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PONE-D-20-29696

A multi-mechanism approach reduces length of stay in the ICU for severe COVID-19 patients

PLOS ONE

Dear Dr. VanBuren,

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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Yu Ru Kou, PhD

Academic Editor

PLOS ONE

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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: No

Reviewer #2: No

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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

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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: The authors present original data on the use of a multiple mechanism therapeutic approach (MMA) on patients with severe COVID-19 hospitalized in ICU. The report that the MMA was assciated with a decreases in average ICU length of stay, thereby causing a relevant unload of the hospital workflow arounf COVID-19, which was a critical issue during the first outbreak.

Specific comments:

- the rapid outbreak of COVID-19 cases especially during the first breakout was responsible for a total derangement of healthcare services. One of the consequences was the generation of a strong selection bias on hospital admissions. In fact, hospital admission for Acute Myocardial Infarction and other acute cardiovascular diseases were dramaticaly reduced (Reduction of hospitalizations for myocardial infarction in Italy in the COVID-19 era. Eur Heart J. 2020;41(22):2083-2088. doi: 10.1093/eurheartj/ehaa409. - COVID-19 pandemic and admission rates for and management of acute coronary syndromes in England. Lancet. 2020;396(10248):381-389. doi: 10.1016/S0140-6736(20)31356-8.). Similarly, a selection bias was also suggested for COVID-19 patients, whereas the most severe cases probably did not make it to the hospital, which might then have caused an underestiation of death. Please comment on this issue;

- the authors report IOT with mechanical ventilation being the only independent predictor of in-hospital death in this cohort. A recent analysis incuding over 75000 COVID-19 patients, of which 4344 were under intensive care found age, cardiovascular risk factors or comorbdities and CV complications were independent predictors of in-hospital death (Impact of cardiovascular risk profile on COVID-19 outcome. A meta-analysis. PLoS ONE 2020; 15(8): e0237131. https://doi.org/10.1371/journal.pone.0237131). Did the authors find similar results in their cohort? please discuss this aspect in the manuscript;

- in this regard, the auhtors report "a strong relationship between treatment and age as predictors of LOS, showing greater benefit in reducing LOS in ICU for older patients". In light of this finding, how do the authors explain the lack of association between age and death? Might it be related with the limited sample size?

- the authors state that "The database analyzed during the current study are available from the corresponding author on request.". HOwever, this doesn't comply to journal policies on data sharing. Please refer to authors' guidelines;

Reviewer #2: The authors assessed the impact of a "multiple mechanism therapeutic approach" (MMA) on the clinical management of patients with severe COVID-19. They found that the "MMA" approach was assciated with a decrease in length of stay in the ICU.

Comments:

- please, describe the criteria for selection of study centers. Please, also report how many centers were invited and the percentage of participating centers from those invited;

- how were clinical endpoints reported? do the authors have information on thrombotic events?

- despite many efforts, clinical information on female patients is still underrepresented compared to males. This issue has been evan larger with COVID-19. (Sabatino J. et al. Women's perspective on the COVID-19 pandemic: Walking into a post-peak phase. Int J Cardiol. 2020:S0167-5273(20)33552-X. doi: 10.1016/j.ijcard.2020.08.025.). Could the authors please report their results stratified by gender (e.g. in a summary table) and comment about eventual differences?

- lenght of stay is an obvious proxy of mortality, how did the authors managed the shorter LOS for early deaths? was any correction applied?

- a recent meta-analysis including over 4000 COVID-19 patients under intensive care identified age as an independent predictor of in-hospital death (Sabatino J. et al. Impact of cardiovascular risk profile on COVID-19 outcome. A meta-analysis. PLoS One. 2020;15(8):e0237131. doi: 10.1371/journal.pone.0237131.). How do the authors explain the lack of association in their cohort?

- Did the authors find any association between cardiovascular comorbidities and in-hospital death?

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Reviewer #1: No

Reviewer #2: No

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A multi-mechanism approach reduces length of stay in the ICU for severe COVID-19 patients

PONE-D-20-29696R1

Dear Dr. VanBuren,

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,

Yu Ru Kou, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The original submission was rated as "minor revision" by reviewer #1 who declined to re-evaluate the R1 version of revised manuscript. I have read through the responses from the authors to reviewer's comments. In my view, the authors have adequately revised their 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

**********

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 authors have revised their manuscript. All comments have been addressed. I have no further comments.

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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 #2: No