-->

PONE-D-26-10765

Safety and feasibility of local anesthesia for full-endoscopic spine surgery: A retrospective cohort study of body weight-based thresholds

PLOS One

Dear Dr. Sairyo,

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.

==============================

ACADEMIC EDITOR:

Thank you for submitting this clinically relevant manuscript. The study addresses an important practical question, and the dataset may be informative. However, a major revision is required before the manuscript can be reconsidered.

Several conclusions are currently stated more strongly than the retrospective design can support. In particular, the 7 mg/kg and 5 mg/kg lidocaine thresholds should be presented more cautiously and more clearly distinguished from established safety limits. The interpretation of LAST should also be revised, as the present data support the absence of documented clinically significant LAST rather than the complete absence of LAST. In addition, the frailty spectrum within the cohort should be clarified, as the frail group appears to consist predominantly of mildly frail patients.

For a revised submission, please: (1) temper the Abstract, Discussion, and Conclusion accordingly; (2) clarify whether dosing was based on actual or ideal body weight; (3) expand the limitations regarding retrospective ascertainment of LAST and postoperative delirium, including the potential masking effect of conscious sedation; and (4) carefully review the pharmacologic rationale and the accuracy of references and comparative statements, including Table 3.

Although one reviewer suggested a minor revision, a major revision is considered more appropriate because these issues affect the framing and interpretation of the manuscript’s main conclusions.

==============================

Please submit your revised manuscript by May 21 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.

Please include the following items when submitting your revised manuscript:

• 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'.

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.

As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only the individual author can complete the verification step; PLOS staff cannot verify ORCID iDs on behalf of authors.

We look forward to receiving your revised manuscript.

Kind regards,

Dr. KOICHIRO ONO

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. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

3. PLOS requires an ORCID 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. 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.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->2. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #2: N/A

**********

-->3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: This retrospective cohort study examines the safety and feasibility of transforaminal full-endoscopic spine surgery (TF-FESS) under local anesthesia in frail versus non-frail patients using body weight-based lidocaine dosing thresholds. While the topic is clinically relevant and addresses an important gap in the literature, there are significant methodological concerns, inconsistencies with established evidence, and issues with completeness and accuracy of references that require in my opinion major revisions before this manuscript can be considered for publication.

1. The authors propose 7 mg/kg for non-frail patients and 5 mg/kg for frail patients as safety thresholds, citing reference (Cuvillon et al., 2022). However, FDA-approved labeling for lidocaine without epinephrine specifies a maximum dose of 4.5 mg/kg, not exceeding 300 mg total. The 7 mg/kg threshold cited by the authors applies only to lidocaine WITH epinephrine, which significantly delays systemic absorption. (Lidocaine Hydrochloride. FDA Drug Label.

Food and Drug Administration. Updated date: 2026-01-16.). Please provide pharmacological justification for any deviation from standard dosing

2. The authors report 0% incidence of LAST, which is presented as a major finding. However, their definition of LAST is problematic: The retrospective design and reliance on medical record documentation (rather than prospective screening) creates high risk of under-detection, which the authors acknowledge only briefly in limitations. The claim of 0% LAST is not credible without prospective, systematic assessment. The authors should reframe this as "no clinically significant LAST requiring intervention" rather than claiming complete absence. Please revise the definition of LAST to acknowledge the spectrum of severity, explicitly state that mild LAST symptoms may have been masked by sedation, tone down claims about safety profile given methodological limitations and add this as a major limitation in the discussion .

3. Questionable Validity of mFI-5 Cutoff: The authors use mFI-5 ≥ 2 to define frailty, but the literature shows: mFI-5 is a continuous variable with incremental risk at each level and most studies use mFI-5 as a continuous predictor or stratify into three groups (0, 1, ≥2). The dichotomization at ≥2 is somewhat arbitrary and may not represent the optimal threshold for anesthetic risk stratificationAdditionally, only 5 patients (4.6%) had mFI-5 = 3, and none had mFI-5 = 4 or 5. This means the "frail" group is predominantly mFI-5 = 2 (82.1%), representing mild frailty at best. The study lacks patients with severe frailty, limiting generalizability.

4. No citation for the conscious sedation protocol (pentazocine + hydroxyzine); No pharmacological references supporting the claim that subcutaneous/fascial/disc injection sites have slow systemic absorption, Limited references on LAST in spine surgery specifically

Reviewer #2: The study provides valuable clinical evidence supporting the safety of transforaminal full-endoscopic spine surgery (TF-FESS) under local anesthesia (LA) in frail populations. The 100% completion rate and zero incidence of Local Anesthetic Systemic Toxicity (LAST) are encouraging. However, the retrospective nature and the lack of serum concentration data for lidocaine limit the pharmacological conclusions. I recommend Minor Revision to address these technical nuances.

Recommendations to the Authors

1.While the study utilizes weight-based thresholds safety limits were set at 7 mg/kg for non-frail patients and 5 mg/kg for frail patients, the authors should specify if these limits were calculated based on actual body weight or ideal body weight, as this is critical for obese or sarcopenic patients

2.The authors hypothesize that slow systemic absorption from poorly vascularized tissues prevents toxicity. The manuscript would be strengthened by citing specific pharmacokinetic literature that supports lidocaine's behavior in the spinal epidural and intradiscal space

3.The study defines postoperative delirium based on medical record reviews rather than a standardized prospective tool like the Confusion Assessment Method (CAM). The authors must more explicitly acknowledge the risk of under-detecting hypoactive delirium in the limitations section.

4.The protocol in the surgeries included pentazocine and hydroxyzine. The authors should discuss whether these sedatives could have masked early neurological signs of mild LAST (e.g., metallic taste or lightheadedness), potentially skewing the safety data.

5.Figure 2 is excellent for visualizing the "safety zone". I suggest adding a trend line or 95% confidence interval to the scatter plot to further illustrate the distribution of dosing relative to the thresholds.

**********

-->6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.-->

Reviewer #1: Yes: Alex Alfieri, M.D., Ph.D.

Hirslanden AndreasClinic

Cham, ZG Switzerland

Reviewer #2: 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.

Safety and feasibility of local anesthesia for full-endoscopic spine surgery: A retrospective cohort study of body weight-based thresholds

PONE-D-26-10765R1

Dear Dr. Sairyo,

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,

KOICHIRO ONO

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.-->

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

-->2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: The Authors revised the manuscript according the reviewers` indications. I have no more concerns.

best

Reviewer #2: The revision has improved the manuscript meaningfully — tone is more cautious, FDA labeling is acknowledged, CIs have been added, and the limitations section is more honest.

However, I still have few comments.

1. The study is fundamentally underpowered to demonstrate "safety."

A 0/108 event rate yields a 95% upper CI of ~3.4% overall and ~12.3% in the frail subgroup (the authors now report this, which is appreciated). A complication rate of up to ~12% in frail patients is not reassuring, and the manuscript should not characterize this as evidence of safety. The title and Conclusion still imply a stronger inference than the data support. I recommend:

Revising the title to something like "Feasibility of TF-FESS under local anesthesia: a single-center retrospective cohort" and removing "Safety" from the title, or qualifying it.

In the Abstract Conclusion, replacing "appears to be a safe and feasible surgical option" with "appears feasible, with no clinically significant complications observed in this small cohort.

2. Reference 16 (Ashton 1992) is cited to support the facet capsule barrier hypothesis, but that paper describes nerve fibers and neuropeptides in the capsule — it does not establish the capsule as a pharmacokinetic barrier. The citation does not support the claim made.

**********

-->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: Yes: Alex Alfieri, M.D., Ph.D., Switzerland

Reviewer #2: No

**********