PONE-D-21-37832RESUSCITATIVE ENDOVASCULAR BALLOON OCCLUSION OF THE AORTA IMPROVES SURVIVAL IN HEMORRHAGIC SHOCKPLOS ONE

Dear Dr. Harfouche,

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,

Zsolt J. Balogh, MD, PhD, FRACS, FACS

Academic Editor

PLOS ONE

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Additional Editor Comments:

Dear Authors,

Your paper generated considerable interest among our senior reviewers. Unfortunately some of them found it quite marginal and some of them even recommended rejection.

My suggestion is to address all the concerns in your revision in an itemised fashion paying special attention to the details related to the actual level of evidence you are providing, the specific biases and the limitations of your study. Due to the nature of this work and the design the conclusions need to be more cautious and reserved.

I hope you consider the revision and provide us opportunity to re-review your work.

Best Regards,

Zsolt J. Balogh

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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: Partly

Reviewer #2: No

Reviewer #3: Partly

Reviewer #4: Yes

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

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: I Don't Know

Reviewer #4: 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

Reviewer #4: 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

Reviewer #4: 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. The authors state that REBOA improves survival in the title of the manuscript and throughout its body. This is a retrospective study, therefore the authors cannot state cause and effect, they can only report associations.

2. It appears the REBOA group consisted of patients treated during the period from 2015-2019 to allow a learning period after REBOA was started in 2011. The contemporary period was chosen between 2013 and 2019 and is not truly contemporary with relationhip to when REBOA was started or when the study of REBOA was started. Please explain the rationale for this choice. It seems the contemporary period should be the same as the period of study of REBOA.

3. The authors state that 60 REBOA catheters are placed in their institution per year but their study group only includes 57 patients who received REBOA over a 4 year period. Please explain.

4. The authors state in the limitations section that a large number of patients were removed from the study due to missing data needed for the propensity scoring. The data used for propensity scoring in this study are straight forward and should be available. Why are these data missing in so many patients? Does the removal of patients due to missing data bias the study? What types of patients were removed for missing data?

5. The authors state patient who received REBOA catheters were treated by highly experienced surgeons. Could the experience of the surgeon play a role in the improved outcome.

6. There are many factors that go into the decision of whether or not to place a REBOA catheter that are not captured in the propensity analysis. Patients may not have received a REBOA catheter because they were either too sick or not sick enough. These unknown factors not included in the propensity study could also bias the study. This should be discussed in the limitations.

7. After excluding all ineligible patients, only 57 patients who received a REBOA remain in this 4 year study. This is a small study. This should be discussed in the limitation section.

Reviewer #2: the authors are very experienced in the REBOA procedure and are leaders in this field. This work is an important contribution. Their stated aim, " The aim of this study was to use the local trauma registry of one high-volume Level 1 Trauma Center to compare outcomes between trauma patients who were managed with REBOA and those who received standard treatment without REBOA," is right on target.

However I find the inclusion of patients from the prereboa historical era distracting and not helpful at all. As they state many things have changed since that early time period. so much so that this groups should be dropped from the paper. Its simply distracting and not helpful. Additionally its not consistent with their stated aim.

The authors state that REBOA improves outcomes. However given that their data are retrospective, all they should say is that its associated with improved outcomes.

There is a trend towards decreased death in the reboa group vs contemporary. Please add a table on the causes of death in these patients.

Since reboa is supposed to decrease bleeding and hemorrhagic death, why wasn't there a decrease in transfusion and 24 hr deaths? Please address in the discussion.

Reviewer #3: Thank you for the opportunity to review this manuscript examining outcomes associated with the use of REBOA in a high-volume trauma centre.

The key limitation is the methodology. Although the authors have attempted to mitigate bias associated with a retrospective comparative study (and also discussed this in their limitations), the most significant issue is the likelihood of selection bias. This should be addressed further in the limitations discussion.

Also it would be helpful to understand what were the institutional indications for REBOA. Did these indications change over time?

Why were other markers of bleeding/shock not utilized in the propensity matching? ie heart rate, base deficit, lactate, MTP activation/number of PRBC transfused in the first 4 hours

Adding further variables would provide a more comparable control group

Why were the specific time periods selected for the dichotomy of “historic” vs “contemporary?” What changes in resuscitation/procedures/approaches occurred?

Although no direct comparison between the baseline characteristics of the historic vs contemporary cohorts was made, it appears that the contemporary group are older, less injured (by ISS, although I don’t understand why the AIS are higher in the contemporary group), and different in ethnicity. The outcomes appear to be improved in the contemporary cohort. Explaining the potential differences in the cohorts will assist the reader in understanding the findings of the study.

Reviewer #4: Nicely written work of relevance.

Main concern is around missing data which despite being discussed as limitation remains somewhat obscure. I suggest the authors provide more information in the methods and results section on what the missing important clinical data is rather than just generically stating this and only providing the total number in the results.

For completeness, the methods should also state that acute kidney injury is accounted for as a measured outcome given that it is.

Lastly, this : "60 times per year" and "but were available to the patients in the contemporary and REBOA groups" is redundant, the authors could remove it if they like.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

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RESUSCITATIVE ENDOVASCULAR BALLOON OCCLUSION OF THE AORTA ASSOCIATED WITH IMPROVED SURVIVAL IN HEMORRHAGIC SHOCK

PONE-D-21-37832R1

Dear Dr. Harfouche,

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,

Zsolt J. Balogh, MD, PhD, FRACS

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

thank you

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: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: (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 #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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: The authors have not substantially changed the manuscript in response to the reviewers comments. The inclusion of historical controls remains problematic due to the many changes that have occurred over time. It remains unclear why so many patients were excluded due to missing data when the data necessary for propensity matching should be present in any version of a trauma registry. The population studies is very small due to all of the exclusions but the conclusions are very bold in the face of the limitations.

Reviewer #2: The authors state the historical control groups is to mitigate selection bias. Since REBOA wasn't available during that time, selection isn't possible. I'm not sure why they use this group at all; selection bias is not a reason.

Reviewer #3: (No Response)

Reviewer #4: All comments adequately addressed except reviewer 2 comment 1, for which a supportive explanation was given. I think the review could be considered reasonably acceptable

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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.

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

Reviewer #3: No

Reviewer #4: No