PONE-D-19-27217

Biochemical recovery from exertional heat stroke follows a 16-day time course

PLOS ONE

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PLOS ONE

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Reviewers' comments:

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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: Yes

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

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Reviewer #1: Yes

Reviewer #2: No

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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 purpose of this manuscript is to document the time course recovery of clinical biomarkers following a heat stroke event in the US Armed Forces. This paper adds to the body of knowledge and will be helpful in developing a targeted and data-driven approach to heat stroke recovery and return to activity/duty/work. There are a couple of items that warrant further clarification within the manuscript.

1) Within the introduction (L26-28) the authors discuss a consensus on EHS RTP/RTD. It may be helpful to provide additional sources of consensus as it relates to sport (NATA Position Statement on Exertional Heat Illness, 2015) and occupational (if any are available) on EHS recovery.

2) L75: The authors mention pre-determined patient demographic and clinical variables within the methodology. It would be helpful to include an explanation of what these variables were at this point in the manuscript.

3) Can the authors provide a rationale for their selection of 60 days here?

4) Within the discussion (L183 - 206), there is a discussion on the interpretation of clinical values and implications for treatment and return to activity, however, more discussion is needed surrounding the implications for return to activity here. The authors reiterate their findings from a liver damage/dysfunction (L188-191) and urinalysis (L202-206), however, there is no discussion on how return to activity should be guided in these instances. Should all activity cease until these values are within normal limits? Would activity in a cool environment (as recommended based on current consensus) be appropriate? This is an important section of the discussion and should be used to provide some insight on the current clinical recommendations on return to activity and how those may (or may not align) with the findings from this study.

5) In table 2, please indicate that the amplitude of the peak is in reference to the relative fold change compared to ULL/LLN

Reviewer #2: I read this article with great interest as it serves to illuminate an area that remains poorly defined in the literature. The manuscript discusses 2,529 exertional heat stroke (EHS) events, and the observed biochemical analysis during recovery. The authors additionally note that these labs are critical in the prognosis and return to duty decisions. The authors then subsequently describe a profile of laboratory recovery concluding that the biochemical recovery spans sixteen days. This summary, while very useful in describing a large cohort, however, is somewhat misleading and fails to address previously described and well documented variation dependent upon clinical presentation and management, in the section on limitations.

The value of laboratory tests and the biochemical profile is first and foremost critical in initial management decisions for clinicians. The tone of the manuscript appears to ignore the critical role of management in the impact on the biochemical profile, almost to the point of suggesting that management differences may have little impact on the shape of the biochemical profiles's recovery. The literature is robust with articles on EHS demonstrating the key impact of time to cooling on EHS parameters at presentation, to include morbidity and mortality and the need for dialysis. The roles of aggressive hydration, intra-vascular cooling in management also have shown an impact on the biochemical profile, and clinical recovery. Accordingly, while clearly this is a value added contribution to the literature in a global description of profiles in non fatal EHS events, I strongly believe the data could be interpreted as misleading in failing to recognize the uniqueness of each EHS event with the critical role of early cooling and its impact, as well as the role of effective management. I would argue that time to cooling and management have an impact on the biochemical profile.

Several article to consider:

Varghese GM. Predictors of multi-organ dysfunction in heatstroke.

Emerg Med J. 2005;22:185-187.

Mil Med. 2009 May;174(5):496-502.

Exertional heatstroke: early recognition and outcome with aggressive combined cooling--a 12-year experience.

Sithinamsuwan P1

A Tale of Two Heat Strokes: A Comparative Case Study. Stearns RL, Casa DJ, O'Connor FG, Lopez RM. Curr Sports Med Rep. 2016 Mar-Apr;15(2):94-7

These articles and others emphasize the the most important point in that all EHS events are not the same, and management strategies can be dramatically different depending upon initial risk stratification, which will impact biochemical profiles. This concept has to be clearly recognized as a study limitation, and reality of EHS management.

Finally, the authors discuss the cost of each EHS event as $5,337 per episode. There is no clear discussion that details how this is concluded; clearly this is markedly underestimated. I do not understand role in this manuscript.

Conclusion: this is an important contribution to the literature, however, it needs to be discussed in proper context.

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Reviewer #1: No

Reviewer #2: No

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Biochemical recovery from exertional heat stroke follows a 16-day time course

PONE-D-19-27217R1

Dear Dr. Leon,

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,

Christopher James Tyler, PhD

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: 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

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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

**********

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: The authors have addressed all concerns from the original draft. This manuscript is going to be a tremendous addition to the scientific literature.

Reviewer #2: The authors have sufficiently addressed all my concerns; this should be a welcome addition to the literature. I look forward to citing in future manuscripts.

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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.

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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