PONE-D-19-20218

ECMO with vasopressor use during early endotoxic shock: Can it improve circulatory support and regional microcirculatory blood flow?

PLOS ONE

Dear Mu,

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 mainly by reviewer 2.

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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: Partly

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

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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: Findings are consistent with previous clinical and research studies. A group with shock and vasopressors without echo would have been interesting.

Reviewer #2: Dear authors

It has been a pleasure to write and comment on your article: “ECMO with vasopressor…”

As you can see below, I have something that need changes and I have some suggestions for improvement.

Introduction:

The section is well written and appropriate.

Line 46: MODS as an abbreviation is not necessary because it is not used again in the text.

Materials and Methods:

Even though the local authorities approved the study, the anesthesia was not in accordance with European standard. In Europe, a protocol with Pentobarbital without analgesics cannot be accepted in surgery. Was the anesthesia as described or is anything missing?

How was the ventilator settings during the experiments? FiO2 and how was the ventilator and oxygenator air flow adjusted?

Extracorporeal Circuit:

Please explain why a cephalad 8-10 Fr catheter was inserted in the jugular vein, line 107

On line 108: arterial cannula placed at the left ventricle? Is it in the aortic arch or in the descending aorta at the level of the left ventricle? If placed in the ventricle it may result in valve insufficiency and backward failure to the pulmonary circulation. In line 96 another catheter is placed via the same internal carotid artery and inserted to the left ventricle. I guess this is a smaller catheter, please mention.

A priming volume 450 ml is very big for a 9 kg pig even the circuit was primed with blood. The donor blood can interfere with pulmonary resistance. Did the control group that was not on ECMO receive donor blood?

Why not use an infant set for ECMO, or bigger pigs, instead of using a 50 kg pig as donor.

I think the extra corporeal system was biocoated, if it was possible to run the ECMO with an ACT below 200 seconds.

Experimental protocol:

The first group, if I understand it correct, please indicate that the pigs were prepared for ECMO with all catheters inserted but the ECMO was not started.

Line 125: n=21. Please mention how many in each group first and then about ET treatment.

Why did you end at 27 pigs? How many pigs did you have from the beginning?

Results:

Line 190: be careful not to conclude something of PAP, but only about PVR, because ECMO in itself will bypass blood from the pulmonary circulation.

Line 2019: Maybe better to change CO with systemic circulation

Discussion:

Line 255 to 270 is strictly not discussion but introduction

The biggest limitation is the species difference.

Very best

Benedict Kjaergaard

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Reviewer #1: No

Reviewer #2: Yes: Benedict Kjaergaard

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ECMO with vasopressor use during early endotoxic shock: Can it improve circulatory support and regional microcirculatory blood flow?

PONE-D-19-20218R1

Dear Dr. Mu,

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.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Michael Bader

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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: (No Response)

Reviewer #2: Yes

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

Reviewer #1: (No Response)

Reviewer #2: 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 Response)

Reviewer #2: 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: (No Response)

Reviewer #2: 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: Revisions complete. Comments worthwhile and appropriately placed in manuscript. Nothing further to add to this review.

Reviewer #2: I find the changes acceptable for publication. Especially that you changed the sections of medication, cannulas and ventilator settings. Your explanation of the statistics is OK.

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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: Yes: Irving Kron

Reviewer #2: Yes: Benedict Kjaergaard