PONE-D-23-05214Effect of one dose of ceftriaxone during endotracheal intubation on the incidence of aspiration pneumonia in cerebral hemorrhage patients: A randomized, controlled, double-blind clinical study protocolPLOS ONE

Dear Dr. Song,

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 Nov 01 2023 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,

Burak Katipoğlu

Academic Editor

PLOS ONE

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Additional Editor Comments :

Dear Authors, Thank you for giving us the opportunity to review this article.

I have some concern for this manuscript.

Could you explain why you chose the cerebral hemorrhage group?

In the discussion section, write down the differences and similarities from the articles in the literature, together with the reasons.

Kind Regards.

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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?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

Reviewer #2: Yes

Reviewer #3: No

**********

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

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

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.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I thank the editor for submitting the work of the Chinese group for review.

This work consists of a double-blind randomized controlled trial protocol that seeks to evaluate whether it is possible to decrease the incidence, with a single dose of cephalosporin, of aspiration pneumonia in a specific test population, those subject to intracerebral hemorrhage.

Keywords.

1. I congratulate the authors for their choice of keywords. All relevant and found in the reference database.

Introduction

2. To check reference #1, as wording or citation.

3. Line 66-74 I advise the authors, in this part of the introduction to include some reference to the sentences said, or, if they are speculations or statements of the authors perhaps rephrase the sentences.

4. Line 76-85 I advise the authors in this passage to specify the type of patients examined by the studies mentioned, for the study in reference no. 2 ALL emergency intubated patients were taken, for studies instead 3 and 4 patients were examined, for study 3 elderly, after the age of 70 years stated, and for study 4 outcome of a population with a median age of 78 years is evaluated.

This is a point to be specified in the introduction for clarity and accuracy.

5. Line 116-121 To be included references to this. They are not in the document.

Study design

6. I would like to ask the authors how they plan to deal with COPD patients, patients who are more delicate and who may also be more prone to pneumonia, both nosocomial but especially community-acquired pneumonia. Will they be excluded or included in the study and then perhaps analyzed separately? This is a subcategory to be carefully evaluated.

Figure 1 and 2

7. Regarding the figures I would have some clarifications for the authors to make. Figure 1 is interesting in that it describes, adequately, the pattern of enrollment, interventions, and assessments done.

8. For Figure 2, it would also be to complete after the intervention and control boxes, with perhaps the patients lost and the amount of patients analyzed.

9. Regarding exclusion criterion 7, however, I would specify the reason for this criterion. Why were those who had a history of alcohol consumption in the week prior to endotracheal intubation not considered? For what reason? Is there a reference that discourages this type of patient in the possibility of being enrolled?

Intervention

10. Line 162-163 Why was the infusion rate of ceftriaxone chosen to be 1 hour and not 30 minutes given that ceftriaxone is known to be a time-dependent drug and acts on the plasma peak and not on maintaining a constant dose? This is a point that needs to be evaluated and clarified in order to be timely in describing the intervention, which is also a cornerstone on which the study is based, the administration of the antibiotic.

11. Line 168. I advise authors to state serious adverse events and not take them for granted, I assume symptoms of severe allergic crisis in patients not known allergic, but to be stated.

Data collection

12. I would advise the authors to subdivide this subsection further, perhaps putting, patient characteristics, intubation characteristics, and antibiotic therapy. So that the data collected can be visualized better and more schematically.

13. Additional data that I would also collect are laboratory tests at admission, at least those related to infectious status, considering that later we are going to evaluate an infection, such as (Body temperature, complete hemogram with complete Leukocyte formula, Thrombus and CRP and procalcitonin, and maybe other values if present and measured), so that we have a start and know possibly whether to exclude from the study patients who do not have obvious fever but maybe had an initial infectious status. And possibly even if there is a possibility, of a bronchial secretion analysis at the time of intubation, or even better a BAL.

Statistical analysis

14. I recommend that the authors also state that the data will be described statistically with mean and standard deviation or median and quartile depending on the distribution

Discussion

15. Line 276-278 Appropriate reference to the authors' statement should be included.

Reviewer #2: 1) There is a mistake in the date in methods and analysis (line 41) :it should be from April 2023 to April 2024.

2) Please provide a copy of ethical committee approval for the trial.

Reviewer #3: Dear Authors, Thank you for giving us the opportunity to review this article titled “Effect of one dose of ceftriaxone during endotracheal intubation on the incidence of aspiration pneumonia in cerebral hemorrhage patients: A randomized, controlled, double-blind clinical study protocol”.

I don't have any conflict of interest.

I have some concern for this manuscript.

First of all, this should be clarified. Should antibiotics be given before or after intubation? In some sentences, antibiotics are mentioned before intubation and in others after.

The introduction part is too long.

bacteria should be given briefly.

exclusion criteria

consciousness changes?

Actually, isn't this the riskiest group?

Therefore, informed consent should be obtained from their relatives. I think excluding the most risky patient group will impoverish this study.

History of drinking in the week before endotracheal intubation. (why? reference?)

Why is ceftriaxone given as an infusion for 1 hour?

Will each patient be paag after intubation? to exclude old infiltrates?

data collection

Has a mechanical application been made or not to prevent aspiration?

Will this information be recorded?

The discussion part should be completely rewritten.

And, The most important question that needs to be explained is this.

Why cerebral hemorrhage patient group?

Kind Regards.

**********

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

Reviewer #2: No

Reviewer #3: No

**********

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Attachments

Attachment

Submitted filename: recommendations.docx

PONE-D-23-05214R1Effect of one dose of ceftriaxone during endotracheal intubation on the incidence of aspiration pneumonia in cerebral hemorrhage patients: A randomized, controlled, double-blind clinical study protocolPLOS ONE

Dear Dr. Song,

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 02 2024 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,

Burak Katipoğlu

Academic Editor

PLOS ONE

[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?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #4: Yes

Reviewer #5: Partly

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #4: Yes

Reviewer #5: No

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #4: Yes

Reviewer #5: No

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 #4: Yes

Reviewer #5: 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 #4: Yes

Reviewer #5: Yes

**********

6. Review Comments to the Author

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.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #4: I thank the editor for giving me the opportunity to review the revised manuscript titled Effect of one dose of ceftriaxone during endotracheal intubation on the incidence of aspiration pneumonia in cerebral hemorrhage patients: A randomized, controlled, double-blind clinical study protocol by Xuan Song and others from China The concept for this study Protocol is praise worthy and covered all relevant aspects for the study The protocol is meticulously planned with the inputs from the reviewer it is further improved it will lead to meaningful outcome The methodology is replicable well written

I have gone through the Manuscript and Reviewer's comments and I have found the authors have made changes asper the recommendations of the reviewer the authors answered all the quarries put by reviewer . With these changes in the manuscript it is fit for acceptance without any further modification

Reviewer #5: While I appreciate the authors' efforts to address limitations in their revised manuscript, serious concerns persist. The continued conflation of aspiration pneumonia and aspiration pneumonitis raises validity issues. Misdiagnosis and inappropriate antibiotic use in pneumonitis cases are major concerns, it has worsened the problem of MDR organisms worldwide as outlined by major guidelines. Implementing additional diagnostic measures, such as bronchoscopy, or lab markers like procalcitonin is crucial to distinguish between these entities before deciding on preemptive antibiotic therapy.

To address these concerns and ensure a robust study, I recommend refining the definition of aspiration pneumonia and clearly defining pneumonitis vs pneumonia, and possibly utilizing additional diagnostic measures. Additionally, authors should provide more data supporting the efficacy of single-dose ceftriaxone specifically for aspiration pneumonia prevention in ICH patients. Before potentially exposing patients to unnecessary risk of inappropriate antibiotic use, authors should conduct a cost-effectiveness analysis to assess the balance between potential benefits and risks associated with prophylactic ceftriaxone use.

Furthermore, the single-center design and small sample size, previously acknowledged by the authors, further limit the generalizability and impact of this research. Given the importance of aspiration pneumonia, it is vital that studies addressing this issue are conducted with the utmost rigor and precision. Finally, collaborating with other centers could enhance the study's generalizability and impact. Unfortunately, the current manuscript falls short of this standard.

**********

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 #4: No

Reviewer #5: 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.

PONE-D-23-05214R2Effect of one dose of ceftriaxone during endotracheal intubation on the incidence of aspiration pneumonia in cerebral hemorrhage patients: A randomized, controlled, double-blind clinical study protocolPLOS ONE

Dear Dr. Song,

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 Apr 19 2024 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,

Burak Katipoğlu

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Dear Authors, I reviewed the article again after revising it.

I still have some concerns.

The manuscript still needs major improvement.

Kind regards.

[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?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #3: No

Reviewer #4: Yes

Reviewer #6: No

Reviewer #7: 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?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #3: No

Reviewer #4: Yes

Reviewer #6: Partly

Reviewer #7: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #3: No

Reviewer #4: Yes

Reviewer #6: No

Reviewer #7: 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 requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 #3: No

Reviewer #4: Yes

Reviewer #6: No

Reviewer #7: 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 #3: Yes

Reviewer #4: Yes

Reviewer #6: Yes

Reviewer #7: Yes

**********

6. Review Comments to the Author

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.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: Dear Authors, thank you for giving me the opportunity to review this article.

However, I still have questions about the study.

Would you like to perform a subgroup analysis regarding mortality prognosis for patients with intracranial hemorrhage?

Would the cost-effectiveness analysis be the same in the geriatric population with comorbid diseases with high mortality rates?

Again, as a subgroup analysis, should the low-risk patient group be evaluated as the same as the patient group with visible stomach contents during intubation, aspiration suspected, and evidence of aspiration by bronchoscopy?

I think that the methodology of the study should be reorganized with a solid justification and a good subgroup analysis.

Kind Regards

Reviewer #4: I thank the editor for giving me the opportunity to review the manuscript entitled Effect of one dose of ceftriaxone during endotracheal intubation on the incidence of aspiration pneumonia in cerebral hemorrhage patients: A randomized, controlled, double-blind clinical study protocol by Xuan Song and others for the second time. The reviewer #5 has made some comments and sought some clarification to which authors have responded. I have gone through the comments and reply given by the authors. Reviewer# 5 pointed in his comments that that the definition of pneumonitis and Pneumonia has to made clear to which the authors have given the explanation which is adequate Present study protocol deals with aspiration pneumonia hence chemical pneumonitis needn't be included secondly the most probable organism responsible for aspiration pneumonia are from throat secretion mostly consists of gram positive and few gram negative organisms sensitive to ceftriaxone .hence the selection of antibiotic is justified thirdly the authors agreed to reviewer comment that multicentric trial should be carried out basing on the result of study to be carried out by present protocol The authors have modified manuscript as per the reviewers comment and I am satisfied with the modification Hence I recommend that the manuscript may be accepted without any further modification

Reviewer #6: thank you very much for giving me the opportunity to review the manuscript" Effect of one dose of ceftriaxone during endotracheal intubation on the incidence of aspiration pneumonia in cerebral hemorrhage patients: A randomized, controlled, double-blind clinical study protocol". I think the main issue with this work is the antimicrobial resistance (AMR) that may happen with the blind consumption of antibiotics that you have mentioned in your exclusion criteria that if you see any sign of regurgitation you will exclude the patients. it means, you don't have any clue for an aspiration and still you use ceftriaxone as a prophylaxis. secondly, you have mentioned that you will exclude your patients if they receive any antibiotic during 48 hours after the surgery. the question is this: is it possible for a patient not to receive antibiotic after those surgeries? thirdly, I even didn't see the result part of this manuscript. you have skipped result and started discussion after method.

Reviewer #7: The revised manuscript is interesting and good written and discussed.

Introduction was good written

Materials and methods were good written

Results were good written

Discussion was good written

**********

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 #3: No

Reviewer #4: No

Reviewer #6: Yes: Kamel Abdi

Reviewer #7: 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.

PONE-D-23-05214R3Effect of one dose of ceftriaxone during endotracheal intubation on the incidence of aspiration pneumonia in cerebral hemorrhage patients: A randomized, controlled, double-blind clinical study protocolPLOS ONE

Dear Dr. Song,

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 provide a detailed point to pint reply to the reviewers' comments

Please submit your revised manuscript by Sep 12 2024 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,

Chiara Lazzeri

Academic Editor

PLOS ONE

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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?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #3: Yes

Reviewer #4: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #3: Yes

Reviewer #4: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #3: Yes

Reviewer #4: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 #3: Yes

Reviewer #4: Yes

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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 #3: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

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.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: Dear authors, I have reviewed your article for re-evaluation.

But I still have some questions that I can't get answers to.

First of all, the dates between April 2023 and April 2024 should be changed.

Could you please state more clearly why patients with intracranial hemorrhage were selected?

For Introduction:

Please give the necessary message by simplifying the numbers in the second paragraph.

Likewise, there are too many names in the fourth paragraph. Simplify and combine this paragraph with the next paragraph, that is, your purpose for choosing Ceftriaxone.

Discussion: In the second paragraph, only information is given.

Information that should be included in the introduction section.

Create a relationship with your work and state what your work will add with this information.

The third and fourth paragraphs likewise contain only information.

Things I hope to see in the discussion section:

Which gap in the literature will be closed with your study?

What is the reason for the conflicting information in the literature regarding your choice of ceftriaxone? What is the difference of your study?

Why were ICH patients chosen? What kind of deficiency is there in the literature regarding this?

Your sample size is quite small. Your results will not be strong for mortality.

Additionally, as a comparison in your study; I recommend that you compare the risk of aspiration pneumonia in intubated patients with ICH in the year before the study in your hospital with the group receiving ceftriaxone in your study.

Please rewrite this beautiful study protocol by enriching the discussion section.

Kind Regards

Reviewer #4: Thanks for giving me the opportunity to review the manuscript which I have already reviewed before, and found it fit for publication. I feel no further modification is required as I am satisfied with the responses given by authors to the reviewers comments and agreeing to incorporate these aspects in the study protocol

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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 #3: No

Reviewer #4: 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.

PONE-D-23-05214R4Effect of one dose of ceftriaxone during endotracheal intubation on the incidence of aspiration pneumonia in cerebral hemorrhage patients: A randomized, controlled, double-blind clinical study protocolPLOS ONE

Dear Dr. Song,

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 Dec 27 2024 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,

Chiara Lazzeri

Academic Editor

PLOS ONE

Journal Requirements:

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?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #8: Yes

Reviewer #9: 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?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #8: Yes

Reviewer #9: Partly

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #8: Yes

Reviewer #9: No

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 #8: Yes

Reviewer #9: 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 #8: Yes

Reviewer #9: No

**********

6. Review Comments to the Author

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.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #8: The sample size needs to be calculated for the protocol. What are the results of the incidence of pneumonia from preliminary data? What test will be used? What attrition rate was assumed?

The statistical analysis needs to be rewritten. Clarify the primary endpoint will be compared using chi-square test/fisher exact test. Will demographics/covariates be adjusted for the primary analysis?

Reviewer #9: 1) The statement “This is a prospective, randomized, controlled, double-blind clinical study, which was reviewed by the ethics committee of Dong E Hospital…” should come under study design.

2) The paragraph that begins with “Patients with ICH undergoing endotracheal intubation in Dong E Hospital of….” Should be captioned inclusion and exclusion criteria

3) Sample size calculation. The authors indicated that a total of 50 patients will be included in the preliminary study. What informed the number 50? How many patients will be in the control, and how many will be in the intervention? Estimation of sample size for clinical trial should be based on the minimum detectable effect (expected change) after the implementation of the intervention, the type of hypothesis, design effect to account for correlation of patient response at the facility level, attrition rate, type I error, power of the study. The sample size of 50 was assumed, and a more detailed sample size must be conducted so that we determine the number of patients required. The section on sample size, which is a critical component of the protocol, is missing. This is also not a pilot study but a full clinical trial protocol.

4) Statistical Analyses of the proposed study must highlight a detailed analytical plan, including how each outcome variable (primary and secondary outcomes) will be measured (continuous, discrete, nominal, ordinal outcomes) and the specific statistical test that will be applied including potential assumption of the test and how violations of the assumptions will be addressed. The current write-up is all lumped together with no clear pattern as which statistical analyses will be used to address the study hypothesis.

**********

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 #8: No

Reviewer #9: 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.

Effect of one dose of ceftriaxone during endotracheal intubation on the incidence of aspiration pneumonia in cerebral hemorrhage patients: A randomized, controlled, double-blind clinical study protocol

PONE-D-23-05214R5

Dear Dr. Song,

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. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

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,

Chiara Lazzeri

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #8: Yes

Reviewer #9: 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?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #8: Yes

Reviewer #9: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #8: Yes

Reviewer #9: 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 requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 #8: Yes

Reviewer #9: 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 #8: Yes

Reviewer #9: Yes

**********

6. Review Comments to the Author

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.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #8: All my concerns are addressed.

Reviewer #9: Comments have been duly addressed and I commend the authors for providing accurate responses and revising the content of the manuscript.

**********

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 #8: No

Reviewer #9: No

**********