PONE-D-19-33669

Different Depths of Sedation Versus Risk of Delirium in Adult Mechanically Ventilated Patients: A Systematic Review and Meta-Analysis

PLOS ONE

Dear Dr Ma,

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.

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We look forward to receiving your revised manuscript.

Kind regards,

Luciane Cruz Lopes, PhD

Academic Editor

PLOS ONE

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Additional Editor Comments:

Dear Authors,

        My assessment is very similar to the two reviewers. I think that paper is described but it needs to add some important analyzes, for example the quality analysis of the body of evidence separately for each outcome (GRADE) as mentioned by one of the reviewers.

   I also didn't see the discussion about sensitivity and heterogeneity analysis.

I also agree with the lack of clarity about the exposure variable definition of depth of sedation with different cut-offs for sedation depths among the included studies.

It would be great if authros could answer point by point suggested by reviewers

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

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

Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: 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: Yes

Reviewer #2: 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

**********

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: The manuscript “Different Depths of Sedation Versus Risk of Delirium in Adult Mechanically Ventilated Patients: A Systematic Review and Meta-Analysis” by Ma and colleagues sought to answer the question whether different sedation depths are associated with higher delirium risk. Based on their findings, they concluded that at present, there is inconclusive evidence whether different sedation depths would change the risk of delirium in adult mechanically ventilated patients. Overall, the manuscript is drafted appropriately, and the authors have looked through the confounding factors that may affect the outcome. I have some comments which are outlined below.

1. I am a little concerned about the exposure variable definition of depth of sedation. As different studies used different cut-offs for sedation depths, sweeping statement based on combining these different exposures may lead us to inconclusive findings as seen in the review. That will be my major concern while trying to conclude depths of sedation as a risk factor for delirium when the exposure depths are not same in the studies. While most studies seem to be using the cut-off of RASS greater than or equal to -3, it is not the same with all the studies. It may be worthwhile to pool studies which are consistent and see if the findings hold.

2. The other major concern I have is regarding the outcome variable which is delirium incidence. How is this defined? In the literature, it has been defined multiple ways and I am not sure how the authors have construed it for their review. This again will result in discrepancy among studies. As there has been debate about how to define incidence versus prevalence especially in ICU settings where patients may have been admitted with delirium, the authors may want to think this over. One suggestion is to keep it general with a term such as delirium occurrence.

3. An interesting finding to note is the absence of a confounding effect of BZD on delirium. This really needs to be highlighted in the discussion. BZD have been thought of as risk factors for delirium, but the authors findings point towards a much-nuanced issue. Are these effects independent of sedation depth or is it a direct effect? The authors need to comment further on this in the discussion.

4. The findings of light sedation increasing delirium risk need to be further elaborated as this seems counter intuitive to current approaches.

5. Based on the mortality findings, in the absence of increasing delirium risk, depth of sedation is independently associated with mortality. Is this cause or could this be due to sicker patients kept deeply sedated. I would suspect that as this finding holds in RCT with randomized approach, the latter is not the case. This will need further discussion in the discussion section. May be an analysis with stratification based on illness severity may help clarify this further.

Reviewer #2: Although the authors did not assess the quality of the evidence set and the strength of the recommendation (GRADE), for each of the results analyzed, I think that the review was very well conducted, that the problem of delusion is the order of the day in intensive care units and, why, the results of the studies may help a lot in making decisions about sedation and analgesia of patients in these units.

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Reviewer #1: No

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 be viewed.]

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PONE-D-19-33669R1

Different Depths of Sedation Versus Risk of Delirium in Adult Mechanically Ventilated Patients: A Systematic Review and Meta-Analysis

PLOS ONE

Dear Dr Ma,

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.

We would appreciate receiving your revised manuscript by Jul 02 2020 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Luciane Cruz Lopes, PhD

Academic Editor

PLOS ONE

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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

Reviewer #3: (No Response)

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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

Reviewer #3: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

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

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

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

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

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

Reviewer #2: I did not notice any problems in the article, therefore, I recommend that it be published as soon as possible, in view of its timeliness and relevance to the scientific community, especially in the field of medicine.

Reviewer #3: With great interest I read the adapted version of the manuscript. The authors addressed the comments of the previous reviewers adequately which led to significant improvement of the research and the manuscript. The authors did a rigorous meta-analysis and show great adherence to existing standards and protocols in place for such research. Doing so, the research is up to current standards and very suitable for publication in Plos One. And although the manuscript is almost in its final version I do have some concerns reading the research for the first time.

My main concern is the fact that the relationship between sedation (depth) and delirium is very complex and influenced by many factors. The effort of the authors to try to include observational studies in their meta analysis is a great effort but introduces the bias of observational research in their meta analysis. Observational research in ICU research is prone to bias and relies on advanced statistical methods including time-varying variables, competing events, confounding by indication, and addressing immortal time bias. T

For example, there is the challenge that light sedation levels interfere with delirium diagnosis and comparing them with deep sedation give therfore regression to the mean (for example patient scoring RASS-2 is CAM-ICU positive (item 1, 2 and 4 present)).

Or the problem that disease severity and dosage of sedatives are not pure confounding factors as both cause deep sedation (placing them in causal chain of high severity of illness-->deep sedation-->delirium). This causal chain is also seen in the risk of deep sedation and risk of mortaltiy; deep sedation being a proxy for severity of illness and thus not surprisingly being associated with higher mortality.

Or the challenge that only patients in light sedation have the oppurtunity to develop adverse events (immortal time biase..you have to be awake enough to remove the ET).

I feel that the authors do address a lot or these issues by reporting the results separetly for RCTs and observational research but I would appreciate it if the authors emphasize the risk of bias of observational research and thus of the reported overall ORs. For example, the overall ORs on the relationship of mortaltiy and adverse events seem to be driven by the observational research.

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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 #2: No

Reviewer #3: 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 be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-19-33669R2

Different Depths of Sedation Versus Risk of Delirium in Adult Mechanically Ventilated Patients: A Systematic Review and Meta-Analysis

PLOS ONE

Dear Dr. Ma,

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 Jul 27 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Luciane Cruz Lopes, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Dear Authors,

Please, could you address the follow topic below?

1) To explain their selection of the study designs for inclusion in the review in method section - Explanation for including both RCTs and NRSI

2) To provide a list of excluded studies and justify the exclusions

3) To report on the sources of funding for the studies included in the review

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[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.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Different Depths of Sedation Versus Risk of Delirium in Adult Mechanically Ventilated Patients: A Systematic Review and Meta-Analysis

PONE-D-19-33669R3

Dear Dr. Ma,

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,

Luciane Cruz Lopes, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear author,

Could you please, check the quality of the figures and review all tables? It is necessary to improve the quality of the presentation and format. Please, review all references checking if the citation is missing. Thank you.

Reviewers' comments: