Original article

The use of therapeutic ultrasound in venous leg ulcers: a randomized, controlled clinical trial J Taradaj*, A Franek*, L Brzezinska-Wcislo†, L Cierpka‡, P Dolibog*, D Chmielewska§, E Blaszczak* and D Kusz**

Katedra i Zaklad Biofizyki Lekarskiej Slaskiego; †Katedra i Klinika Dermatologii Slaskiego; ‡Katedra i Klinika Chirurgii Ogo´lnej Naczyniowej i Transplantacyjnej Slaskiego, Uniwersytetu Medycznego w Katowicach; §Zaklad Fizykoterapii Akademii Wychowania Fizycznego w Katowicach; **Katedra i Klinika Ortopedii i Traumatologii Slaskiego, Uniwersytetu Medycznego w Katowicach, Katowice, Ligota, Poland 

Abstract Objectives: To estimate the usefulness of therapeutic ultrasound for healing of venous leg ulcers. Methods: Eighty-one patients were included in this study. Patients in groups 1 and 2 were treated surgically. Patients in groups 3 and 4 were treated conservatively. Patients in groups 1 and 3 were additionally treated with the ultrasound (1 MHz, 0.5 W/cm2) once daily, six times a week for seven weeks. Results: Comparison of the number of complete healed wounds indicated statistically significant differences between groups 1 and 4 (P ¼ 0.03), 2 and 4 (P ¼ 0.03), 3 and 4 (P ¼ 0.03) in favour of groups 1, 2 and 3. Comparison of the other parameters also demonstrated more efficient therapy effects in groups 1, 2 and 3 than in group 4. There were no statistical differences in all examined parameters between groups 1, 2 and 3 (P . 0.05). Conclusions: The ultrasound is an efficient and useful method only in conservatively treated venous leg ulcers. There are no special reasons for application of the ultrasound in surgically treated patients. A well-conducted surgical operation is much more effective for a healing process than conservative pharmacological procedures. Keywords: ultrasound; venous leg ulcers

Introduction Ultrasound has been employed therapeutically for decades and is currently used by clinicians to treat a wide variety of disorders. Most studies have examined the promising effects of ultrasound on pain,1,2 musculoskeletal2,3 and neurological4,5 dysfunctions. Application of ultrasound may also produce a number of biophysical effects that are relevant to wound healing. These include alternations in Correspondence: Dr Jakub Taradaj PhD PT, Department of Medical Biophysics, Medical University of Silesia, ul. Medykow 18, bud. C2 40 – 752 Katowice, Ligota, Poland. Email: [email protected] Accepted 25 April 2008

cellular protein synthesis and release,6 blood flow and vascular permeability,7,8 angiogenesis8 and collagen content and alignment.9 Such effects have been suggested to provide a rationale for the use of therapeutic ultrasound at each stage of the wound-healing process. In the management of cutaneous wounds; mainly frequencies from 0.5 to 3 MHz have been found to enhance the healing process in incisional lesions, diabetic and venous ulcers.7,10 The waveform may be continuous or pulsed (duty cycle from 1/4 to 1/9). The power density delivered to a treatment site is between 0.1 and 1 W/cm2 (mainly 0.5 W/ cm2). The procedures usually last up to 20 minutes. The utility of this therapy for wound healing application remains still controversial. For example, while many of clinical trials find healing of soft tissue wounds significantly improved by

Phlebology 2008;23:178–183. DOI: 10.1258/phleb.2008.008015

J Taradaj et al. Use of therapeutic ultrasound in venous leg ulcers

ultrasound,11 – 14 some (representative and wellcontrolled) do not.15,16 It is unclear whether ultrasound accelerates the wound healing and, if it does, whether any particular treatment regimen is optimal. In this randomized controlled clinical trial we investigated the use of ultrasound in the treatment of venous leg ulcers. The aim was to estimate the usefulness of therapeutic ultrasound for healing of venous leg ulcers in surgically and conservatively treated patients. Study endpoints were number of completely healed wounds and the clinical parameters predicting the outcome.

Methods The methods, the plan and scope of therapy, inclusion of patients into the groups and other procedures of the scientific research were reviewed, approved and accepted by the Bioethical Commission of Medical University of Silesia in Katowice, Poland. Eighty-one patients with venous leg ulcers were included in this study. Forty-one individuals – who agreed on surgical operation and were qualified for this therapy by research team – were ultimately allocated into two comparative groups 1 and 2. Other individuals – who did not agree on surgical procedure – were ultimately allocated into two comparative groups 3 and 4. Inclusion and exclusion criteria are presented in Table 1. Patients in groups 1 and 2 were surgically treated in the General, Vascular and Transplant Surgery Department at the Medical University of Silesia in Katowice. Patients in groups 3 and 4 were conservatively treated in the Dermatology Department of the Medical University of Silesia in Katowice. Group 1 consisted of 21 patients (14 females, seven males). After surgical operation they were treated with ultrasound, compression stockings and drug therapy. Group 2 consisted of 20 patients (12 females, eight males). After surgical procedure Table 1 Inclusion and exclusion criteria Inclusion criteria

Exclusion criteria

Venous leg ulcers (ABPI . 1.0)

Diabetes Arteriosclerosis Rheumatoid arthritis Ventricular arrhythmia Cardiac pacemaker Metal implants Pregnancy After steroid therapy

ABPI, ankle brachial pressure index

Original article

they were only treated with the compression and drug therapy, administered identically as in group 1. Group 3 consisted of 20 patients (12 females, eight males). They were treated with ultrasound as in group 1, and compression and drug therapy administered identically as in groups 1 and 2. Group 4 consisted of 20 patients (13 females, seven males). They were only treated with compression and drug therapy, administered identically as in groups 1, 2 and 3. Other details of the examined persons and ulcers are shown in Tables 2 and 3. Patients were evaluated using the clinical, aetiological, anatomical and pathological elements (CEAP) classification of chronic venous insufficiency (CVI) (Table 4). All ulcers in the groups were diagnosed as venous. In order to rule out the arterial component and to verify the localization of CVI, patients were examined by duplex scanning (EUB 555, Hitachi Inc, Japan). All patients had the symptoms of CVI, i.e. oedema, hyperpigmentation and lipodermatosclerosis of the affected limb. The body mass index (BMI) was calculated for all patients by the following equation: BMI ¼

real mass of body in kilograms ðheight in metresÞ2

According to international reference values, the BMI higher than 30 kg/m2 indicated adipositas. The number of smokers was recorded as well. All patients in comparative groups were treated with elastic compression stockings (Sigvaris, Gianzoni & Cie AG, Switzerland – certified in Poland) providing pressure 30 – 40 mmHg at the ankle (30 – 35 mmHg in superficial venous reflux and 35– 40 mmHg in superficial with deep venous reflux). The pressure values were standardized in use of Kikuhime manometer (Hartmann, Germany). The stockings were put on the leg, at the outpatient clinic, each morning and worn whole day (about 10– 12 hours), and removed at night. Drug therapy followed a standard regimen. All patients received micronized flavonoid fraction (450 mg diosmin, 50 mg hesperidin), two tablets of 500 mg once daily. The ulcer ground was covered with wet dressings of 0.9% sodium chloride. Dressings were changed once a day and exclusively at the clinic. Before beginning the compression and drug therapy, patients in the groups were surgically operated on. The spectrum of the following procedure included crossectomy, partial (short) stripping of the greater (GSV) or lesser (LSV) saphenous vein, local phlebectomy and ligation of insufficient perforators. Phlebology 2008;23:178–183

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Table 2 Characteristics of patients and ulcers Group 1 Number of patients Age (years) Average SD Range Gender Female Male Body weight (kg) Average SD Range Body height (cm) Average SD Range Localization of ulcers Medial ankle Lateral ankle Anterior crural surface Posterior crural surface Duration of disorder (months) Average SD Range Initial wound total area (cm2) Average SD Range Initial wound volume (cm3) Average SD Range

Group 2

Group 3

Group 4

P

21

20

20

20

.0.05

62.30 9.22 49 –85

61.86 9.59 48– 86

62.12 10.02 44 –85

62.33 9.87 43 –86

.0.05

14 7

12 8

12 8

13 7

.0.05

74.72 12.17 54 –94

73.55 11.75 53– 92

74.33 12.02 54 –93

73.74 11.11 52 –94

.0.05

172.23 9.11 159– 191

171.17 8.67 160–188

172.89 9.08 160– 187

172.49 9.33 160– 188

.0.05

10 3 5 2

9 3 6 2

10 3 5 2

9 4 4 3

.0.05

32.04 22.12 2– 130

32.89 20.89 12–120

30.99 20.09 10– 100

30.87 20.12 9– 136

.0.05

18.66 10.22 6.45– 36.33

18.02 10.72 8.69–35.01

17.07 10.42 8.159–35.51

18.06 11.09 8.04– 40.01

.0.05

2.77 2.31 0.13– 13.54

2.45 2.81 0.15–13.03

2.83 2.44 0.10– 10.11

3.49 2.25 0.22– 12.88

.0.05

x 2 independence test

Patients in groups 1 and 3 were treated with the ultrasound. The ultrasound beam was generated by a Sonicator 730 apparatus (Mettler Electronics Inc, USA). The power density was 0.5 W/cm2 (spatial average – temporal average). The type of wave was a pulsed one with a duty cycle of 1/5 (impulse time ¼ 2 mseconds, interval ¼ 8 mseconds) and frequency 1 MHz. The procedures

were performed in a bath of water, with a temperature of 34ºC; the ultrasound probe had an area of 10 cm2 and was placed at a distance of 2 cm above the wound. The time duration of a single procedure was dependent on the ulceration size. An ulcer of 5 cm2 or less was exposed for five minutes; for every ulcer 1 cm2 in excess of this figure, the time lengthened by one minute. For ulcers larger than

Table 3 History and physical findings of patients with venous leg ulcers Findings Oedema, hyperpigmentation, lipodermatosclerosis of affected extremity Adipositas Smokers Type of surgical operation GSV LSV

x 2 independence test

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Group 1 n (%)

Group 2 n (%)

Group 3 n (%)

Group 4 n (%)

P

21 (100)

20 (100)

20 (100)

20 (100)

.0.05

4 (19) 5 (24)

4 (20) 5 (25)

4 (20) 5 (25)

4 (20) 5 (25)

.0.05 .0.05

19 (90) 2 (10)

17 (85) 3 (15)

.0.05

J Taradaj et al. Use of therapeutic ultrasound in venous leg ulcers

Original article

Table 4 Classification of chronic venous insufficiency CEAP class

Group 1

Group 2

Group 3

Group 4

P

C6EPAS2,3PR C6EPAS4PR C6EPAS2D13PR C6EPAS3D13PR C6EPAS2,3D13,14P18PR C6ESAS2,3D13,14P18PR Total number of patients

9 3 3 2 3 1 21

7 3 3 2 3 2 20

9 3 3 2 2 1 20

8 2 4 2 3 1 20

.0.05 .0.05 .0.05 .0.05 .0.05 .0.05

CEAP, clinical, aetiological, anatomical and pathological elements x 2 independence test

20 cm2 the total area was divided into two parts and exposed for a corresponding time. The procedures were performed once daily, six days a week over a seven week period. The total time of treatment, in all comparative groups, lasted seven weeks. Treatment progress was evaluated by observation of the number of completely healed ulcers, and measuring the area of the ulceration by planimetry of congruent projections of these wounds onto transparency paper using a digitizing pallet. Depth of the ulceration was precisely measured at various points by micrometer. Later, noted results were transferred to software. The electronic equipment for the measurement of area and volume of the ulcers consisted of the digitizer (Kurta XGT, Altek Inc, USA) wired to a personal computer with modified software C – GEO v. 4.0 (Nadowski, Poland), thus allowing the calculation of these parameters. Measurements of area and volume were performed on each person before therapy, each week during treatment and after therapy. From this data, the software calculated the area and volume of tissue deficiency in ulcerations. Measurements were also made of length and perpendicular width dimensions (for observation, the correlation between surface area and linear dimensions). The observation of the healing process was supported by precisely calculated parameters, such as Gilman Index and relative changes. These indicators were defined as follows: d – Gilman Index (cm) d¼

DS SI  S1;2...F 2ðSI  S1;2...F Þ ¼ ¼ ðC1;2...F þ CI Þ=2 p C1;2;...F þ CI

SI – initial total area S1, 2, . . ., F – total area after first, second, . . ., seventh week (final) CI – initial circumference C1, 2, . . ., F – circumference after first, second, . . . , seventh week (final)

DS% – relative change of the total surface area (%) ðSI  S1;2...F Þ100% DS% ¼ SI SI – initial total area S1, 2, . . ., F – total area after first, second, . . . , seventh week (final) DL% – relative change of the length (%) ðLI  L1;2...F Þ100% DL% ¼ LI LI – initial length L1, 2, . . ., F – length after first, second, . . ., seventh week (final) DW% – relative change of the width (%) ðWI  W1;2...F Þ100% DW% ¼ WI WI – initial width W1, 2, . . ., F – width after first, second, . . ., seventh week (final) DV% – relative change of the volume (%) ðVI  V1;2...F Þ100% DV% ¼ VI VI – initial volume V1, 2, . . ., F – volume after first, second, . . ., seventh week (final) The x 2 independence test (greatest reliability level) was used for analysis of indicators, which characterized patients in all comparative groups. Differences in number of the completely healed ulcers, and mean values of Gilman Index, total area, length, width and volume were evaluated with analysis of variance ANOVA and post hoc Tukey test. Two-sided P values of ,0.05 were considered to be statistically significant. The power of test for comparing between groups, for P  0.2 and value of effect – 1.6 cm2 for ulcer size and 0.5 cm3 for ulcer volume (difference in means) – was .0.8. Phlebology 2008;23:178–183

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Results The examined groups were homogeneous in terms of patients’ characteristics (Table 2 – 4). Treatment proved effective in all groups. After seven-week assessment, six patients in group 1 (mean ulcer size 12.66 cm2, SD 3.04 cm2), six patients in group 2 (mean ulcer size 13.87 cm2, SD 4.01 cm2), six patients in group 3 (mean ulcer size 10.97 cm2, SD 4.21 cm2) and three in group 4 (mean ulcer size 9.79 cm2, SD 3.66 cm2) were healed completely. Comparison of the treatment efficacy demonstrated statistically significant differences between groups 1 and 4 (P ¼ 0.02), 2 and 4 (P ¼ 0.02), 3 and 4 (P ¼ 0.02) in favour of groups 1, 2 and 3. Comparison between groups 1, 2, 3 and 4 in terms of Gilman Index, indicated statistically significant differences between groups 1 and 4 (P ¼ 0.002), 2 and 4 (P ¼ 0.002), 3 and 4 (P ¼ 0.002) in favour of groups 1, 2 and 3 (Table 5). Comparison between groups 1, 2, 3 and 4, in terms of relative change of the total surface area, indicated a significant differences between groups 1 and 4 (P ¼ 0.004), 2 and 4 (P ¼ 0.004), 3 and 4 (P ¼ 0.004) in favour of groups 1, 2 and 3 (Table 5). Detailed process of the total surface area decreasing in all comparative groups is presented in Figure 1. In terms of relative length and width changes noticed, similar differences as before were noted between groups 1, 2 and compared with group 4 (Table 5). Comparison between groups 1, 2, 3 and 4 in terms of relative change of the volume also indicated a significant differences between groups 1 and 4 (P ¼ 0.01), 2 and 4 (P ¼ 0.01), 3 and 4 (P ¼ 0.01) in favour of groups 1, 2 and 3 (Table 5). Detailed process of the volume decreasing in all comparative groups is presented in Figure 2. There were no statistical differences in all examined parameters between groups 1, 2 and 3 (P . 0.05).

Figure 1 Dynamics of total surface area change in groups 1, 2, 3 and 4

Figure 2 Dynamics of volume change in groups 1, 2, 3 and 4

In all comparative groups the change of wound area occurred simultaneously with changes of linear dimensions. This was beneficial for wound healing, which had progressed steadily.

Discussion Ultrasound has been used for the treatment of a variety of cutaneous wounds, particularly venous ulcers. Many of the published articles demonstrate that ultrasound strongly accelerates the healing process of venous leg ulcers.11 – 14

Table 5 Results in groups 1, 2, 3 and 4 Parameter of the wound

Group

d (cm)

DS%

DL%

DW %

DV %

Mean parameter value in the groups

1 2 3 4 P(1,2) P(1,3) P(1,4) P(2,3) P(2,4) P(3,4)

0.92 0.91 0.92 0.61 .0.05 .0.05 0.002 .0.05 0.002 0.002

58.21 58.36 56.67 36.09 .0.05 .0.05 0.004 .0.05 0.004 0.004

39.99 41.21 38.89 26.64 .0.05 .0.05 0.01 .0.05 0.01 0.01

42.55 43.13 40.78 28.63 .0.05 .0.05 0.01 .0.05 0.01 0.01

70.23 69.21 71.22 46.88 .0.05 .0.05 0.01 .0.05 0.01 0.01

ANOVA

ANOVA, analysis of variance

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J Taradaj et al. Use of therapeutic ultrasound in venous leg ulcers

However, in literature there are a few critical randomized controlled trials. Eriksson et al. 15 observed that after two weeks of therapy, the reduction of wound sizes was only 7% better in experimental group (ultrasound þ compression bandaging) than in control (only compression therapy). After one-month therapy, the difference between both groups was 8% and after two months only 6%. Lundeberg et al. 16 did not report any special influence of ultrasound therapy on the healing process when compared with standard compression bandages and stockings, either. After one-month observation, the authors noticed two completely healed ulcers in ultrasound group and one in control. After three months, they noticed 10 completely healed ulcers in ultrasound group and eight in control. Before a new treatment is introduced into practice it should have been shown to be beneficial and ideally be either better than – or at least equal in efficacy to – alternative methods. Our findings did not confirm the expectations completely. The present results support the use of therapeutic ultrasound only in conservative treated ulcers. In surgically treated venous leg ulcers, the application of ultrasound therapy was not efficient enough. According to our results, we strongly believe that basal therapy is most important in the healing process. Whenever possible, surgical treatment should be provided as it seems to be the most efficient one (especially with compression therapy after surgical procedure). However, invasive procedures are not always recommended. The problem mainly affects elderly people, often burdened with other diseases, which may constitute surgical contraindications. In these cases, the ultrasound therapy appeared very effective.

References 1

2 3

4

5

6 7 8 9

10

11

12

13

14

Conclusions Ultrasound is an efficient and useful method only in conservatively treated venous leg ulcers. There are no special reasons for application of the ultrasound in surgically treated patients. A well-conducted surgical operation is much more effective for a healing process than conservative pharmacological procedures.

Original article

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16

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