Association between acute respiratory acidosis and hyperkalemia during esophageal cancer surgery in the prone position: A multicenter retrospective observational study protocol

Sakura Okamoto; Tokiko Tochii; Jyunya Nakada; Hideaki Note

doi:10.1371/journal.pone.0337018

Peer Review History

Original SubmissionNovember 6, 2025
8 Jan 2026 Decision Letter - Paolo Aurello, Editor Dear Dr. Sakura Okamoto, 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 Feb 19 2026 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. A 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'. We look forward to receiving your revised manuscript. Kind regards, Paolo Aurello Academic Editor PLOS One Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. 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. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section. 3. 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. 4. 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. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? Reviewer #1: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??> Reviewer #1: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??> Reviewer #1: Yes ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete??> The PLOS Data policy Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes ****** Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. Reviewer #1: This is a well-structured and transparently reported research protocol that explores a clinically relevant and physiologically compelling question. The authors propose a retrospective, multicenter observational study to investigate the association between acute respiratory acidosis and hyperkalemia during prone esophagectomy—a phenomenon that appears to challenge traditional physiology teaching. 1. Defining the “intervention” time point: While selecting the lowest pH blood gas during the prone position is an effective and targeted strategy, pre-defining the criteria for data extraction is helpful. For example, should the lowest pH value be used initially, or should a minimum PaCO2 threshold (e.g., > 50 mmHg) be set to ensure that this time point truly represents a significant respiratory challenge? This would enhance consistency between the two centers. 2. Covariate selection for the multivariate model: To further strengthen the pre-description, consider listing candidate variables to be included in the model (e.g., ΔPaCO2, ΔLactate, baseline eGFR, fluid balance, norepinephrine dose, duration of prone position). Briefly describing the variable selection strategy (e.g., based on clinical relevance and/or univariate association with p-values < 0.1) will help further clarify the process. 3. Discussion of Confounding Factors: Briefly mention other perioperative factors that may affect potassium (such as the use of diuretics, insulin, or β2 agonists), and state that if the distribution is uneven, it will be recorded and considered as a covariate to further strengthen the causal inference. 4. Sample Size Justification: A minor supplement is to briefly explain why a difference of 0.5 mmol/L is considered clinically significant, or to link the increase in potassium to arrhythmic potentials by citing literature. ****** 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.] To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation. NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications. https://doi.org/10.1371/journal.pone.0337018.r001
Revision 1
9 Jan 2026 Author Response Response to Reviewers Manuscript ID: [PONE-D-25-58930] Title: Association between acute respiratory acidosis and hyperkalemia during esophageal cancer surgery in the prone position: A multicenter retrospective observational study protocol We would like to thank the editor and the reviewer for their time and valuable comments. We have revised the manuscript in accordance with the suggestions, which have significantly improved the quality and clarity of our protocol. Our point-by-point responses are detailed below. Comment 1. Defining the “intervention” time point: While selecting the lowest pH blood gas during the prone position is an effective and targeted strategy, pre-defining the criteria for data extraction is helpful. For example, should the lowest pH value be used initially, or should a minimum PaCO2 threshold (e.g., > 50 mmHg) be set to ensure that this time point truly represents a significant respiratory challenge? This would enhance consistency between the two centers. Response: We appreciate this valuable suggestion regarding the definition of the intervention timepoint. As this is a retrospective study, our priority is to analyze the overall clinical picture without reducing the sample size unnecessarily; therefore, we have chosen not to apply a strict PaCO₂ threshold for the primary analysis. However, we agree that confirming the specific impact of significant respiratory acidosis is important. To address this, we have added a sensitivity analysis restricted to patients with PaCO₂ ≥ 50 mmHg. This allows us to verify whether the association holds true in the population with strictly defined respiratory acidosis, as you suggested. We have updated the Methods section (Secondary Outcomes) accordingly. Comment 2. Covariate selection for the multivariate model: To further strengthen the pre-description, consider listing candidate variables to be included in the model (e.g., ΔPaCO2, ΔLactate, baseline eGFR, fluid balance, norepinephrine dose, duration of prone position). Briefly describing the variable selection strategy (e.g., based on clinical relevance and/or univariate association with p-values < 0.1) will help further clarify the process. Response: Thank you for this constructive comment. We agree that clarifying the variable selection process is essential. As suggested, we have explicitly listed the candidate covariates in the Methods section (Statistical Analysis). Regarding the variable selection strategy, we have adopted the approach based on clinical relevance and the sufficiency of outcome events to prevent overfitting, as mentioned in your comment. Comment 3. Discussion of Confounding Factors: Briefly mention other perioperative factors that may affect potassium (such as the use of diuretics, insulin, or β2 agonists), and state that if the distribution is uneven, it will be recorded and considered as a covariate to further strengthen the causal inference. Response: We agree with your insightful suggestion. Perioperative medications such as diuretics, insulin, and β2-agonists can indeed influence potassium levels. Accordingly, we have added these medications to our data collection and will assess their association with the outcome in the univariate analysis. However, since our study population primarily consists of patients undergoing cancer resection who generally lack significant comorbidities (other than the malignancy), we anticipate that the number of patients using these medications may be very small. If the number of cases is insufficient to include these variables in the multivariable model, we will report the descriptive data and address this as a limitation in the Discussion section. We have updated the Methods section (Data Collection) to reflect this addition. Comment 4. Sample Size Justification: A minor supplement is to briefly explain why a difference of 0.5 mmol/L is considered clinically significant, or to link the increase in potassium to arrhythmic potentials by citing literature. Response: We appreciate this opportunity to clarify our rationale. While the exact threshold at which an acute potassium increase becomes pro-arrhythmic is not definitively established, meta-analyses have demonstrated a U-shaped relationship between serum potassium levels and cardiovascular risk [Ref 5]. Moreover, recent studies emphasize that the magnitude of potassium change is a critical predictor of electrocardiographic abnormalities [Ref 6]. In the specific context of esophagectomy, which involves the prone position and surgical manipulation near the heart, we determined that capturing a 0.5 mmol/L increase is clinically meaningful to identify patients at potential risk. We have added this rationale and cited the relevant literature in the Methods section (Sample Size Calculation). Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0337018.r002
14 Jan 2026 Decision Letter - Paolo Aurello, Editor <p>Association between acute respiratory acidosis and hyperkalemia during esophageal cancer surgery in the prone position: A multicenter retrospective observational study protocol PONE-D-25-58930R1 Dear Dr. Sakura Okamoto, 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, Paolo Aurello Academic Editor PLOS One https://doi.org/10.1371/journal.pone.0337018.r003
Formally Accepted
Acceptance Letter - Paolo Aurello, Editor PONE-D-25-58930R1 PLOS One Dear Dr. Okamoto, 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. Paolo Aurello Academic Editor PLOS One https://doi.org/10.1371/journal.pone.0337018.r004

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