 25 patients are described in the Tables 4-7 and the following text. All RCTs used MIST therapy and, other than Beheshti et al (2014)^10, and Olyaie et al (2013),^11, which did not report funding sources, all were industry-funded. One study addressed diabetic foot ulcers. Four RCTs included patients with venous leg ulcers and another evaluated treatment of split-thickness graft donor sites. All studies except that on split-thickness graft donor sites included patients with nonhealing wounds; eligibility criteria included wounds that had not healed after at least four weeks. Standard care interventions varied, but generally consisted of wound cleaning, noncontact dressings, compression and, if deemed necessary by providers, débridement. In 2 studies (White et al [2016]^12,, Gibbons et al [2015]^13,), authors mentioned following national guidelines for the standard of care intervention. Prather et al (2015)^14, did not describe the standard care intervention and Beheshti et al (2014) reported only that compression was used.


Table 4. Summary of RCT Characteristics^a

					Interventions
Author (Year)	Countries	Sites	Dates	Participants	Active	Comparator
White et al (2016)12,	UK	1	Aug 2012-Nov 2013	Patients with venous leg ulcers (≥6 wk)	·   n=17 ·   NLFU: 3´/wk for 8 wk (after 2-wk run-in) + SOC	·   n=19 ·   SOC: >1 visit per week for 8 wk
Gibbons et al (2015)13,	US	22	Apr 2012-Mar 2014	Patients with venous leg ulcers (≥30 d)	·   n=40 ·   NLFU: 3´/wk for 4 wk + SOC	·   n=41 ·   SOC: 3´/wk for 4 wk
Prather et al (2015)14,	US	1	Feb 2012-Jul 2013	Patients with split-thickness graft donor sites	·   n=16 ·   NLFU: 1´/wk for 5 consecutive days (after 2-wk run-in) + SOC	·   n=15 ·   SOC: 1´/wk for 5 consecutive days (after 2-wk run-in)
Olyaie et al (2013)11,	Iran	1	Apr 2011-Apr 2012	Patients with venous leg ulcers (≥4 wk)	·   n=30 ·   NLFU: 3´/wk for 3 mo or until healed + SOC ·   n=30 ·   HFU: 3´/wk for 3 mo or until healed + SOC	·   n=30 ·   SOC: 3´/wk for 3 mo or until healed
Beheshti et al (2014)10,	Iran	1	Apr 2011- Aug 2012	Patients with venous leg ulcers (≥4 wk)	·   n=30 ·   NLFU: 3´/wk until healed + SOC ·   n=30 ·   HFU: 3´/wk until healed + SOC	·   n=30 ·   SOC: Compression therapy (visit frequency NR)
Kavros et al (2007)9,	US	1	2004-2006	Patients with nonhealing foot, ankle, or leg wounds (≥8 wk)	·   n=35 ·   NLFU: 3´/wk for 12 wk + SOC	·   n=35 ·   SOC: daily visits
Ennis et al (2005)6,	US, Canada	26	NR	Patients with diabetic foot ulcers	·   n=70 ·   NLFU: 3´/wk for 12 wk + SOC	·   n=63 ·   SOC: 3´/wk for 12 wk

NLFU: noncontact low-frequency ultrasound; NR: not reported; RCT: randomized controlled trial; SOC: standard of care.
^a Includes trials with ≥25 participants.

Table 5. Summary of RCT Results^a

Study (Year)	Time to Complete Wound Healing	% With Complete Wound Healing	Change in Wound Size	Pain Outcomes	Adverse Events
		At 8 Wk	Mean % Change in Wound Area at 8 Wk	Mean Reduction in VAS Pain Score at 8 Wk	No. of Events
White et al (2016)12,
N	NR	36	36	36	36
NLFU+SOC		3 (16%)	-46.6%	-14.35	24
SOC		1 (6%)	-39.2%	-5.27	36
TE (95% CI)		NR	Diff = -7.4 (-33.4 to 18.6); p=0.57	Diff = -9.08 (-19.23 to 1.06); p=0.08	NR
		At 7 Wk	Mean % Change In Wound Area at 4 Wk	Mean % Reduction in VAS Pain Score at 4 Wk
Gibbons et al (2015)13,
N	NR	81	81	81	NR
NLFU+SOC		11 (28%)	-61.6%	-80%
SOC		6 (15%)	-45.0%	-20%
TE (95% CI)		NR	Diff/CI NR; p=0.02	Diff/CI NR; p=0.01
		At 14 Days		Mean VAS Pain Score  at 3 Wk
Prather et al (2015)14,
N	NR	NR	NR	NR	NR
NLFU+SOC	12.1 d	92%		0.04
SOC	21.3 d	64%		1.0
TE (95% CI)	HR/CI NR; p=0.04	NR		NR
			Mean Wound Size  at 4 Mo	Pain on 0-20 Scale  at 4 Mo
Olyaie et al (2013)11,
N	90	NR	90	90	NR
HFUS+SOC	6.86 mo		3.23 cm2	3.96
NLFU+SOC	6.65 mo		2.72 cm2	3.26
SOC	8.50 mo		4.28 cm2	5.10
TE (95% CI)	Diff/CI NR; between 3 groups p=0.001		Diff/CI NR; between 3 groups p=0.02	Diff/CI NR; between 3 groups p=0.02
				Pain on 0-20 Scale  at 4 Mo
Beheshti et al (2014)10,
N	90	NR	NR		NR
HFUS+SOC	6.10 mo			4.20
NLFU+SOC	5.70 mo			4.20
SOC	8.13 mo			6.56
TE (95% CI)	Diff/CI NR; p<0.001b			Diff/CI NR; p<0.001b
			% With 50% Reduction in Wound Volume at 12 Wk
Kavros et al (2007)9,
N	NR	NR		NR	NR
NLFU+SOC			63%
SOC			29%
TE (95% CI)			Ratio/CI NR; p<0.001
		At 10 Wk		No. With Pain During Treatment, Pain Scale Not Described	% of Patients With Event
Ennis et al (2005)6,
N	55c	133	NR	133	133
NLFU+SOC	9.2 wk	26%		1	·   Mild: 51% ·   Moderate: 41% ·   Severe: 7%
SOC	11.0 wk	22%		3	·   Mild: 46% ·   Moderate: 39% ·   Severe: 15%
TE (95% CI)	HR NR; p<0.014	Ratio/CI NR; p=0.69			Ratios/CIs NR; p=0.27

CI: confidence interval; Diff: difference; HFUS: high-frequency ultrasound; HR: hazard ratio; NLFU: noncontact low-frequency ultrasound; NR: not reported; RCT: randomized controlled trial; SOC: standard of care; TE: treatment effect; VAS: visual analog scale.
^a Includes trials with ≥25 participants.

^b The comparison for this p-value is unclear.

^c Per-protocol analysis.

Limitations in the body of evidence are summarized in Tables 6 and 7 and the following paragraphs. Ennis et al (2005) published findings of a double-blind, multicenter, sham-controlled trial of MIST therapy for recalcitrant diabetic foot ulcers in 133 patients.^6, Patients with were treated with active or sham MIST therapy three times per week, with débridement as needed and a weekly evaluation by an independent investigator. Twenty-four patients were lost to follow-up, and data from 54 patients were excluded from analysis due to protocol violations (5 centers inverted the treatment distances for the active and sham devices), leaving 55 (41%) patients for the per-protocol analysis. Investigators reported significant improvement in the active treatment group (11/27 [41%] patients) compared with the control group (4/28 [14%] patients) in the proportion of wounds healed (defined as complete epithelialization without drainage). However, intention-to-treat analysis showed no difference in wound healing between the active (n=70 [26%]) and control (n= 63 [22%]) groups. In addition to the 59% loss to follow-up, there was a difference in the ulcer area at baseline (1.7 cm²vs 4.4 cm², respectively) and chronicity of wounds (35 weeks vs 67 weeks, respectively) that favored MIST therapy in the per-protocol groups. Due to the serious limitations of this trial, these results are considered inconclusive.

In the White et al (2016),^12, Gibbons et al (2015),^13, and Prather et al (2015)^14, studies, patients, and providers were not blinded, but outcome assessment was blinded. The other studies did not mention blinding. All but one RCT reported improved (statistically significant) results for the primary outcome with NLFU than with standard of care. However, these studies had methodologic limitations. Regarding outcome assessment, complete healing is considered the most clinically relevant outcome.^15, Complete healing was reported in a subset of the studies, and most were not poweredfor this outcome or the outcome used to power the study was unclear. Only Prather et al (2015)^14,and Ennis et al (2005)^6, conducted blinded outcome assessments and reported complete healing. Another limitation of the body of evidence is that some of the standard care interventions involved different visit schedules than the NLFU intervention, and the effects of this differential in face-to-face contact could partially explain the difference in findings between intervention and control groups.


Table 6. Relevance Gaps in RCTs

Study	Population	Intervention	Comparator	Outcomes	Follow-Up
White et al (2016)12,		3. Follow-up schedule for SOC involved fewer visits than NLFU	3. Follow-up schedule for SOC involved fewer visits than NLFU
Gibbons et al (2015)13,				3. Adverse events not reported
Prather et al (2015)14,			1. Did not describe SOC	3. Adverse events not reported
Olyaie et al (2013)11,				3. Adverse events not reported
Beheshti et al (2014)10,			2. Only compression used 3. Details about frequency of SOC administration not provided	3. Adverse events not reported
Kavros et al (2007)9,		3. Follow-up more intensive in SOC	3. Follow-up more intensive in SOC	1. Complete wound healing not reported 3. Adverse events not reported
Ennis et al (2005)6,	None noted	None noted	None noted	None noted	None noted
Key	1.Intended use population unclear 2.Clinical context for test is unclear 3.Study population unclear 4.Study population not representative of intended use 5.Study population is subpopulationof intended use	1.Not clearly defined 2.Version used unclear 3.Delivery not similar intensity as comparator	1.Not clearly defined 2.Not standard or optimal 3.Delivery not similar intensity as intervention 4.Not delivered effectively	1.Key health outcomes not addressed 2.Physiologic measures, not validated surrogates 3.No CONSORT reporting of harms 4.Not established and validated measurements 5.Clinically significant difference not prespecified 6.Clinically significant difference not supported	1.Not sufficient duration forbenefits 2.Not sufficient duration for harms

NLFU: noncontact low-frequency ultrasound; SOC: standard of care

Table 7. Study Design and Conduct Gaps in RCTs

Study	Allocation	Blinding	Selective Reporting	Follow-Up	Power	Statistical
White et al (2016)12,		1. Not blinded assignment 2. Not blinded assessment
Gibbons et al (2015)13,		1. Not blinded assignment 2.Not blinded assessment
Prather et al (2015)14,		1. Not blinded assignment
Olyaie et al (2013)11,		1. Not blinded assignment 2. Not blinded assessment	1. Registration not documented in publication		1. No power calculations
Beheshti et al (2014)10,		1. Not blinded assignment 2. Not blinded assessment	1. Registration not documented in publication		1. No power calculations
Kavros et al (2007)9,		1. Not blinded assignment 2. Not blinded assessment	1. Registration not documented in publication		1. No power calculations
Ennis et al (2005)6,				1, 5. High number of protocol deviations and exclusions	1. No power calculations
Key	1.Participants not randomly allocated 2.Allocation not concealed 3.Allocation concealment unclear 4.Inadequate control for selection bias	1.Not blinded to treatment assignment 2.Not blinded outcome assessment 3.Outcome assessed by treating physician	1.Not registered 2.Evidence of selective reporting 3.Evidence of selective publication	1.High loss to follow-up or missing data 2.Inadequate handling of missing data 3.High number of crossovers 4.Inadequate handling of crossovers 5.Inappropriate exclusions 6.Not intention-to-treat analysis (per-protocol for noninferiority trials)	1.Power calculations not reported 2.Power not calculated for primary outcome 3.Power not based on clinically important difference	1.Test is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event 2.Test is not appropriate for multiple observations per patient 3.Confidence intervals and/or p values not reported 4.Comparative treatment effects not calculated

RCT: randomized controlled trials.

Summary of Evidence

For individuals who have any wound type (acute or nonhealing) who receive noncontact ultrasound therapy plus standard wound care, the evidence includes randomized controlled trials (RCTs) and systematic reviews. The relevant outcomes are symptoms, change in disease status, morbid events, quality of life, and treatment-related morbidity. The single, double-blinded, sham-controlled randomized trial, which included patients with nonhealing diabetic foot ulcers, had substantial methodologic flaws (eg, high dropout rate, baseline differences between groups) that limit the validity of the findings. In the remaining studies comprising the evidence base, all but one RCT comparing NLFU with standard wound care reported improved (statistically significant) results on the primary outcome with NLFU. However, these studies also had several methodologic limitations. Complete healing is the most clinically relevant outcome. None of the RCTs evaluating venous leg ulcers reported complete healing as its primary outcome measure, and none had blinded outcome assessment. Only one RCT, which addressed split-thickness graft donor sites, reported on the proportion of patients with complete healing and had blinded outcome assessment. Another limitation of the body of evidence is that some standard of care interventions involved fewer visits than the NLFU intervention, and the differences in intensity of care resulting from this differential in face-to-face contact could partially explain the difference in findings between intervention and control groups. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

Association for the Advancement of Wound Care

The Association for the Advancement of Wound Care 2014 published guidelines on the care of pressure ulcers.^16, Noncontact low-frequency ultrasound therapy was included as a potential second-line intervention if first-line treatments did not result in wound healing.

The Association guidelines on the treatment of venous ulcers, updated in 2015, stated that low-frequency ultrasound treatment requires additional evidence before it can be considered an appropriate treatment.^17,

Society for Vascular Surgery, American Venous Forum, American Podiatric Medical Association

The Society for Vascular Surgery in collaboration with the American Venous Forum (2014) published joint guidelines on the management of venous leg ulcers.¹⁸ The guidelines recommended adjuvant wound therapy options for venous leg ulcers that fail to demonstrate improvement after four to six weeks of standard wound therapy (strength of recommendation: grade 1; quality of evidence: level B), but recommended against routine ultrasound therapy for venous leg ulcers (strength of recommendation: grade 2; quality of evidence: level B).

The Society for Vascular Surgery in collaboration with the American Podiatric Medical Association (2016) published joint guidelines on the management of diabetic foot ulcers.^19, The guidelines recommended adjuvant therapy for diabetic foot ulcers that fail to demonstrate more than 50% wound area reduction after 4 weeks of standard wound therapy. The adjunctive wound therapy options listed in the guidelines included negative pressure therapy, biologics (platelet-derived growth factor, living cellular therapy, extracellular matrix products, amniotic membrane products), and hyperbaric oxygen therapy. Ultrasound therapy was not mentioned as a recommended adjuvant option.

U.S. Preventive Services TaskForceRecommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in November 2018 did not identify any ongoing or unpublished trials that would likely influence this review.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Non-Contact Ultrasound Treatment for Wounds
Non Contact Ultrasound Treatment for Wounds
Noncontact Ultrasound Treatment for Wounds
MIST Therapy
Ultrasound, Non-Contact Treatment for Wounds
Wounds, Non-Contact Ultrasound Treatment for
Celleration Mist
AR1000 Ultrasonic Wound Therapy System
Qoustic Wound Therapy System

References:
1. Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Center for Devices and Radiological Health. Guidance for Industry: Chronic Cutaneous Ulcer and Burn Wounds -- Developing Products for Treatment. Rockville, MD: Food and Drug Administration; 2006 June.

2. Food and Drug Administration. MIST[TM] Therapy System: 510(k) Premarket Notification: K050129. https://www.accessdata.fda.gov/cdrh_docs/pdf5/K050129.pdf. Accessed January 2, 2018.

3. Food and Drug Administration. 510(k) Summary: 510(k) -AR1000 Series K131096, Arobella Medical, LLC. 2014; https://www.accessdata.fda.gov/cdrh_docs/pdf13/K131096.pdf. Accessed January 2, 2018.

4. Tricco AC, Antony J, Vafaei A, et al. Seeking effective interventions to treat complex wounds: an overview of systematic reviews. BMC Med. Apr 22 2015;13:89. PMID 25899006

5. Voigt J, Wendelken M, Driver V, et al. 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. Dec 2011;10(4):190-199. PMID 22184750

6. Ennis WJ, Foremann P, Mozen N, et al. Ultrasound therapy for recalcitrant diabetic foot ulcers: results of a randomized, double-blind, controlled, multicenter study. Ostomy Wound Manage. Aug 2005;51(8):24-39. PMID 16234574

7. Peschen M, Weichenthal M, Schopf E, et al. Low-frequency ultrasound treatment of chronic venous leg ulcers in an outpatient therapy. Acta Derm Venereol. Jul 1997;77(4):311-314. PMID 9228227

8. Chang YR, Perry J, Cross K. Low-frequency ultrasound debridement in chronic wound healing: a systematic review of current evidence. Plast Surg (Oakv). Feb 2017;25(1):21-26. PMID 29026808

9. 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. Apr 2007;20(4):221-226. PMID 17415030

10. Beheshti A, Shafigh Y, Parsa H, et al. Comparison of high-frequency and MIST ultrasound therapy for the healing of venous leg ulcers. Adv Clin Exp Med. Nov-Dec 2014;23(6):969-975. PMID 25618125

11. Olyaie M, Rad FS, Elahifar MA, et al. High-frequency and noncontact low-frequency ultrasound therapy for venous leg ulcer treatment: a randomized, controlled study. Ostomy Wound Manage. Aug 2013;59(8):14-20. PMID 23934374

12. White J, Ivins N, Wilkes A, et al. Non-contact low-frequency ultrasound therapy compared with UK standard of care for venous leg ulcers: a single-centre, assessor-blinded, randomised controlled trial. Int Wound J. Oct 2016;13(5):833-842. PMID 25619411

13. 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. Jan 2015;61(1):16-29. PMID 25581604

14. Prather JL, Tummel EK, Patel AB, et al. Prospective randomized controlled trial comparing the effects of noncontact low-frequency ultrasound with standard care in healing split-thickness donor sites. J Am Coll Surg. Aug 2015;221(2):309-318. PMID 25868409

15. Gottrup F, Apelqvist J, Price P, et al. Outcomes in controlled and comparative studies on non-healing wounds: recommendations to improve the quality of evidence in wound management. J Wound Care. Jun 2010;19(6):237-268. PMID 20551864

16. Association for the Advancement of Wound Care (AAWC). Guideline of Pressure Ulcer Guidelines. 2010; https://s3.amazonaws.com/aawc-new/memberclicks/AAWCPressureUlcerGuidelineofGuidelinesAug11.pdf. Accessed January 2, 2018.

17. Association for the Advancement of Wound Care (AAWC). International Consolidated Venous Ulcer Guideline (ICVUG) 2015 (Update of AAWC Venous Ulcer Guideline, 2005 and 2010). 2015; https://aawconline.memberclicks.net/assets/appendix%20c%20guideline%20icvug-textformatrecommendations-final%20v42%20changessaved18aug17.pdf. Accessed January 2, 2018.

18. O'Donnell TF, Jr., Passman MA, Marston WA, et al. Management of venous leg ulcers: clinical practice guidelines of the Society for Vascular Surgery (R) and the American Venous Forum. J Vasc Surg. Aug 2014;60(2 Suppl):3s-59s. PMID 24974070

19. Hingorani A, LaMuraglia GM, Henke P, et al. The management of diabetic foot: A clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine. J Vasc Surg. Feb 2016;63(2 Suppl):3s-21s. PMID 26804367

Codes
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

97610