Dear Dr. He Han,

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 24 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.

• 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,

Shweta Rahul Yemul Golhar, MD

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. Thank you for stating in your Funding Statement:

“This work was supported by Ningbo Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation (2024L004).

The peer review comments of the funding body have not been made public, so we are unable to provide specific peer review opinions.”

Please provide an amended statement that declares *all* the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now. Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement.

Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf.

3. PLOS requires an xlink:type="simple" iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager.

4. Thank you for stating the following in the Acknowledgments Section of your manuscript:

“This work was supported by Ningbo Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation (2024L004).”

We note that you have provided additional information within the Acknowledgements Section that is not currently declared in your Funding Statement. Please note that funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

“This work was supported by Ningbo Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation (2024L004).”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

5. 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.

6. Please include a separate caption for each figure in your manuscript.

7. 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.

Additional Editor Comments (if provided):

Thank you for submitting your research protocol to PLOS One. Upon review of the protocol there are numerous suggestions on statistical analysis and methodology proposed by reviewers. Please review the reviewers questions as noted in the email.

Some additional suggestions are as follows:

Exclude patients with auditory or visual deficiencies as they may be prone for perioperative delirium and difficult to assess.

Specific time of day and number of times per day that assessment will be done.

Specify what post operative pain control modality will be used and ensure its uniformity.

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

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #2: Partly

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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: Thank you for submitting this very clearly written study on an important topic of postoperative delirium after use of benzodiazepines. the protocol is clear, and they have demonstrated proper ethics oversight. I look forward to seeing the results of this study and subgroup analysis.

Reviewer #2: Thank you for the opportunity to review this protocol. I have several comments and suggestions for the authors:

Benefit of Midazolam:

The study focuses primarily on the potential harms of midazolam; however, it remains unclear whether midazolam provides meaningful benefit in reducing anxiety in older adults. A balanced risk–benefit assessment requires an understanding of both harm and benefit. The authors should consider including a measure of postoperative anxiety or patient experience to determine whether midazolam meaningfully improves patient-centered outcomes.

Timing of CAM Assessment:

The protocol does not specify when the CAM is administered (morning, afternoon, or evening) or whether timing is standardized across participants. Since delirium symptoms can fluctuate throughout the day, standardizing the assessment time—or documenting it carefully—is important for ensuring consistency and interpretability. Additionally, if timing is being analyzed as a secondary outcome, clarification is needed on how this will be meaningful without standardized measurement timing.

Loss to Follow-Up:

The authors should clarify how they plan to handle participants lost to follow-up in their analysis. Furthermore, for participants who remain intubated on postoperative day (POD) 1, it would be helpful to describe how these cases will be managed in the assessment of delirium and other outcomes.

Discharge and Population Heterogeneity:

It is unclear whether all participants will remain hospitalized for three days postoperatively. If some are discharged earlier, how will data collection and outcome assessment be handled? Additionally, including both single-level discectomy and multilevel fusion patients in the same cohort may introduce heterogeneity, as these groups differ in surgical magnitude and recovery trajectories. The authors should clarify whether these populations will be analyzed separately.

Reviewer #3: Title: Protocol: Effects of midazolam on postoperative delirium in elderly patients undergoing spinal surgery: a randomized, double-blind, placebo-controlled non-inferiority trial

This is a well-structured, ethically approved, and SPIRIT-compliant trial protocol. The non-inferiority design is appropriate for the study question. The statistical and data-management components are generally sound but require clarification on several points (margin justification, randomization integrity, missing data handling, and consistency of intervention dose)

Major Statistical/Methodological Comments

1. Non-inferiority margin justification: The 9% non-inferiority margin is insufficiently justified. Please explain the clinical rationale (why a 9% higher POD rate is acceptable) and provide supporting references or pilot data. Specify the direction of the hypothesis (upper bound of CI for risk difference).

2. Dose inconsistency: Midazolam dose is reported as 2 mg in the abstract and 5 mg in the Methods. This inconsistency affects both design and power assumptions; correct and harmonize throughout the text.

3. Randomization and allocation concealment: Clarify who generates, stores, and secures the random sequence, and whether allocation concealment is audited independently. The plan to reuse envelopes from withdrawn subjects should be revised to preserve randomization integrity.

4. Analysis population: Specify whether the primary non-inferiority analysis will use intention-to-treat (ITT) or per-protocol (PP) data. Both are expected in non-inferiority frameworks; clarify which is primary.

5. Primary analysis method: Define the statistical test explicitly—e.g., risk difference or odds ratio with one-sided 97.5% CI. For non-inferiority, risk difference is typically preferred for interpretability.

6. Interim analysis and alpha control: Provide criteria for early termination or continuation (e.g., conditional power, safety threshold). Describe whether alpha-spending or multiplicity adjustments will be applied to maintain type I error.

7. Missing data handling: Specify how missing POD outcomes (e.g., due to ICU transfer or death) will be treated. Conservative imputation (e.g., 'missing = event') or multiple imputation methods should be described.

8. Data validation and audit: Data entry via the Research Manager system is appropriate, but please detail procedures for double entry, range checks, and audit trails to ensure reproducibility and data integrity.

9. Multiplicity of secondary outcomes: Numerous secondary outcomes (pain, biomarkers, agitation, LOS, etc.) may increase false positives. Clarify that these are exploratory and will not be adjusted for multiplicity, or specify correction methods.

10. Data Monitoring Committee (DMC): Provide more detail on DMC independence, data access, and decision-making authority. Clarify whether members are independent of the sponsor and investigators.

Minor Comments

• Align the SPIRIT figure and text (the GAD-7 scale appears in Fig 1 but not described in Methods).

• Confirm all software versions (SPSS 19.0, PASS 15.0.5) and ensure reproducibility details (parameters, seed).

• Consider depositing the data and analysis code plan in a named repository per PLOS ONE data policy.

• Proofread for small typographical issues and ensure all references have complete DOIs.

**********

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: Yes:  Dr Shah-Jalal Sarker

**********

[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.

Protocol: Effects of midazolam on postoperative delirium in elderly patients undergoing spinal surgery: a randomized, double-blind, placebo-controlled non-inferiority trial

PONE-D-25-37876R1

Dear Dr. He Han,

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,

Shweta Rahul Yemul Golhar, MD

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?

Reviewer #2: Yes

Reviewer #3: 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 #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: 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 #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #2: Yes

Reviewer #3: 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 #2: The authors have sufficiently addressed my concerns. I do believe they could add one additional questionnaire about anxiolysis but the rationale they provide is sufficient.

Reviewer #3: The authors have addressed all of my comments appropriately. There are no more comments to address.

**********

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 #2: No

Reviewer #3: Yes:  Dr Shah-Jalal Sarker

**********