Stroke has a significant impact on morbidity, mortality and healthcare expenditure globally. In addition to the motor and cognitive consequences, as well as on functional independence and social participation, it can produce alterations in the respiratory function. Scientific evidence supports the application of both therapeutic exercise programs and respiratory muscle training (RMT). However, studies that combine both interventions are limited, and to date no study has been published that examines the effectiveness of this combination in the subacute phase of stroke, which is the one that presents the widest range of neuroplasticity. Objectives: To analyze the effects of a combined therapeutic exercise and RMT program, compared to the therapeutic exercise and sham RMT program, on different variables related to functional, respiratory, swallowing and speech/voice capacity, in patients in the subacute phase of a stroke. Type of research: double-blind randomized controlled clinical trial. Design: The study will be carried out at the University Hospital Complex of A Coruña (CHUAC), where 64 patients with more than three and less than six months of evolution after a stroke will be recruited. Participants will be randomly assigned to two groups: the intervention group will perform a combined therapeutic exercise and RMT program, while the control group will combine the same therapeutic exercise program and sham RMT. The duration of the intervention will be eight weeks. The therapeutic exercise program will be carried out three days per week and will consist of a cardiovascular exercise part and a strength-endurance part. The RMT protocol will involve both the inspiratory and expiratory muscles, using the Orygen-Dual Valve® device. The control group will use the same valve but without resistance, generating a sham RMT. It will have a frequency of five days per week and will be carried out at the home of each patient. Additionally, half the subjects in the intervention group will continue the RMT protocol once the eight-week period has ended, with a frequency of two days per week, until the six-month follow-up. Possible differences between groups will be analyzed before and after the intervention, and at three and six months of follow-up, in relation to the following domains: functional capacity, functional independence, lung and respiratory muscle function, swallowing and speech/voice function, respiratory signs and symptoms, and quality of life.
This protocol is designed to analyze the effects of a therapeutic exercise program combined with an RMT protocol in patients with subacute stroke, compared to another group that will perform the therapeutic exercise program combined with sham RMT in relation to different functional variables. Sample size assessment: The sample size calculation was performed using the G\*Power software and based on the 6 Minute Walk Test (6MWT), chosen as the main variable. The minimum clinically important difference (MCID) data from the study by Fulk et al. (MCID=130) and the standard deviation (SD) from the study by Baker et al. (conducted in patients with subacute stroke in the United Kingdom, SD=143) were used. For a two-sided hypothesis, with a statistical power of 90% and a significance level of 0.05, a sample size of 32 subjects per group would be required (assuming a 20% loss over the course of the study). Additionally, a pilot phase will be developed at the beginning of the study with eight other subjects who will not be part of the final sample, in order study the feasibility of the project. Plan for missing data: At the end of each assessment session, all questionnaires will be checked to ensure they are complete and filled out correctly. If a participant does not attend a session, they will be phone called and rescheduled for that session. In cases where data are reported as missing, unavailable, or uninterpretable due to inconsistencies or out-of-range results, a plan will be implemented to manage these cases. Strategies will include imputing missing data and excluding cases. Statistical analysis plan: Anaconda® software and the Python 3.8.8 programming language will be used. A descriptive analysis of the variables included in the study will be performed initially. For qualitative variables, absolute frequencies and percentages will be presented, and for quantitative variables, measures of central tendency (mean/median) and dispersion (range/standard deviation) will be presented, depending on whether they are normal or non-normal. The normality of the sample will be tested using the Shapiro-Wilk test. Per-protocol and intention-to-treat analyses will be performed to determine the effectiveness of the treatment both under ideal conditions of protocol adherence and in a more realistic context of losses throughout the intervention. To compare the results of the outcome measures between the study groups throughout the intervention, a repeated-measures ANOVA will be applied with a within-subject factor, time, which has four levels (pre-training, post-training, and at three and six months post-training), and a between-subject factor, the type of intervention (therapeutic exercise + RMT or therapeutic exercise + sham RMT). Another repeated-measures ANOVA will be applied with the same within-subject factor, and the presence or absence of maintenance sessions as a between-subject factor (only for the intervention group). The level of statistical significance will be set at p\<0.05.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
64
For the RMT protocol, the Orygen-dual valve® device will be used. Each participant will start with a load of 30% of the maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP). Once every 10 days, the performance will be reviewed and the resistance will be increased by 10cmH2O of the initial MIP/MEP of each patient. Each session will consist of breathing through the device for 20 minutes (10 minutes dedicated to each muscle group). This process will be repeated once a day, five days a week, for eight weeks. The therapeutic exercise program will be common to both groups and will be carried out at CHUAC hospital, in group sessions. The sessions will be held three days a week, for eight weeks. Each session will consist of a 10-minute warm-up part, 45 minutes of the main part (aerobic and strength-resistance exercise), and five minutes of cooling down.
The sham RMT protocol will have the same frequency as in the intervention group. The therapeutic exercise program will be common to both groups and will be carried out at CHUAC hospital, in group sessions. The sessions will be held three days a week, for eight weeks. Each session will consist of a 10-minute warm-up part, 45 minutes of the main part (aerobic and strength-resistance exercise), and five minutes of cooling down.
University Hospital of A Coruña (CHUAC)
A Coruña, Spain
Exercise capacity
The metric used to characterize the primary outcome measure will be the 6MWT. The 6MWT is a constant-load walking test that evaluates submaximal functional capacity. It consists of determining the distance a patient is able to walk at the maximum possible speed in six minutes, using standardized instructions. It will be carried out following the international standards of the American Thoracic Society (ATS) and the European Respiratory Society (ERS). The test will be performed in a hallway, with two markers delimiting the 30-meter distance. Every minute during the test, oxygen saturation, heart rate (HR), and dyspnea and fatigue of the lower limbs will be recorded, and blood pressure (BP) will be measured both before and after the test. In the first assessment session, two attempts will be made due to the learning effect, separated by a 30-minute rest period or as long as necessary until vital signs recover. A single attempt will be made in subsequent measurements.
Time frame: The 6MWT will be assessed before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Sociodemographic data
Description: The following characteristics will be collected during the personal interview:(15,16) * Sociodemographic data: sex, age, nationality, employment status. * Toxic habits: information on smoking habits. * Medical history. * Medication use. * Information on the stroke: time elapsed, type, affected region. * Rehabilitation process: type, disciplines involved, weekly duration, technical aids.
Time frame: The personal interview will take place once, before the intervention.
Anthropometrics
Height, weight, and body mass index (BMI) will be recorded. Weight and height will be measured without shoes and without clothing that significantly increases weight and is easy to remove. Participants must also remove any items they may carry in their pockets that increase their weight (e.g., keys, cell phone, or wallet). BMI will be calculated using the formula BMI = weight (kg) / height (m2).
Time frame: Height, weight and BMI will be recorded in the first session (before intervention), and weight and BMI will be recorded in all assessment sessions (before and after intervention, and at the 3rd and 6th month of follow-up).
Upper and lower limb motor function
It will be assessed through the motricity index (MI). It is an ordinal method for measuring motor function and limb strength developed by Demeurisse et al. in 1980. It assesses the following movements: digital pinch between the thumb and index finger, elbow flexion, shoulder abduction, ankle dorsiflexion, knee extension, and hip flexion. It has a minimum score of 0 and a maximum of 100, with each test being given a value between 0 and 33. All tests are performed with the patient in a sitting position.
Time frame: The MI will be assessed before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Fall risk
The Timed Up and Go test (TUG) assesses mobility, balance, gait ability, and fall risk. The test begins with the patient seated in a chair with their back against the backrest. Upon command from the therapist, the patient must rise from the chair, walk three meters as quickly as possible to a marker (e.g., a cone), turn around the marker, return to the chair, and sit down. Timing begins upon the therapist's command to rise and ends when the patient is seated again. One attempt will be performed, accompanied by a practice pretest that will not be included in the score. For the stroke population, it has a minimum detectable change of 2.9 seconds and excellent test-retest reliability and criterion- and construct-related validity.
Time frame: The TUG will be administered before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Balance
It will be assessed using the Berg Balance Scale (BBS), which is an objective 14-item measure that evaluates static balance and the risk of falling in adults. The items that comprise it include static and dynamic activities of varying difficulty. The scores for each item range from 0 to 4, depending on the execution of the activity evaluated. Finally, the scores for all items are summed (maximum score = 56). The Berg scale has been frequently used in other studies with stroke samples, since it is associated with quality of life, and is sensitive (80%) and specific (78%) in identifying subjects at risk of falling after a stroke. In addition, it has excellent test-retest reliability, inter- and intra-rater reliability, internal consistency, criterion validity, and construct validity in the stroke population.
Time frame: The BBS will be administered before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Lower limb strength
The Five Times Sit to Stand test (5TSTS) provides a method for quantifying functional lower extremity strength and identifying movement strategies that a patient uses to complete a transfer. The test begins with the patient sitting in a chair, arms crossed over the chest and back against the backrest. At the therapist's command, the patient must rise from the chair and return to sitting for five repetitions, as quickly as possible. Timing ends when the patient reaches the sitting position after the last repetition. An attempt will be made, accompanied by a pre-test practice that will not be included in the score. Failure to complete the five repetitions without assistance or use of the upper extremities indicates test failure. The test has a cutoff point of 12 seconds to discriminate between healthy subjects, the elderly, and those with chronic stroke.
Time frame: The 5TSTS will be administered before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Functional independence
The Functional Independence Measure (FIM) provides a uniform system for measuring disability based on the International Classification of Functioning, Disability and Health (ICF). It measures a patient's level of disability and indicates the amount of assistance required to perform ADLs. Tasks are rated on a seven-point ordinal scale ranging from full assistance (or total dependence) to complete independence. Scores range from 18 (lowest) to 126 (highest), indicating the level of function. It contains 18 items, comprised of 13 motor tasks and five cognitive tasks. This scale has an MCID of 22 points in stroke subjects and exhibits excellent internal consistency and criterion validity, adequate construct validity, minimal ceiling and floor effects, and high sensitivity in stroke patients.
Time frame: The FIM will be administered before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Functional ambulation
The Functional Ambulation Category (FAC) assesses the patient's dependence for functional gait. The evaluator must check one of the following six boxes: 0\) The patient is unable to walk or requires assistance from two or more people. 1. The patient requires firm, continuous support from a person to assist with weight bearing and balance. 2. The patient requires continuous or intermittent support from a person to assist with balance and coordination. 3. The patient requires verbal supervision or assistance from a person without physical contact. 4. The patient can walk independently on level ground but requires assistance on stairs, slopes, or uneven surfaces. 5. The patient can walk independently anywhere. A difference greater than four points in stroke patients has a sensitivity of 100% and a specificity of 78% in predicting community ambulation at six months. It also presents excellent test-retest reliability values and both intra-rater and inter-rater reliability.
Time frame: The FAC will be assessed before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Pulmonary function (FEV1/FVC)
Pulmonary volumes and flows will be obtained by forced spirometry, which consists of a maximum deep inspiration followed by a forced and sustained expiration through a spirometer. Additionally, another maximum inspiration will be performed at the end of the maneuver to obtain an inspiratory branch in the graph resulting from the test, as a quality criterion. The patient will remain seated during the test and will use a nose clip while executing the maneuvers. Forced spirometry will be performed following the recommendations of the ATS and ERS, and using a Datospir Aira spirometer (Sibelmed®, Barcelona, Spain). A minimum of three technically acceptable maneuvers will be obtained, with two being reproducible (\<150 ml or \<5% forced vital capacity (FVC) or forced expiratory volume in 1 second (FEV1) difference). FVC and FEV1 will be recorded. FVC and FEV1 will be combined to report FEV1/FVC.
Time frame: The forced spirometry will be assessed before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Pulmonary function (PEF)
Pulmonary volumes and flows will be obtained by forced spirometry. Forced spirometry will be performed following the recommendations of the ATS and ERS, and using a Datospir Aira spirometer (Sibelmed®, Barcelona, Spain). Peak expiratory flow (PEF) will be obtained.
Time frame: The forced spirometry will be assessed before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Pulmonary function (FEF25-75%)
Pulmonary volumes and flows will be obtained by forced spirometry. Forced spirometry will be performed following the recommendations of the ATS and ERS, and using a Datospir Aira spirometer (Sibelmed®, Barcelona, Spain). Forced expiratory flow between 25% and 75% of the FVC (FEF25-75%) will be obtained.
Time frame: The forced spirometry will be assessed before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Strength of the inspiratory and expiratory muscles
Respiratory muscle strength will be obtained from the MEP and MIP. The recommendations of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) will be followed. The measures will be determined using a pressure transducer with a diving-type mouthpiece, and the patient will perform the maneuvers in a sitting position with a nose clip. Forced and maximum expiration and inspiration will be performed, respectively, for three to five seconds, trying to maintain a constant force against the resistance offered by the device. The MicroRPM® Carefusion device (Vyaire Medical GmbH, Hoechberg, Germany) will be used, connected to the PUMA® software (Vyaire Medical GmbH, Hoechberg, Germany). A minimum of six maneuvers will be performed (out of a maximum of ten), with the goal of obtaining three technically correct, reproducible maneuvers with a variation of less than 5%.
Time frame: The maximal respiratory pressures will be assessed before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Cough capacity
It will be measured using a portable peak cough flow (PCF) meter connected to an orofacial mask (to prevent potential air leaks in the presence of mild facial paralysis), designed to quantify the maximum air flow expelled during a forced cough. This procedure evaluates the effectiveness of coughing in clearing secretions from the airways and is especially relevant in patients with neuromuscular or respiratory conditions. The patients will perform the maneuver in a seated position. They will be instructed to take a maximum inspiration from total lung capacity, after which they will adjust the orofacial mask around their mouth and cough forcefully. The device records the maximum air flow generated during the cough, expressed in liters per minute (L/min). Three attempts will be made, and the highest value will be recorded.
Time frame: The PCF will be assessed before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Severity of dysphagia
The Gugging Swallowing Screen (GUSS) is a bedside dysphagia screening tool for patients with acute stroke. It assesses the severity of dysphagia as well as the level of aspiration. It evaluates the ability to swallow saliva, semisolid, liquid, and solid textures. It also notes the presence of a cough or throat clearing at rest, as well as changes in voice. Oxygen saturation is monitored using a pulse oximeter during the test. Several studies have reported that the GUSS has a sensitivity of approximately 100% and a specificity of 50% to 69%.
Time frame: The GUSS will be administered before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Swallowing-related quality of life
The Swallowing Quality of Life Questionnaire (SWAL-QoL) is a self-administered questionnaire designed to assess quality of life in patients with oropharyngeal dysphagia. It consists of 44 items divided into 11 different domains. Each item is scored on a 5-point Likert scale. Each item is weighted and summed to obtain an overall score (0-100), with a lower score indicating poorer swallowing-related quality of life.
Time frame: The SWAL-QoL will be administered before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Voice parameters
Perceptual auditory assessment is the gold standard for defining voice disorders and providing an immediate measure of voice severity. PRAAT is a freely distributed program widely used in clinical practice. This program performs an acoustic analysis of the voice, providing objective information. It analyzes the average fundamental frequency, intensity, and all its variations. It provides disturbance indices and irregularity and noise measurements, which are used to analyze the harmonic component and emission regulation. The sample recording should be made at a frequency of 20,000 hertz (Hz), with ambient noise less than 50 decibels (dB), and the microphone should be placed at a distance of 10 centimeters, at an angle of 45° to 90°. Each patient is recorded saying a simple sentence at a comfortable pitch and intensity, recording three attempts to assess whether there is variability in vocal quality, one slightly more intense attempt to assess possible changes in quality.
Time frame: The PRAAT recordings will be assessed before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Vocal quality
The GRABS scale is the most reliable and widely used scale for the perceptual assessment of vocal quality. It consists of five parameters and four categories based on the severity of the disorder. These parameters are: G (grade), which assesses the overall degree of vocal disorder, dysphonia, or hoarseness; R (roughness), which assesses hoarseness and harshness; A (asthenic), which assesses the degree of asthenia and fatigue in the voice; B (breathy), which assesses a voice that is airy, muffled, or breathy; and S (strain), which assesses a tense, spastic, and constricted voice. Scores range from 0 to 3, with 0 being normal, 1 being mild, 2 being moderate, and 3 being severe. This scale has been validated and used in several studies and exhibits high diagnostic quality. It is a non-invasive test that is easy to use, requires no training for its application and does not require a high cost. The sample is collected through conversational speech heard during the interview.
Time frame: The GRABS scale will be administered before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Aerodynamics (MPT)
Maximum Phonation Time (MPT) consists of producing the vowel /a/ at a comfortable intensity and pitch for as long as possible. A prior demonstration is required. Three attempts are made, selecting the longest one to compare with the standard. If the value obtained is less than ten seconds, it would indicate abnormal respiratory function, poor glottal closure, or exaggerated glottal closure.
Time frame: The aerodynamics will be assessed before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Aerodynamics (MBT)
Maximum blow time (MBT) allows the relationship between phonation and expiration to be analyzed through the so-called s/z ratio.
Time frame: The aerodynamics will be assessed before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Aerodynamics (s/z ratio)
The s/z ratio or phonorespiratory coefficient is the result of dividing the maximum emission time of a consonant /s/ by the maximum phonation time of an /a/, with the purpose of relating pulmonary and laryngeal function. Under normal circumstances, it should be approximately 1. When glottal efficiency is impaired, high values are obtained, with 1.4 being the normal limit.
Time frame: The aerodynamics will be assessed before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Severity of dysarthria
The National Institute of Health Stroke Scale (NIHSS) will be used. This scale measures the severity of symptoms associated with a stroke, is used as a quantitative measure of neurological deficit and has good psychometric properties. Item 10, dedicated to dysarthria, will be recorded: a speech sample is obtained from the patient, asking them to read or repeat a series of words. It will be scored as follows: 0 = normal; 1 = mild to moderate dysarthria (can be understood with some difficulty); 2 = severe dysarthria (unintelligible or anarthria); 9 = unverifiable, if the patient is intubated or has other physical barriers to speech production (the justification for this choice must be given).
Time frame: The item 10 of the NIHSS will be assessed before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Dyspnea
The Modified Medical Research Council (mMRC) dyspnea scale determines the severity of shortness of breath during everyday activities, classified into 5 grades: 0\) No dyspnea, except with intense exercise. 1. Dyspnea when walking briskly or climbing a gentle slope. 2. Difficulty maintaining a pace when walking on level ground or keeping pace with other people of the same age. 3. Need to stop after walking 100 meters or a few minutes. 4. Severe dyspnea resulting in inability to leave the house or dress without assistance. This scale is recommended by various clinical practice guidelines and is used as an inclusion criterion for clinical trials.
Time frame: The mMRC will be administered before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Self-perceived effort
The Modified Borg Scale measures self-rated exertion, as determined by dyspnea and fatigue, during physical activity. It has the potential to provide rapid and easy information on a patient's subjective state of dyspnea and fatigue. It has 11 levels, from 0 (minimum) to 10 (maximum). It is a valid and reliable assessment tool for dyspnea.
Time frame: The Modified Borg Scale will be assessed before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
Respiratory complications
They will be recorded through an interview and review of medical history. The following situations are understood to be respiratory complications: hospital admissions for respiratory reasons, emergency room visits for respiratory reasons, and/or lung infections requiring medication.
Time frame: The number and type of respiratory complications will be registered at baseline and until the 6-month follow-up period.
Quality of life (SIS-16)
The Stroke Impact Scale (SIS-16) assesses physical function after stroke. The SIS-16 consists of 16 items from the four physical domains (strength, hand function, mobility, and ADL/instrumental ADL) of the SIS 3.0. It has an MCID of 9.4-14.1 for subacute stroke and excellent test-retest reliability, internal consistency, and criterion- and construct-related validity.
Time frame: The SIS-16 will be administered before the intervention, at the end of it (after 8 weeks) and at 3rd and 6th month of follow-up.
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