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. 2026 Apr 17;21(4):e0347524. doi: 10.1371/journal.pone.0347524

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

Weifeng Wang 1,2,#, Xianli Meng 3,#, Yan Zhao 4,#, Wei Gong 5,#, Xiaochen Jiang 1,2, Wenjuan Cao 1,2, Xueling Qiu 2,6, Chenxi Sun 2,7, Fan Sun 2,8, Yuchen Wang 2,7, Lu Tang 2,*
Editor: Gisele Viana de Oliveira9
PMCID: PMC13089730  PMID: 41996373

Abstract

Background

To alleviate pain in burn patients during dressing changes, it is necessary to identify an effective analgesic method. Conventional opioid analgesics have many limitations. Nitrous oxide is a fast-acting, safe and reversible inhaled analgesic gas. This systematic review will evaluate the effectiveness and safety of nitrous oxide in the treatment of pain during dressing changes in burn patients.

Method

The protocol was developed according to the PRISMA-P checklist and registered on PROSPERO (CRD42024550197). A systematic search will be performed in the following databases: PubMed, EMBASE, Web of Science, Cochrane Library to identify clinical trials comparing nitrous oxide inhalation with standard care in pain management during dressing changes in burn wounds. The search of all databases will be conducted on October 15, 2025.Our search scope will include studies published between each database creation and search date.Two researchers will independently screen studies, extract data, and evaluate study quality using the Risk of Bias2 tool. Primary outcomes will include pain, anxiety, side effects, among others.R statistical software (version 4.3.1) and R studio will be used to perform meta-analyses.Effect size will be expressed by 95% confidence interval (Cl) of weighted mean difference (MD) and risk ratio (RR). Subgroup analyses and sensitivity analyses will be performed to explore sources of heterogeneity and assess the robustness of the results.Publication bias will be assessed using funnel plot and Egger test. We will use the Grading of Recommendation, Evaluation, Development and Evaluation (GRADE) to assess the quality of the evidence.

Discussion

Operative pain has always been a difficult problem for burn patients. This study will evaluate the analgesic effect of nitrous oxide on dressing change in burn patients through comprehensive search and rigorous methods, and provide evidence support for clinical decision-making.

Introduction

Pain control in burn patients has always been a challenge. Effective pain management can significantly reduce suffering for burn patients and prevent neuropathic pain and chronic pain [1].

Burn debridement and dressing changes can lead to great pain in patients. Extremely severe pain may cause serious negative emotions and even psychological problems for patients [2]. Uncontrolled moderate to severe pain can hinder wound care and physical therapy, and directly affect the speed and quality of burn wound healing. Therefore, appropriate analgesic measures are essential [3]. The application of analgesic drugs for burn prevention should consider not only the burn site, burn depth, burn area and debridement time but also changes in the pharmacodynamics and pharmacy [4,5]. Drugs should have the characteristics of quick onset, short action time, fewer active metabolites, and fewer adverse reactions [6].

Medications are usually used to reduce pain in burn patients. Even without surgery, burn patients can suffer greatly. The American Burn Association (ABA) guidelines state that opioids are considered the primary method of controlling burn pain [7]. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as gabapentin, lidocaine, and ketamine, can also be used to treat pain in burn patients. However, long-term use of these drugs, especially opioids, may cause some compilations. These side effects include dizziness, nausea, respiratory depression and addiction [8]. Burn patients receive medication for pain relief every other day or even every day, so the probability of side effects is greatly increased [9].

Nitrous oxide is a colorless and odorless gas that has been used in the field of analgesia for 150 years and is still widely used in conscious analgesia [10]. Nitrous oxide has been shown to be a safe and fast-acting analgesic gas, with rapid induction and rehabilitation, mild adverse reactions, a low incidence of side effects, simple manipulation, and satisfactory analgesic effects in most cases [11–13]. However, some studies suggest that nitrous oxide has limited analgesic effects [14]. In addition, nitrous oxide also has sedative and antianxiety effects and is often used in combination with oxygen at a specific ratio for conscious anesthesia and analgesia outside the operating room [15], such as dental surgery sedation and analgesia [16], acute injury sedation and analgesia [17], and labor analgesia [18].

Nitrous oxide may be administered by a trained nurse who is not specialized in anesthesia. Previous studies on pain management mostly focused on the research of narcotic analgesics administered by anesthesiologists or clinicians, but few methods that can be administered by nurses according to doctors’ advice without the presence of anesthesiologists.

At present, there is no strong evidence to analyze the effect of nitrous oxide in burn debridement and dressing changes. We will conduct a systematic review and meta-analysis of published clinical trials to evaluate the analgesic effectiveness and adverse effects of nitrous oxide compared with placebo or other measures during debridement and dressing change in burn patients. These findings will inform evidence-based clinical practice on pain management for debridement and dressing changes in burn patients.

Materials and methods

The protocol was developed from the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) declaration checklist [19]. The protocol has been registered in the PROSPERO database and assigned an identifier: CRD42024550197. This review is based on published studies, so the study design, process and results do not require patients or public participation or ethical approval.

Search strategy

To complete this study, we will perform searches in the following databases: PubMed, EMBASE, the Cochrane library and the Web of Science. Completed but unpublished studies will also be included in this review. We will conduct a literature search using the following MeSH terms and text words related to nitrous oxide and burn debridement dressing changes: ‘Nitrous Oxide’; ‘Laughing Gas’; ‘Burns’; ‘Dressing’; ‘Bandages’; ‘Anesthesia and Analgesia’; ‘Conscious Sedation’; ‘Analgesia’; and ‘Pain’.The search strategies are shown in Tables 1–4. We will supplement the literature by searching the following websites: the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov. We will also conduct a manual search of gray literature (e.g., unpublished conference literature, reports) on sites such as Google Scholar, Open Access Theses and Dissertations.

Table 1. The search strategy for PubMed.

ORDER STRATEGY
#1 Search: “Nitrous Oxide”[Mesh]
#2 Search: “laughing gas”[Title/Abstract]
#3 Search: “dinitrogen oxide”[Title/Abstract]
#4 Search: “N2O”[Title/Abstract]
#5 Search: “Burns”[Mesh]
#6 Search: “burn”[Title/Abstract]
#7 Search: “burn injury”[Title/Abstract]
#8 Search: “burn wound”[Title/Abstract]
#9 Search: “scald”[Title/Abstract]
#10 Search: “dressing change”[Title/Abstract]
#11 Search: “wound dressing”[Title/Abstract]
#12 Search: “bandage change”[Title/Abstract]
#13 Search: “Analgesia”[Mesh]
#14 Search: “pain relief”[Title/Abstract]
#15 Search: “pain management”[Title/Abstract]
#16 Search: “analgesic effect”[Title/Abstract]
#17 Search: “Pain”[Mesh]
#18 Search: “ache”[Title/Abstract]
#19 Search: “soreness”[Title/Abstract]
#20 Search: “discomfort”[Title/Abstract]
#21 #1 OR #2 OR #3 OR #4
#22 #5 OR #6 OR #7 OR #8 OR #9
#23 #10 OR #11 OR #12
#24 #13 OR #14 OR #15 OR #16
#25 #17 OR #18 OR #19 OR #20
#26 #24 OR #25
#27 #21 AND #22 AND #23 AND #26
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Table 2. Search strategies for Embase.

ORDER STRATEGY
#1 ‘nitrous oxide’/exp
#2 ‘laughing gas’:ab,ti
#3 ‘dinitrogen oxide’:ab,ti
#4 ‘N2O’:ab,ti
#5 ‘burns’/exp
#6 ‘burn’:ab,ti
#7 ‘burn injury’:ab,ti
#8 ‘burn wound’:ab,ti
#9 ‘scald’:ab,ti
#10 ‘dressing change’:ab,ti
#11 ‘wound dressing’:ab,ti
#12 ‘bandage change’:ab,ti
#13 ‘redressing’:ab,ti
#14 ‘analgesia’/exp
#15 ‘pain relief’:ab,ti
#16 ‘pain management’:ab,ti
#17 ‘analgesic effect’:ab,ti
#18 ‘pain’/exp
#19 ‘ache’:ab,ti
#20 ‘soreness’:ab,ti
#21 ‘discomfort’:ab,ti
#22 #1 OR #2 OR #3 OR #4
#23 #5 OR #6 OR #7 OR #8 OR #9
#24 #10 OR #11 OR #12 OR #13
#25 #14 OR #15 OR #16 OR #17
#26 #18 OR #19 OR #20 OR #21
#27 #25 OR #26
#28 #22 AND #23 AND #24 AND #27
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Table 3. Search strategies for Web of Science.

ORDER STRATEGY
#1 TS=(“nitrous oxide”)
#2 TS=(“laughing gas”)
#3 TS=(“dinitrogen oxide”)
#4 TS=(“n2o”)
#5 TS=(burns)
#6 TS=(burn)
#7 TS=(“burn injury”)
#8 TS=(“burn wound”)
#9 TS=(scald)
#10 TS=(“dressing change”)
#11 TS=(“wound dressing”)
#12 TS=(“bandage change”)
#13 TS=(analgesia)
#14 TS=(“pain relief”)
#15 TS=(“pain management”)
#16 TS=(“analgesic effect”)
#17 TS=(pain)
#18 TS=(ache)
#19 TS=(soreness)
#20 TS=(discomfort)
#21 #1 OR #2 OR #3 OR #4
#22 #5 OR #6 OR #7 OR #8 OR #9
#23 #10 OR #11 OR #12
#24 #13 OR #14 OR #15 OR #16
#25 #17 OR #18 OR #19 OR #20
#26 #24 OR #25
#27 #21 AND #22 AND #23 AND #26
Open in a new tab

Table 4. Search strategies for Cochrane.

ORDER STRATEGY
#1 [mh "Nitrous Oxide"]
#2 (“laughing gas”):ti,ab,kw
#3 (“dinitrogen oxide”):ti,ab,kw
#4 (N2O):ti,ab,kw
#5 [mh Burns]
#6 (burn):ti,ab,kw
#7 (“burn injury”):ti,ab,kw
#8 (“burn wound”):ti,ab,kw
#9 (scald):ti,ab,kw
#10 (“dressing change”):ti,ab,kw
#11 (“wound dressing”):ti,ab,kw
#12 (“bandage change”):ti,ab,kw
#13 [mh Analgesia]
#14 (“pain relief”):ti,ab,kw
#15 (“pain management”):ti,ab,kw
#16 (“analgesic effect”):ti,ab,kw
#17 [mh Pain]
#18 (ache):ti,ab,kw
#19 (soreness):ti,ab,kw
#20 (discomfort):ti,ab,kw
#21 #1 OR #2 OR #3 OR #4
#22 #5 OR #6 OR #7 OR #8 OR #9
#23 #10 OR #11 OR #12
#24 #13 OR #14 OR #15 OR #16
#25 #17 OR #18 OR #19 OR #20
#26 #24 OR #25
#27 #21 AND #22 AND #23 AND #26
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No restrictions will be imposed on the study design, date or language.The search of all databases will be conducted on October 15, 2025, and all identified studies will be included in the title and abstract screening. Our search scope will include studies published between the creation of each database and the date of the search. We will perform a manual search of reference lists for prospective systematic reviews and meta-analyses to identify reports that may be relevant but omitted through electronic searches.

Eligibility criteria

Studies that meet the following criteria will be included in this review.

Study type.

We will consider randomized controlled trials(RCTs) that follow the PICOS framework, which structured the research question into its key components: P (Population), I (Intervention), C (Comparison), O (Outcomes), and S (Study design). A detailed explanation of each component is provided in the subsequent section.

Participants.

The study was performed in burn patients and focused on debridement and dressing change.The subjects were patients of all ages who were hospitalized for the first time due to burns.This study mainly evaluates the effect of nitrous oxide on manipulative pain, therefore, there is no limit on dressing type.

Intervention.

Inhalation of nitrous oxide during debridement and dressing change aims to reduce patient suffering.

Comparators.

The control group received placebo or other analgesic methods. Approaches considered include: opioid analgesia, regional block analgesia,and non-pharmacological therapies for analgesia by diversion. Because these are common methods used clinically.

Outcome measures.

Primary outcome for included trials must show the intensity of pain in the patient numerically, including the VAS(Visual Analogue Scale) score, NRS(Numerical Rating Scale) score, or FLACC(Face, Legs, Activity, Cry, Consolability scale) score.Different burn severities and depths affect pain scores, so we used the change in pain scores before and after the intervention as the primary outcome measure. Different scales can also lead to heterogeneity, so we will use standardized mean differences for statistical analysis. The secondary outcomes included at least one of the following: level of anxiety, side effects, duration of surgery, or patient satisfaction.

Screening

Two reviewers(WFW and XLQ) will independently screen for titles and abstracts selected from the search and identify studies based on inclusion and exclusion criteria. Reviewers (WFW and XLQ) then assess the eligibility of the full-text content to determine whether it is ultimately included. When multiple publications appeared in the same study population, the most recent report with the largest sample size and outcomes that met the eligibility criteria was selected. When there is a dispute, it is discussed by two reviewers to reach a consensus, and if necessary, with a third researcher(XCJ). For studies with non-English titles and abstracts, we will use machine translation tools such as Google Translate to translate them into English for initial evaluation. If there are still doubts after machine translation, the research will enter the full-text screening stage. For non-English full texts, we will use high-quality translation tools such as Google Translate or DeepL to generate an English translation of the full text as the basis for evaluation. In view of the advanced nature of today’s translation tools, the probability of encountering ambiguous content is very low. The risk of bias assessment will be based on the translated text. In case of uncertainty, it will be noted in the text and taken into consideration in sensitivity analysis. The screening process and reasons for exclusion are shown in the PRISMA flowchart (Fig 1).

Fig 1. PRISMA flow diagram of systematic reviews and meta-analyses.

Fig 1

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Data extraction and records

The extraction of the data was performed independently by two reviewers(WFW and XLQ). Data that need to be extracted include: first author name, year of publication, year of baseline study, country, interventions, controls, blinding, subject race, number, sex, age, quantitative results,tool of measurement, narrative summary of findings(e.g., side effects). The results of all data are presented in tabular form. For studies with missing or incomplete data (e.g., missing mean or standard deviation), we attempted to contact the corresponding author by email. If no response is received or no data is provided. We will estimate missing means and standard deviations of available statistics (median and interquartile range) using validated methods. If data are always unavailable or calculated, we will exclude this study.We will prioritize extracting and pooling pain scores during the intervention. If the study reports multiple time points, we will treat each time point as an independent analysis and perform subgroup analyses grouped by time to avoid repeated inclusion of data from the same group of patients in the same Meta-analysis. We do not make statistical adjustments for repeated measures.

Subgroup analysis

If there is a sufficient number of subgroup samples, we will conduct subgroup analysis according to the following criteria: 1. Adults and children, because the FLACC scale used by children is mostly evaluated by medical staff through facial expressions and leg movements, while adults are mostly self-rated by VAS or NRS scale. 2. Different control group types, including placebo, opioid, regional block analgesia, and non-drug analgesia. 3. Different burn sites, burn depths or nitrous oxide concentrations. 4. The first or subsequent dressing changes will also affect the level of pain, so we will also conduct subgroup analysis based on the number of dressing changes.

Assessment of risk of bias.

The study’s risk of bias will be independently assessed by two researchers (WFW and XLQ) using the Cochrane Collaboration Risk of Bias 2 (RoB 2) tool. The RoB 2 tool includes five domains: bias arising from the randomization, bias due to deviation from established interventions, bias from missing outcome data, bias from outcome measures, and bias from selective reporting.Each domain will be classified as ‘low risk’ “some concern,” or “high risk,” and each trial overall risk of bias follows its highest risk of bias. The results of the quality assessment will be presented in tabular form, with each judgment accompanied by a brief justification [20].

Data analysis

In this study, we will use R statistical software (version 4.3.1) and R studio. The meta-analysis will be conducted using the ‘meta’ package. The combined effect size of the quantitative data will be expressed by the weighted Standardized Mean Difference(SMD) with 95% confidence interval(Cl) and dichotomous outcomes will be expressed by the risk ratio (RR) with 95% confidence interval (CI).Descriptive outcomes for which combined effect size cannot be calculated will be evaluate qualitatively. Q statistic (p < 0.1 indicates significance) and I2 test will be used to analyze the heterogeneity of the included studies. I2 values of 0–30%, 30%−50%, 50%−70% and 70–100% will be respectively considered low, moderate, considerable and substantial heterogeneity.If p < 0.1 and I2 value is < 50%, the included studies have low heterogeneity, using the fixed-effect model; If p ≤ 0.1and I2 values are ≥ 50%,the heterogeneity of the included studies is high and the random effects model will be used. When the heterogeneity is large, the source of heterogeneity is explored through subgroup analysis. Potential heterogeneity will be explored by sensitivity analysis (sequentially excluding one study observing changes in pooled effect size), as well as the robustness of the outcome was assessed.

Assessment of reporting bias

Two independent reviewers(WFW and XLQ) will use the Risk of Bias due to Missing Evidence tool to assess the risk of bias due to missing evidence [21], and if there is a disagreement, it will be resolved through discussion or consultation with the third reviewer (XCJ). We will assess publication bias with Egger’s test (p < 0.05 for bias). When at least 10 studies are included, we will plot funnel plots.If bias is detected, the trim-and-fill method will be used to evaluate its impact on the results.

Quality of the evidence

The certainty of the evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach by two researchers(WFW and XLQ) and disagreements will be resolved by consultation with the third investigator (XCJ). The scoring method considers the limitations of the study, including the risk of study bias, directness, consistency, precision and publication bias, in order to evaluate the certainty of the combined effect size [22].

Discussion

Pain in burn victims has always been a serious problem. Wound dressing changes are the most common surgery performed by burn patients. Pain is a problem that can’t be ignored in the process of dressing change, which is directly related to the recovery process, quality of life and psychological state of patients. Chronic neuralgia has also been plaguing burn patients, and its causes are complex, including direct nerve damage in burn patients, and long-term pain stimulation can also cause central sensitivity. Opioids are mainstream drugs, and long-term use will reduce the pain threshold and cause hyperalgesia, which will also aggravate the development of chronic neuralgia. Opioid reduction, multimodal analgesia is a good option. Nitrous oxide appears to be a highly safe, fast-acting, and easy-to-operate analgesic for pain management procedures.

A recent systematic review and meta-analysis provided a pooled analysis of the efficacy of nitrous oxide in wound care in adults, including some burn patients [23]. However, this study only performed subgroup analyses based on wound type. Currently, there are no studies evaluating the efficacy and safety of this treatment in burn patients.

The protocol outlines a systematic review and meta-analysis designed to assess the effectiveness and adverse effects of nitrous oxide for pain management in burn dressing change patients. Based on the PRISMA-P checklist and following the methodological guidance provided in the Cochrane Handbook of Systematic Reviews of Interventions, we assessed the methodological quality of existing studies using the GRADE method to comprehensively assess evidence from multiple study designs. These findings will validate the efficacy and safety of nitrous oxide, fill gaps in evidence synthesis, and provide evidence-based treatment options for operational pain relief in burn patients.

Conclusion

If the results of this meta-analysis show that nitrous oxide has a good analgesic effect on the process of burn dressing changes and does not cause serious side effects, it will promote the clinical promotion and application of nitrous oxide.

Limitations

  • Nitrous oxide concentrations used in different studies may differ.This also affects heterogeneity if the number of studies does not allow for subgroup analysis based on gs concentration.

  • The timing of patient inhalation of intervention gases and different time points of measurement results may also constitute a potential source of clinical heterogeneity.

Supporting information

S1 Checklist. PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) 2015 checklist completed for the study protocol.

(DOCX)

pone.0347524.s001.docx (23.1KB, docx)

Acknowledgments

We sincerely thank all those involved in the study and all investigators and clinical staff involved in the trial for their efforts.

Data Availability

This is a systematic review study protocol and will not generate new data. All relevant data for this study are available from the corresponding author upon completion of the study.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

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23 Jan 2026

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[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

**********

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PLoS One. 2026 Apr 17;21(4):e0347524. doi: 10.1371/journal.pone.0347524.r002

Author response to Decision Letter 1

28 Jan 2026

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!

Attachment

Submitted filename: Response to Reviewers.docx

pone.0347524.s002.docx (11.9KB, docx)

Decision Letter 1

Gisele Viana de Oliveira

16 Feb 2026

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'.

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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.

PLoS One. 2026 Apr 17;21(4):e0347524. doi: 10.1371/journal.pone.0347524.r004

Author response to Decision Letter 2

20 Feb 2026

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!

Attachment

Submitted filename: Response_to_Reviewers_auresp_2.docx

pone.0347524.s003.docx (11.3KB, docx)

Decision Letter 2

Gisele Viana de Oliveira

5 Apr 2026

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

**********

Attachment

Submitted filename: PubMed Strategies.pdf

pone.0347524.s004.pdf (35.5KB, pdf)

Acceptance letter

Gisele Viana de Oliveira

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

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Checklist. PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) 2015 checklist completed for the study protocol.

    (DOCX)

    pone.0347524.s001.docx (23.1KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    pone.0347524.s002.docx (11.9KB, docx)
    Attachment

    Submitted filename: Response_to_Reviewers_auresp_2.docx

    pone.0347524.s003.docx (11.3KB, docx)
    Attachment

    Submitted filename: PubMed Strategies.pdf

    pone.0347524.s004.pdf (35.5KB, pdf)

    Data Availability Statement

    This is a systematic review study protocol and will not generate new data. All relevant data for this study are available from the corresponding author upon completion of the study.

    Articles from PLOS One are provided here courtesy of PLOS

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