Active expiration reduces hypercapnia in lung failure – results of the prospective interventional ActiveEx study and development of a prototype device for automated application

Denis Witham; Julius Valentin Kunz; Ann-Christin Krebs; Karoline Brückner; Roland Körner; Mareen Pigorsch; Kai-Uwe Eckardt; Paul Uwe Thamsen; Philipp Enghard; Julija Peter

doi:10.1371/journal.pone.0333579

Peer Review History

Original SubmissionJanuary 25, 2025
20 May 2025 Decision Letter - Yusuke Hoshino, Editor PONE-D-25-02100Active Expiration Reduces Hypercapnia in Lung Failure – Results of the Prospective Interventional ActiveEx Study and Development of a Prototype Device for Automated ApplicationPLOS ONE Dear Dr. Kunz, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Jul 04 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. 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The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Please upload a new copy of Figure 5 as the detail is not clear. Please follow the link for more information: "https://blogs.plos.org/plos/2019/06/looking-good-tips-for-creating-your-plos-figures-graphics/" https://blogs.plos.org/plos/2019/06/looking-good-tips-for-creating-your-plos-figures-graphics/ 3. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information . Additional Editor Comments: There are quite a few clarifications suggested. Be sure to reply point-by-point in your revised submission. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: No ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors present a small study to investigate Intermittent Abdominal Pressure Ventilation (IAPV) and Expiratory Rib Cage Compression (ERCC) in adult patients with hypercapnia. The paper is clearly written, but I have several concerns. • The manuscript and the study protocol indicate that because this was deemed a pilot study, no sample size calculations were conducted. However, the protocol calls for 20 patients. However only 10 were enrolled, one withdrew, and nine were analyzed. There is no explanation for stopping enrollment after 10 patients. • All patients were treated first with IAPV for twenty minutes, rested for 20 minutes, and then treated with ERCC. It would have been preferable to randomize the order in which the patients received the treatments. • Reference number 12 lists the year incorrectly; it is The R Journal, 2023; 15(1):142-158. • The most serious concern is that the statistical test used to compare the pre- and post- respiratory and hemodynamic outcome measures, the Brunner-Munzel test, is inappropriate for these data. This test is for data arising from two independent samples, but the data are collected before and after treatment on the same nine individuals, and thus are paired data, not from two independent samples. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy . Reviewer #1: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0333579.r001
Revision 1
11 Jul 2025 Author Response Dear Dr. Chenette, Dear Academic Editors and Reviewers, We are grateful for the opportunity to revise and resubmit our manuscript to PLOS ONE. We sincerely thank the academic editor and reviewer for their insightful comments and helpful suggestions. We have carefully addressed each of the points raised and made appropriate changes to the manuscript as required. All changes made to the manuscript have been marked in blue font for clarity. In the attached response to reviewers document, each point is addressed in detail. We firmly believe that the insightful comments we received have substantially augmented the quality of our manuscript. Once again, we extend our deepest thanks for your expert guidance and unwavering support. Sincerely, The Authors Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0333579.r002
30 Jul 2025 Decision Letter - Yusuke Hoshino, Editor PONE-D-25-02100R1Active Expiration Reduces Hypercapnia in Lung Failure – Results of the Prospective Interventional ActiveEx Study and Development of a Prototype Device for Automated Application PLOS ONE Dear Dr. Julius Valentin Kunz, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. The reviewers believe there are some minor concerns which you should address before this manuscript is forwarded to the publisher. The suggestions and comments can be found at the end of this email. Please submit your revised manuscript by Sep 13 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols . We look forward to receiving your revised manuscript. Kind regards, Yusuke Hoshino Academic Editor PLOS ONE Journal Requirements: If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments: Be sure to reply point-by-point in your revised submission. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This revised manuscript is considerably improved. I just have a few minor comments regarding the revision. line 150 - denoting relative effect by 'p' is confusing vis a vis p-values. please choose another symbol for relative effect. Table 1: adjust column width so that the word 'ventilation' in the column heading is not split over two lines line 205 - most measures are reported as median and IQR, but the manual compression pressure is reported as mean and IQR. Why switch from median to mean for this variable? Also, reporting IQR along with a mean is unusual. Generally one reports the standard deviation with means and IQR with medians. Typos - next to last sentence in Results section of Abstract 'rapid' should be 'rapidly' - line 137 - need a space between 'pressure' and 'was' - line237 'from' should be 'for' There are a few places in the revised manuscript where the marked changes remain (ie, were not accepted or cleared, such as in line 248) ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy . Reviewer #1: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0333579.r003
Revision 2
26 Aug 2025 Author Response Response to Reviewer We sincerely thank the reviewer for the careful re-evaluation of our revised manuscript and for the constructive minor comments. We very much appreciate the reviewer’s acknowledgment that the revised version has considerably improved, and we are grateful for the additional suggestions, which helped us to further enhance the clarity, precision, and overall quality of the manuscript. All comments have been carefully considered, and the requested corrections have been implemented accordingly. Our detailed responses are provided below, point by point: R.1 Line 150 – Symbol for relative effect We agree that the previous notation “p” for relative effect was confusing given its association with p-values. To avoid ambiguity, we have removed the symbol altogether. The results are now consistently reported as “relative effect” without using any additional symbol. We believe this wording is clearer and prevents potential misinterpretation by the reader. R.2 Table 1 – Column width The column width has been adjusted so that the term “ventilation” in the column heading is displayed on a single line. R.3 Line 205 – Reporting of manual compression pressure We thank the reviewer for pointing this out. The indication of “mean” was a typographical error. Manual compression pressure was in fact analyzed and reported as median (IQR), consistent with the other variables. This has now been corrected in the text. R.4 Typos Abstract, Results section: corrected “rapid” → “rapidly” Line 137: inserted missing space between “pressure” and “was” Line 237: corrected “from” → “for” All previously marked changes have now been accepted and cleared. Off-topic correction – Age data in Table To further ensure patient anonymity, the exact ages originally shown in Table 1 have been replaced by decade ranges (e.g., “43” → “40-50”). This modification has no impact on the results or interpretation but strengthens data protection. Changes to the Manuscript Line 109: To ensure patient confidentiality, exact ages were not reported; instead, all ages were categorized into decade ranges (e.g., 43 years → 40–50 years). We are grateful for these helpful suggestions, which have further improved the clarity and consistency of our manuscript. Sincerely, The Authors Attachments Attachment Submitted filename: Response_to_Reviewers_auresp_2.docx https://doi.org/10.1371/journal.pone.0333579.r004
16 Sep 2025 Decision Letter - Yusuke Hoshino, Editor Active Expiration Reduces Hypercapnia in Lung Failure – Results of the Prospective Interventional ActiveEx Study and Development of a Prototype Device for Automated Application PONE-D-25-02100R2 Dear Dr. Kunz, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Yusuke Hoshino Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewer #1: Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: (No Response) ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: (No Response) ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: (No Response) ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Previous comments have been addressed ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy . Reviewer #1: No ******** https://doi.org/10.1371/journal.pone.0333579.r005
Formally Accepted
Acceptance Letter - Yusuke Hoshino, Editor PONE-D-25-02100R2 PLOS ONE Dear Dr. Kunz, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Yusuke Hoshino Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0333579.r006

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