The primary objective of this study is to explore the impact of MDRT on the diaphragm’s function, particularly on the length-tension relationship and chest wall expansion (CWE) in people suffering from asthma. Secondary improvements are expected in the domain of dyspnea, asthma control and dysfunctional breathing. The MDRT in people with asthma may contribute to better disease management.

The present RCT will be a single centric, two arm parallel equivalence randomized clinical trial. This RCT followed the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement. ²⁵ The completed SPIRIT checklist of the study is uploaded into an approved open repository (Reporting guidelines paragraph). The study’s flowchart is shown in Figure 1.

The laboratory of Advanced Physiotherapy at the Physiotherapy Department of the University of West Attica (UNIWA) in Athens will be responsible for coordinating the trial. The recruitment of the patients will be conducted from the Pulmonology Department of the General Oncology Hospital of Kifissia “Agii Anargiri” (GOHK) in Athens (Greece). The hospital’s research committee approved the protocol (4479/09-03-22). Interventions and assessments will take place individually (home-based treatment) in Athens (Greece).

The participants will be recruited from the GOHK. All participants will be out-patients with diagnosed stable asthma, referred by the director, pulmonologist, of the Pulmonary Department of the GOHK. The same pulmonologist will perform lung function testing on all participants (well-maintained and regularly calibrated equipment), will diagnose asthma and perform the measure of chest expansion. A radiologist will perform the ultrasonography (US) and a statistician will process the required analysis. Two separate physical therapists will implement the DMRT and BRE. All participants will read and sign the consent form. The declaration of consent refers to personal data privacy and participation protection. They will subsequently be informed about a) the objectives, methods, and details of the study, (b) that it will be the volunteers’ decision whether to take part or not, (c) they will always have the right to withdraw from the research even after signing, (d) they can also refuse to answer questions they will not wish or remain in the survey and (e) that the patient’s decision to participate will not affect the provision of our research services.

Following the initial assessment, eligible volunteers will be randomly assigned to two experimental groups if they meet the inclusion criteria by the secretariat of the Pulmonology Department of the GCHAA. The randomization will be carried out using sealed envelopes. Individuals will have their allocation concealed through the use of sealed envelopes that are sequentially numbered and opaque. ²⁶ The envelopes will be opened only by the primary researcher, who is responsible for the research project and coordination of the study. The pulmonologist who will perform lung function testing on all participants (well-maintained and regularly calibrated equipment), diagnose asthma and perform the measure of chest expansion, the radiologist who will perform the ultrasonography (US), and the two separate physical therapists, who will implement the DMRT and BRE will be unaware of the group allocation.

The pulmonologist of the trial will approach all eligible patients for recruitment into the study. They will be assessed through a set of questions to confirm eligibility. All patients will be requested to provide written informed consent (signed by the main researcher, the subject, and two witnesses) to participate in the study, including permission to publish results, with the understanding that they can withdraw at any time.

At least 24 adults will be recruited for the study.

Inclusion criteria: aged – 8-60 years, diagnosed with stable asthma ²⁷ and correct use of the inhaler technique.

Exclusion criteria: Participation in other physical therapy methods, the presence of cardiopulmonary conditions, prior cardiothoracic or abdominal surgeries, recent chest wall or abdominal trauma, unstable hemodynamic parameters (systolic arterial pressure >140 mmHg and diastolic >90 mmHg), inability to comprehend verbal instructions required for outcome assessments, pregnancy, neurological ailments, and concurrent involvement in interventional programs.

A pulmonologist of GOHK with years of experience diagnosing and treating asthma patients will examine the chest expansion, the pulmonary function, and diagnosis of asthma. The radiologist will perform the US assessment, and the secretariat of the GOHK will administer the questionnaires in a random order and collect all data.

Interventions

The pulmonologist and the main researcher of the protocol will organize two online sessions with all the participants after the randomization. In one session, participants will be informed by the pulmonologist about (a) general asthma information, (b) asthma triggers, (c) recognition of asthma symptoms, (d) medication and proper use of asthma medications (inhaler techniques), (e) smoking, and (f) asthma control (symptom control/future risk domains/long-term goals). ²⁸ As for the last domain (asthma control), information will be provided regarding, (i) the dynamic changes of asthma, (ii) the recognition of these changes based on PEF values and symptoms, (iii) the importance of early detection of clinical signs of worsening and the immediate initiation of appropriate medication.

At the second online session the participants will be informed by the main researcher about (a) the breathing pattern, (b) the pathological pattern of breathing that is developing both in stable phase and in paroxysm, ²⁹ (c) the role of physiotherapy and specifically about the BRE in PR, (d) the formation of a trusting relationship between a person living with asthma and a medical professional (e) the importance of self-efficacy in asthma self-management ^{30 – 33} and (f) the self-efficacy enhancement process.

Following the two online sessions, there will be a discussion between patients and health professionals (pulmonologist - main researcher) lasting approximately one hour, during which patients can share their objectives, values, apprehensions, support and commendations. The structure of the online session will be determined by a) the long-term objectives for asthma management ⁵ and b) the health belief model. ^{34 , 35} Regarding the treatment sessions, every participant will receive twelve sessions twice weekly for six weeks, lasting one hour per session. Individual sessions will be provided in patients’ homes under the same conditions ( e.g., day, time of day, temperature, therapeutic bed, and patient’s position).

Physiotherapy intervention will be provided by two physical therapists, trained by the professor of chest physiotherapy and the professor of manual therapy respectively, at the Physiotherapy Department, UNIWA. Any departure from the administration of treatment sessions (such as missing more than one appointment) or any exacerbation of symptoms will lead to exclusion. Brief descriptions of the interventions planned for each group are provided below.

Intervention Group: This group will receive MDRT plus BRE. MDRT is intended to stretch and mobilize the diaphragmatic muscle fibers indirectly. MDRT will be applied as described by Rocha and his colleagues. ¹⁶

MDRT: Participants will be instructed to lie in a supine position with relaxed limbs. The therapist will be positioned at the patient’s head. Manual contact will be made using the hypothenar region and the last three fingers bilaterally, placed under the seventh to tenth rib costal cartilages. The therapist’s forearms will align towards the patient’s shoulders. During inhalation, the therapist will apply gentle pulling and lateral elevation of the ribs in the inspiratory phase at the points of contact. As the participant exhales, the therapist’s touch will deepen towards the inner costal margin while maintaining resistance. This connection will further deepen within the costal margin in subsequent respiratory cycles. The entire process will consist of two sets of 10 repetitions, separated by a 1-minute interval lasting 10 minutes. ³⁶

BRE: BRE will be conducted for 30 minutes. The primary objective of these exercises is to mitigate hyperventilation, hypocapnia, and dysfunctional breathing—common symptoms in individuals with asthma. ³⁷ The initial step involves identifying and inhibiting an abnormal upper thoracic respiratory pattern and re-education of diaphragmatic and slow nasal breathing. Additionally, brief respiratory pauses will be introduced after each exhalation. ³⁸ Subsequently, BRE aims to integrate the new breathing pattern into daily life. This stage focuses on incorporating diaphragmatic and slow nasal breathing into various daily activities, encompassing physical activities (e.g., speaking, swimming, walking, gardening), social activities (e.g., playing with children or pets), and work-related activities (e.g., managing work stress). ³⁹

The phases of BRE will consist of: i) identification of the abnormal breathing pattern, ii) diaphragmatic breathing, ii) nose breathing, iii) slow breathing with controlled breath-holding at the end of exhalation, iv) adaptation of the new breathing pattern in everyday life activities and various positions (supine, semi-sitting, sitting), and v) breathing control in speech.

Control Group: This group will receive only BRE, as mentioned in the intervention group.

The evaluations will take place at three time - points: prior to treatment (week 0), post-treatment (week 6), and three months subsequent (week 12). The primary outcomes will entail the measurement of diaphragm excursion using ultrasound ⁴⁰ and chest expansion (CE) using a tape measure. ⁴¹ Secondary outcomes will also be employed: maximal inspiratory and expiratory pressures (MIP/MEP), ^{42 , 43} dysfunctional breathing (Nijmegen questionnaire – - NQ), ⁴⁴ asthma Control (ACT), ^{45 , 46} quality of life (SF-12v2), ⁴⁷ and dyspnea (Borg scale). ⁴⁸ Table 1 illustrates the SPIRIT schematic protocol of the study along with the schedule of assessments.

Primary outcome measures

Diaphragmatic excursion assessment with ultrasonography: Numerous studies have confirmed the effectiveness of the US to evaluate diaphragmatic function. Since 1970, ⁴⁹ the US has been utilized to assess the diaphragm’s mobility. Modern medicine accepts its use as a completely safe method. The diagnostic US has 93% sensitivity and 100% specificity. ¹⁵ The examiners are not exposed to any radiation, and there is no need for special preparation, allowing for as many safe applications as required. The US offers the option of a dynamic inspection of the affected area in real time. The diaphragmatic excursion is measured in cm/mm.

Chest wall expansion (CWE): In clinical and research practice, the inch tape measure is an alternative method for assessing chest expansion. ⁵⁰ By placing the tape measure at the level of the axilla (about the level of the sternal angle of Louis), the level of the xiphoid process, or between the xiphoid process and the umbilicus, the therapist identifies the upper, middle, and lower chest wall expansion, respectively. The therapist should repeat the measurement at least three times for each level for higher fidelity. ⁴¹ A tape measure (in centimeters) will assess the variance between values recorded during deep inhalation and exhalation, with greater values signifying improved results. ⁴¹ Norms have been developed according to age and sex. ⁵¹

Secondary outcome measures

Nijmegen Questionnaire (NQ): The Nijmegen Questionnaire is a reliable and valid tool for assessing dysfunctional breathing in clinical practice and research. It is designed to identify the Hyperventilation Syndrome (HS). A score greater than 23 indicates the presence of HS in the general population. The NQ has shown 91% sensitivity and 95% specificity. ⁵² In previous research, NQ scores of 20, 22 and 23 have been used as cut-off scores to detect HS in subjects with and without asthma. ^{53 – 55} The NQ questionnaire has been validated in Greek adults with asthma, providing evidence of validity and reliability of measurements with a cut-off score of >17. ⁵⁶

Asthma control test (ACT): The ACT questionnaire is a valid and reliable clinical and research tool. ⁵⁷ Its quick completion time is one of its key features. It has five items, all about the most recent four weeks. ^{57 , 58} The ACT evaluates the frequency of wheezing and other general asthma symptoms and the need for emergency control self-assessment. The score ranges from 5 (poor control of asthma) to 25 (good control of asthma). An ACT score >19 indicates controlled asthma. The ACT has been validated in the Greek population with asthma and has shown high indices of internal consistency (0.72) and test–retest reliability (IR = 0.85). ⁴⁹

Sf-12v2 questionnaire: A simplified version of the SF-36 includes medications, and how well asthma affects daily functioning and overall asthma. The SF-12v2 is a practical, reliable, and valid way to assess physical and mental health. With one or two questions per domain, it assesses the exact eight health dimensions as the SF-36v2, which includes Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. The SF-12 is a valid alternative to the lengthy SF-36 for the self-assessment of quality of life by assessing the health status of healthy and patient population groups. ⁵⁹ Higher ratings indicate better physical and mental wellbeing, ranging from 0 to 100. ⁶⁰ It has been suggested that a cut-off of 50 or less can be used to identify a physical condition, while a score of 42 or less may signify clinical depression. ⁶⁰ The Sf-12v2 has been weighted in the Greek general population. ⁶¹

Borg scale: The Borg dyspnea scale is a simple, non-proprietary scoring system. It is extensively used in clinical and research practice to evaluate symptoms of shortness of breath and provides valuable data. ^{62 , 63} It begins with 0 (no dyspnea), and goes up to 10 (extreme dyspnea). As a result, healthcare professionals must give patients enough time to learn and ensure they comprehend it before using it. ⁶⁴

The study started in January 2023 and is scheduled to be completed in January 2024.

Sample size estimation was conducted using G*Power, version 3.1 software. For a study design involving two separate groups and three repeated measurements (pre-treatment, post-treatment, and one follow-up) to attain a statistical power of 0.80 for detecting an effect size (d) of 1.36 in the interaction effect (22), with a significance level of 5% (0.05), a minimum of 6 participants per group was determined as necessary. Accounting for a potential dropout rate of 10% and based on the calculated sample size, it was anticipated that approximately 12 individuals per group would need to be initially recruited. ⁶⁵

Data collection methods

Data regarding the outcomes pre and post-intervention will be meticulously collected from the main researcher. The collected information will undergo a thorough examination to analyze the outcomes. Throughout the study, the professor of chest physiotherapy (supervisor) will closely oversee the main researcher administering the study’s data. To ensure the patient adheres to the study, timely messages will be sent to their mobile phones, providing information and reminders regarding upcoming sessions. A 10% drop-out rate has been considered in the sample size calculation, thus minimizing potential interference with the study results.

Data management

Evaluation data will be sourced from a predefined spreadsheet containing baseline characteristics. A secure database will be employed to store all research-related data securely. Paper copies of evaluation forms signed informed consent forms, and other non-electronic documents will be securely stored in the study environment. A comprehensive backup of the data entries will be generated once a month until the conclusion of the trial.

Upon completion of the study, the Excel spreadsheet will be published and forwarded to the statistician for the necessary analysis. A checklist will help prevent data loss from inefficient staff procedures. Given the extensive follow-up assessment for this experiment, participant retention and completion of follow-up assessments will be notably high. After six weeks from the end of interventions, the participants will be invited to a follow-up examination (12 weeks from the beginning of the trial).

The IBM SPSS software, specifically version 28, will be utilized for all data processing. The distribution of the data will be displayed using descriptive statistics. For each dependent variable independently (US, CWE, ACT, NQ, SF-12v2 and Borg scale), 2×3 ANOVA repeated measures, with Bonferroni adjustment will be used to examine the interaction between intervention (experimental and control group) and time (0, 6, and 12 weeks). The level of statistical significance was chosen at 0.05.

Monitoring

Data monitoring

A data monitoring committee of members from the UNIWA Physiotherapy Department will periodically review the accumulating data, determining if the trial should be modified or discontinued.

Harms

A clinical staff is going to supervise the entire procedure. Any adverse events will be immediately reported throughout the trial to the Physiotherapy Department of the UNIWA committee.

Auditing

An evaluation of the experiment will be performed each month. Every deviation from the protocol will be recorded and addressed.

Ethics and dissemination

Research ethics approval

The Ethics Committee of the UNIWA in Greece approved this study under protocol 90853/04-10-2022. The study follows the Helsinki Declaration’s “Ethical Principles of Medical Research Involving Human Subjects.” Protocol modifications will be disclosed to the Ethics Committee as soon as possible. The trial has been proactively registered in the ClinicalTrials.gov database with the identification number NCT05709054.

Protocol amendments

The study has already been modified and accepted in accordance with the Ethics Committee of the UNIWA in Greece suggestions. As a result, further modifications could not be made.

Consent

Study participants will receive a translated version of the study protocol. Prior to participation, all individuals involved in the study will be fully informed, and written consent will be obtained from each participant.

The main researcher will collect personal data during the trial. A confidentiality statement on the permission form will be signed by the main researcher, the subject, and two witnesses. Whenever necessary to disclose information for the study, consent from the patients will always be obtained with utmost assurance of confidentiality.

The main researcher and the statistician will have access to the final trial datasheet.

The entire procedure will be conducted under the oversight of clinicians and the physiotherapy department of the UNIWA committee. After the trial sessions, the participants will be under supervision for about four weeks so that they can take care if there is any harm.

The study started in January 2023.

This work will be presented in International Conference Proceedings and published in an indexed journal.