PONE-D-20-10699

Continuous ultrafiltration during extracorporeal circulation and its effect on lactatemia: A randomized controlled trial

PLOS ONE

Dear Dr. Marín-Paz,

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.

As you will gather from their comments, the referees raised several important issues (see below) that deserve specific attention. Therefore, a major revision is required before we can consider the manuscript for publication in PLOS ONE. Please read the entire contents of this letter and address carefully all of the comments and the reviewers' critiques. Please note that the paper cannot be accepted until you have addressed all the reviewers' critiques. Depending upon the editors' evaluation of the revision, your paper may or may not have to go back to the reviewers.

Please submit your revised manuscript by Aug 29 2020 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,

Gianpaolo Reboldi, MD, MSc, PhD

Academic Editor

PLOS ONE

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Could you therefore please include the title page into the beginning of your manuscript file itself, listing all authors and affiliations.

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As per the journal’s editorial policy, please include in the Methods section of your paper:

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Please also ensure you report the date at which the ethics committee approved the study as well as the complete date range for patient recruitment and follow-up in the Methods section of your manuscript.

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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: Partly

Reviewer #3: Yes

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

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: 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

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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: No

Reviewer #2: Yes

Reviewer #3: 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: this paper looks at a randomised controlled trial of 64 patients of whom 54 contributed data.

The English needs some minor attention throughout (eg. potency should be power, and I think variables of confusion may actually mean confounders).

Given the fact that 64 patients with data were required why was no margin for error built in - there would appear to be about a 15% dropout; it would also appear that these dropouts may be informative given that they are associated with clinical outcome. How was this allowed for in the analysis? Why are no aptietns ewcluded from analysis in the CONSORT diagram - 10 are excluded from a full ITT analysis.

Patients were randomised into one of 2 arms, not 8 blocks - do you mean the block size in the randomisation was 8? Was there any stratification?

It is statistically incorrect to test baseline characteristics by arm. Units are missing from table 2.

The numbers male and female are wrong as the HG numbers add up to 29 not 27

It is incorrect to analyse the primary outcome within arm - please perform a proper repeated measures analysis adjusted for baseline. As such the contrast between groups and the CI are not given here- I also assume the GC really means CG.

The data require a proper analysis to give the treatment effect and CI with inferences based upon the CI. Until these are done the value of the intervention is not assessable.

Table 4 uses intervention and cnotrl - the rest of the paper uses HG and CG.

Reviewer #2: Dear Authors,

I have read with interest your paper entitled "Continuous ultrafiltration during extracorporeal circulation and its effect on lactatemia: A randomized controlled trial".

In my opinion, the biggest flaw is that the main outcome of this trial was the “only” reduction of lactatemia, which it may be interesting per sè, but you should provide further insights to better interpret the findings of the study. Accordingly, you declare in the abstract that the aim of study is “whether continuous ultrafiltration…. decreases post-operative lactatemia and its consequences”.

What are these consequences? You reported the reduction of lactatemia in methods (in the abstract and in the main body) as unique outcome. In the phase of the trial design did you think other secondary outcomes in addition to reduction of blood lactate levels?

Moreover, how do you interpret the reduction of lactatemia? Is it a result of better depuration or a consequence of the general improvement of hemodynamic conditions and/or inflammation? Can you provide further insight to clarify this point?

Furthermore, there is a formal issue, because style of this manuscript is similar to a narrative review (mostly in the introduction and discussion sections). It needs a further effort to improve this point.

Following my point-by-point considerations:

- Abstract:

o Please clarify the points described above, changing it accordingly.

- Introduction section:

o Please reduce this section, providing only the information tightly related to the topic of the manuscript (e.g.: please

cancel the paragraph about use of type of solutions, etc.).

- Methods section:

o Please cancel table 1 and move the information from the table to text.

o Please add secondary endpoints, if it is possible.

- Results section:

o Please add information about patients’ hemodynamics and other vital parameters for improving the interpretation of findings.

o Please add in the table 3 the value at baseline and the intragroup differences (pre- and – post continuous UF).

o Please use regression analysis to analyze the effect after correction for confounders (ECC time, etc.)

o Please clarify the legend and the parameters included in the table 4.

- Discussion section:

o Depending on these additional results, please reconsider the discussion section and the limitations of the study.

o Please rewrite discussion, highlighting the main findings of study and focused on the interpretation of these findings.

I hope that my comments may be helpful for improving your manuscript.

Kind regards

Reviewer #3: In this randomized controlled trial, the Authors have explored the effects of high-volume hemofiltration with a polyethersulfone membrane versus conventional treatment on postoperative lactate levels in patients undergoing extracorporeal circulation normothermic surgical procedure. Although there are multiple studies on the role of high-volume hemofiltration in critically ill patients with AKI and sepsis, the number of randomised trials on high-volume hemofiltration post-cardiac surgery is quite limited, so additional evidence is very welcome. The paper is well written and scientifically sound and has been appropriately reported according to the CONSORT checklist. Hence, the paper might deserve publication on Plos One, provided that the Authors can satisfactorily address some comments, as detailed below:

1) Although I do appreciate that the topic is complex and requires some background information, the introduction is probably a bit too long and could be slightly shortened

2) As there is no universal consensus on the definition of high-volume hemofiltration, the Authors should provide additional information on the rate of hemofiltration. Based on the results of two large randomized-controlled trials (N Engl J Med 2009, 361:1627–1638; N Engl J Med 2008, 359:7–20) and subsequent systematic reviews (Crit Care Med 2010, 38:1360–1369;Clin J Am Soc Nephrol 2010, 5:956–963)3, the adequate dose of hemofiltration treatment for acute kidney injury ) has been defined as an effluent rate between 25 and 30 ml/kg/hour, which is consistent

with HVHF being defined by an effluent rate exceeding 35 ml/kg/hour. How was the hemofiltration rate in this trial? On page 9, line 11 the Authors have mentioned some information on the blood flow (between 100 and 500 mL/min depending on the time of the surgery), but I could not find any information on the average effluent rate. Please provide this information.

3) Page 6, design. Please specify the name of the hospital in Andalusia. Similarly, in the ethics section on page 7, please provide the name of the hospital where the ethics committee was based.

4) Page 7, line 3 from bottom. Please provide additional details on the "hemophilia technique". Was this a typo for hemofiltration?

5) Page 8, line 1. Please provide additional details on the allocator and the randomization technique. Who was the allocator? Was he one of the Authors or an external allocator? How were the patient assigned to the eight different blocks?

6) Page 8, line 7 from bottom. Please provide the full definition of the acronym "PVC"

7) Page 9, line 9. Please provide a supporting reference got the analyzer which was used in the study (including the name of the manifacturer)

8) Page 9, line 2 from bottom. Please provide the rationale for data collection at 24 hours from the surgery only. For example, the HEROICS study collected data up to 48 hours post-procedure (https://doi.org/10.1164/rccm.201503-0516OC). Do you have any additional data after 24 hours from the surgery?

9) Table 1 (page 10) is probably unnecessary and could be reported in the text instead.

10) On page 11, line 4 the Authors did mention the usage of the Mann-Whitney U-test for non-normally distributed variables. However, on page 10, line 2 from bottom the Authors did mention that all variables were reported as means and standard deviations. If there are any non-normally distributed variables (for whom the U-test was used), medians and interquartile ranges should be reported instead. Please clarify this point.

11) Page 12, table 2. The row on sex (female) is not necessary and both rows (males and females) could be merged into a single one (M/F, numbers and percentages). Please also specify all units of measurement (height, cm; weight, kg; serum lactate)

12) Page 13, table 3. Please provide additional details on the "time spent on ITU". Is that hours or days? (I would imagine the latter)

13) Page 13, table 4. Please specify the unit of measurement of C-reactive protein

14) Page 14, line 2 from bottom, and page 15, line 1 please amend the word "hyperlactation" (which would refer to breast-feeding)

15) Abstract, conclusions. Please substitute "could prevent postoperative complications" with "could potentially prevent postoperative complications"

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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

Reviewer #3: Yes: Dr Giorgio Gentile

[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-20-10699R1

Continuous ultrafiltration during extracorporeal circulation and its effect on lactatemia: A randomized controlled trial

PLOS ONE

Dear Dr. Marín-Paz,

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.

All referees found you manuscript substantially improved but a few minor issues deserve your attention. Therefore, we invite you to submit a revised version of the manuscript that addresses the minor points raised by reviewer #2.

Please submit your revised manuscript by Nov 19 2020 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,

Gianpaolo Reboldi, MD, MSc, PhD

Academic Editor

PLOS ONE

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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

Reviewer #3: 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

Reviewer #3: Yes

**********

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

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: 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: (No Response)

Reviewer #2: (No Response)

Reviewer #3: 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: (No Response)

Reviewer #2: Yes

Reviewer #3: 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: The authors have significantly improved the manuscript. However, it needs some minor revisions:

- Abstract:

o Please declare secondary endpoints (Reduction in the intubation time, etc.)

- Methods section:

o Please declare secondary endpoints (Reduction in the intubation time, etc.)

- Results section:

o I think that there is typo in table 2 (Euroscore: 94.5±72.40 in low risk CG group)

I advise the authors to make an extra effort to reduce the introduction and improve the discussion

Reviewer #3: The authors have satisfactorily addressed my previous comments. Hence, in my opinion the manuscript is now suitable for publication in Plos One.

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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: Yes: Dr Giorguo Gentile

[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.

Continuous ultrafiltration during extracorporeal circulation and its effect on lactatemia: A randomized controlled trial

PONE-D-20-10699R2

Dear Dr. Marín-Paz,

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,

Gianpaolo Reboldi, MD, MSc, PhD

Academic Editor

PLOS ONE