PONE-D-24-44664Clinical efficacy and safety of automatic remifentanil administration based on Analgesia Nociception Index monitoring during general anesthesia: A randomized controlled clinical trialPLOS ONE

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Reviewers' comments:

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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

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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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: No

Reviewer #2: Yes

Reviewer #3: Yes

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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

Reviewer #3: Yes

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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: Thank you for reporting your findings.

Abstract: in the results, what quantity is the total decision for the estimates? State it is 95% confidence intervals or interauartile range the first time it is shown in the abstract if this is the case.

Reviewer #2: Dear author(s)

First I congratulate you for your successful, well designed randomized controlled study entitled ‘Clinical efficacy and safety of automatic remifentanil administration based on Analgesia Nociception Index monitoring during general anesthesia: A randomized controlled clinical trial’. However I have some comments.

1)The title accurately reflects the focus of the study, describing the intervention (automatic remifentanil administration), the context (based on the Analgesia Nociception Index), and the study design (a randomized controlled clinical trial) but could include the patient population or surgical context (e.g., burn surgery) to further enhance specificity.

2) The abstract highlights the study's main findings, including reduced remifentanil dosage and maintained safety. It effectively communicates the significance of findings, especially the applicability of ANI monitoring. But you can provide additional context on the potential broader applications of the technology to strengthen the abstract's impact.

3)The introduction outlines the need for improved nociception monitoring and provides background on ANI. It justifies the study by referencing the limitations of current methods and describes the novel ANI-REMI-LOOP system. I think , this section is well-written, with clear context on the problem and study rationale.The hypothesis and objectives are well-stated, aligning with the study design. You can add a brief mention of how this research contributes to existing literature or fills identified gaps.

4)The objectives are stated indirectly within the introduction, focusing on assessing the efficacy and safety of ANI-based remifentanil administration.The study’s objectives are clear but could be outlined in a dedicated section for ease of reference. Please include a standalone section for explicitly stated objectives to improve structure and accessibility.

5)The methodology is robust, describing randomization, ethical considerations, intervention specifics, and outcome measures. Statistical analyses are detailed and appropriate for the study design. However You have to provide additional details on how external validity was ensured, particularly for generalizing findings to other surgical types.

6)The results demonstrate a significant reduction in remifentanil use and improved hemodynamic stability in the automatic group, without compromising safety or postoperative outcomes. Data is presented clearly with adequate use of tables and figures. In this section also you can emphasize clinical relevance of findings to make the benefits more relatable for practitioners.

7)The discussion contextualizes the findings within existing literature, emphasizing the benefits and potential limitations of ANI-based automatic remifentanil administration.The discussion of ANI’s potential in broader surgical settings is particularly strong. But please elaborate on alternative explanations for findings and explore how automation might reduce anesthetist workload.

8)The conclusions summarize the study's key findings, highlighting safety, efficacy, and potential for broader application. Please reiterate the significance of findings for clinical practice and patient outcomes.

9)For Table 1, please consider reformatting the table to separate demographic and clinical characteristics from procedural data for better readability. Also you can add a column for p-values where applicable, comparing the control and automatic groups for baseline variables.

10) For Table 2, please add a column explicitly showing the percentage reduction in remifentanil usage between groups for easier clinical interpretation and include a note clarifying whether the ITT and PP results differ due to excluded patients (e.g., patients with major protocol deviations).

11) For Table 3, draw attention to the most clinically significant differences (e.g., time spent in hemodynamic reactivity) using bold font or separate headings. A brief note summarizing the main findings of this table could help contextualize the results. For example, “The automatic group exhibited significantly reduced time in hemodynamic reactivity, but other outcomes showed no significant differences.”

12) Please emphasize in the manuscript text the potential clinical benefits of trends toward lower pain scores in the automatic group, even if not statistically significant.Discuss whether the pain score differences at later time points (e.g., H0 + 1h, H0 + 1h 45min) are likely clinically meaningful. Also you can include a brief note on how adverse events were assessed and whether the single case of nausea in the automatic group may be attributable to the intervention.

Thank you.

Reviewer #3: The authors present the results of a randomized study conducted in patients scheduled for excision of burns and skin grafts. The aim of the study was to assess the safety and the efficacy of an innovative closed-loop system to automatically deliver remifentanil based on the continuous monitoring of hemodynamic parameters and of the ANI. The study is very original, and the results correspond to a proof-of-concept of the innovation tested. The manuscript is well written and easy to read. Figures and tables are of high quality and adequate. Nonetheless, the manuscript raised the following concern.

MAJOR CONCERNS

1. Methods: page 6: the closed-loop system defines as the 1st priority to protect the patient’s safety. The priority cannot be bypassed. That is a good thing for the patients, but it raises several concerns. This priority appears to be very close to the “old” management of anesthesia that was based on the fluctuations of hemodynamic parameters to adapt the infusion rate of anesthetic drugs. Considering that point, what is the added value of using ANI to monitor intraoperative analgesia? By analogy, BIS monitoring allows to differentiate hemodynamic impairment related to anesthesia overdosage from other causes of hemodynamic impairment. I guess ANI would be useful to apply the same reasoning in the management of intraoperative analgesics. Finally, is the closed-loop system designed to provide adequate intraoperative analgesia or to optimize intraoperative hemodynamics? Please comment that point and discuss the potential impact on results.

2. Eligible patients were burned patients. How many of these patients were treated with beta-blockers to reduce the hypermetabolic response? Could the treatment with beta-blockers impact the measurement of the ANI?

3. Page 7: exclusion criteria: how did you define “sustained tachycardia” and “impaired blood pressure”?

4. Methods: page 8-9: the protocol of induction of anesthesia differs between the 2 groups. Could the authors explain how they proceed to define this protocol for induction and comment on the potential impact of this difference in the management of patients on the results of the study? In particular, the remifentanil dose for induction appears to be higher in the manual group.

5. Methods: one of the main concerns is the protocol of anesthesia in the manual group. How did the authors proceed to define this protocol of management? What was the experience of the investigators in this anesthetic protocol (learning curve)? The sample size is quite small with 25 patients in each group, and it could have been difficult to adequately apply a new anesthetic protocol in patients included in the study. Did the authors measure the good applicability of the anesthetic protocol and the rate of deviance to the anesthetic protocol? Please comment that points and their potential impact on the results of the study.

6. Results: page 12: what is the clinical relevance of the intergroup difference observed on the intraoperative remifentanil dose? In particular, the results suggest that it had no impact on early postoperative analgesia. Is the conclusion of the study: “no matter with how intraoperative analgesia is managed, the main concern is hemodynamics”?

7. Results: what is the potential impact on prognosis to decrease the cumulative time of hemodynamic reactivity, hypotension or bradycardia? The results of the outcome are presented as percentage of time spent, but it could be informative to have these results as absolute time spent with hemodynamic reactivity, hypotension or bradycardia in min, and the duration of the longer episode of hemodynamic reactivity, hypotension or bradycardia in min in each group. This supplemental data would help to assess the clinical relevance of this result.

8. Figure 3: the difference observed on hemodynamics seem to be mainly related to bradycardia. Is this correct? If yes, one explanation could be that investigators in the manual group could have been more concern by hypotension than tachycardia, especially when the decrease in heart rate did not reach critical thresholds. Please comment that point.

9. In the automatic group, the investigator was assisted by an engineer to manage intraoperative administration of remifentanil. Did the authors think that the presence of an additional member of the anesthesia team (the engineer) in the operating room could have impacted the quality of intraoperative administration of remifentanil? Please comment.

10. Table 3: please reformulate the 2nd line: “time spent relative to intervention duration”. What “time spent” refers to?

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Reviewer #1: No

Reviewer #2: Yes:  Fazli Yanik

Reviewer #3: No

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<p>Clinical efficacy and safety of automatic remifentanil administration based on Analgesia Nociception Index monitoring during burn surgery under propofol anesthesia: A randomized controlled clinical trial

PONE-D-24-44664R1

Dear Dr. De jonckheere ,

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.

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Stefano Turi

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: All comments have been addressed

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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: (No Response)

Reviewer #2: Yes

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

Reviewer #1: (No Response)

Reviewer #2: Yes

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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: (No Response)

Reviewer #2: Yes

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

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

Reviewer #1: (No Response)

Reviewer #2: Yes

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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: (No Response)

Reviewer #2: Dear authors; I read and reviewed the revised article according to my suggestions.

Thank you for your revised article.

My opinion for revised article is 'Accept'.

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

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

Reviewer #1: No

Reviewer #2: Yes:  Fazli Yanik

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