The Effect of Inspiratory Muscle Training on Gastroesophageal Reflux Disease Characteristics: A Systematic Review
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors The article is interesting and valuable in terms of looking at reflux from a different perspective. I believe it would be appropriate to publish Kind regardsAuthor Response
We would like to thank the reviewer for taking the time to review our manuscript and for his/her positive comments.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsThis was a very well-done systematic review of research and focus on the effect of Inspiratory 15 Muscle Training (IMT) in GERD characteristics. The data reported is succinct and well-presented. After carefully review this paper, I think this paper was still need further revision and add some detail information for future decision.
1. In study design; authors just included "randomized controlled trials (RCTs) or clinical trials" and only 3 studies had included. Because such research is not easy to conduct, the author may consider adding a research direction and relaxing the conditions, and also include articles related to clinical observational studies, which may provide a more complete picture.
2. These 3 tables need to be rearranged for easier reading by the audience
3. In line 209 "3.3.3Ε. ffects of Intervention" might re-write to "3.3 Effects of Intervention"
Author Response
We would like to thank the reviewer for taking the time to review our manuscript and for his/her constructive comments. We have been studying this topic for quite some time, starting from the general effect of breathing exercises. As we wanted to further examine a more structured exercise intervention that of IMT, we wanted to have studies with high methodological quality like RCTs to fully examine the effectiveness having a control group as well. When we came across studies that didn’t follow our search terms and conditions, we believed it would be best to include them in the manuscript in discussion to present more data on the topic. From this point of view, we keep the high standards for our systematic review but we also include all relevant studies.
Reviewer Comment: These 3 tables need to be rearranged for easier reading by the audience
Thank you for pointing this out. We have rearranged the tables. We moved table 2 higher in the manuscript and moved table 3 in the discussion.
Reviewer comment :In line 209 "3.3.3Ε. ffects of Intervention" might re-write to "3.3 Effects of Intervention"
Thank you for pointing this out, we corrected it.
Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for AuthorsThe manuscript comprehensively reviews the potential therapeutic effects of Inspiratory Muscle Training (IMT) on the gastroesophageal reflux disease (GERD) population. It successfully outlines the key mechanisms involved and the current research gaps. However, several critical issues need to be addressed to improve clarity, strengthen the interpretation of the results, and ensure methodological transparency.
Comments:
1. Line 48, the explanation of the "reflex relaxation" and "transient relaxation" phenomenon is unclear. Simplify and provide more context on their relevance to GERD. Add proper references for better understanding.
2. Line 209, 3.3.3Ε. ffects of Intervention should be 3.3.3. Εffects of Intervention?
3. The study identification and search criteria are presented in a structured manner, but some minor edits for readability and consistency are needed. For example, the search terms section could be more succinctly phrased.
4. The manuscript could benefit from a more detailed discussion of the statistical methods used to assess heterogeneity among studies. While some results are reported, there is limited discussion of how data variability was addressed.
5. The connection between COVID-19 infection and GERD-related respiratory dysfunction is intriguing but needs more careful evaluation. More discussion is needed to discuss the potential mechanisms.
6. Please expand on the mechanistic insights linking IMT to GERD symptom improvement. Discuss the neuromuscular adaptation to IMT, specifically its potential effects on autonomic regulation and the diaphragm’s role in GERD pathology.
7. Provide a clearer description of the process for resolving disagreements in the quality assessment process, including the role of the third author.
Author Response
We would like to thank the reviewer for his/her cumulative comments. GERD is most common pathology than anticipated, yet as the reviewer pointed out its pathophysiological mechanics are quite complex.
Comments:
- Line 48, the explanation of the "reflex relaxation" and "transient relaxation" phenomenon is unclear. Simplify and provide more context on their relevance to GERD. Add proper references for better understanding.
We would like to thank the reviewer for this comment because it offered us the opportunity to look into this matter. There is a lack of clarity in the literature as both of this phenomenon are included in the general term of transient lower esophageal sphincter (LES) relaxation (TLESR). Yet, there are two separate phenomena, but closely related. To better describe the two relaxation phenomenon, it would be better to change the term “reflex relaxation” to “ shallow induced relaxation”. Also, we rephrased and added the following in the manuscript (lines 48-67): “The two sphincters relax (shallow induced relaxation) during swallowing and the opening of the LES and diaphragmatic sphincter allows the swallowed bolus to be easily pushed into the stomach [4,5] and then contract. They create a pressure that is higher than the intra-abdominal, preventing reflux of gastric contents. Yet, LES and diaphragmatic sphincter distensibility are increased in reflux disease, thus leading to a greater opening of the diaphragmatic sphincter allowing reflux to happen. A less distensible LES and diaphragmatic sphincter will result in a smaller opening, which causes a relative outflow obstruction to the bolus [5]. The diaphragmatic sphincter is also affected by the diaphragmatic excursion. Abnormal changes of intra-thoracic and intra-abdominal pressures could lead to a decreased excursion and diaphragmatic dysfunction. This weakens the barrier’s effect of the lower oesophageal sphincter against regurgitation [6,7-8]. There is also the case of transient LES relaxation (t LRESR) that accounts for small amounts of regurgitation during the day. TLESR is a physiological mechanism for the retrograde flow of stomach contents into the esophagus in cases of benching, vomiting etc. The presence of tLESR is defined by the absence of a pharyngeal swallow signal for 4 seconds before to 2 seconds after the onset of LES relaxation. An important component of tLESR is the complete inhibition of the diaphragmatic sphincter. The normal reflux barrier is disrupted in cases of increased frequency of transient relaxation of the lower oesophageal sphincter and diaphragmatic sphincter. When considering that GERD population has an increased number or tLERS and its effect on the diaphragmatic sphincter we could easily understand how this could further contribute to reflux [5].”
And the relative reference: Mittal RK. The sphincter mechanism at the lower end of the esophagus: an overview. Dysphagia. 1993 Fall;8(4):347-50.
- Line 209, 3.3.3Ε. ffects of Intervention should be 3.3.3. Εffects of Intervention?
We have corrected this.
- The study identification and search criteria are presented in a structured manner, but some minor edits for readability and consistency are needed. For example, the search terms section could be more succinctly phrased.
In order to have the search terms more succinctly phrased as proposed by the reviewer we changed the format as seen in lines 106-112 and inserted bullets.
”The search terms used following PICO framework were:
- Population: GERD OR Reflux gastroesophageal disease OR anti-reflux barrier,
- Intervention: respiratory physiotherapy OR inspiratory muscle training OR respiratory muscle training and
- Outcome: maximal inspiratory pressure OR lower esophageal sphincter.
- The manuscript could benefit from a more detailed discussion of the statistical methods used to assess heterogeneity among studies. While some results are reported, there is limited discussion of how data variability was addressed.
This is a systematic review and due to a limited number of studies included we couldn’t continue to a meta-analysis and presenting data on heterogeneity. Yet, we noticed clinical heterogeneity due to differences in the populations included. Souza et al included also healthy participants and Widjanantie et al included people after COVID-19 infection. Also, due to limited studies included and different outcome measures used variability could n’ t be further addressed. All these are noted in the discussion and in the limitations of the study.
- The connection between COVID-19 infection and GERD-related respiratory dysfunction is intriguing but needs more careful evaluation. More discussion is needed to discuss the potential mechanisms.
This is indeed a most interesting point. In order to better present its potential mechanism we included : “ Additionally, we should note that COVID-19 has been associated with phrenic nerve paralysis which innervates the diaphragm” with the relative reference “Abdeldayem EH, Abdelrahman AS, Mansour MG. Recognition of phrenic paralysis as atypical presentation during CT chest examination of COVID-19 infection and its correlation with CT severity scoring: a local experience during pandemic era. Egypt J Radiol Nucl Med. 2021;52:156.”
- Please expand on the mechanistic insights linking IMT to GERD symptom improvement. Discuss the neuromuscular adaptation to IMT, specifically its potential effects on autonomic regulation and the diaphragm’s role in GERD pathology.
Disturbances in the activity of the autonomic nervous system affect both contraction and relaxation of the lower esophageal sphincter (which usually functions as a reflux barrier), leading to the onset and progression of GERD. Inspiratory muscle training (IMT) has positive responses in the autonomic nervous system modulation in chronic diseases such chronic heart failure. Studies have shown that IMT promotes the increase in the respiratory metaboreflex activation threshold and that changes in the respiratory pattern encourage baroreflex activity.
REF : 1. “de Abreu RM, Rehder-Santos P, Minatel V, Dos Santos GL, Catai AM. Effects of inspiratory muscle training on cardiovascular autonomic control: A systematic review. Auton Neurosci. 2017 Dec;208:29-35. doi: 10.1016/j.autneu.2017.09.002.)”
2.Mello, P.R.; Guerra, G.M.; Borile, S.; Rondon, M.U.; Alves, M.J.; Negrão, C.E.; Dal Lago, P.; Mostarda, C.; Irigoyen, M.C.; Consolim-Colombo, F.M. Inspiratory muscle training reduces sympathetic nervous activity and improves inspiratory muscle weakness and quality of life in patients with chronic heart failure: a clinical trial. J Cardiopulm Rehabil Prev 2012, 32, 255-61.
Under this perspective we added the following line 295-300: Besides the effect of IMT on the diaphragm as a muscle we should also consider its effect on the autonomous nervous system, whose neural pathways mediate the function of LES [31] Inspiratory muscle training has positive responses in the autonomic nervous system modulation in chronic diseases such chronic heart failure[32]. Studies have shown that IMT promotes the increase in the respiratory metaboreflex activation threshold and that changes in the respiratory pattern encourage baroreflex activity [31].
- Provide a clearer description of the process for resolving disagreements in the quality assessment process, including the role of the third author.
As we noted in the manuscript, if there was a different rate or unclear issue, these were discussed between the two raters and if consensus was not reached a third author resolved the issue by adjudiction. In order to make this more clear we added the following in lines 118-119 into “Different rates and unclear issues were discussed, and disagreements were resolved by adjudication of a third author by adjudication of a third author”.
Author Response File: Author Response.pdf
Reviewer 4 Report
Comments and Suggestions for AuthorsIn the paper entitled “the effect of inspiratory muscle training on gastroesophageal reflux disease characteristics: a systematic review” the authors tried to demonstrate the potential effect of inspiratory muscle training on GERD symptoms. The paper is interesting, and the fact that includes only RCTs ensures a good level of evidence. There is a major issue that has to be addressed:
- in the result section, is said that the total number of participant was 98, 91 of which with GERD. The total number of patients doesn’t match with the total number of patients in TABLE 2. Moreover, GERD should be defined following international standards, such as the Lyon 2.0 consensus, the Demeester score, ecc….
Author Response
We would like to thank the reviewer for taking the time to comment on our work and assist us in highlighting this important topic.
In the studies included in the systematic review we had 98 participants- 91 GERD population and 7 healthy volunteers. In the table, we have in the 1st study 20 GERD patients in the intervention and 9 in the control group, in the 2nd study we have 12 GERD population in the intervention and 7 healthy as a control group whose role was only to compare values of LES, and in the 3rd study we have 25 GERD population and 25 GERD in the control.
We would like to thank the reviewer for pointing out the consensus on diagnosing GERD. We added the following information in the introduction lines 38-43: “Due to the complexity of diagnosing and managing GERD, a consensus (The Lyon Consensus 2.0) was formulated to updated criteria for diagnosing gastro-oesophageal reflux disease (GERD), focusing on the necessity of conclusive evidence from oesophageal testing to support diagnosis and management. The modern definition of requires conclusive evidence of reflux-related pathology on endoscopy and/or abnormal reflux monitoring (using Lyon consensus thresholds) in the presence of compatible troublesome symptoms.”
“Gyawali CP, Yadlapati R, Fass R, Katzka D, Pandolfino J, Savarino E, Sifrim D, Spechler S, Zerbib F, Fox MR, Bhatia S, de Bortoli N, Cho YK, Cisternas D, Chen CL, Cock C, Hani A, Remes Troche JM, Xiao Y, Vaezi MF, Roman S. Updates to the modern diagnosis of GERD: Lyon consensus 2.0. Gut. 2024 Jan 5;73(2):361-371.”
Author Response File: Author Response.pdf
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThis was a very well done study and the data reported is succinct and well-presented. Authors had complete response the previous reviewers’ suggestion and revised well. May consider accepted this article.
Author Response
We would like to thank the reviewer for taking the time to look into our work, and for his/her valuable comments.
Reviewer 3 Report
Comments and Suggestions for AuthorsAll my concerns have been addressed.
Author Response
We would like to thank the reviewer for all his/her valuable comments.
