Extracorporeal Shockwave Therapy for Chronic Venous Ulcers: A Randomized Controlled Trial

Background: Chronic venous ulcers (CVUs), demanding specialized care, are still a major socioeconomic problem facing health care systems worldwide. This study’s main goal was evaluating the efficacy of ESWT application as an AT in the treatment of wounds for curing CVUs. Materials and Methods: 50 patients presenting with CVUs were divided into two groups of ESWT and control randomly. Then, ESWT was applied one session per week, during four weeks, along with routine CB. The control group also received sham ESWT together with CB. In this respect, pain score, wound size, patient satisfaction and quality of life (QoL) using the Charing Cross Venous Ulcer Questionnaire (CCVUQ) were consequently assessed at baseline, week four, and week eight and then compared between both groups. Results: The findings showed that patients receiving ESWT along with CB had significantly lower pain and were also feeling more satisfied than the cases undergoing CB alone (P<0.05). The significant efficiency of ESWT in improving the healing process of CVUs was further observed (P<0.05). In addition, QoL, assessed by the CCVUQ, was significantly higher in patients receiving ESWT (P<0.05). Conclusion: These findings established that ESWT was a feasible and safe option to treat patients presenting with CVUs in another word,ESWT seems to be a safe and effective adjunct therapy (AT) compared with CB in patients with CVUs.


Introduction
C hronic venous ulcers (CVUs) are open complex wounds caused by chronic venous insufficiency (CVI) in the lower extremity below the knee on the leg or the foot that have been present for at least six weeks [1]. The frequency of these wounds is rising, associated with impaired quality of life (QoL), reduced mobility, pain, stress, and loss of dignity.
Therefore, such ulcers demand specialized care that may challenge patients and medical teams, as a major socioeconomic problem facing health care systems worldwide [2,3]. The management of ulceration is accordingly dependent on the associated causes, and it can include both conservative and surgical options. Multi-layer compression bandaging (MLCB), hyperbaric oxygen therapy (HBOT), CVI surgery, radiofrequency (RF) radiation, endovenous laser treatment (EVLT), GMJ.2021;10:e1931 www.gmj.ir and sclerotherapy (ST) are thus among wellknown minimally invasive procedures for the management of these ulcers [4]. The MLCB, that aims to improve venous returns and to reduce venous hypertension, has been so far acknowledged as an effective standard treatment in the management of CVUs [5,6]. The healing rates for such wounds within six months of MLCB in some specialist clinics has been also reported to be around 70% [6], whereas, other studies have reported the rate of unhealed CVUs up to 50% after two years [7]. Therefore, alternative therapies may be desirable, because of long treatment time and rate of unhealed wounds, since they accelerate the healing of refractory wounds with multimodal treatments, improve patients' health-related QoL, and minimize health care expenses [8].
In this regard, extracorporeal shockwaves are low-energy pulse waves that have been clinically implemented as an effective treatment of urinary stones as well as some orthopedic and traumatic indications over the past decades [9][10][11][12][13]. Recently, extracorporeal shock wave therapy (ESWT) has been exercised to treat acute and chronic non-healing wounds [8,13] and it is believed that this modality induces neovascularization and mechanical stimuli causing proliferation of a number of cells including osteoblasts [14]. The effectiveness of ESWT on treatment of chronic wounds with different etiologies has been further reported in previous studies. Hence, chronic wounds such as CVUs in DM patients, pressure ulcers, and PAD have demonstrated promising healing signs [15][16][17][18][19]. Having no control group, selecting patients with different causes of chronic wounds, and recruiting a relatively low number of samples have been among limitations of prior studies. In this respect, Zhang et al., had demonstrated that the healing process of chronic lesions, compared with the standard care treatment alone, could be significantly augmented by adding ESWT as an adjunct therapy (AT). Among the limitations of this systematic review was that the subjects involved in the selected studies were patients with chronic wounds irrespective of their etiologies [20]. Therefore, this research designed to compare the efficiency of ESWT along with CB versus CB alone in the healing of CVUs.

Materials and Methods
The current double-blind parallel-group randomized clinical trial in a multi-centered design was conducted on the patients with chronic venous ulcers in hospitals of Isfahan, Iran, in 2018-2019. A venous ulcer was characterized as a split in the epithelial surface in the gaiter region, with proof of reflux of greater than 0.5 seconds in the venous system. Besides, an over two-week ulcer span with a size of more than 1 cm2 was required for trial purposes [21]. The sample size included 50 patients (25 in the intervention group receiving ESWT along with routine treatment and 25 in the control group receiving sham ESWT along with routine treatment), who met the study inclusion criteria and selected by random sampling method. The inclusion criteria were over 18 years of age, the presence of leg ulcer due to underlying venous insufficiency, the ulcer size of greater than 1 cm2 and the persistence of the ulcer for more than 6 weeks. The exclusion criteria were the history of vascular surgery in the last 6  group (receiving ESWT: MP 100, Storz Medical, Switzerland) and the control group (receiving sham ESWT) using random allocation software version 2 and block randomization method. In the intervention group, the extracorporeal shock wave therapy was performed in addition to routine compression bandaging once a week for 4 weeks. Each ESWT session consisted of 100 pulses per square centimeter of wound area. The total energy for each pulse was 3.5 mJ and the frequency was 5 Hz. The control group did not receive the waves (the device was turned off for this group for blinding and used as a sham), and only routine compression bandaging was performed for patients. The electromagnetic device (DUOLITH SD1 standard device, Storz Medical, Tägerwilen, Switzerland) was used to perform the shock. The method of blinding in this study was that participants were treated with the device with a four-layer dressing. But for the control group, in addition to the four-layer dressing, the off device was used.
The analyzer was also unaware of the blinding conditions. In order to collect data and evaluate the ulcers at the baseline, the patients were visited at 4 and 8 weeks.  [21]. This questionnaire was completed by the researcher. Visual Analogue Scale (VAS) was used to assess pain intensity. The VAS is a simulated self-report visual scale. In this study, the VAS was a simple ruler numbered from zero (no pain) to 10 (maximum pain intensity). After explaining about this tool, the patients were asked to determine the intensity of their pain according to the given explanations [22]. The collected data were analyzed by SPSS version 24 software (SPSS Inc. Chicago, Illinois, USA) using descriptive statistics, Fisher's exact test to compare qualitative variables between the two groups, repeated measures ANOVA to compare of the two groups at different times, and independent t-test to compare the means between the two groups at a statistically significance level of P-value<0.05 for all tests.

Results
According to Figure-1 Table-2 and Figure-2. Based on the results, only the patient satisfaction index exhibited a significant difference between the two groups, so that the ESWT group had more satisfaction than the control group (P<0.001), but pain intensity and ulcer size in the two groups showed no significant difference (P>0.05).
In this study, the patient's quality of life in general and separately into four subscales (social interaction, domestic activities, emotion-al state, and aesthetics) was evaluated by the repeated measures ANOVA test between the two groups, the results of which are reported in Table-2 and Figure-3. The results of the analysis indicated the two groups represented a considerable difference regarding three subscales, including aesthetics, emotional state as well as the total CCVUQ, whose values, in comparison with the control group, were elevated in the ESWT group; however, subscales differed no significantly concerning the social interaction and domestic activities (P>0.05).

Discussion
Given the significant effects of chronic wounds on patients' comfort and QoL, any interventions accelerating their healing process will be considerable. ESWT, as a new therapeutic option, has been recently exercised in the treatment and control of such ulcers [15,20]. This study's main goal was evaluating the efficacy of ESWT application as an AT in the treatment of wounds for curing CVUs.
The findings showed that patients receiving ESWT along with CB had significantly lower pain and were also feeling more satisfied than the cases undergoing CB alone. The significant efficacy of ESWT in improving the healing process of CVUs was further observed. In addition, QoL, assessed by the CCVUQ, was significantly higher in patients receiving ESWT. These findings established that ESWT was a feasible and safe option to treat patients presenting with CVUs.
The existing evidence indicates that the use of ESWT can be safe and effective in the control and treatment of chronic wounds. In this re-spect, Wolff et al. had conducted an RCT to evaluate the impact of ESWT in 282 patients with unsuccessfully treated chronic wounds and had found that positive treatment had been achieved in 74.03% of the cases [15]. In a clinical study, Saggini et al. had similarly assessed the use of ESWT along with regular conservative dressings to treat 40 patients affected with chronic post-traumatic, venous, and diabetic foot ulcers, had reported significant improvements in wound size, pain score, and healing process in patients undergoing ESWT compared with the controls [16]. In one other study by Schaden et al., a total number of 208 patients with a variety of acute and chronic wounds (including traumas, post-operative wounds, venous or arterial insufficiency, pressure necrosis, or burns) had been treated through a combination of debridement, ESWT, and moist wound dressings. Reports indicated a 75% treatment completion rate among patients, representing the feasibility of ESWT. Also, it was concluded that ESWT was tolerable by patients having soft tissue wounds with acute and chronic states [17]. In this line, 28 patients with CVUs had  [19]. A recent review studying ESWT effectiveness as an AT for the chronic wound treatment had used seven CRTs involving 301 subjects.
The results of meta-analyses indicated that the application of ESWT could considerably speed up the weakened, inefficient healing process of such wounds, despite the suggestions to conduct more high-quality trials to assess ESWT efficacy in chronic wound treatment since the reviewed research were limited and had a small sample size [20]. The results of this study represent the considerably positive, reducing impacts of using ESWT  ia-inducible factor 1-alpha, which exist in the normal trend of post-treatment wound healing [23][24][25]. On the other hand, post-ESWT increased angiogenesis and cell activity can lead to improvements in tissue regeneration and accelerate wound healing process [26]. In addition, it has been established that ESWT boost extracellular signal-regulated kinase 1/2 (ERK1/2) by activating purinergic receptors in response to the release of cellular ATP [27]. Although its mechanism is not widely understood but some advantages of ESWT such as non-invasiveness, no serious complications, superiority to other standard treatments, and cost-effectiveness [12] can make this modality considerable as an easy method to implement for clinicians and acceptable for the majority of patients with positive wound healing outcomes.
One of the limitations of this study is the ES-WT-induced pain, which initially caused patients to suffer, but after obtaining the results of the intervention, they expressed their satis-faction. Moreover, due to the heterogeneity of ulcer shape in the patients, there was a possibility of error in measuring the ulcer size.

Conclusion
The finding of this research demonstrated that ESWT as an AT for chronic wound treatment could be effective in treatment and control of CVUs and result in improvements in wound healing, higher levels of satisfaction in patients, pain reduction, and a better QoL. More CRTs are thus needed to assess the exact efficacy of ESWT in these patients.