PONE-D-22-06434Use of volatile anesthetics for sedation in the ICU after the COVID-19 pandemic: A national survey in France (VOL’ICU 2 study)PLOS ONE

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“The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: MJ is a principal investigator of the SEvoflurane for Sedation in ARds (SESAR) (ClinicalTrials.gov Identifier: NCT04235608) and the ISCA study (ClinicalTrials.gov Identifier: NCT04383730), which are co-funded and funded, respectively, by grants from Sedana Medical. JMC and MJ received fees from Sedana Medical for participation in a scientific advisory panel; MJ received consulting fees from Abbvie. Other authors have no competing interest. There are no patents, products in development or marketed products to declare”

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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?

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Reviewer #1: Yes

Reviewer #2: Partly

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

Reviewer #1: Yes

Reviewer #2: N/A

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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: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: 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: 1. Title should be changed - from "...in the ICU AFTER COVID 19..." in "...in the ICU DURING COVID 19...." because the survey questions were related to COVID19 period.

2. Figure no. 1 has to changed into a more clear one. Legend should be chnaged (grey shades used can lead to mistakes - "no answer" and "> 100 patients" having a similar colour). Also the legend is not intelligible and not totally compatible with the text description.

Reviewer #2: I would like to express my gratitude for the opportunity to review the submitted intriguing work on the use of volatile sedation in France. Unfortunately, the work in its current form still has a number of shortcomings.

I am sorry, but I have to criticise the inadequate referencing work. The study by your French colleague (reference 5 ) does not describe an actual shortage of sedatives! The colleagues describe aptly in their introduction to your study project: “Another major concern was to ensure access to mandatory anesthetics drugs medications, or neuromuscular blockade agents. In response to such shortages, we decided to diversify our sedative agents panel and thus to use volatile agents…”. However, authors should not be guided by the title of a paper without allowing its content to be presented in the referenced study! So far, the manuscript fails to provide appropriate references for the presentation of a real drug shortage. This applies equally to the corresponding section of the discussion.

How do the authors conclude that volatile substances are an "abundant" resource? Whereas, according to them, intravenous sedatives are a scarce resource?

I'm not sure, but if I'm not mistaken, the MIRUS is the MIRUS device from the company Technologie Institut Medizin, which is distributed in by carelide, Dahlhausen, Anandic or Pall?

In another passage, the authors cite a well-done Narrative Review by the esteemed colleague Jerath on Volatile Sedation in COVID-19 (reference 11), which raises the hypothesis outlined, but does not substantiate it with appropriate COVID-19-specific data. Such data should present masterful performance 3 months after the global COVID-19 outbreak as well. A corresponding referencing with current data would be exciting.

Regarding the acquisition of medical devices, it seems that 34% new acquisitions during the pandemic is a quite high rate of observation. However, it should be discussed that the purchase of a Sedaconda ACD membrane is around 16€ and a MIRUS device costs several thousand euros. Therefore, the MIRUS Device is not suitable for short-term acquisitions and would be an explanation for the clear dominance of the Anaesthetic conserving Device: AnaConDa/SeDaConDa.

How do the authors explain that 47/62 respondents did not use the device due to lack of availability, when the majority of them used Sedaconda as a patient-specific single-use material?

The authors disclose early on that numerous uses of volatile sedatives are under study conditions. Has it been evaluated on your part whether the center determining intravenous gas concentrations of volatiles is a study condition determination? I can't explain it any other way. And it does seem a bit confusing to someone not versed in the field.

“Thus, COVID-19 patients, especially when they develop ARDS, need higher doses of sedatives to reach the sedation objective compared to non-COVID19 patients [11].” As noted above, this source does not reflect the aggravated sedation per se, here the evidence has already been provided elsewhere: https://doi.org/10.1371/journal.pone.0253778/ https://doi.org/10.1371/journal.pone.0253778.

„The respondents also reported potential interest in the bronchodilator effect and…” also the bronchodilator properties could already be demonstrated several times and is accordingly not only an assumption of individual responders. Accordingly, the use in asthma is also found explicitly in your survey as one of the most frequently selected fields of application. https://doi.org/10.1111/pan.12577

„However, inhaled sedation should be avoided when there is a risk of increased intracranial pressure.” Considering that volatiles are used for the treatment of status epilepticus as well as in the neurosurgical ICU, I would be interesting to know the underlying recommendation. In your data, volatiles were used for the therapy of status epilepticus in 22% of the respondents. Please provide references.

I think it is problematic to primarily use the RAAS to monitor the level of sedation. This score may be helpful to measure shallow sedation or agitation, but deep sedation in severe ARDS in particular is not adequately captured by the assessment on which the score is based. Please specify your recommendations.

It might be worth mentioning that the titration of the desired sedation state using the minimum alveolar concentration with the closed loop system of the MIRUS system works without intervention depending on age, gender and weight, whereas this has to be done manually with the Anaconda device.

„always with a good satisfaction among the users” I think that it is not possible to speak of "always" with just under 74% of the users being very satisfied!

A problem not discussed appears to be the high number of ECMO treatments among COVID-19 patients and the impossible use of volatile sedatives in this patient population.

It should perhaps be mentioned that in the meantime activated charcoal systems exist on international markets to capture the volatile sedative no longer absorbed by the ACD, which even allows recycling. This would provide an approach to the ecological concerns expressed by 27 respondents.

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Reviewer #1: No

Reviewer #2: No

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Use of volatile anesthetics for sedation in the ICU during the COVID-19 pandemic: A national survey in France (VOL’ICU 2 study)

PONE-D-22-06434R1

Dear Dr. Blondonnet,

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.

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Kind regards,

Silvia Fiorelli

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

congratulations to the authors and thanks to the reviewers for the suggestions provided which really helped improve the quality of the manuscript

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 #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 #2: Yes

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

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 #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 #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 #2: I once again would like to thank you for the opportunity to review this work.

Furthermore, I would like to thank the authors for their very conscientious revision.

It appears to be a matter of taste, but did the authors consider using colour instead of patterned greys for Figure1?

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Reviewer #2: No

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