The effect of manual therapy on diaphragm function in adults with asthma: Protocol for a randomized controlled trial

Dimitrios Tsimouris; Eirini Grammatopoulou; Maria Papandreou; George Gioftsos; George Koumantakis

doi:10.12688/f1000research.141455.2

. 2024 Mar 19;12:1361. Originally published 2023 Oct 18. [Version 2] doi: 10.12688/f1000research.141455.2

The effect of manual therapy on diaphragm function in adults with asthma: Protocol for a randomized controlled trial

Dimitrios Tsimouris ^1,^a, Eirini Grammatopoulou ¹, Maria Papandreou ¹, George Gioftsos ¹, George Koumantakis ¹

PMCID: PMC11445601 PMID: 39359613

Version Changes

Revised. Amendments from Version 1

Revisions made include changes to the text, new or revised/updated figures, updates to the author list, and additional data. Specifically, in response to the reviewers' comments and our own observations, we made 15 modifications at the level of text editing in sections including Introduction, Methods, Outcome Measures, Sample Size Calculation, Statistical Analysis, Declaration of Interests, and Discussion. We have adjusted sentences and paragraphs to enhance the clarity of sections, provided a brief overview of the impact of asthma on diaphragmatic function and respiratory muscle strength, and emphasized the potential of the manual diaphragm release technique as a therapeutic intervention. This allows readers to better grasp the significance of the study and its potential implications for asthma management. We have also highlighted the impact on the research field and the research gap in the discussion section as requested. Additionally, we have added a table to enhance the reader's understanding of the therapeutic plan of our study. Furthermore, we have incorporated 11 new references into the main text where necessary. Finally, we have adjusted the reference list to the correct order during the typesetting process. We believe that these revisions significantly strengthen the quality and impact of our study and are confident that it will contribute meaningfully to the literature on asthma management.

Abstract

Background

Diaphragm dysfunction is prevalent among individuals with asthma due to lung hyperinflation and hyperventilation in asthma paroxysm. This study was designed to evaluate the effect of the manual diaphragm release technique (MDRT) on diaphragm function in individuals with asthma.

Methods

Adults with diagnosed stable asthma (n = 24), will be recruited from the General Hospital of Kifissia “Agioi Anargyroi” in Athens, Greece. The volunteers who meet the inclusion criteria will be randomly allocated to two groups: (a) the experimental group (n = 12) that will receive 12 sessions of MDRT in conjunction with breathing retraining exercises (BRE), and (b) the control group (n = 12) that will receive 12 sessions of BRE. Measurements will occur at three time points: before the initiation of treatment sessions (week 0), followed by 12 treatment sessions (week 6), and three months from the beginning of the trial (week 12). The main outcomes will be the diaphragm excursion (ultrasonography) and chest expansion (inch tape), with secondary outcomes the maximal respiratory pressures (digital pressure manometer), dysfunctional breathing (Nijmegen questionnaire), asthma control (ACT), dyspnea (Borg scale) and quality of life (SF-12v2).

Discussion

The proposed protocol is the first to examine the effectiveness of MRDT on diaphragm’s function in individuals with asthma. Manual Therapy (MT) is a low-cost alternative and supplementary therapy to standard treatment procedures that might improve the biomechanics of respiration in pulmonary rehabilitation.

Trial Registration

Registered on Clinical Trials.gov (ID: NCT05709054)

Protocol version

29/09/2023

Keywords: Key Words: Asthma; Manual Therapy; Diaphragm; Breathing retraining exercises; Diaphragm mobility, Ultrasound

Abbreviations

ACT: Asthma Control Test
BRE: Breathing Retraining Exercises
COPD: Chronic Obstructive Pulmonary Disease
CWE: Chest Wall Expansion
GOHK: General Oncology Hospital of Kifissia
MDRT: Manual Diaphragm Release Technique
MT: Manual Therapy
NQ: Nijmegen Questionnaire
PR: Pulmonary Rehabilitation
RCT: Randomized Controlled Clinical Trial
US: Ultrasonography
ZOA: Zone Of Apposition

Introduction

Due to its anatomical structure and contribution to minute ventilation (60–80%), the diaphragm is the most important respiratory muscle. ¹ ^– ³ An impaired diaphragm is associated with respiratory symptoms such as dyspnea, intolerance to exercise and sleep problems. ⁴

Chronic obstructive pulmonary disease (COPD) and asthma are umbrella terms for various conditions characterized by chronic airway disease. ⁵ COPD and asthma patients frequently experience diaphragmatic dysfunction (DD). ⁶ The diaphragm’s ability to raise and expand the lower ribcage within the zone of apposition (ZOA), where the lower ribcage directly interacts with the diaphragm becomes compromised due to mechanical challenges. This is due to the diaphragm functioning at a disadvantageous shortened position caused by air trapping, which hinders its contraction capacity and increases the respiratory workload. ⁷

In COPD, air progressively remains trapped in the lungs due to airway constriction. The architecture of the thoracic cage is disrupted by this clinical condition during exercise and rest, reducing the diaphragm’s physiological advantage. ⁸ ^, ⁹ Similarly, Individuals with moderate to severe asthma may have pulmonary overstretching (asthma paroxysm), which can cause functional problems because it reduces expiratory flow (early airway closure), activates inspiratory muscles at the end of expiration, and reduces lung flexibility. ¹⁰ ^– ¹² Although the underlying mechanisms for these two lung conditions, COPD and asthma, differ, both cause secondary complications (pulmonary hyperinflation, hyperventilation syndrome). These features lead to similar pathological changes that impair the diaphragm’s ability to elevate and expand the lower ribcage. ¹³ Consequently, during inspiration, the lower ribcage’s transverse diameter may decrease. ¹⁴ It’s also important to note that the mechanical disadvantage of the diaphragm in asthma can result in an increased workload for all inspiratory muscles, particularly during exercise, where dynamic hyperinflation may occur, leading to heightened dyspnea. ¹⁵ ^, ¹⁶

Over the past few decades, two research questions have emerged concerning how physiotherapy can enhance the mechanical efficiency of the thorax and the effectiveness of respiratory muscles during breathing in people with obstructive lung diseases. Researchers, from 1990 ¹⁷ up to 2015, ¹⁸ have made several hypotheses and implemented physiotherapy interventions to find which procedure is more appropriate to improve the effectiveness of mechanical functioning of the thoracic cage in people with pulmonary diseases. Breathing retraining exercises (BRE) are a widely used, productive method, ¹⁹ ^– ²¹ simple, safe, accessible, with a high level of evidence-based efficacy. ²² ^– ²⁴

Finally, although specific diaphragm MT techniques have not been documented yet, recent studies have reported evidence for their positive effect on pulmonary rehabilitation (PR). ²⁵ In particular, the manual diaphragm release technique (MDRT) aims to directly stretch the muscle fibers of the diaphragm, as detailed in Rochas’ research. ¹⁸ The study showed an improvement in diaphragm’s mobility, maximum inspiratory pressure (MIP), and exercise capacity (EC) in people suffering from COPD. ¹⁸ We deem it pertinent to mention that previous studies have demonstrated that even a single MT session can have a positive effect on chest wall mechanics, dyspnea, and peripheral oxygen saturation (SpO2) in individuals with COPD. ²⁶ ^, ²⁷ Therefore, dyspnea, being one of the primary symptoms of asthma, can adversely affect both exercise capacity (EC) levels and overall quality of life (QoL). ²⁸ ^– ³¹ According to a study ²⁶ a single MT session of soft tissue and joint mobilization immediately improved dyspnea (Borg Scale 0-10, pre: 2.3 ± 0.8 vs 1.8 ± 0.5). The authors reported that the mechanism underlying this improvement could be the increase in respiratory muscle length and thoracic cage flexibility induced by MT, consequently reducing breathing effort and the development of dyspnea in individuals with COPD. ³² As for asthma, there is currently no data regarding the efficacy of diaphragm MT methods, except for the pilot study conducted by Macias and colleagues, ²⁴ and the study by Elnaggar and colleagues, ³³ which investigated the efficacy of MDRT in children.

Considering the growing clinical interest in asthma and the recent publications in the field, we believe that a randomized controlled trial (RCT) targeting intervention on the zone of apposition of the diaphragm using the MDRT in adults with asthma for outcomes assessment is warranted.

Objective of the proposed trial

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.

Methods

Study design

The present RCT will be a single centric, two arm parallel equivalence randomized controlled study conducted in accordance with the CONSORT statement. This RCT followed the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement. ³⁵ 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.

Setting

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).

Recruitment procedures

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.

Randomization and blinding procedures

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. ³⁶ 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.

Participants and eligibility

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.

Participants’ characteristics

At least 24 adults will be recruited for the study.

Inclusion criteria: aged 18-60 years, diagnosed with stable asthma ³⁷ 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.

Initial assessments

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). ³⁸ 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, ³⁹ (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 ⁴⁰ ^– ⁴³ 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. ⁴⁴ ^, ⁴⁵ 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. ¹⁸

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. Regarding respiratory volumes, patients will be instructed to breathe progressively deeper from set to set, aiming for maximal diaphragmatic excursion and stretch. It is essential to ensure that the therapist’s grip on the lower thoracic aperture is maintained throughout. The entire process will consist of two sets of 10 repetitions, separated by a 1-minute interval lasting 10 minutes. ⁴⁶

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. ⁴⁷ 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. ⁴⁸ 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). ⁴⁹

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. The repetitions and sets of BRE are indicative, given that our priority was the progression and individualization during the sessions. For instance, the first session may only include recognition of the abnormal breathing pattern exercise and practice diaphragmatic and nose breathing retraining exercise. At the beginning of every session, each participant will be assessed for their compliance concerning the exercises (use of a calendar or via questions about their exercise). If a patient has not comprehended or cannot perform the exercises correctly, the previous session will have to be repeated. Once they have fully understood the instructions and execution, they will proceed to the subsequent BRE.

The Table 1 illustrates the Key parameters of the rehabilitation program.

Table 1. Key parameters of the rehabilitation program.

Intervention		Patient position	Instructions to participants	Time	Sets/Breathing cycles	Weekly repetition
MDRT		- Lie supine with relaxed limbs - 90 degrees flexion of the knees & hips		20-25 min	2S x 10BC	2/Week
BRE	Recognition of the abnormal breathing pattern	- A pillow between the knees & head. - Half-lying supine (45 degrees of spine flexion from the neutral supine position).	- “Put one relaxed hand on your upper chest and the other on your stomach and clavicle” - “Breathe normally, slowly, in your own manner” - “Take a big breath”	30 min	1S x 5BC	2/Week
	Practice diaphragmatic and nose breathing retraining	- Half-lying supine position - Pillows behind the head & knees - one relaxed hand over the stomach and the other on the upper chest and clavicle	- “Close your mouth and try to breathe easily, slowly and softly through your nose” - “Be careful not to inhale with “big” breaths, try during inhalation to raise only the stomach” - “Exhalation is passive through the nose and lets your stomach fall gently”		1S x 5BC
	Slow breathing and controlled breath holding after exhalation	- Half-lying supine position - Pillows behind head and knees - One relaxed hand over stomach and the other on upper chest and clavicle	- “Close your mouth and try to breathe easily, slowly and softly through your nose” - “Relax your shoulder & chest” - “Try to slow down your breaths” - “Sometimes it helps to count in your mind while you are breathing, e.g. breathe in for a slow count of 2 and breathe out for a slow count of 3until feel empty your stomach” - “Keep empty your stomach for 3-5 seconds”		1S x 10BC
	New breathing pattern in everyday life activities and various positions	- Supine - Semi-sitting - Sitting	- “Try to breathe in and out slowly and through the nose, even in the most challenging conditions” - “You will be able to recognize faulty breathing patterns, and you will be able to correct them” - “Try to use a calendar or a mobile phone reminder to implement a diaphragmatic slow nose breathing pattern and breathing exercises”		3S x 5BC
	Breathing control in speech	- Supine - Semi-sitting - Sitting	- “You must budget airflow to control the number of words you say per breath and the tone and loudness of particular words in a sentence” - “Apply a slow, through the nose, diaphragmatic breathing pattern at speech (max 4-6 words spoken during slow exhalation, with breathing pauses, and slow inhalations)” - “Breathe out so that your lungs feel empty, and, before inhaling again” - “At yawning and at sighing close your mouth” - “Poor voice quality (hoarseness, roughness, or a strained/strident voice) results from inadequate or badly controlled airflow. Speech prosody: rhythm and intonation”		3S x 5BC

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

Outcome measures

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 ⁵⁰ and chest expansion (CE) using a tape measure. ⁵¹ Secondary outcomes will also be employed: maximal inspiratory and expiratory pressures (MIP/MEP), ⁵² ^, ⁵³ dysfunctional breathing (Nijmegen questionnaire – - NQ), ⁵⁴ asthma Control (ACT), ⁵⁵ ^, ⁵⁶ quality of life (SF-12v2), ⁵⁷ and dyspnea (Borg scale). ⁵⁸ Table 2. illustrates the SPIRIT ³⁴ schematic protocol of the study along with the schedule of assessments.

Table 2. Standard protocol items: recommendations for interventional trials of this study (SPIRIT).

TIME POINT	Enrollment (-T1)	Allocation (T0)	Pre-intervention (T1)	Intervention	Post-Intervention
TIME POINT	Enrollment (-T1)	Allocation (T0)	Pre-intervention (T1)	Intervention	(T2)	(T3)
ENROLLMENT:
Eligibility screen	X
Informed consent	X
Demographic information	X
Allocation		X
Intervention
MDRT + BRE
BRE
ASSESMENTS
Neurological and cardiovascular assessments	X
Primary outcomes: US			X		X	X
CE			X		X	X
Secondary outcomes: MIP/MEP			X		X	X
NQ			X		X	X
ACT			X		X	X
Borg scale			X		X	X
SF-12v2			X		X	X

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-T1: one month before first treatment; T0: one week before first treatment (week 0); T1: 20 minutes before first treatment; T2: after the last treatment, (week 6); T3: follow-up 6 weeks from the last treatment (week 12).

Primary outcome measures

Diaphragmatic excursion assessment with ultrasonography: Numerous studies have confirmed the effectiveness of the US to evaluate diaphragmatic function. Since 1970, ⁵⁹ 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. ¹⁷ 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. In this study the excursion of the diaphragm will be measured using the ultrasound device, E-CUBE 8LE (Seoul, Republic of Korea).

Chest wall expansion (CWE): In clinical and research practice, the inch tape measure is an alternative method for assessing chest expansion. ⁶⁰ 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. ⁵¹ A tape measure (in centimeters) will assess the variance between values recorded during deep inhalation and exhalation, with greater values signifying improved results. ⁵¹ Norms have been developed according to age and sex. ⁶⁰

Secondary outcome measures

Nijmegen Questionnaire (NQ): The Nijmegen Questionnaire is a reliable and valid tool for assessing dysfunctional breathing ⁶² 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. ⁶¹ ^, ⁶² 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. ⁶³ ^– ⁶⁵ 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. ⁶⁶

Asthma control test (ACT): The ACT questionnaire is a valid and reliable clinical and research tool. ⁶⁷ Its quick completion time is one of its key features. It has five items, all about the most recent four weeks. ⁶⁸ ^, ⁶⁹ 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). ⁵⁹

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. ⁶⁹ Higher ratings indicate better physical and mental wellbeing, ranging from 0 to 100. ⁷⁰ 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. ⁷⁰ The Sf-12v2 has been weighted in the Greek general population. ⁷¹

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. ⁷² ^, ⁷³ 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. ⁷⁴

Anticipated dates of trial commencement and completion

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

Sample size calculation

The sample size calculation was based on an alpha (α) level of 0.01, a power (β) of 0.85, and a large effect size, Cohen’s d, of 1.86 for a two-tailed independent t-test. This effect size was calculated based on the results reported by Rocha et al. (2015), ¹⁸ specifically from the mean (SD) values of the control and experimental groups following six manual therapy intervention sessions. Furthermore, the calculation accounted for an anticipated attrition rate of approximately 15%, foreseeing the potential for participant dropout or exclusion. This comprehensive approach to sample size calculation ensures the robustness and reliability of the study’s findings, enabling a precise detection of the large effect size with high statistical confidence. This resulted in a total sample size of 24 people (12 per group) considering a withdrawal rate of 15%. ⁷⁵

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).

Statistical analysis

The investigation will employ IBM SPSS software, specifically version 28, as the primary analytical tool for comprehensive data processing. Descriptive statistics will be employed to elucidate the distributional characteristics of the dataset. Subsequently, the Shapiro-Wilk test will be utilized to assess data normality for each dependent variable (including US, CWE, ACT, NQ, SF-12v2, and Borg scale) independently. Should normality assumptions be met, parametric tests, specifically the 2×3 ANOVA repeated measures, will be employed, accompanied by Bonferroni adjustment, to investigate the interaction between intervention (experimental and control groups) and time points (0, 6, and 12 weeks). Moreover, to evaluate the homogeneity of variance, Levene’s test will be conducted. The predetermined level of statistical significance is set at p<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.

Confidentiality

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.

Access to data

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

Ancillary and post-trial care

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.

Discussion

Although several studies assessing the efficacy of MT in obstructive lung diseases (OLD) have been conducted, drawing definitive conclusions is challenging due to their conflicting results. ⁴⁵ A recent systematic review (SR) of the existing literature aimed to identify indications that may underscore the need for differentiated manual therapy (MT) approaches targeting the zone of apposition (ZOA) of the diaphragm in individuals with OLD suffering from pathological adaptations of their chest wall or from respiratory symptoms. ⁷⁶ This SR outlined a model illustrating how MT delays the onset of fatigue in respiratory muscles. Additionally, it demonstrated that there is no evidence supporting the effectiveness of MT on the diaphragm for treating individuals (adults) with asthma. ⁷⁶ It is noteworthy that two previous studies have examined how MT on the ZOA of the diaphragm hampers the diaphragm’s function and pulmonary function in childhood asthma (RCT) ³³ and in adults with asthma ²⁴ (pilot study) accordingly. Up to this point, no RCT has comprehensively examined the impact of MDRT, in particular, on the ZOA by MDRT of the diaphragm in adults suffering from asthma.

The primary objective of this RCT is to address the existing literature gap concerning the impact of MDRT on enhancing the functional parameters of individuals with asthma, thereby indicating the need for further research in this domain. Additionally, considering the prevalent pathological changes in the diaphragm muscle among individuals with asthma, it is crucial to determine which anatomical regions and hands-on therapy techniques are most effective for increasing diaphragm excursion in adults with asthma.

The protocol of this study is designed in accordance with accepted practices concerning randomization, concealed allocation, blinding of examiners, and appropriate sample size calculation. This rigorous approach ensures the reliability and robustness of the study’s findings. What sets this study apart is its original investigation into the mechanism of the MDRT on the ZOA of the diaphragm in individuals living with asthma. Finally, several significant constraints must be considered. The study sample is drawn exclusively from a single hospital, potentially limiting the generalizability of the findings. Additionally, the extended experimental period and the substantial number of sessions may lead to participant dropouts.

Study status

The study started in January 2023.

Study dissemination

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

Conclusions

This RCT will be innovative as it will, for the first time, provide evidence of the effect of the MDRT on diaphragm function in people with asthma. MT is a low-cost alternative and supplementary therapy to standard treatment procedures that might improve the biomechanics of respiration in pulmonary rehabilitation.

Data availability

Underlying data

No data are associated with this article.

Reporting guidelines

Figshare: SPIRIT checklist for ‘The effect of manual therapy on diaphragm function in adults with asthma: Protocol for a randomized controlled trial’, https://doi.org/10.6084/m9.figshare.24191106. ⁷⁷

Funding Statement

The author(s) declared that no grants were involved in supporting this work.

[version 2; peer review: 2 approved]

References

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F1000Res. 2024 Apr 25. doi: 10.5256/f1000research.163150.r257334

Reviewer response for version 2

Ragab Elnaggar ^1,²

I appreciate the authors' thorough efforts in addressing the concerns raised in the previous review round. Their revisions have significantly improved the manuscript.

Is the study design appropriate for the research question?

Partly

Is the rationale for, and objectives of, the study clearly described?

Partly

Are sufficient details of the methods provided to allow replication by others?

Partly

Are the datasets clearly presented in a useable and accessible format?

Not applicable

Reviewer Expertise:

Physical Therapy

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

F1000Res. 2024 Apr 4. doi: 10.5256/f1000research.163150.r257335

Reviewer response for version 2

Luis Vicente Franco Oliveira ¹

I am satisfied with the changes made by the authors. All suggestions were accepted.

I declare that I have no conflict of interest with the manuscript or the authors.

Is the study design appropriate for the research question?

Yes

Is the rationale for, and objectives of, the study clearly described?

Yes

Are sufficient details of the methods provided to allow replication by others?

Yes

Are the datasets clearly presented in a useable and accessible format?

Not applicable

Reviewer Expertise:

PhD in Health Sciences, specialist in Respiratory Physiotherapy and Pulmonary Rehabilitation and Cardiorespiratory Sleep Disorders.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

F1000Res. 2024 Feb 20. doi: 10.5256/f1000research.154901.r223569

Reviewer response for version 1

Ragab Elnaggar ^1,²

This protocol for a prospective, randomized clinical trial will assess the effect of manual diaphragm release technique (MDRT) on diaphragm function in individuals with asthma. While, based on a brief search of the database, previous evidence on the effect of this intervention is likely scarce, there is, therefore, a need for more well-controlled trials, employing adequate methodology, to conclusively evaluate the role of MDRT for patients with asthma.

I partially disagree with the assertion that “The proposed protocol is the first to examine the effectiveness of MRDT on diaphragm function in individuals with asthma”. There is a previous publication on the role of MRDT in pediatric patients with asthma (1).

Asthma encompasses heterogeneous phenotypes that vary widely in terms of their underlying causes, triggers, clinical manifestations, and response to treatment. Furthermore, the severity of asthma can range from mild and intermittent symptoms to severe and persistent symptoms that require frequent medical intervention. Understanding the heterogeneity of asthma is important because it helps healthcare professionals tailor treatment approaches to individual patients. It is unclear in this protocol which type/severity of asthma would be considered.

While reading the introduction section, I noticed that it lacks a comprehensive background on patients with asthma, their diaphragmatic function, and the potential benefits of MDRT in addressing this issue. I believe that including these key elements would greatly enhance the clarity and contextual understanding of the intended study. Providing a brief overview of the impact of asthma on diaphragmatic function, respiratory muscle strength, or altered breathing patterns, and emphasizing the potential of MDRT as a therapeutic intervention would help readers grasp the significance of the study and its potential implications for asthma management. I encourage the authors to consider revising the introduction accordingly to provide a more comprehensive background and set a firm foundation for the remainder of the study.

The significance of the study is not clear. Authors may need to justify the importance of their work, highlight the impact it has on the research field, and define its contribution to new knowledge.

More importantly, they need to pinpoint the research gap (in light of the related literature) and make it clear what drove them to conduct the study.

Again, the statement “As for asthma, there is no data for the efficacy of diaphragm MT methods, except for one pilot study” is not true and should be revised in light of the aforementioned publication.

I have a concern regarding the study power. A sample size of 24 is a considerably small sample. The authors conducted an a priori power analysis to determine the minimum sample size necessary for detecting clinically significant results. They employed a substantial effect size (d = 1.36) and the minimum acceptable power level (80%) in their analysis. However, this approach may present challenges in detecting moderate or small changes in the outcome variable, potentially resulting in inconclusive findings and limiting the interpretability of the study conclusions.

The authors aim to recruit a minimum of 24 participants, encompassing a broad age range from 8 to 60 years. However, it is recommended that the authors consider prioritizing either pediatric or adult patients for a more focused investigation.

It is crucial to incorporate a thorough and detailed description of the pulmonary rehabilitation program within this protocol, as its current absence hinders the comprehensive understanding of the intervention being studied.

The data analysis plan is appropriate. The utilization of 2x3 repeated measures ANOVA with Bonferroni adjustment will be used to examine the interaction between intervention offer advantages for allowing for the examination of within-subject changes across multiple conditions or time points and accounting for the correlated nature of data within subjects.

In summary, the implementation of the study as outlined in this protocol has the potential to offer supplementary or corroborating evidence concerning the efficacy of MDRT in individuals diagnosed with asthma.

Is the study design appropriate for the research question?

Partly

Is the rationale for, and objectives of, the study clearly described?

Partly

Are sufficient details of the methods provided to allow replication by others?

Partly

Are the datasets clearly presented in a useable and accessible format?

Not applicable

Reviewer Expertise:

Physical Therapy

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

References

1. : Prospective Effects of Manual Diaphragmatic Release and Thoracic Lymphatic Pumping in Childhood Asthma. Respir Care .2019;64(11) : 10.4187/respcare.06716 1422-1432 10.4187/respcare.06716 [DOI] [PubMed] [Google Scholar]

F1000Res. 2024 Feb 20.

DIMITRIOS TSIMOURIS ¹

Dear Ragab Elnaggar,

Thank you for your thorough review and insightful feedback on our study protocol. Your contributions have significantly enhanced the quality of our work. We will meticulously address all the concerns raised and further refine our manuscript.

Yours sincerely,

Mr Dimitrios Tsimouris

PhD candidate

Department of Physiotherapy

University of West Attica

Athens, Greece

F1000Res. 2024 Feb 26.

DIMITRIOS TSIMOURIS ¹

Dear Prof. Ragab Elnaggar,

We would like to thank you for reviewing our manuscript and giving us the opportunity to revise it. We appreciate the time and effort you put into this to further improve our work.

Before presenting our responses to your comments, we deemed it important to clarify that our study will only focus on adults with mild to moderate severity of asthma. Unfortunately, we found a typographical error in the inclusion criteria of our study, where "18" was mistakenly written as "8." We acknowledge that this significantly affected your assessment. Given the above, we here by provide our responses in the same order as you presented your comments. Please find our replies below:

Comment 1: « I partially disagree with the assertion that “The proposed protocol is the first to examine the effectiveness of MRDT on diaphragm function in individuals with asthma”. There is a previous publication on the role of MRDT in pediatric patients with asthma (1).»

Thank you for this comment. We agree that this part of the manuscript was a bit overstated. Following your suggestion, we decided to delete the sentence to improve the clarity of this section.

Comment 2: « While reading the introduction section, I noticed that it lacks a comprehensive background on patients with asthma, their diaphragmatic function, and the potential benefits of MDRT in addressing this issue. I believe including these key elements would greatly enhance the clarity and contextual understanding of the intended study. Providing a brief overview of the impact of asthma on diaphragmatic function, respiratory muscle strength, or altered breathing patterns and emphasizing the potential of MDRT as a therapeutic intervention would help readers grasp the significance of the study and its potential implications for asthma management. I encourage the authors to consider revising the introduction accordingly to provide a more comprehensive background and set a firm foundation for the remainder of the study.»

Thank you for this comment. We agree that this part of the manuscript was inadequate. Following your suggestion, we have modified the introduction, providing a more comprehensive background. We have added the text as follows:

« It's also important to note that the mechanical disadvantage of the diaphragm in asthma can result in an increased workload for all inspiratory muscles, particularly during exercise, where dynamic hyperinflation may occur, leading to heightened dyspnea ¹⁵ ^,16»

« Finally, although specific diaphragm MT techniques have not been documented yet, recent studies have reported evidence for their positive effect on pulmonary rehabilitation (PR). ²⁵In particular, the manual diaphragm release technique (MDRT) aims to directly stretch the muscle fibers of the diaphragm, as detailed in Rochas’ research. ¹⁸The study showed an improvement in diaphragm’s mobility, maximum inspiratory pressure (MIP), and exercise capacity (EC) in people suffering from COPD. ¹⁸ We deem it pertinent to mention that previous studies have demonstrated that even a single MT session can have a positive effect on chest wall mechanics, dyspnea, and peripheral oxygen saturation (SpO2) in individuals with COPD. ^{26, 27} Therefore, dyspnea, being one of the primary symptoms of asthma, can adversely affect both exercise capacity (EC) levels and overall quality of life (QoL). ^28-31 According to a study ²⁶ a single MT session of soft tissue and joint mobilization immediately improved dyspnea (Borg Scale 0-10, pre: 2.3 ± 0.8 vs 1.8 ± 0.5). The authors reported that the mechanism underlying this improvement could be the increase in respiratory muscle length and thoracic cage flexibility induced by MT, consequently reducing breathing effort and the development of dyspnea in individuals with COPD. ³² As for asthma, there is currently no data regarding the efficacy of diaphragm MT methods, except for the pilot study conducted by Macias and colleagues ²⁴, and the study by Elnaggar and colleagues ³³, which investigated the efficacy of MDRT in children.

.»

Comment 3: « The significance of the study is not clear. Authors may need to justify the importance of their work, highlight the impact it has on the research field, and define its contribution to new knowledge.»

Comment 4: « More importantly, they need to pinpoint the research gap (in light of the related literature) and make it clear what drove them to conduct the study.»

Thank you for your suggestions. As requested, we highlighted the impact on the research field and the research gap at the discussion session. The text has been correspondingly modified as follows:

“Although several studies assessing the efficacy of MT in obstructive lung diseases (OLD) have been conducted, drawing definitive conclusions is challenging due to their conflicting results. ⁴⁵A recent systematic review (SR) of the existing literature aimed to identify indications that may underscore the need for differentiated manual therapy (MT) approaches targeting the zone of apposition (ZOA) of the diaphragm in individuals with OLD suffering from pathological adaptations of their chest wall or from respiratory symptoms. ⁷⁶This SR outlined a model illustrating how MT delays the onset of fatigue in respiratory muscles. Additionally, it demonstrated that there is no evidence supporting the effectiveness of MT on the diaphragm for treating individuals (adults) with asthma. ⁷⁶It is noteworthy that two previous studies have examined how MT on the ZOA of the diaphragm hampers the diaphragm's function and pulmonary function in childhood asthma (RCT) ³³ and in adults with asthma ²⁴ (pilot study) accordingly. Up to this point, no RCT has comprehensively examined the impact of MDRT, in particular, on the ZOA of the diaphragm by MDRT in adults suffering from asthma.

The protocol of this study is designed in accordance with accepted practices concerning randomization, concealed allocation, blinding of examiners, and appropriate sample size calculation. This rigorous approach ensures the reliability and robustness of the study's findings. What sets this study apart is its original investigation into the mechanism of the MDRT on the ZOA of the diaphragm in individuals living with asthma. Finally, several significant constraints must be considered. The study sample is drawn exclusively from a single hospital, potentially limiting the generalizability of the findings. Additionally, the extended experimental period and the substantial number of sessions may lead to participant dropouts.

”

Comment 5: «Again, the statement “As for asthma, there is no data for the efficacy of diaphragm MT methods, except for one pilot study” is not true and should be revised in light of the aforementioned publication.»

We believe that this comment has been addressed based on our previous replies. After clarifying that there was confusion due to the typographical error, we believe that this statement is now correct. Please do not hesitate to reach out for any further clarification.

Comment 6: « I have a concern regarding the study power. A sample size of 24 is a considerably small sample. The authors conducted an a priori power analysis to determine the minimum sample size necessary for detecting clinically significant results. They employed a substantial effect size (d = 1.36) and the minimum acceptable power level (80%) in their analysis. However, this approach may present challenges in detecting moderate or small changes in the outcome variable, potentially resulting in inconclusive findings and limiting the interpretability of the study conclusions.»

Thank you for your comment. We understand your concerns about the sample study calculation, and we would like to explain the rationale behind the participant number determined by our power analysis. In 2023, we conducted a systematic review ( Is manual therapy of the diaphragm effective for people with Obstructive Lung Diseases? A Systematic Review, Respir Med Res. 2023 Jun:83:101002. doi: 10.1016/j.resmer.2023.101002. Epub 2023 Feb 15.) investigating the effects of specialized mobilization techniques applied to the zone of apposition of the diaphragm in patients with obstructive respiratory diseases, including asthma and COPD. The results of this study revealed a literature gap indicating that the applied techniques on the ZOA of the diaphragm have not been applied in people with asthma beyond, of course, your study (in the pediatric population) and that of Macias et al. 2018 ( Effects of manual therapy on the diaphragm in asthmatic patients: A randomized pilot studyhttps://doi.org/10.1016/j.ijosm.2018.07.006). The two studies included in our research represented the closest in design to our own protocol (participants, manual therapy techniques of the diaphragm, diaphragm excursion measured by the US), thus necessitating the power analysis calculation based on them. For your convenience, we hereby provide the two studies in our research, which served as the basis for our study power.

Rocha T, Souza H, Brandão DC, et al.: The Manual Diaphragm Release Technique improves diaphragmatic mobility, inspiratory capacity and exercise capacity in people with chronic obstructive pulmonary disease: a randomised trial. J. Physiother. 2015;61(4):182–189. 26386894 10.1016/j.jphys.2015.08.009
Nair A, Alaparthi GK, Krishnan S, et al.: Comparison of Diaphragmatic Stretch Technique and Manual Diaphragm Release Technique on Diaphragmatic Excursion in Chronic Obstructive Pulmonary Disease: A Randomized Crossover Trial. Pulm. Med. 2019;2019:1–7. 30719351 10.1155/2019/6364376 PMC6335861

These studies closely aligned with the design of our protocol and thus informed our power analysis calculation. The sample size calculation was based on an alpha (α) level of 0.01, a power (β) of 0.85, and a large effect size, Cohen's d, of 1.86 for a two-tailed independent t-test. This effect size was calculated based on the results reported by Rocha et al. (2015), specifically from the mean (SD) values of the control and experimental groups following six manual therapy intervention sessions. Furthermore, the calculation accounted for an anticipated attrition rate of approximately 15%, foreseeing the potential for participant dropout or exclusion. This comprehensive approach to sample size calculation ensures the robustness and reliability of the study's findings, enabling precise detection of the large effect size with high statistical confidence. This resulted in a total sample size of 24 people (12 per group), considering a withdrawal rate of 15%.

Comment 7: « The authors aim to recruit a minimum of 24 participants, encompassing a broad age range from 8 to 60 years. However, it is recommended that the authors consider prioritizing either pediatric or adult patients for a more focused investigation.»

We agree that this is a mistake. Thank you for pointing this out. We have modified the text according to your comment.

Comment 8: « It is crucial to incorporate a thorough and detailed description of the pulmonary rehabilitation program within this protocol, as its current absence hinders the comprehensive understanding of the intervention being studied.»

Thank you for prompting us to share the treatment regimen with our readers. It was an oversight, not to mention it in detail. The following paragraphs and Table 1. (Key parameters of the rehabilitation program) have been added to the manuscript (Interventions Section):

“Regarding respiratory volumes, patients will be instructed to breathe progressively deeper from set to set, aiming for maximal diaphragmatic excursion and stretch. It is essential to ensure that the therapist's grip on the lower thoracic aperture is maintained throughout.”

“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. The repetitions and sets of BRE are indicative, given that our priority was progression and individualization during the sessions. For instance, the first session may only include recognition of the abnormal breathing pattern exercise and practice diaphragmatic and nose breathing retraining exercise. At the beginning of every session, each participant will be assessed for their compliance concerning the exercises (use of a calendar or via questions about their exercise). If a patient has not comprehended or cannot perform the exercises correctly, the previous session will have to be repeated. Once they have fully understood the instructions and execution, they will proceed to the subsequent BRE.”

Comment 9: « The data analysis plan is appropriate. The utilization of 2x3 repeated measures ANOVA with Bonferroni adjustment will be used to examine the interaction between intervention offer advantages for allowing for the examination of within-subject changes across multiple conditions or time points and accounting for the correlated nature of data within subjects.»

Thank you for reviewing and confirming that our statistical approach is appropriate.

F1000Res. 2023 Oct 25. doi: 10.5256/f1000research.154901.r216768

Reviewer response for version 1

Luis Vicente Franco Oliveira ¹

This RCT will be innovative as it will, for the first time, provide evidence of the effect of the manual diaphragm release technique on diaphragm function in people with asthma. Manual Therapy is a low-cost alternative and supplementary therapy to standard treatment procedures that might improve the biomechanics of breathing in pulmonary rehabilitation.

Studies aimed at investigating intervention strategies that seek to improve the functioning of the main muscle of our breathing (diaphragm) are extremely important around the world. The authors propose a low-cost intervention strategy without any risk to patients. I believe that the results of this study protocol will make important contributions to Pulmonology and Respiratory Physiotherapy around the world. Below I describe some suggestions to improve the presentation of the study protocol.

The title of the study complies with the PICOS strategy, characterizing the proposal well. It is noteworthy that the study protocol is already registered at Clinical Trials.gov (ID: NCT05709054). The manuscript contains all sessions necessary for a study protocol. The abstract of the manuscript is well written and well designed, summarizing the study proposal very well.

I suggest stating in the title of Figure 1. Design of the trial that the flowchart was prepared in accordance with the SPIRIT statement.
In the “Methods - Study design” section I suggest maintaining what is described about the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement, in relation to the protocol design, however adding that the study will be a randomized controlled study conducted in accordance with the CONSORT statement.
I suggest adding the acronym SPIRIT to the end of the title of Table 1.
In the primary outcome assessment item, add the commercial references of the ultrasound equipment that will be used to analyze the movement of the diaphragm. These details are important to allow other researchers to reproduce the study.
I suggest improving the description of the statistical analysis, adding more details about the analyses. In this same item, please add the commercial description of the software to be used.
The study does not mention whether there are conflicts of interest between the authors. It would be interesting to mention if there is any type of conflict.
I suggest that the authors standardize bibliographic references. There are some non-standard ones.

I would also like to congratulate the authors for the brilliant proposal.

Is the study design appropriate for the research question?

Yes

Is the rationale for, and objectives of, the study clearly described?

Yes

Are sufficient details of the methods provided to allow replication by others?

Yes

Are the datasets clearly presented in a useable and accessible format?

Not applicable

Reviewer Expertise:

PhD in Health Sciences, specialist in Respiratory Physiotherapy and Pulmonary Rehabilitation and Cardiorespiratory Sleep Disorders.

F1000Res. 2023 Oct 26.

DIMITRIOS TSIMOURIS ¹

Dear Luis Vicente Franco Oliveira,

I extend my sincere thanks for your meticulous evaluation of our study protocol and for providing valuable feedback that helped us improve our work's quality. Please be reassured that we will address all the issues mentioned and further improve the manuscript.

We are excited to share our findings with the broader research community and hope they interest readers. The publication of our study will provide new insights and stimulate further research in this area.

Yours sincerely,

Mr Dimitrios Tsimouris

PhD candidate

Department of Physiotherapy

University of West Attica

Athens, Greece

F1000Res. 2024 Feb 26.

DIMITRIOS TSIMOURIS ¹

Dear Prof. Luis Vicente Franco Oliveira,

We would like to thank you for allowing us to revise the manuscript. We appreciate the time and effort you put into this to improve our work further. We have responded to all the comments. Please find our replies below.

Comment 1: «I suggest stating in the title of Figure 1. Design of the trial that the flowchart was prepared in accordance with the SPIRIT statement.»

Thank you for the suggestion. The heading of Figure 1 has been changed.

Comment 2: «In the “Methods - Study design” section, I suggest maintaining what is described about the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement in relation to the protocol design, however adding that the study will be a randomized controlled study conducted in accordance with the CONSORT statement»

Thank you for your comment. We apologize for the mistake you pointed out. We have now added that our study is a randomized controlled study conducted in accordance with the CONSORT statement.

Comment 3: «I suggest adding the acronym SPIRIT to the end of the title of Table 1»

Thank you for this suggestion. The acronym SPIRIT has been added to the end of the title of Table 1, as you suggested.

Comment 4: «In the primary outcome assessment item, add the commercial references of the ultrasound equipment that will be used to analyze the movement of the diaphragm. These details are important to allow other researchers to reproduce the study.»

Thank you for your comment. As you suggested, the commercial references to the ultrasound equipment were added to the main text.

Comment 5: «I suggest improving the description of the statistical analysis, adding more details about the analyses. In this same item, please add the commercial description of the software to be used»

Following your suggestion, we have improved the subsection on statistical analysis as requested. As you suggested, we have uploaded details about both the analyses and the commercial description of the software to be used.

Comment 6: «The study does not mention whether there are conflicts of interest between the authors. It would be interesting to mention if there is any conflict.»

Thank you for pointing out. Here and in the main text, we would like to disclose no conflicts of interest between the authors.

Comment 7: «I suggest that the authors standardize bibliographic references. There are some non-standard ones.»

Thank you for your comment. We apologize for the mistake you pointed out. We have now tried to upload the bibliographic references standardized to the best.

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Underlying data

No data are associated with this article.

Reporting guidelines

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PERMALINK

The effect of manual therapy on diaphragm function in adults with asthma: Protocol for a randomized controlled trial

Dimitrios Tsimouris

Eirini Grammatopoulou

Maria Papandreou

George Gioftsos

George Koumantakis

Roles

Version Changes

Revised. Amendments from Version 1

Abstract

Background

Methods

Discussion

Trial Registration

Protocol version

Abbreviations

Introduction

Objective of the proposed trial

Methods

Study design

Figure 1. Design of the trial that the flowchart was prepared in accordance with the SPIRIT statement.

Setting

Recruitment procedures

Randomization and blinding procedures

Participants and eligibility

Participants’ characteristics

Initial assessments

Table 1. Key parameters of the rehabilitation program.

Outcome measures

Table 2. Standard protocol items: recommendations for interventional trials of this study (SPIRIT).

Anticipated dates of trial commencement and completion

Sample size calculation

Statistical analysis

Confidentiality

Access to data

Ancillary and post-trial care

Discussion

Study status

Study dissemination

Conclusions

Data availability

Underlying data

Reporting guidelines

Funding Statement

References

Reviewer response for version 2

Ragab Elnaggar

Roles

Reviewer response for version 2

Luis Vicente Franco Oliveira

Roles

Reviewer response for version 1

Ragab Elnaggar

Roles

References

DIMITRIOS TSIMOURIS

DIMITRIOS TSIMOURIS

Reviewer response for version 1

Luis Vicente Franco Oliveira

Roles

DIMITRIOS TSIMOURIS

DIMITRIOS TSIMOURIS

Associated Data

Data Availability Statement

Underlying data

Reporting guidelines

ACTIONS

PERMALINK

RESOURCES

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