A Novel Randomized Trial Protocol for Evaluating Wound Healing Interventions

To evaluate correct correlation between an intermediate rate of wound reduction (40% wound area reduction after 4-weeks treatment) and complete healing at 24 weeks in patients with a venous leg ulcer (VLU). A retrospective follow-up study of patients completing a multicenter randomised controlled trial (RCT) comparing the number of patients achieving at least 40% healing of their VLU within 4-weeks of treatment with either dehydrated human amnion/chorion membrane (dHACM) allograft or multilayer compression only was conducted. Outcomes assessed were rates of complete healing within 24 weeks of enrolment and days to healing. Data were divided into two groups based on status at RCT completion (healed at least 40% yes or no). Correct correlation with status at 4 weeks and complete healing within 24 weeks was determined. Clinical characteristics were also compared for patients with and without correct correlation between 4-week and 24-week status. We identified 55 patients at 5 study sites. Some 47 without complete healing during the initial study were eligible. As three patients were lost to follow-up we evaluated 44 records. Of these, 20 (45.4%) had reduced wound size of ≥40% and 24 (55%) had <40% reduction during the initial study. Complete healing occurred in 16/20 (80%) of the ≥40% group at a mean of 46 days, p=0.0027 and 8/24 (33.3%) of the <40% group at a mean of 103.6 days, p=0.0023. Overall, correct correlation of status at 4 weeks and ultimate healing status of VLU occurred in 32/44 patients (73%). These results confirm that the intermediate outcome used in our initial study is a viable predictor of ultimate VLU healing.

Hard-to-heal wounds refractory to standard of care (SoC) therapy pose a major clinical and economic burden on healthcare systems. A dual-layer hydrated human amniotic membrane (HAMA) allograft, pre-hydrated with saline, is an emerging advanced therapy for complex hard-to-heal wounds. The aim of this study was to evaluate the real-world effectiveness of Membrane Wrap Hydro (BioLab Holdings, Inc., US) in achieving complete closure and relative percentage area reduction (PAR) across hard-to-heal diabetic foot ulcers (DFUs), venous leg ulcers (VLUs), pressure injuries (PIs) and open wounds. This was a retrospective multicentre analysis of patients treated from November 2024 to July 2025 after ≥30 days of optimised SoC with <50% healing. Weekly applications of HAMA were performed in outpatient clinics, nursing homes or home settings. The primary endpoint was complete wound closure (99.99-100% re-epithelialisation). Secondary endpoints were: PAR (paired samples t-test); applications to closure; and time-to-healing (Kaplan-Meier). The cohort included 80 patients (83 wounds). Complete closure occurred in 46/83 (55.4%) wounds with a median six applications (mean: 6.54±3.22). Closure rates were: 53.3% (DFUs); 50.0% (VLUs); 47.1% (PIs); and 59.6% (open wounds). Mean PAR was 84.3%, with significant area reduction from baseline (p<0.001; Cohen's d=0.79). Large effect sizes were observed across aetiologies (d=1.01-1.84). Median time-to-healing was 42 days (range: 7-110). Membrane Wrap Hydro achieved clinically meaningful closure and substantial PAR across diverse refractory hard-to-heal wounds, with outcomes in PIs and open wounds comparable or superior to DFUs and VLUs. These findings support the role of HAMA as a versatile advanced therapy in multimodal hard-to-heal wound management.

Objective: The objective of this open-label, interventional, prospective clinical study was to evaluate the effectiveness of a multimodal wound matrix (MWM) in moving chronic, nonhealing wounds that had failed prior therapies onto a healing trajectory. The overall response rate was the proportion of subjects who had greater than 40% reduction in size after 4 weeks of treatment. Secondary objectives included the percentage area reduction (PAR) after 4 and 12 weeks, incidence of ulcer closing, and changes in quality of life. Approach: An open-label, interventional, prospective cohort, real-world evidence study was conducted following the STROBE criteria. Criteria included chronic nonhealing wounds of multiple etiologies in subjects with extensive comorbidities. Results were compared with data from the U.S. Wound Registry. Results: A total of 111 subjects entered the screening phase and 64 were treated. Fifty-three wounds were eligible for the dataset that included 18 diabetic foot ulcers, 19 venous leg ulcers, 2 pressure injuries, 1 surgical, 1 lower extremity wound, and 12 unclassified etiologies. The objective response rate was 42%. The 4-week PAR was 34%. The 12-week PAR was 66%. Eighteen wounds closed by week 12. Innovation: MWM is a formulation technology developed to address the major obstacles that prevent healing. Results were evaluated in a patient population with extensive comorbidities that had failed prior treatments and would be generally excluded from controlled trials. Conclusion: The results from this study support the contention that MWM achieves substantial clinical improvement in a complex patient population not enrolled in clinical trials and demonstrates an advancement in wound management.

To perform a service evaluation of neuromuscular electrostimulation (NMES) as an adjunct to compression therapy, comparing the rate of wound margin advance and time to closure with a matched retrospective control group. Fifteen patients with venous leg ulcers were prescribed NMES for 6 hours per day for 56 days or until wound closure (whichever occurred first), in addition to multilayer compression. Wounds were selected for size, with an inclusion criterion of a maximum of 12 cm 2 . Wound progress was compared with 15 retrospective control patients who were matched for ulcer size and duration. The retrospective group had a healing rate of 0.31 mm per week (95% CI, 29-37 mm/week), whereas the prospective compression plus NMES group had a healing rate of 0.56 mm per week (95% CI, 50-62 mm/week; P = .004). All wounds in both groups healed completely during the service evaluation. Mean time to closure for the retrospective group was 77 days (95% CI, 66-88 days), whereas the NMES group had a mean time to closure of 40 days (95% CI, 37-43 days; P = .005). Adding NMES of the common peroneal nerve to a care bundle including multicomponent compression resulted in significantly faster wound margin advance and significantly less time to heal in comparison with retrospective matched controls. Future randomized controlled trials or self-controlled studies of this approach would be of great interest to inform clinical practice.

The care of patients with leg ulceration has developed over the past 15 years, although there is little information available to determine how these changes have affected clinical and patient defined outcomes. To describe and evaluate the implementation of a leg ulcer strategy. This study used a pre- and postimplementation evaluation within population-based services within the boundaries of community services providing leg ulcer care. Evidence-based leg ulcer services were developed, including standardized assessment using Doppler ultrasound, rationalization of treatment using multilayer elastic high compression, development of referral criteria and acute service support. Complete ulcer healing rates, health-related quality of life and use of health resources were evaluated after 12 weeks in both pre- and postimplementation cycles. A total of 955 patients were evaluated (518 preimplementation, 437 postimplementation). The levels of assessment and treatment were poor prior to the change in practice with just one patient having evidence of correct assessment and 49 (11%) receiving high compression therapy. Postimplementation, this improved to 412 of 437 (94%) having evidence of measurement of the ankle brachial pressure index, and 85% receiving compression. Twelve-week healing rates preimplementation ranged between 9% and 24%, and postimplementation rose from 19% to 39%. Combined overall healing rates improved from 71 of 518 (14%) to 160 of 437 (37%), odds ratio =3.53, P < 0.001. Frequency of treatment visits reduced from a mean (SD) of 24.0 (16.1) over 12 weeks to 13.5 (8.6), P < 0.001. Intervention led to major improvements in health-related quality of life (measured using the Nottingham Health Profile), with significant improvements for energy, pain, sleep and mobility (P < 0.01). Rationalization of leg ulcer services through a total service change results in improvements in professional practice, better patient outcomes, and efficient use of current resources. This study highlights the importance of a multifaceted approach to improve practice focused on the needs of individual organizational settings.

1. Co-chaired this panel2. University of South Florida, Tampa, FL3. Healthpoint Ltd., Fort Worth, TX4. University of California, San Francisco, CA5. University of Texas Medical Branch, Galveston, TX6. University of Cardiff, Cardiff, Wales, UK7. University of Pennsylvania, Philadelphia, PA8. Private practice, Warren, PA9. Private practice, Tamarac, FL10. University of Pittsburgh, Pittsburgh, PA11. St. Louis University, St. Louis, MO, and12. Washington University, St. Louis, MO

Healing of venous leg ulcers is improved by the use of compression bandaging but some venous ulcers remain unhealed, and some people are unsuitable for compression therapy. Pentoxifylline, a drug which helps blood flow, has been used to treat venous leg ulcers. An earlier version of this review included 9 randomised controlled trials, but more research has been since been conducted and an updated review is required. To assess the effects of pentoxifylline (oxpentifylline or Trental 400) for treating venous leg ulcers, compared with placebo, or other therapies, in the presence or absence of compression therapy. For this second update we searched the Cochrane Wounds Group Specialised Register, CENTRAL, MEDLINE, EMBASE and Cinahl (date of last search was February 2007), and reference lists of relevant articles. Randomised trials comparing pentoxifylline with placebo or other therapy in the presence or absence of compression, in people with venous leg ulcers. Details from eligible trials were extracted and summarised by one author using a coding sheet. Data extraction was independently verified by one other author. Twelve trials involving 864 participants were included. The quality of trials was variable. Eleven trials compared pentoxifylline with placebo or no treatment; in seven of these trials patients received compression therapy. In one trial pentoxifylline was compared with defibrotide in patients who also received compression. Combining 11 trials that compared pentoxifylline with placebo or no treatment (with or without compression) demonstrated that pentoxifylline is more effective than placebo in terms of complete ulcer healing or significant improvement (RR 1.70, 95% CI 1.30 to 2.24). Significant heterogeneity was associated with differences in sample populations (hard-to-heal samples compared with "normal" healing samples). Pentoxifylline plus compression is more effective than placebo plus compression (RR 1.56, 95% CI 1.14 to 2.13). Pentoxifylline in the absence of compression appears to be more effective than placebo or no treatment (RR 2.25, 95% CI 1.49 to 3.39). A comparison between pentoxifylline and defibrotide found no statistically significant difference in healing rates. More adverse effects were reported in people receiving pentoxifylline (RR 1.56, 95% CI 1.10 to 2.22). Nearly three-quarters (72%) of the reported adverse effects were gastrointestinal. Pentoxifylline is an effective adjunct to compression bandaging for treating venous ulcers and may be effective in the absence of compression. The majority of adverse effects were gastrointestinal disturbances.

Venous leg ulcers are open skin wounds on the lower leg which can be slow to heal, and are both painful and costly. The point prevalence of open venous leg ulcers in the UK is about 3 cases per 10,000 people, and many people experience recurrent episodes of prolonged ulceration. First-line treatment for venous leg ulcers is compression therapy, but a wide range of dressings and topical treatments are also used. This diversity of treatments makes evidence-based decision-making challenging, and a clear and current overview of all the evidence is required. This review is a network meta-analysis (NMA) which assesses the probability of complete ulcer healing associated with alternative dressings and topical agents.To assess the effects of (1) dressings and (2) topical agents for healing venous leg ulcers in any care setting and to rank treatments in order of effectiveness, with assessment of uncertainty and evidence quality.In March 2017 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also scanned reference lists of relevant included studies as well as reviews, meta-analyses, guidelines and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. We updated this search in March 2018; as a result several studies are awaiting classification.We included published or unpublished randomised controlled trials (RCTs) that enrolled adults with venous leg ulcers and compared the effects of at least one of the following interventions with any other intervention in the treatment of venous leg ulcers: any dressing, or any topical agent applied directly to an open venous leg ulcer and left in situ. We excluded from this review dressings attached to external devices such as negative pressure wound therapies, skin grafts, growth factors and other biological agents, larval therapy and treatments such as laser, heat or ultrasound. Studies were required to report complete wound healing to be eligible.Two review authors independently performed study selection, 'Risk of bias' assessment and data extraction. We conducted this NMA using frequentist meta-regression methods for the efficacy outcome; the probability of complete healing. We assumed that treatment effects were similar within dressings classes (e.g. hydrocolloid, foam). We present estimates of effect with their 95% confidence intervals (CIs) for individual treatments focusing on comparisons with widely used dressing classes, and we report ranking probabilities for each intervention (probability of being the best, second best, etc treatment). We assessed the certainty (quality) of the body of evidence using GRADE for each network comparison and for the network as whole.We included 78 RCTs (7014 participants) in this review. Of these, 59 studies (5156 participants, 25 different interventions) were included in the NMA; resulting in 40 direct contrasts which informed 300 mixed-treatment contrasts.The evidence for the network as a whole was of low certainty. This judgement was based on the sparsity of the network leading to imprecision and the general high risk of bias in the included studies. Sensitivity analyses also demonstrated instability in key aspects of the network and results are reported for the extended sensitivity analysis. Evidence for individual contrasts was mainly judged to be low or very low certainty.The uncertainty was perpetuated when the results were considered by ranking the treatments in terms of the probability that they were the most effective for ulcer healing, with many treatments having similar, low, probabilities of being the best treatment. The two most highly-ranked treatments both had more than 50% probability of being the best (sucralfate and silver dressings). However, the data for sucralfate was from one small study, which means that this finding should be interpreted with caution. When exploring the data for silver and sucralfate compared with widely-used dressing classes, there was some evidence that silver dressings may increase the probability of venous leg ulcer healing, compared with nonadherent dressings: RR 2.43, 95% CI 1.58 to 3.74 (moderate-certainty evidence in the context of a low-certainty network). For all other combinations of these five interventions it was unclear whether the intervention increased the probability of healing; in each case this was low- or very low-certainty evidence as a consequence of one or more of imprecision, risk of bias and inconsistency.More research is needed to determine whether particular dressings or topical agents improve the probability of healing of venous leg ulcers. However, the NMA is uninformative regarding which interventions might best be included in a large trial, largely because of the low certainty of the whole network and of individual comparisons.The results of this NMA focus exclusively on complete healing; whilst this is of key importance to people living with venous leg ulcers, clinicians may wish to take into account other patient-important outcomes and factors such as patient preference and cost.

Objective: To assess real-world effectiveness of Innovamatrix™, a dehydrated porcine placental extracellular matrix (PPECM), in chronic wounds refractory to 30 days of optimized standard-of-care (SOC) therapy. Methods: Multicenter retrospective analysis of 72 chronic wounds (18 diabetic foot ulcers (DFUs), 4 venous leg ulcers (VLUs), 12 pressure injuries, 38 open wounds) in 66 patients treated with sequential PPECM applications (between October 2023 and June 2025). All wounds showed &lt;50% area reduction during SOC run-in and met Medicare Local Coverage Determination (LCD) eligibility. Primary endpoint focused on complete re-epithelialization (99.99% to 100% percent area reduction (PAR)). Secondary endpoints included PAR, applications to closure, and time-to-closure. Results: Wounds presented with a mean baseline area of 9.75 ± 15.97 cm2 and achieved a mean PAR of 85.92%. Complete closure occurred in 46/72 wounds (63.9%): 61.1% of DFUs healed, 50.0% pressure injuries healed, 76.3% open wounds healed, and 0% VLUs healed. Among healed wounds, the median number of applications to closure was 6 (mean 6.28 ± 3.58) with open wounds healing the fastest (median 4). Paired t-test showed statistically significant area reductions (t(71)=10.47, p&lt;0.001; Cohen’s d=0.65). Etiology-specific effect sizes were moderate to large. Kaplan-Meier median time-to-closure was 43 days (95% CI 36-56). Conclusion: In complex, previously non-responsive, chronic wounds, PPECM achieved a 63.9% complete closure rate and 85.92% mean PAR. Healing outcomes in pressure injuries and open wounds were comparable or superior to DFUs. These data support broader, etiology-agnostic use of PPECM as an effective advanced therapy when combined with comprehensive SOC.

Leg ulcers associated with chronic venous disease (CVD) are characterized by prolonged healing and high recurrence. This study describes the effectiveness and tolerability of venoactive drugs (VAD) combined with compression as part of conservative therapy for active venous leg ulcers among patients treated in routine clinical practice. This prospective, multicenter, observational, 6-month study recruited patients diagnosed with Clinical, Etiology, Anatomy, and Pathophysiology (CEAP) clinical class C6 and active venous ulcer area, 5-30 cm2. VAD pharmacotherapy was at the discretion of the treating physician and consistent with national guidelines at the time of the study. Primary outcome was the proportion of patients with a healed venous ulcer at 6 months. Change from baseline in the mean Venous Clinical Severity Score (VCSS), the proportion of patients with a reduction in CEAP clinical class, and Quality of life (QoL - Chronic Venous Insufficiency Questionnaire [CIVIQ-14]) were also assessed. The study enrolled 349 patients: 66.8% were women; mean age was 61.0±12.7 years; and mean Body Mass Index (BMI) was 27.9±4.1 kg/m2. Mean duration of the reference venous ulcer was 18.3±23.0 weeks and mean ulcer area was 9.2±6.9 cm2. All patients were prescribed VAD at baseline, most commonly micronized purified flavonoid fraction (MPFF) (98.3% patients). Compression therapy was prescribed to 91.1% of patients. After 6 months, venous ulcers had completely healed in 69.6% of patients; 13.5% had experienced complete healing at 3 months. Mean physician-assessed VCSS decreased from 15.5±4.1 at baseline to 9.7±4.5 at 6 months (P<0.001). There was a progressive decrease in mean reference ulcer area from 9.2±6.9 cm2 at baseline to 1.2±2.8 cm2 at 6 months. QoL was significantly improved with a reduction in mean CIVIQ-14 global index score from 53.9±20.5 at baseline to 24.5±16.3 at 6 months (P<0.001). Treatment was well tolerated. Combined treatment with VAD and compression therapy was associated with complete venous leg ulcer healing in 70% of patients with a mean time to healing of 7.4 months. A significant improvement in QoL compared with baseline was also observed.

Aims: To evaluate the efficacy of adjunct use of several cellular, acellular and matrix-like products (CAMPs) with standard of care (SOC), compared to SOC alone in the treatment of nonhealing diabetic foot ulcers (DFUs) or venous leg ulcers (VLUs) using a novel modified platform trial design. Methods: This is a multicentre, prospective, randomized controlled trial utilizing a modified platform design. Patients with non-healing DFUs or VLUs will be randomized into two groups: SOC alone or SOC plus several CAMPs; initial design is for up to 5 CAMPs per wound type, but the modified trial design can include additional CAMPs. The primary endpoint is complete wound closure within 12 weeks. Secondary outcomes include time to closure, percentage area reduction (PAR), patient-reported pain, adverse events, and quality of life, as measured by the Forgotten Wound Score and the Wound Quality of Life questionnaire. Exploratory objectives include assessment of offloading compliance and the proportion of subjects aged ≥65 years achieving complete wound closure. Results: The results will be reported following trial completion. Pooled results for DFUs and VLUs will be published separately, with a master publication for all pooled treatment arms vs pooled SOC arms. Conclusion: This trial is expected to provide high-quality efficacy data on several CAMPs used in addition to SOC and contribute to evidence-based practice in DFU and VLU management. The modified platform design offers a flexible and efficient approach to evaluating multiple interventions within a single clinical trial.

Chronic venous ulcer healing is a complex clinical problem that requires intervention from skilled, costly, multidisciplinary wound-care teams. Compression therapy has been shown to help heal venous ulcers and to reduce the risk of recurrence. It is not known which interventions help people adhere to compression treatments. To assess the benefits and harms of interventions designed to help people adhere to venous leg ulcer compression therapy, and thus improve healing of venous leg ulcers and prevent their recurrence after healing. In May 2013 we searched The Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; EBSCO CINAHL; trial registries, and reference lists of relevant publications for published and ongoing trials. There were no language or publication date restrictions. We included randomised controlled trials (RCTs) of interventions that help people with venous leg ulcers adhere to compression treatments compared with usual care, or no intervention, or another active intervention. Our main outcomes were number of people with ulcers healed, recurrence, time to complete healing, quality of life, pain, adherence to compression therapy and number of people with adverse events. Two review authors independently selected studies for inclusion, extracted data, assessed the risk of bias of each included trial, and assessed overall quality of evidence for the main outcomes in 'Summary of findings' tables. Low quality evidence from one trial (67 participants) indicates that, compared with home-based care, a community-based Leg Club® clinic that provided mechanisms for peer-support, assistance with goal setting and social interaction did not result in superior healing rates at three months (12/28 people healed in Leg Club clinic group versus 7/28 in home-based care group; risk ratio (RR) 1.71, 95% confidence interval (CI) 0.79 to 3.71); or six months (15/33 healed in Leg Club group versus 10/34 in home-based care group; RR 1.55, 95% CI 0.81 to 2.93); or in improved quality of life outcomes at six months (MD 0.85 points, 95% CI -0.13 to 1.83; 0 to 10 point scale). However, the Leg Club resulted in a statistically significant reduction in pain at six months (MD -12.75 points, 95% CI -24.79, -0.71; 0 to 100 point scale), although this was not considered a clinically important difference. Time to complete healing, recurrence of ulcers, adherence and adverse events were not reported.Low quality evidence from another trial (184 participants) indicates that, compared with usual care in a wound clinic, a community-based and nurse-led self-management programme of six months' duration promoting physical activity (walking and leg exercises) and adherence to compression therapy via counselling and behaviour modification (Lively Legs®) may not result in superior healing rates at 18 months (51/92 healed in Lively Legs group versus 41/92 in usual care group; RR 1.24 (95% CI 0.93 to 1.67)); may not result in reduced rates of recurrence of venous leg ulcers at 18 months (32/69 with recurrence in Lively Legs group versus 38/67 in usual care group; RR 0.82 (95% CI 0.59 to 1.14)); and may not result in superior adherence to compression therapy at 18 months (42/92 people fully adherent in Lively Legs group versus 41/92 in usual care group; RR 1.02 (95% CI 0.74 to 1.41)). Time to complete healing, quality of life, pain and adverse events were not reported. We found no studies that investigated other interventions to promote adherence to compression therapy. There is a paucity of trials of interventions that promote adherence to compression therapy for venous ulcers. Low quality evidence from two trials was identified: one promoting adherence via socialisation and support (Leg Club®), and the other promoting adherence to compression, leg exercises and walking via counselling and behaviour modification (Lively Legs®).These trials did not reveal a benefit of community-based clinics over usual care in terms of healing rates, prevention of recurrence of venous leg ulcers, or quality of life. One trial indicated a small, but possibly clinically unimportant, reduction in pain, while adverse events were not reported. The small number of participants may have a hidden real benefit, or an increase in harm. Due to the lack of reliable evidence, at present it is not possible either to recommend or discourage nurse clinic care interventions over standard care.

Venous leg ulcers are a type of chronic, recurring, complex wound that is more common in people aged over 65 years. Venous ulcers pose a significant burden to patients and healthcare systems. While compression therapy (such as bandages or stockings) is an effective first-line treatment, ultrasound may have a role to play in healing venous ulcers. To determine whether venous leg ulcers treated with ultrasound heal more quickly than those not treated with ultrasound. We searched the Cochrane Wounds Specialised Register (searched 19 September 2016); the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library 2016, Issue 8); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations, MEDLINE Daily and Epub Ahead of Print) (1946 to 19 September 2016); Ovid Embase (1974 to 19 September 2016); and EBSCO CINAHL Plus (1937 to 19 September 2016). We also searched three clinical trials registries and the references of included studies and relevant systematic reviews. There were no restrictions based on language, date of publication or study setting. Randomised controlled trials (RCTs) that compared ultrasound with no ultrasound. Eligible non-ultrasound comparator treatments included usual care, sham ultrasound and alternative leg ulcer treatments. Two authors independently assessed the search results and selected eligible studies. Details from included studies were summarised using a data extraction sheet, and double-checked. We attempted to contact trial authors for missing data. Eleven trials are included in this update; 10 of these we judged to be at an unclear or high risk of bias. The trials were clinically heterogeneous with differences in duration of follow-up, and ultrasound regimens. Nine trials evaluated high frequency ultrasound; seven studies provided data for ulcers healed and two provided data on change in ulcer size only. Two trials evaluated low frequency ultrasound and both reported ulcers healed data.It is uncertain whether high frequency ultrasound affects the proportion of ulcers healed compared with no ultrasound at any of the time points evaluated: at seven to eight weeks (RR 1.21, 95% CI 0.86 to 1.71; 6 trials, 678 participants; low quality evidence - downgraded once for risk of bias and once for imprecision); at 12 weeks (RR 1.26, 95% CI 0.92 to 1.73; 3 trials, 489 participants; moderate quality evidence - downgraded once for imprecision); and at 12 months (RR 0.93, 95% CI 0.73 to 1.18; 1 trial, 337 participants; low quality evidence - downgraded once for unclear risk of bias and once for imprecision).One trial (92 participants) reported that a greater percentage reduction in ulcer area was achieved at four weeks with high-frequency ultrasound, while another (73 participants) reported no clear difference in change in ulcer size at seven weeks. We downgraded the level of this evidence to very low, mainly for risk of bias (typically lack of blinded outcome assessment and attrition) and imprecision.Data from one trial (337 participants) suggest that high frequency ultrasound may increase the risk of non-serious adverse events (RR 1.29, 95% CI 1.02 to 1.64; moderate quality evidence - downgraded once for imprecision) and serious adverse events (RR 1.21, 95% CI 0.78 to 1.89; moderate quality evidence downgraded once for imprecision).It is uncertain whether low frequency ultrasound affects venous ulcer healing at eight and 12 weeks (RR 3.91, 95% CI 0.47 to 32.85; 2 trials, 61 participants; very low quality evidence (downgraded for risk of bias and imprecision)).High-frequency ultrasound probably makes little or no difference to quality of life (moderate quality evidence, downgraded for imprecision). The outcomes of adverse effects, quality of life and cost were not reported for low-frequency ultrasound treatment. It is uncertain whether therapeutic ultrasound (either high or low frequency) improves the healing of venous leg ulcers. We rated most of the evidence as low or very low quality due to risk of bias and imprecision.

In people with chronic obstructive pulmonary disease (COPD), the use of neuromuscular electrostimulation (NMES) either alone, or together with conventional exercise training, might improve the condition of the peripheral muscles, increase exercise capacity and functional performance, reduce symptoms and improve health-related quality of life (HRQoL). To determine the effects of NMES, applied in isolation or concurrently with conventional exercise training to one or more peripheral muscles, on peripheral muscle force and endurance, muscle size, exercise capacity, functional performance, symptoms, HRQoL and adverse events in people with COPD. We searched the Cochrane Airways Group Specialised Register, the Physiotherapy Evidence Database, clinical trial registries and conference abstracts on 14 March 2018. Randomised controlled trials that recruited adults with COPD if they had compared outcomes between a group that received NMES and a group that received usual care or compared outcomes between a group that received NMES plus conventional exercise training and a group that participated in conventional exercise training alone. Two review authors independently extracted data and assessed risk of bias using the Cochrane 'Risk of bias' tool. We expressed continuous data as either the standardised mean difference (SMD) or mean difference (MD) with the corresponding 95% confidence interval (CI). We assessed the quality of evidence using the GRADE approach. Nineteen studies met the inclusion criteria of which 16 contributed data on 267 participants with COPD (mean age 56 to 76 years and 67% were men). Of these 16 studies, seven explored the effect of NMES versus usual care and nine explored the effect of NMES plus conventional exercise training versus conventional exercise training alone. Six studies utilised sham stimulation in the control group. When applied in isolation, NMES produced an increase in peripheral muscle force (SMD 0.34, 95% CI 0.02 to 0.65; low-quality evidence) and quadriceps endurance (SMD 1.36, 95% CI 0.59 to 2.12; low-quality evidence) but the effect on thigh muscle size was unclear (MD 0.25, 95% CI -0.11 to 0.61; low-quality evidence). There were increases in six-minute walk distance (6MWD) (MD 39.26 m, 95% CI 16.31 to 62.22; low-quality evidence) and time to symptom limitation exercising at a submaximal intensity (MD 3.62 minutes, 95% CI 2.33 to 4.91). There was a reduction in the severity of leg fatigue on completion of an exercise test (MD -1.12 units, 95% CI -1.81 to -0.43). The increase in peak rate of oxygen uptake (VO2peak) was of borderline significance (MD 0.10 L/minute, 95% CI 0.00 to 0.19).For NMES with conventional exercise training, there was an uncertain effect on peripheral muscle force (SMD 0.47, 95% CI -0.10 to 1.04; very low-quality evidence) and there were insufficient studies to undertake a meta-analysis on the effect on quadriceps endurance or thigh muscle size. However, there was an increase in 6MWD in favour of NMES combined with conventional exercise training (MD 25.87 m, 95% CI 1.06 to 50.69; very low-quality evidence). In people admitted to either in an intensive care unit or a respiratory high dependency centre, NMES combined with conventional exercise reduced the time taken for participants to first sit out of bed by 4.98 days (95% CI -8.55 to -1.41; very low-quality evidence), although the statistical heterogeneity for this analysis was high (I2 = 60%). For both types of studies (i.e. NMES versus usual care and NMES with conventional exercise training versus conventional exercise training alone), there was no risk difference for mortality or minor adverse events in participants who received NMES. NMES, when applied in isolation, increased quadriceps force and endurance, 6MWD and time to symptom limitation exercising at a submaximal intensity, and reduced the severity of leg fatigue on completion of exercise testing. It may increase VO2peak, but the true effect on this outcome measure could be trivial. However, the quality of evidence was low or very low due to risk of bias within the studies, imprecision of the estimates, small number of studies and inconsistency between the studies. Although there were no additional gains in quadriceps force with NMES plus conventional exercise training, there was evidence of an increase in 6MWD. Further, in people who were the most debilitated, the addition of NMES may have accelerated the achievement of a functional milestone, that is, the first time someone sits out of bed.

Pentoxifylline for treatment of venous leg ulcers: a systematic review