PONE-D-19-25111

Impact of Blood Glucose Abnormalities on Outcomes and Disease Severity in Patients with Severe Sepsis: An Analysis from a Multicenter, Prospective Survey of Severe Sepsis

PLOS ONE

Dear Prof. Kushimoto,

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.

==============================

Before your manuscript can be sent out for review, please review the journal's data availability policy (https://journals.plos.org/plosone/s/data-availability) paying particular attention to the following paragraph:

Data made available to all interested researchers upon request

The Data Availability Statement must specify “Data available on request” and identify the group to which requests should be submitted (e.g., a named data access committee or named ethics committee). The reasons for restrictions on public data deposition must also be specified. Note that it is not acceptable for an author to be the sole named individual responsible for ensuring data access.

Thank you for your attention to this matter. I look forward to reviewing your manuscript once the necessary changes have been made.

==============================

We would appreciate receiving your revised manuscript by Oct 28 2019 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Robert Ehrman, MD, MS

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

1. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.

We additionally ask that you please include a list of the names of all of the ethics committees that reviewed and approved this study. Please include these as a Supporting Information file.

2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

[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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-19-25111R1

Impact of Blood Glucose Abnormalities on Outcomes and Disease Severity in Patients with Severe Sepsis: An Analysis from a Multicenter, Prospective Survey of Severe Sepsis

PLOS ONE

Dear Prof. Kushimoto,

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.

==============================

Thank you for this interesting paper on an important and incompletely understood topic. Some concerns were raised by the reviewers in the methods and results sections that will require clarification prior to acceptance for publication. Changes in these sections should also be reflected in discussion, where appropriate.

==============================

We would appreciate receiving your revised manuscript by Feb 06 2020 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Robert Ehrman, MD, MS

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

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: (No Response)

**********

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: Partly

Reviewer #2: Yes

**********

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

Reviewer #1: No

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: Summary

Thank you for the opportunity to review this paper. This is a very interesting study that aims to elucidate the predictive role of hypoglycemia in septic patients. The authors utilize a large prospective cohort study to answer the question of whether initial hypoglycemia is predictive of outcome. The results are interesting, but I have issues with how the data was analyzed and presented. Hepatic failure needs to be accounted for specifically in the analyses. As it is currently presented, I think this study is at risk of making the assumption that hypoglycemia is predictive of death, when it is actually just associated with severe disease.

Major points

The study objective to elucidate dysglycemia in a sepsis population is clinically relevant

The authors state “initial blood glucose” level but do not provide timing of this initial glucose or how this was obtained. Was this from finger stick measurements, blood chemistries, etc? Also what was the mean time to measurement of this value from enrollment into the study? It is important to know where in the course of their disease the hypoglycemia occurred.

Even though the parent study (FORECAST) was designed prior to Sepsis-3, they should still report the proportion of patients meeting Sepsis-3 definitions. This should not be difficult given that the authors have SOFA score data available and will make the study more directly comparable to more recent studies.

The authors provide data to support for their choice of blood glucose groups. It would be important to know what they learned from their own data, rather than to utilize prior categorizations of blood glucose from other work. Separating the blood glucose measurements of their patients by quartiles (or similar) and looking at outcomes based on this would be informative.

How did the authors handle censored data for SOFA score in patients who died early?

A larger proportion of patients in the hypoglycemia group had glucose mod to severe liver disease. It is not surprising that those patients are more prone to hypoglycemia. Also, the SOFA scores of the hypoglycemia patients are significantly higher. It is important to know what the Hepatic SOFA scores are for the patients with hypoglycemia. The predictive ability of hypoglycemia could be confounded by liver disease or acute liver failure.

Given the potential interaction between liver disease/failure above it is important to add lactate levels (initial and repeat) to Table 1 and compare across groups.

Corticosteroid requirement is much higher in hypoglycemia group. Is there any data on whether the glucose levels were obtained prior to administration of corticosteroids or if these are post-steroid measures?

The presentation of the data is confusing. The authors mention Kaplan-Meier curves for survival, but then use a Cox regression. But they also report unadjusted odds ratios. If the outcome of interest is the association with mortality, I don’t think a Cox regression is needed as the time to death is not really that relevant. I also do not think unadjusted odds ratios should be presented, and should only be added as supplementary material. The Cox regression shows a higher hazard ratio for glucose < 70, which was robust to sensitivity analysis I think components of SOFA, specifically liver failure should be evaluated in the model as well as Charlson score for mod to severe liver disease. I think we are at risk of finding that hypoglycemia is associated with severely ill patients at risk of mortality, rather than predictive of itself.

Why are unadjusted odds ratios displayed in Table 3 and 4, rather than adjusted?

Minor

Would prefer to see the tables separately and not in the body of the text, which makes it harder to read

Also the authors should indicate units appropriately in tables (N, %) in the first column

Odds ratios should only be reported to 1 or 2 places after the decimal

Reviewer #2: An interesting subgroup analysis highlighting the association between hypoglycemia on admission and mortality in severe sepsis patients from a previously performed multicenter prospective cohort. Highlighting an association between hypoglycemia in non-diabetic sepsis patients and increased mortality is a relevant finding.

Appropriate statistics used for the most part and findings correctly described as an association only in need of further study to determine causation.

The fact that the cohort is a mixed ICU population including medical and trauma patients may confound some of the data a bit. Would be interesting to see if the association still stands in both the trauma and medical ICU subgroups or if it would change.

Abstract still has a few errors and needs some rewording to aid in understanding for readers.

**********

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

[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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachments

Attachment

Submitted filename: Plos One dysglycemia.docx

PONE-D-19-25111R2

Impact of Blood Glucose Abnormalities on Outcomes and Disease Severity in Patients with Severe Sepsis: An Analysis from a Multicenter, Prospective Survey of Severe Sepsis

PLOS ONE

Dear Prof. Kushimoto,

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.

==============================

Thank you for your time and effort revising the manuscript, which has been substantially improved. I am in agreement with the reviewer about the potential confounding effect of liver disease--are the poor outcomes related to hypoglycemia itself, or is this simply a manifestation of liver disease? With only 26 patients in this category, I think it would be difficult to make any firm conclusions about which factor drove the outcome (ie, an analysis comparing liver disease with vs without hypoglycemia would be under-powered).

However, I do think it is worth addressing, most substantively in the discussion, as well mentioning this in the abstract. Can you also include in the methods what criteria were used to classify patients as "moderate to severe liver disease"? I think this would also be informative to readers.

Also, I think the first line of the abstract should read "Dysglycemia is..." not "Dysglycemia are..."

==============================

We would appreciate receiving your revised manuscript by Mar 20 2020 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Robert Ehrman, MD, MS

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

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

**********

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

**********

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

Reviewer #1: I Don't Know

**********

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

**********

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

**********

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: Overall the authors have addressed most of my concerns. However, now that they have identified the significant influence of hepatic disease (elevated hepatic SOFA) in the subgroup with glucose < 70, the reader needs to be sure that hepatic failure isn't driving most of the difference seen in this group. I am not sure based on reviewing their regression models that liver failure was fully accounted for here. It is not explicitly stated nor made clear in the methods. This point may require a statistical review. Moreover, I believe the finding of significantly elevated hepatic SOFA should be mentioned in the abstract, discussion and conclusion.

**********

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

[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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

Impact of Blood Glucose Abnormalities on Outcomes and Disease Severity in Patients with Severe Sepsis: An Analysis from a Multicenter, Prospective Survey of Severe Sepsis

PONE-D-19-25111R3

Dear Dr. Kushimoto,

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.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. 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 enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and 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.

With kind regards,

Robert Ehrman, MD, MS

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: