Abstract
Chronic venous insufficiency, which is defined as a condition relevant to persistent ambulatory venous hypertension, is a common cause of venous leg ulcers. Compression therapy is commonly used to relieve ambulatory venous hypertension and heal leg ulcers. Exercise is considered as adjunctive therapy, targeting calf muscle pump function, to additionally favor the compression treatment for facilitating the healing process. Different exercise training regimens for promoting wound healing and its relevant outcomes are reviewed and discussed in this study.
Introduction
Chronic venous insufficiency (CVI), which is defined as a condition of venous dysfunction relevant to persistent ambulatory venous hypertension, is a common cause of venous leg ulcers (VLUs). 1 The venous dysfunction can be either primary or secondary etiology. The primary venous dysfunction is caused by an uncertain etiology, while the secondary venous dysfunction is referred to an acquired condition from acute deep vein thrombosis. 2 The pathology of CVI can be classified as an obstruction or reflux. 3 Obstruction occurs as a consequence of thrombosis, whereas reflux is primarily resulted from venous valve incompetence and venous hypertension. 3 Inability to mobilize blood from lower limb deep veins into the inferior vena cava, as a consequence of obstructive or reflux conditions, results in various clinical signs including edema, pain, skin change, and ulceration. 2 Lower limb muscle pump activity, especially by calf muscles, has been documented as the greatest importance to drive blood flow from superficial into deep vein due to generating highest pressure during muscle contraction. 4 This process reduces ambulatory venous hypertension and is likely to induce wound healing as a consequence of a diminished systematic inflammatory process in CVI patients. 5 Previous evidence has revealed that calf muscle pump deficiency is a significant determinant of increased severity of venous ulceration. 6 Furthermore, impaired calf muscle function relates to reduced ankle mobility and results in venous hypertension in patients with chronic venous disease.7,8 Compression therapy is a commonly employed treatment that increases the healing rate of VLU in this patient group. 9 However, up to 30% of the active VLU condition has no response to compression therapy alone, resulting in incomplete healing which remains problematic in CVI patients who have VLU. 9 Several researchers have attempted to add exercise, targeted at increasing calf muscle pump function, as an adjunctive care to the compression therapy for facilitating the healing process. However, the role of exercise to increase calf muscle pump function and thus the healing rate in CVI patients has been controversial. While some evidence suggests that performing an exercise increases calf muscle pump function and promotes ulcer reduction,10‐12 others showed no additional benefits of exercise training on these outcomes.10,11,13,14 Thus, this article aims to review the existing evidence of the type of exercise as an adjunctive therapy on leg ulcer healing and further explore other healing-associated outcomes in all patients suffering from primary and secondary CVI.
Treatment for CVI
This review focuses only on non-pharmacological therapies. Compression therapy is the mainstay of care for CVI patients. This therapeutic modality is aimed at lowering venous pressure via narrowing veins, salvage vein competence, thereby reducing venous reflux and edema, and consequently promoting wound healing. 15 There are many compression systems used for this condition. Each system has advantages and disadvantages itself. 16 For instance, inelastic bandages have low extensibility and high working pressure but need to be used at full stretch, while multilayer bandaging is comfortable but needs to be applied by a well-trained physician. A recent meta-analysis suggests that compression therapy provided better benefits for promoting faster wound healing in VLU patients than those with no compression therapy. 9 The meta-analysis further showed that, in particular, the multicomponent bandage was associated with higher rates of wound healing compared to a single component bandage. Four layered bandages (including orthopedic wool, crepe bandage, elastic compression, and cohesive compression layers) also resulted in significantly faster healing rates compared to short-stretch bandages (SSBs). In addition to compression therapy, the role of exercise is further recommended for CVI patients. The effect of exercise prescriptions is reviewed in the following section.
Exercise as an Adjunctive Therapy
We classified exercise programs into 3 different groups: resistance exercise training, physical activity, and combined exercise training. Table 1 illustrates a summary finding in a comparison among these programs in patients with CVI.
Changes in Outcome Measures After Resistance, Physical Activity, and Combined (Resistance, Aerobic, and Flexibility) Exercise Training in Patients With Chronic Venous Insufficiency.
Summary findings from randomized controlled trials (RCTs),7,8,15,19,20 non-RCTs,10,11,16,17,21 and systematic review and meta-analysis 18 in patients with chronic venous insufficiency (CVI). Favor indicates significantly better changes after adding an exercise training program to compression therapy. No favor indicates non-significant changes. N/A indicates no assessment.
Resistance Exercise Training in CVI
Resistance exercise training is defined as an exercise strategy whereby muscles contract against an external resistance. 17 This exercise type aims to improve performance capacities such as strength and endurance, and further increase joint motion. 18 It is expected that improvements in muscle function, particularly the calf muscles, and ankle mobility which are accounted as factors associated with healing rate will facilitate a faster wound healing. One randomized controlled trial (RCT), containing CVI patients with active ulceration (clinical score 6: C6) compared 12 weeks of combined dorsiflexion (10 times per waking hour, every waking hour, every day) plus compression program and compression alone. This study showed that participants in the exercise group had a 69.9% significant reduction in ulcer area after exercise (median, interquartile range: pretraining 2.39, 3.51-1.16; posttraining 0.72, 1.17-0.12) compared to no changes in ulcer area in the compression alone group (median, interquartile range: pretraining 2.52, 4.18-0.63; posttraining 2.52, 3.34-0.63). 19 The same study also explored whether there are alterations at the vascular tissue level. The researcher found a significant increase in skin oxygenation as reflected by an increased transcutaneous PO2 in patients who completed 12 weeks of dorsiflexion exercises compared to patients in the nonexercise group. 19 Moreover, one previous prospective study investigated whether lower leg venous hemodynamics is improved in CVI patients with active ulcer (C6) following short-term heel raise training, along with the use of a short-stretch compression bandage. 20 The addition of simple heel raises had significantly greater improvements in ejected venous volume and ejection fraction, indicating an improved function of calf muscle pump, compared to participants using short-stretch compression alone. 20 Of all findings above, a simple resistance exercise training program seems to be possible to benefit ulcer size reduction, skin oxygenation promotion, and venous hemodynamic enhancement, which are likely to improve wound healing in the CVI patients who have active ulceration. Nevertheless, whether or not wound healing is improved after this program remains unknown due to no data available.
In addition to resistance exercise training, progressive resistance exercise training is another form, focusing on a progression in exercise component (ie, intensity and frequency of exercise). 18 Several single-arm studies and RCTs have employed progressive resistance exercise training programs, mainly targeting heel raises, with varied training periods between 6 and 24 weeks in primary and secondary CVI patients C5 to 6. A single-arm study of progressive heel raises training programs found a significantly improved ankle mobility after training. 21 Two RCTs also support significantly better benefits of the progressive heel raises training program on calf muscle pump and ankle mobility when compared to multilayer compression therapy alone.10,11 One of the progressive resistance exercise training by Yang 1999 has explored changes in calf muscle pump function measured by calf muscle strength and endurance, and venous ejection fraction in CVI patients who had healed ulcer (C5). 13 This study only found a significant enhancing in venous ejection fraction but not in calf muscle strength and endurance after training. It is not as we expect that improved calf muscle strength and endurance assists venous hemodynamics. In addition to the wound healing-related outcomes (ie, ankle mobility and calf muscle pump function) mentioned above, 2 RCTs containing primary CVI patients (C6) also have looked at healing rate after progressive resistance training programs in addition to multilayer compression therapy.10,11 The studies failed to find additional benefits of the programs on healing rate as reflected by no difference in healing rate between groups. One of the 2 RCTs has given the reason that an inadequate sample size might affect low power to detect a significant difference between groups. 11 In summary of current evidence, progressive resistance exercise training can be concluded as a simple resistance exercise training that it may benefit improvement in wound healing-related outcomes but not in wound healing rate.
Physical Activity in CVI
Walking is the most common form of physical activity that can be performed without using any devices. Previously, only one prospective study, conducting in CVI patients with active ulcer (C6), compared the effect between 12 weeks of daily walking at 10 000 steps with multilayer compression versus multilayer compression alone on healing rate. 14 This study showed that, at week 4, 8, and 12 of training, the rates of completed healing were not different between intervention and control groups (week 4: 11% vs 18%; week 8: 67% vs 35%; week 12: 83% vs 76%). However, at week 4, the author found a positive significant correlation between daily steps and time taken for completing ulcer healing in 14% of all participants who were fully healed regardless of the study group. Of the 14 percentage participants, study participants who took more steps were more likely to have significantly faster wound healing within 4 weeks compared to those who took fewer steps.
Combined Exercise Training in CVI
A combined exercise training program is one in which 2 or more exercise regimens are integrated together. In addition to resistance exercise and physical activity which are described in the previous section, aerobic exercise and flexibility exercise are also carried out. The goal of aerobic exercise is not only to enhance cardiovascular performance but to also increase muscle strength. Flexibility exercise is another form of exercise that allows joint moves independently.
Several non-RCT and RCTs have evaluated the impact of different combined exercise training programs on healing rate and other healing-associated outcomes (calf muscle pump function and ankle mobility). A previous meta-analysis pooling 2 RCTs of the combined exercise training program with compression therapy suggests that a combined exercise training program plus compression therapy had a superior effect on wound healing rate when compared to compression alone in primary CVI patients. 22 While the recent RCT, enrolling CVI patients with active ulcer (C6), opposes this finding that the combined exercise program with short-stretch bandages did not result in greater improvement in wound healing when compared to the use of short-stretch bandages alone. 23 However, the author of this study highlighted the need for sufficient sample size for ensuring the effectiveness of the combined exercise training program on facilitating wound healing. Other outcomes relevant to wound healing (calf muscle pump function and ankle mobility) have also been examined. A study by Padberg et al, 24 investigating the effect of the 24 weeks of combined resistance, aerobic, and flexibility training with stocking found significantly greater benefits of the additional exercise program on calf muscle pump function as measured by changes in venous hemodynamics in primary and secondary CVI patients (C4-6) when compared to the stocking alone. Some combined training programs do not support this finding as they demonstrated nonsignificant improvement in calf muscle pump function as indicated by unaltered venous hemodynamics and calf muscle strength.23,25 One of these studies mentions that the combined exercise training significantly increased venous hemodynamics in primary and secondary CVI patients who had less severity (C2). 25 Thus, the different findings may be implied that CVI participants who had a different severity may respond to combined exercise training programs differently. Changes in ankle mobility after completing combined exercise training are also inconclusive. A study, containing CVI patients with active ulcer (C6) found significantly higher ankle mobility, 23 whereas another study enrolling primary and secondary CVI patients (C4-6) did not find a greater improvement in ankle mobility after combined exercise training in addition to compression therapy when compared to compression alone. 24
Discussion
On the whole, this review summarized that exercise training programs could be used as adjunctive therapy with mainstay care of compression treatment. However, based on existing, published literature, we cannot strongly recommend a specific exercise regimen that would be able to provide the most advantage for the CVI patients as there are no studies directly comparing different exercise regimens on wound healing and wound healing-related outcomes. In addition, we are unable to specify whether primary and secondary CVI patients would have a similar response to adjunctive exercise therapy due to insufficient details available. Of the evidence, most of the included studies had no details of CVI etiology,14,19‐21,23 3 of them contained primary CVI patients,10‐12 and the other 3 studies had mixed primary and secondary CVI patients.13,24,25 For the exercise effect on wound healing, a recent meta-analysis has only identified that, compared to compression therapy alone, adding progressive resistance exercise and aerobic exercise training resulted in improved wound healed rate. 22 However, adding only progressive exercise or simple physical activity to compression therapy provided no additional benefits on this outcome. 22 As a result, based on this single meta-analysis, a combined exercise program remains recommended for the severe stage of CVI patients with active leg ulcers. 22 Although the combined exercise training program is the most effective on wound healing, it may not be practical in some situations due to the required equipment and spending longer time to do exercise. Simple exercises including resistance exercise and walking are simpler to employ although current data suggests these only have impacts on other healing-relevant outcomes such as improved calf muscle pump and ankle mobility and do not improve wound healing rates.
In our review, the number of evidence investigating the impact of incorporating exercise training programs with compression therapy on the healing rate is limited. Approximately one-half available studies, containing CVI patients who have active ulceration have focused on healing-relevant outcomes (ie, calf muscle pump function and ankle mobility) other than the healing rate. It is difficult to tell that improved healing-relevant outcomes could ensure an improvement of the healing rate. We would recommend for a further single study to conduct not only wound healing-relevant outcomes, but also healing rate, together with sufficient sample size. Furthermore, it would be better if there is a comparison between different programs within a study to explore the most optimal exercise training program to promote wound healing-relevant outcomes and healing rate. Otherwise, a network meta-analysis is an alternative solution for determining the best effective program among existing evidence for CVI patients that should be administered.
Conclusion
This review summarizes that exercise may provide a beneficial effect to improve wound healing and other wound healing-related outcomes including ulcer area, calf muscle pump function, skin oxygenation, and ankle mobility in primary and secondary CVI patients. The most proper exercise program should be further explored.
Footnotes
Acknowledgments
The authors thank the CMU Presidential Scholarship (Postdoctoral Fellowship), Chiang Mai University, Thailand, for supporting this research. We also thank Dr Vit Suwanvanichkij for English editing and comment.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship and/or publication of this article.
