A systematic review protocol: Efficacy and safety of nitrous oxide in analgesia in burn patients with dressing change

Weifeng Wang; Xianli Meng; Yan Zhao; Wei Gong; Xiaochen Jiang; Wenjuan Cao; Xueling Qiu; Chenxi Sun; Fan Sun; Yuchen Wang; Lu Tang

doi:10.1371/journal.pone.0347524

Peer Review History

Original SubmissionSeptember 15, 2025
23 Jan 2026 Decision Letter - Gisele Viana de Oliveira, Editor Dear Dr. Tang, 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 Mar 09 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.. When you’re ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. 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 . 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, Gisele Viana de Oliveira 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 provide a complete Data Availability Statement in the submission form, ensuring you include all necessary access information or a reason for why you are unable to make your data freely accessible. If your research concerns only data provided within your submission, please write "All data are in the manuscript and/or supporting information files" as your Data Availability Statement. 3. We notice that your supplementary figures are uploaded with the file type 'Figure'. Please amend the file type to 'Supporting Information'. Please ensure that each Supporting Information file has a legend listed in the manuscript after the references list. 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.] Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? Reviewer #1: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??> Reviewer #1: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??> Reviewer #1: 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 ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes ****** Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. Reviewer #1: Major Comments 1. Inconsistency in Study Design Eligibility The protocol states that RCTs will be considered but also indicates that observational studies may be included based on article content. Clarify one of the following: • Restrict inclusion strictly to RCTs, or • Explicitly define observational study types, specify a separate risk-of-bias tool 2. Participant Definition and Age Restriction The protocol limits participants to patients >18 years old with a first burn, yet: • Many burn dressing studies include pediatric populations. • No justification is provided for excluding children. • The term “first burn” is unclear and not standard. • Clarify whether “first burn” refers to a first-degree burn or first burn episode. • Provide a rationale for adult-only inclusion or consider pediatric subgroup analysis. 3. Outcome Definition and Measurement Issues The primary outcome is defined as change in pain scores before and after intervention, yet: • Different pain scales (VAS, NRS, FLACC) are proposed. • FLACC is primarily pediatric, conflicting with adult-only inclusion. • Change scores vs post-intervention scores may introduce heterogeneity. • Clarify how different pain scales will be standardized (e.g., standardized mean difference). 4. Comparator Definition Is Too Broad The comparator includes placebo or other analgesic methods, which may include: Opioids • Ketamine • Regional techniques • Non-pharmacological interventions Pooling these comparators risks clinical heterogeneity. • Predefine comparator categories. • State whether separate meta-analyses or subgroup analyses will be performed by comparator type. 5. Search Strategy and Language Claims The protocol states no language restrictions, yet: • Search terms are predominantly English. • No plan for translation of non-English studies is described. Describe how non-English articles will be screened, translated, and assessed to ensure the claim of no language restriction is credible. 6. Statistical Analysis Plan Needs Refinement The plan specifies MD and RR but does not address: • Use of standardized mean difference (SMD) when different pain scales are used. • Add explicit plans for crossover designs. • Clarify whether repeated measures will be adjusted or excluded. • Specify SMD use where appropriate. 7. Publication Bias Assessment Thresholds Egger’s test is proposed with p < 0.1, which is unconventional. Justify the use of p < 0.1 or align with conventional thresholds (p < 0.05), particularly given expected small study numbers. Minor Comments 1. Grammar and Style •Numerous minor grammatical errors and spacing issues (e.g., missing spaces after periods). •Recommend professional language editing. 2. Terminology •Use consistent terms: dressing change vs dressing replacement vs “wound care. ****** what does this mean? ). If published, this will include your full peer review and any attached files.). 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 For information about this choice, including consent withdrawal, please see our Privacy Policy .--> Reviewer #1: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation. NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications. https://doi.org/10.1371/journal.pone.0347524.r001
Revision 1
28 Jan 2026 Author Response To editor: Thank you very much for your help! We have made corrections as per your request.Sorry I didn't specifically indicate that the uploaded image is not supplementary figures, it was uploaded as an image file, the legend is on line 209.Please feel free to contact me if you still have questions. I wish you all the best! Reviewer 1: Thank you very much for your careful review!We have made the following corrections to your problem. 1. After careful consideration, we decided to strictly limit the inclusion of RCTs, which can improve the quality of evidence. 2. The reason why we only include adults is that the pain scores of children's burns are mainly assessed by medical staff through facial expressions and leg movements (FLACC scale), while adults mostly use VAS or NRS scales for self-evaluation. Different evaluation subjects may lead to heterogeneity. But you're right, it's true that burns in children are more common, and we can do subgroup analysis of children, so we made a modification in the text to include patients of all ages and do subgroup analysis according to age. The word "first time" was also clarified. 3. Different scales cannot be directly compared. We will use standardized mean differences for meta-analysis. 4. We did overlook this point, and we have added content to the "Comparators" section and the "Subgroup analysis" section. 5. You are very rigorous and the issues you point out are very important. We have added an evaluation method for non-English articles in the Screening section. 6. We corrected this error in the "Data analysis" section. Different scales do use standardized mean differences. We have added the solution to the problem of multiple measurements in the "Data extraction and records" section. 7. We agree that p < 0.05 is a more conventional threshold for hypothesis testing, and this error has been corrected. I wish you all the best! Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0347524.r002
16 Feb 2026 Decision Letter - Gisele Viana de Oliveira, Editor Dear Dr. Tang 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. publication criteria . . Please submit your revised manuscript by Apr 02 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.. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. 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 . 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, Gisele Viana de Oliveira Academic Editor PLOS One Journal Requirements: If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? Reviewer #2: 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 ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??> Reviewer #2: 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 #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #2: 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: This paper is the good protocol paper and can be used as an alternative method for burn patients. It is well organized and easy to be understand. However, there is some issue need to be address by the authors. Methods: 1. Kindly please list down as many or much as possible for another synonym name or keywords for every word used or apply during the search strategies as other authors might use different word, but it refers to the similar meaning or words. 2. As this review will use or focus the clinical trial study design, maybe authors might consider putting or write study design during the search strategies. 3. Kindly please standardized the search strategies as well. For example, for the Embase database in table 2, the EXP is writing in the 1 column. The application of EXP is similar with the MESH term. Kindly, please use MESH for the Nitrous Oxide in the PubMed (Table 1) and Cochrane (Table 4). Similar comment is applied for other keywords that search with EXP in the Embase database (Table 2). 4. The gold standard of performing any systematic review and meta-analysis is by following the Cochrane database guideline. Cochrane encourages other people to perform the search strategies by searching the words one per one, not pull all the keywords in the one column. For example, in Table 1, author write Search: "Nitrous Oxide"[Title/Abstract]OR"Laughing Gas"[Title/Abstract]. Author should search the word one by one and later combined it. The correct way to do it is Search: "Nitrous Oxide"[Title/Abstract], #1. Then do another searching, Search: "Laughing Gas"[Title/Abstract], #2. Then combine the words using OR. #1 OR #2. 5. Under the study type section, for statement follow the PICOS framework (line no 169), it will be better if the author can write: P refers to “Population”, I refer to “Intervention etc. The details on the PICOS will be explain in the next section. 6. Suggest changing the ‘word so’ in line 174 to, ‘therefore’. Same comments for other word that used ‘so’. 7. Under the outcome measures in line 183, kindly please spell out the full name of the tools used: VAS, NRS, or FLACC score. 8. How do authors contact the corresponding author if the authors unable to obtain the data needed such as mean or SD? Is it via email? How many times will the authors follow-up with the corresponding authors to obtain the data. If 9. In line 202, kindly please change the capital C at the control to the lowercase c. Others: 1. Kindly, please provide the PRISMA Checklist for systematic review. ****** what does this mean? ). If published, this will include your full peer review and any attached files.). 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 For information about this choice, including consent withdrawal, please see our Privacy Policy .--> 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. https://doi.org/10.1371/journal.pone.0347524.r003
Revision 2
20 Feb 2026 Author Response To editor: Thank you very much for your help!Please feel free to contact me if you still have questions. I wish you all the best! Reviewer 1: Thank you very much for your careful review!We have made the following corrections to your problem. 1. We have listed more synonyms and revised the search strategy. 2. We did not list the study design in the search strategy to prevent the omission of eligible studies. We will limit the type of study during manual screening. 3. We have optimized the search strategy according to your requirements in the table. 4. We have modified the retrieval strategy according to your example. According to your comments on articles 5, 6, 7 and 9, we have revised the text. 8. We have made modifications in the Data extraction and records section of the article. PRISMA Checklist We have uploaded as other files. I wish you all the best! Attachments Attachment Submitted filename: Response_to_Reviewers_auresp_2.docx https://doi.org/10.1371/journal.pone.0347524.r004
5 Apr 2026 Decision Letter - Gisele Viana de Oliveira, Editor A systematic review protocol:efficacy and safety of nitrous oxide in analgesia in burn patients with dressing change PONE-D-25-49811R2 Dear Dr. Tang 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 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, Gisele Viana de Oliveira 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 ******** 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 ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??> Reviewer #2: 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 #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #2: 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: Dear Author, Thank you for answering the comments very well. However, there is a comment I would like to address in the search strategies. I had attached the correct way to do the searching in the PubMed. Kindly, please made amendment for your search strategies mainly in the PubMed. It is a very good practice that author make a Boolean operator (OR or AND) after the author list down all the synonym by the component. For example, if the study focused on the children: P (population), it should be written as this: #1: ("Child"):ti,ab,kw #2: ("Neonate"):ti,ab,kw #3: ("Toddler"):ti,ab,kw #4: #1 OR #2 OR #3 OR #4 Thanks ******* what does this mean? ). If published, this will include your full peer review and any attached files.). 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 For information about this choice, including consent withdrawal, please see our Privacy Policy .--> Reviewer #2: No ******** Attachments Attachment Submitted filename: PubMed Strategies.pdf https://doi.org/10.1371/journal.pone.0347524.r005
Formally Accepted
Acceptance Letter - Gisele Viana de Oliveira, Editor PONE-D-25-49811R2 PLOS One Dear Dr. Tang, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS One. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Gisele Viana de Oliveira Academic Editor PLOS One https://doi.org/10.1371/journal.pone.0347524.r006

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