This is an evaluator-blinded, randomized controlled superiority trial with 2 parallel groups, and a 1:1 allocation ratio, with a 8-week intervention period and outcomes measured at baseline, 8 weeks and 16 weeks as a follow-up evaluation.
Study setting
The evaluations will be performed at the Pneumocardiovascular laboratory, and the intervention program will be performed at the Physical Therapy Office, both located in the University Hospital of Natal/RN, Brazil.
Recruitment
Participants will be recruited at the medical clinic of the University Department of Clinical Medicine in the city of Natal/RN - Brazil. This outpatient facility has 5 physicians specialized in vascular surgery. The inclusion and exclusion criteria will be presented to the physicians personally. The physicians will be asked to refer all participants who meet the inclusion criteria for the study. All the participants will sign the informed consent form which will be explained by the evaluator before the evaluation.
Participants
Potential participants with stable CVI that meet the eligibility criteria have been recruited from the vascular surgery outpatient clinic. They have been invited to participate through an informed consent process. The initial evaluation will be performed by a blinded evaluator through a questionnaire that will include socio-demographic data, co-morbidities, time of CVI diagnosis, and detailed clinical and functional information. The disease classification will be based on the CEAP (clinical, etiology, anatomical, pathophysiology) criteria including: clinical manifestations (C), etiologic factors (E), anatomic distribution of disease (A), and underlying pathophysiologic findings (P) [4]. Ulcer morphological characteristics (if present), range of motion (ROM), exercise capacity, muscle endurance and parameters related to QOL will also be assessed.
The inclusion criteria for this study are male and female patients aged between 35-69 years, with chronic venous insufficiency diagnosed by venous vascular echo-Doppler (VED), CEAP between 2 to 6, and without Peripheral Arterial Disease (PAD) (ankle-brachial index < 0.9) [19]. The exclusion criteria for this study are participants who do not agree to participate, have ulcers > 4 cm diameter, or clinical signs and/or confirmed diagnosis of infection as well as the patients who already perform any type of supervised or unsupervised exercise programme (whereas exercise is a subset of physical activity that is both regular and structured) [20], are unable to attend physiotherapy sessions twice a week, and/or have co-morbidities incompatible with moderate to intense exercises [21] such as: acute or uncontrolled congestive heart failure, uncontrolled or unstable angina, uncontrolled cardiac dysrhythmia causing hemodynamic symptoms, severe symptomatic aortic stenosis, recent deep venous thrombosis, recent pulmonary embolism, acute pericarditis or myocarditis, dissecting aneurysms (known or suspected), unstable or uncontrolled blood pressure (systolic pressure > 160 mmHg, diastolic pressure > 100 mmHg), acute systemic infection, or uncontrolled diabetes, limiting musculoskeletal diseases, or difficulty to understand the activities.
All participants will sign the informed consent form that will be explained before the evaluation. During the functional tests, hemodynamic cardiac parameters (cardiac output, ejection fraction, and systolic volume) and bilateral electrical activity of the calf and tibialis anterior muscles will be assessed.
Design
The evaluations will start in January 2020. After evaluation, participants will be randomly allocated to 2 evaluator-blinded groups: treatment group (TG) and control group (CG). The randomization.com program will be used to randomize the participants and stratification will be performed to ensure balance between the groups within 2 strata (CEAP 2 and 3 and CEAP 4 to 6). A separate, blinded researcher will contact the participants by telephone to ensure allocation concealment during screening, consent and initial assessment. A study researcher responsible for implementation will apply the exercise program.
Patients in the TG will perform the exercise program as described in this protocol and will start 1 week after the initial evaluation. The patients in the CG group will continue their usual treatments (medication use, compression stockings and medical guidance). After 8 weeks of intervention, the patients will be reevaluated (using the same initial evaluation questionnaire) by the same blinded evaluator for each group. The primary outcomes will be calf muscle endurande and QOL and second outcomes will be exercise capacity, ROM electrical muscle activity and cardiac output. A final reassessment will be performed 8-weeks after the reevaluation, as shown in Figures 1 and 2.
All participants will receive educational information regarding the disease, as well as the usual care (hygiene and compressive techniques) and treatments to improve symptoms and quality of life (QOL).
|
STUDY PERIOD
|
TIME POINT
|
Evaluation
|
Baseline
|
Session
1-16
|
Re-evaluation
(8-weeks)
|
Follow up
(16-weeks)
|
ENROLMENT
|
|
|
|
|
|
Eligibility screen
|
x
|
|
|
|
|
Informed consent
|
x
|
|
|
|
|
Allocation
|
|
x
|
|
|
|
INTERVENTIONS
|
|
|
|
|
|
Health education speech
|
|
x
|
|
|
|
Exercise programme treatment (Intervention group)
|
|
|
X
|
|
|
Usual care treatment (Control Group)
|
|
|
X
|
|
|
ASSESSMENT
|
|
|
|
|
|
Strength and endurance of
plantar flexors
|
x
|
|
|
x
|
X
|
Quality of Life
|
x
|
|
|
x
|
X
|
Exercise Capacity
|
x
|
|
|
x
|
X
|
Range of motion
|
x
|
|
|
x
|
X
|
Sample size
The sample size will be calculated based on a pilot study with 8 patients (4 patients in each group). It will be used a Manova test with repeated measures, within-between interaction with 2 groups and 2 measurements. The power will be 95%. A G*Power (Germany) version 3.1- program will be used for statistical analysis.
Blinding
The researcher who will perform the initial and final evaluations will be blinded to the participants’ allocation groups. The participants will be instructed not to make any comments regarding group allocation. The evaluator will not have access to the treatment site where the protocol will be performed to reduce the possibility of interfering with the blinding.
INTERVENTIONS
Exercise prescription
The exercise program will consist of 1) cardiovascular training; 2) strengthening; and 3) unsupervised stretching exercises performed at home. The cardiovascular exercises will be performed using a cycle ergometer and the rubber step. The muscle strengthening will be performed using resistive loads for the calf muscles. The participants will receive a written and illustrated guide for performing active stretching exercises of the calf and tibialis anterior muscles once a day for 20 seconds (each muscle group) at home 24 hours after supervision [22]. The exercise program will last ~40 minutes and will be performed twice a week, for a total of 16 sessions. The heart rate and blood pressure will be checked at the beginning and end of the training, as well as at the end of each series.
1. Cardiovascular training
a) Cycle ergometer exercise
The perceived fatigue of the participants will be measured using the modified 0-10 BORG scale [23], every five minutes. The participants will warm up for 5 minutes on the cycle ergometer without load at the beginning of the protocol. Next, the participants will perform the aerobic exercises using the cycle ergometer for 15 minutes. The load will be adjusted at a setting up to moderate intensity (between 4 -6 of the modified BORG scale 0-10).
b) Bench step up exercise
The bench step-up exercise will be performed on a rubber step at a height of 20 cm. The participants will be instructed to walk up and down on steps with one foot at a time using free cadence. They will be instructed to perform the movement as fast as possible for a maximal of 12 repetitions and exercise progression (5 to 10 repetition) will be weekly increased, according to individual tolerance.
The load during the program execution may be decreased, the rest time increased or the session interrupted if the subject reports very intense perceived fatigue (7 or above, BORG scale), complains of limiting pain, or develops symptoms incompatible with physical activity. The participants will perform only the exercises under supervision of the physiotherapist responsible for the study protocol. The patients showing exercise limitation due to pain, change in medication, undergo any alternative treatment, or miss 3 consecutive intervention sessions will be excluded. The data will be included in records for further analysis even after exclusion. Medical assistance will be provided to any participant who has an injury caused by the study in accordance with the resolution 466/12 of the National Health Council.
2. Resistance training
To strengthen and increase endurance of the calf muscle, the patients will perform at 80% of 1 RM. The submaximal load of 10 RM (repetition maximum) estimated percentage 80% of 1RM [24] will be individually calculated based on momentary muscle failure (inability to perform 10 concentric contractions without significant posture change and repetition velocity during changes against a certain resistance) [25]. To calculate the submaximal load of 10 RM, weight will be added until momentary muscle failure of the individual is achieved during calf raise exercises. The last load successfully lifted before momentary muscle failure will be used. The calculated load will be used to customize the training level and will be changed according to the patient´s weekly performance. The exercise will consist of 3 sets of 10 repetitions with a 1-minute rest interval. Successive load progression will be made during the programme, maintaining the same volume according to the patient’s performance. The exercises during the initial sessions will be performed without any load. The loads will be applied using an adjustable weight vest according to each patient.
Health education speeches
All the participants will be invited to attend an educational speech about the disease, risk factors, lifestyle changes, and lower limb care (hygiene, exercises, dressings), as well as the benefits of using compressive techniques. The speeches will be performed (immediately after the first assessment) by a blinded evaluator for allocation group who will perform the evaluations and reassessments.
Prescription for compression stockings
Compression stockings will be prescribed for those participants not using compressive techniques yet. Prescription will be based on clinical severity. CEAP C2-C3 compression of 20-30 mmHg, CEAP C4 to C6 30 to 40 mmHg compression and, patients with recurring ulcers compression of 40 to 50 mmHg [2]. Compliance (adherence to the use of socks) will be recorded daily in a notebook.
Strategies to improve adherence to intervention protocols
After the first session of the exercise programme, the participants will receive a follow-up guide containing questions regarding compressive therapy, stretching and lower limb positioning during rest.
Relevant concomitant care and interventions that are permitted or prohibited during the trial:
The controls will be instructed to maintain their usual activities and treatments and not perform any type of supervised exercises during the 2 months after their first evaluation.