PONE-D-19-24231

Factors associated with hemolysis during adult extracorporeal membrane oxygenation (ECMO) – comparison of VA- versus VV ECMO

PLOS ONE

Dear Prof. Lehle,

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Additional Editor Comments (if provided):

First of all thanks to all the authors for this interesting paper dealing with the factors associated with hemolysis during adult V-V and V-A ECMO. On the basis of the reviews i received i deem the manuscript suitable for publication but after major revision only.

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: 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

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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 article presents the analysis of 1063 patients having undergone ECMO support for different reasons (VA 606 vs VV 457)

The article is interesting and is a hot topic but in my opinion, more details could enrich the article.

- You have to complete the abstract including the years of the study and “consecutive patients” in the Methods section.

- The authors stated the aims of the study was to disclose similarities and differences in VA and VV ECMO associated hemolysis but only in the abstract. In my opinion, it must be clearer also in the main text. Furthermore, the two population are really different in the pre ECMO treatment values in terms of age, BMI, FHb pre, LDH, Bilirubin, CRP pre, and TNF. There was also a difference in age. Even if the authors try to explain these differences probably, a propensity-matched analysis could be useful to better understand the proposed aim and avoid any other bias.

- The references must be order for the number of appearance in a consecutive way.

- Moreover, in my opinion the clinical outcomes could be more important than the simple hemolysis so it could be useful to investigate the adverse clinical events in terms of transfusion and AKI during the ECMO treatment between groups.

- What about the CVVH treatment? Are there any patients that required it during ECMO?

- The differences between VA and VV ECMO in terms of PHT is very interesting but in my opinion a deeper analysis for risk factors could be made even if the duration of ECMO treatment itself maybe is the simplest and easier explanation.

Reviewer #2: Very interesting analysis on hemolysis in ECMO patients, underlying similarities and differences between VV and VA.

A few comments:

- In your analysis ECMO (be it VV or VA) did not seem to promote hemolysis per se, while abnormally high levels of fHb in ECPR and post-cardiotomic VA ECMO seem to be "washed out". Do you believe this is due to a rapid restoration of adequate CO? Possible reasons for high fHb in these subgroups? Liver stasis?

- Was haptoglobin tested?

- How do you define pump head thrombosis? Do you routinely measure fibrinogen and D-dimers? Or is it a clinical/visual diagnosis? Does this prompt a circuit change?

- Smaller cannulae (even if blood flow was not so high) do not seem to increase fHb. Is this because blood flow was reduced (i.e. we generally go up to 2.6 BFI with a 15F)? Please comment.

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Reviewer #1: No

Reviewer #2: Yes: Dr. Fabio Sangalli, MD, FASE

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Factors associated with hemolysis during extracorporeal membrane oxygenation (ECMO) – Comparison of VA- versus VV ECMO

PONE-D-19-24231R1

Dear Dr. Lehle,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

Andrea Ballotta

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for all your comments. in the basis of the reviewers' evaluation i deemed the paper suitable for publication.

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: All comments have been addressed

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 #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

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 #1: Yes

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 #1: Yes

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 #1: (No Response)

Reviewer #2: All comments were addressed by the Authors and the paper was edited accordingly. This reviewer has 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 #1: No

Reviewer #2: Yes: Dr. Fabio Sangalli, MD, FASE