PONE-D-20-37630

Early use of barbiturates is associated with increased mortality in traumatic brain injury patients—a propensity score-based analysis of a prospective cohort.

PLOS ONE

Dear Dr. Léger,

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.

Both reviewers have identified specific concerns with the analytical approach and a careful response and revision will be required.

Please submit your revised manuscript by Feb 25 2021 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,

Belinda J Gabbe, PhD

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

3. Thank you for stating the following financial disclosure:

"The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

At this time, please address the following queries:

1. Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution.
2. State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”
3. If any authors received a salary from any of your funders, please state which authors and which funders.
4. If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

4. One of the noted authors is a group or consortium (AtlanREA). In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address.

[Note: HTML markup is below. Please do not edit.]

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: No

Reviewer #2: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

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

**********

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: Thanks for asking me to review this study evaluating the association between barbiturate use and mortality in TBI patients. I have a number of comments:

1. The stated aim of this study is evaluate the effect of barbiturate therapy in patients with TBI and intracranial hypertension on outcomes including ICU survival; however, whether patients received barbiturate therapy or not is clearly subject to indication bias. Patients who received barbiturate therapy did so because the clinicians looking after them considered that this was indicated; presumably clinicians looking after the comparator patients did not give them barbiturates because they did not think barbiturates were indicated. Fundamentally, I do not think that it is valid to draw any conclusions about the effect of barbiturate therapy on outcomes based on these data. I do not consider that this problem is overcome in any meaningful way by the propensity score based analysis.

2. ICU mortality is a dichotomous variable and yet the primary analysis is presented as a time to event analysis with a hazard ratio. This analysis does not make sense from a clinical perspective. The relevant consideration is surely whether or not the patient dies in ICU rather than how long it takes for them to die?

3. As 3-month GOSE data are available in the study database, I would also presume that mortality data at 3 months must also be available. It is not clear to me why ICU mortality would be evaluated if mortality data were available at later time points. From the perspective of the patient, differences in ICU mortality rates that are not apparent by 3 months are probably not very important.

4. The proportion of patients with pneumonia is more clinically relevant that the time until 1st diagnosis of pneumonia and so, again, the analysis of pneumonia rates with the effect estimate presented as a hazard ratio does not really make clinical sense.

5. Findings limited to the subgroup of patients with confirmed elevated ICP are alluded to in the Discussion but do not appear to be included in the results.

6. There are some typographical and grammatical errors:

(i) "external ventricular derivations" (p4, line 70) should presumably be "external ventricular drainage" or similar

(ii) "wad" should be "was" (p6, line 98)

(iii) "All patients of the database..." (p6, line 105) should be "All patients in the database..."

(iv) "patient's comorbidities" (p7, line 121) should be "patients' comorbidities"

(v) "may beneficiate" (p14, line 253) should be "may benefit"

Reviewer #2: The authors present a propensity score-based analysis of a cohort of French TBI patients to determine the effect of early use of barbiturates on mortality, ventilated-associated pneumonia and functional outcome (GOS) at 3 months. Barbiturates are a commonly used therapy and understanding the risks and benefits is essential. The study has been well-conducted however I have some concerns which should be addressed to improve the quality of the manuscript.

1. Patents were reported as eligible if they had brain trauma, however no definition has been provided. Was a particular GCS required (e.g. <9) and were CT brain changes required? It is important for readers to understand the severity of TBI for included patients.

2. The barbiturates group was defined as patients receiving barbiturates in combination with other incremental therapies. It is assumed that this is barbiturates within the first 24 hours however this should be clearly stated. In addition, it should be clearly stated whether there was a minimum dose required or whether any administration of a barbiturate resulted in a patient being included in the barbiturates group. It is unclear why the authors chose barbiturates within 24 hours. Given they are recommended as a second or third tier therapy, many patients may receive barbiturates after 24 hours (after failure of other therapies). The discussion reports that 19.8% of control patients received barbiturates after 24 – a sensitivity analysis excluding these patients appears to have been conducted but not results are presented; this data should be included in the supplement.

3. It is unclear why a GCS <8 is reported rather than GCS<9 which is the commonly used definition for severe TBI. It is also of concern that GCS has not been used to determine the propensity weights. While the difference between the barbiturates group and control group is not significant, this may be due to the small sample size and a lack of power. Given the strong association between GCS and outcome, the authors should justify why it has not been included (taking into account the small sample size and likely reduced power to detect differences between groups).

4. The authors report that the CT severity of the injuries did not differ between the two groups. While there is not a statistically significant difference, the small sample size mean the power to detect a difference is low. There are 28.6% of patients with a category 1 or 2 Marshall score in the control group compared to only 17.7% in the barbiturates group.

5. There are other variables available that are known to be strongly predictive of outcome which have not been included in determining the propensity score. As with GCS above, the authors should provide information as to why pupil reactivity was not included (especially as there is a significant difference between groups).

6. The finding are not in agreement with the result of a Cochrane review of RCTs. The authors report this is not surprising, since barbiturates have been shown to impair cerebral oxygenation and may thus impair outcomes. This ignores the difference in study design and the authors should acknowledge the weaknesses of an observational design compared to RCTs.

7. The authors report that influential values were detected by a Cook distance greater than one in absolute value, however no information is provided about how many influential values there were. Given that observations with high weights can be unduly influential in a propensity score weighting, the authors should report how many values had a Cook distance greater than 1.

8. In Table S3, it is unclear if the proportion of missing data differed by group (barbiturates versus no barbiturates).

Minor concerns:

1. The financial disclosure statement is not complete and does not list the funder.

2. The results report that there were 1396 polytrauma patients however the discussion reports that there were 1396 TBI patients – please clarify which is correct.

**********

6. 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.

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 Privacy Policy.

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.]

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.

PONE-D-20-37630R1Early use of barbiturates is associated with increased mortality in traumatic brain injury patients—a propensity score-based analysis of a prospective cohort.PLOS ONE

Dear Dr. Léger,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Mar 26 2022 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: 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 https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Aurel Popa-Wagner

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

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: (No Response)

**********

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: Partly

**********

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

Reviewer #2: 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

**********

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

**********

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: The reviewers have resubmitted their article which presents a propensity score-based analysis of a cohort of French TBI patients to determine the effect of early use of barbiturates on mortality, ventilated-associated pneumonia and functional outcome (GOS) at 3 months. The author have addressed many of my previous concerns and the analysis including the IMPACT-TCI score has strengthened the manuscript.

The following concerns should be addressed before publication:

1. The aim of the study is evaluate the effect of barbiturate therapy in patients with TBI and intracranial hypertension on outcomes including ICU survival. Patients who received early barbiturate therapy did so because clinicians believed there was an indication for barbiturates (and control patients did not receive barbiturates as clinicians presumably did not think barbiturates were indicated). It is challenging to draw conclusions about the effect of barbiturate therapy on outcomes where all factors leading to a clinician decision to prescribe barbiturates cannot be controlled for. This significant limitation should be clearly outlined in the discussion.

2. The authors also report that the findings are not in agreement with the result of a Cochrane review of RCTs. The authors report this is not surprising, since barbiturates have been shown to impair cerebral oxygenation and may thus impair outcomes. This ignores the difference in study design and the authors should acknowledge the weaknesses of an observational design compared to RCTs.

3. Please be consistent in the use of TBI patients (at times TBI patients is used and at times, brain-injured patients is used).

**********

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.

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 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.]

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.

Early use of barbiturates is associated with increased mortality in traumatic brain injury patients—a propensity score-based analysis of a prospective cohort.

PONE-D-20-37630R2

Dear Dr. Léger,

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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

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,

Aurel Popa-Wagner

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: