PONE-D-22-17886Association between insulin administration method and six-month neurological outcome in survivors of out-of-hospital cardiac arrest who underwent targeted temperature managementPLOS ONE

Dear Dr. Lee,

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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ACADEMIC EDITOR: Thank you very much for having submitted this paper. As you can see in the comments one of the Reviewer has raised many concerns about the present version of the paper.  I would give you the opportunity do address the comments. 

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Additional Editor Comments:

Thank you very much for having submitted this paper. As you can see in the comments one of the Reviewer has raised many concerns about the present version of the paper. I would give you the opportunity do address the comments.

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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: No

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3. Have the authors made all data underlying the findings in their manuscript fully available?

ThePLOS 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

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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: This is a retrospective study (although the data were collected prospectively in a multicenter registry) comparing different methods of glucose administration (subcutaneous -SQI, intravenous bolus infusion -IBI, continuous intravenous infusion -CII) in patients admitted for OHCA (out of hospital cardiac arrest) undergoing targeted temperature management.

Insulin administration method was not associated with the 6-month neurological outcomes, however the continuous infusion was associated with lower mean glucose and lower standard deviation of glucose.

Moreover (even if that was not the endpoint of the study), it adds on the evidence that glucose variables (mean value, maximum value, SD, episodes of moderate hypoglycemia) are associated with neurological outcome after OHCA.

It is also interesting to note that SQI and IBI method were associated with a mean glucose level (respectively 181 and 184 mg/dl) higher than the cutoff of <180 mg/dl recommended in the guidelines, being the CII method the only one with a mean glucose level in target (168 mg/dl) according to the guidelines.

Finally, although there was no association between the insulin administration method and neurological outcomes, lower mean glucose levels and lower SD of glucose were associated with favorable neurological outcomes and CII was associated with ower mean glucose levels and lower SD of glucose, suggesting that the CII may be the best measure to control glycemic status in cardiac arrest survivors.

Some issues come to mind:

- It would be interesting to know if there were statistical differences in terms of total unit of insulin administered between the three methods.

- At line 261 “A landmark trial regarding glucose control in critically ill patients revealed that intensive glucose control (< 180 mg/dL) increased mortality in the intensive care unit” is probably a typo since, according to the reference (6), the intensive glucose control in the trial was between 81 and 10mg/dl.

Other than this minor issues, the article seems fit for publication

Reviewer #2: Review PONE-D-22-17886

In this article authors retrospectively investigate the association between insulin administration method and neurological outcomes in out-of-hospital cardiac arrest (OHCA) survivors; data were extracted from a multicentre registry of patients with OHCA who underwent targeted temperature management (TTM). Authors ambitiously tried to use Cerebral Performance Category Scale as primary endpoint, evaluating its association with insulin administration method. Insulin regulating mechanism is known to be altered in patient with cardiac arrest.

However, the physiopathological mechanism according to which it has been hypothesized that insulin administration method would be associated with neurological outcome is not clearly described: maybe one way of administration (CII) should better achieve the optimal glucose target? In this case, first step analysis should address this physiopathological mechanism; the association between insulin administration method and neurological outcomes in OHCA should be investigated secondarily.

Major issues

1. The three different groups according to way of insulin administration (SQUI, IBI and CII) are characterized by significantly different glucose values, prevalence of diabetes mellitus and other parameters which are described to influence neurological outcome (witnesses to collapse, cardiac aetiology, time from collapse to ROSC). Based on above findings, the groups can't be considered homogeneous.

2. Why patient with adequate glucose control with insulin therapy within 24 hours from ROSC were not included?

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Reviewer #1: No

Reviewer #2: No

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Association between insulin administration method and six-month neurological outcome in survivors of out-of-hospital cardiac arrest who underwent targeted temperature management

PONE-D-22-17886R1

Dear Dr. Lee,

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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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 contactonepress@plos.org.

Kind regards,

Simone Savastano

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you very much for having submitted this paper and for having addressed all the reviewers' comments. I congratulate you on work work

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: Partly

**********

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?

ThePLOS 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: Yes

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: All issues were addressed and typos corrected, overall the article seems now fit for publication.

Reviewer #2: All comments have been adressed. However, since primary purpose and endpoint have been changed, the manuscript title must be modified.

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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 ourPrivacy Policy.

Reviewer #1: No

Reviewer #2: No

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PONE-D-22-17886R1

Association between insulin administration method and six-month neurological outcome in survivors of out-of-hospital cardiac arrest who underwent targeted temperature management

Dear Dr. Lee:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contactonepress@plos.org.

If we can help with anything else, please email us atplosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Simone Savastano

Academic Editor

PLOS ONE