Effects of different modalities of inspiratory muscle training as an add-on to conventional treatment of patients with chronic obstructive pulmonary disease (COPD): study protocol for a randomized controlled trial

The PR protocol will be performed three times a week for 10 consecutive weeks. All activities will be supervised by a previously trained respiratory therapist in a room with a controlled temperature set between 23 and 26 °C. All individuals will be instructed to perform the rehabilitation program 5 days a week — 3 days with supervision and 2 without supervision — for at least one hour a day, according to the recommendations of the guideline on PR in adults [13]. Subjects will receive orientation to fill in the unsupervised exercise diary regarding type of exercise, duration, and frequency as well as for symptoms referenced during the activity using the modified Borg scale (from 4 to 6) to limit the intensity of the exercise [14].

All three groups will submit to a conventional rehabilitation program consisting of aerobic exercise on a treadmill. For the first week, the subjects will perform 20 min of activity. A resting period lasting 2 min maximum will be allowed whenever requested by the subject. The training time will be increased after the 5th week to reach 30 min of daily activity [15]. Aerobic exercise will be performed on a treadmill, with a velocity corresponding to 70% of the maximum velocity achieved in the Incremental Shuttle Walking Test (ISWT) [16]. Ten percent of the starting time (2–3 min) of the training will be at a speed of 40% of the maximum speed reached in the ISWT for heating, 80% of the training time (17–25 min) will be at the target speed (70% ISWT), and the remaining 10% of the time will be cooling, with the same speed as for heating, reducing the speed to zero at the end of the training period [17, 18]. The physical activity training will be interrupted whenever the degree of dyspnea sensation reaches 4–6 (intense) on the Borg scale [14] or the heart rate (HR) exceeds 85% of the individual maximum HR value (220 – age). If the saturation drops (SpO₂ < 90%) [19] during the exercise, we will administer supplemental oxygen at minimal flow with a nasal cannula to maintain higher than 90% saturation. The patients will be monitored every 5 min. Participants will be instructed to maintain aerobic activities on days that they are not performing the supervised PR program. Strength training for lower and upper limb muscles will be performed through a program consisting of 3 sets of 12 repetitions, initially using 60% of 1 maximal repetition (1RM), and this load will be increased to 70% by the 5th week and 80% in the 8th week of training [20]. For the upper limbs the training will be directed to the biceps, triceps, pectoral, and deltoid muscles, and for the lower limbs, the training will be for quadriceps and triceps femoris [3]. Guidance in energy conservation techniques as well as educational speeches regarding self-management of the disease will be provided [13]. The PRWIMT group will perform PR and IMT without any load; the PRIMTLL group will perform PR and IMT with a linear load; the PRIMTIVH group will perform PR and IMT with isocapnic voluntary hyperpnea.

Patients will be assessed for their height and body weight through an anthropometric scale coupled with a Filizola stadiometer (Filizola PL200®, São Paulo, Brazil) and a maximum capacity of 200 kg in order to calculate body mass index (BMI). As proposed by Quetelet (1835), BMI has been used by the World Health Organization (WHO) since 1997 as a reference measure of obesity worldwide and is expressed as the weight in kilograms divided by the square of the height in meters (weight/height²) [27].

Lung function will be assessed using a KoKo DigiDoser spirometer (Nspire Health, Longmont, CO, USA). Technical procedures, acceptability, and reproducibility will follow the recommendations of the American Thoracic Society/European Respiratory Society (ATS/ERS) [28]. Subjects will perform between three to eight maneuvers, and the best three will be recorded with variability less than 5% or 200 ml. The test will be performed before and after the use of an inhalation bronchodilator. Absolute and predicted values of FEV₁, FVC, and FEV₁/FVC will be considered and analyzed using a previously published equation for the study population [29].

The dynamic muscular endurance test (MVV) will also be performed. The dynamic test will be performed by MVV during 15 s (MVV_15s) using a KoKo DigiDoser spirometer (Nspire Health). The individual will be positioned in a seated position on a bench with a nose clip and will be instructed before the beginning of the test to “breathe as fast and deep as possible.” During the test, active stimulation will be carried out with the cadence “pull and drop, pull and drop” to maintain a constant and regular rhythm with the same volume and frequency during the whole test. The maneuver will be assessed by three tests of 15 s. The highest value will be considered the best test. A difference less than 10% among the tests will be set [28, 29].

Respiratory muscle strength will be measured using a MicroRPM digital manometer (NEPEB-LabCare/UFMG, produced in Belo Horizonte, Brazil). Technical procedures, acceptability, and reproducibility will follow the recommendations of the ATS/ERS (2002) [30]. To obtain MIP, the individual will be instructed to perform one maximal expiration (close to residual volume, RV) followed by a maximal inspiration (close to total lung capacity, TLC). To obtain maximal expiratory capacity (MEP), the individual will be instructed to perform a maximal inspiration (close to TLC) followed by a maximal expiration (close to RV) [31]. A maximum of five maneuvers will be performed for each evaluation, and the highest value will be considered so that the difference among the maneuvers does not exceed 10% among the best three tests. Obtained values will be compared to reference values for the Brazilian population [32].

The SNIP, or sniff, test will be performed with one nostril occluded by a nose clip connected to the manometer through a catheter measuring approximately 1 mm. The maneuver will be performed from functional residual capacity (FRC). The individual will be instructed to perform a slow sustained expiration followed by a maximal sniff (inspiration) through the contralateral nostril. All subjects will perform 10 maneuvers with a 30-s interval among them [33]. The highest maneuver will be compared to previously described equations to determine reference values for the studied population [34].

To measure SPImax, the same manometer will be used. The manometer will be connected to a diver through an acrylic piece with an air leak orifice of 2 mm and a 6-mm occlusion orifice. The manometer will communicate with software (Manovac 3.0-A), whereby the data will be accessed after being collected [35‐37]. Individuals will be instructed to breathe quietly close to tidal volume through the nozzle connected to the manometer for three consecutive breaths. The evaluator will give the following verbal command: “Push the air out, push the air into ... ”. The next steps are as follows: (1) slow exhalation, close to the residual volume at the verbal command “Push all the air out ... ”; (2) signaling the end of the total and slow exhalation by the patient, shown by raising the left arm; (3) obstruction of the occlusion hole by the evaluator, and (4) achieving a maximum inspiratory effort, near to total lung capacity, which will be sustained as long as possible, at the command: “Take a deep breath! And hold it, hold it ... ... ... hold it” [30, 37, 38]. The test will be considered complete when the subject performs at least three acceptable efforts, which means with no air leakage between the lips and the mouthpiece and/or nose clip, and of these, two reproducible efforts (with variation equal to or less than 10% of the test, with the variable area under the pressure-time curve value, since it was not the last test). Up to eight inspiratory efforts will be performed, with a one-minute interval between the tests [39].

Analysis of respiratory kinematics integrated to signals of lung volumes, flow, pressure, and respiratory muscle activity will be assessed during a spirogram (one minute of quiet breathing [QB] followed by a maximum respiratory cycle, 20 s of QB, a maximum voluntary ventilation for 15 s, and one minute of QB). All signals will be integrated using Optoelectronic Plethysmography (OEP) System; BTS, Milan, Italy). The evaluation of flow and pressure generated in the airways will be performed using a Series 0–800 lpm pneumotachograph (flow measurement head), interconnected to a Series RSS100HR amplifier (Research Pneumotach System, Hans Rudolph, Inc.; Shawnee, KS, USA). The chest wall volumes and its compartments (rib cage pulmonary, rib cage abdominal, and abdomen) will be assessed by OEP System. This system allows the computational kinematic analysis of the three dimensions of the chest wall complex through 89 optical sensors placed on the chest wall. The sensors, small hemispheres (5 mm in diameter) coated with a reflective substance, will be circumferentially placed on the three horizontal regions of the chest wall between the collarbone and the superior iliac spine. Sensors will be placed in five vertical columns on the anterior and posterior regions and in two additional columns on the axillary line [40‐43]. The limit between the pulmonary and abdominal rib cage will be assumed at the xiphoid process level, and the limit between the abdominal rib cage and abdomen will be assumed as the lower anterior costal margin and lower posterior costal margin. Coordinates of the sensors will be assessed by using a kinematic configuration system in eight photosensitive cameras (four on the front region and four on the back region) with an acquisition frequency of 60 Hz. Based on the captured images, the volumes of the chest wall will be computed by a triangulation surface. Respiratory pattern volume, flow, and time will be considered for the analysis. Additionally, operational volumes (end inspiratory volume and end expiratory volume) will be evaluated [44].

Upper limb muscle strength will be obtained by hand dynamometry on the dominant side using Jamar equipment (Sammons Preston, Bolingbrook, IL, USA). Three reproducible tests will be performed (≤ 5%), and the highest obtained value will be considered for analysis using a previously described reference equation [45]. Lower limb muscle strength will be assessed using the maximal repetition (MR) test of the dominant limb on an extension board (405 Embreex Physicus, Brazil) with a load capacity of 50 kg [46].

The 6MWT will be performed following the technical procedures described by the ATS [47]. Respiratory rate, heart rate, and peripheral oxygen saturation (SpO₂) by portable pulse oximeter (Nonim Medical, Inc., 2500A, Plymouth, MN, USA) and systemic arterial pressure (SAP) using an analogue tensiometer (Becton Dickinson - BD®, Brazil) and a stethoscope (Littmann® classic II, 3M, Saint Paul, MN, USA) will be assessed before, immediately after, and 2 min after the end of the test. The subjective symptoms of dyspnea and fatigue of lower limbs will be evaluated with the modified Borg scale, from 0 to 10 [14]. Heart rate and SpO₂ will be monitored every minute during the test. At the end of the test, the total distance walked will be calculated, and the equation of Iwama et al. [48] will be used to calculate the predicted walking distance during the test. To evaluate the maximum work (Wmax) performed during the 6MWT, the equation proposed by Hill et al. [49], which is based on the subject’s body weight, will be used. The predicted values of distance will be calculated according to Iwama et al. [48].

The ISWT will be performed according to Singh et al. [50]. The test will be interrupted by subject exhaustion or if the individual is not able to keep the proposed speed. Respiratory and cardiac frequency, SpO₂, SAP, and subjective symptoms of dyspnea and lower limb fatigue will be measured before and after the test with the modified Borg scale [14, 51]. The equation of Probst et al. [52] will be used to calculate predictive walking distance in the study.

Perceived dyspnea will be evaluated by the modified Medical Research Council (mMRC) scale, which has five different items in which the subject chooses the one that corresponds to the limitation caused by dyspnea in their activities of daily living (ADL) [53].

The Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) aims to determine the impact of COPD on health status [54]. This questionnaire is simple and easy to apply, consisting of 8 questions about general symptoms and limitation in ADL. The score varies from 0 to 5 points in each item, totaling a maximum of 40 points, and this score has been included in the new classification of patients with COPD, to direct medication treatment and define mortality risk. Lower scores correspond to a low impact of the disease on health status and scores above 10 are representative of patients with higher risk, with poorer health status due to COPD [1]. The Portuguese version will be used, validated for the Brazilian population [55].

The sample size was calculated using two-way analysis of variance (ANOVA) for repeated measures by analyzing walking distance and the standard deviation in meters on the 6MWT from previously published data [15]. A two-tailed alpha error of 0.01 was implemented with a power of 95%, considering clinical improvement for COPD patients after PR and a difference of 30 m between groups on the walking test. For the calculations, the following means and standard deviations of the time observed in the 6MWT in the rehabilitation and control groups were used: pre-PR 312.43 ± 51.26 and post-PR 342.85 ± 48.82 m (rehabilitation group); pre-PR 305.13 ± 54.60 and post-PR 298.20 ± 52.81 m (control group), and a sample size of 32 subjects was found (effect size = 1.04). As the study of Elci et al. [15] was composed of two groups (rehabilitation and controls) and ours will be composed of three groups, we will assume that the 32 subjects will be part of the rehabilitation program (the PRIMTLL and PRIMTIVH groups), and 16 more subjects will be added as a study control group for a total sample of 48 subjects. In addition, 12 more subjects will be added into the study, because we will also assume a 20% loss to follow-up as well as 5% missing data, for a total sample size of 60 subjects.

The research team is responsible for monitoring the study. At each supervised training session, participants will be asked if they have had any changes during the course of their activities, in addition to being monitored with parameters, as described previously, that may be implied in interruption of the activity or withdrawal of the subject from the PR program.

The results found in this study will be presented in specific scientific conferences and will be submitted for publication in peer-reviewed journals.