PONE-D-19-18070

Pre-warming before general anesthesia with isoflurane delays the onset of hypothermia in rats

PLOS ONE

Dear Dr. Pang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we have decided that your manuscript does not meet our criteria for publication and must therefore be rejected.

Specifically:

The authors investigated theeffect of pre-warming at delaying the onset of hypothermia during general anesthesia. They compared different pre-warming temperature regimens and performed a comprehensive analysis. However, there were enormous concerns regarding the current manuscript.

1. Reviewers and I all especially concerned about the novelty of the article.

2. The effectiveness and clinical implicationof pre-warming treatment could not be ensured.Specially, the protection of pre-warming against hypothermia was no more valuable, because in clinical practice, the duration of anesthesia is often longer than 15 minutes or even hours. In addition, the core temperature is greatly affected by numerous environmental factors, not just general anesthetics.

3. The safety of pre-warming treatment was another important issue. The upper limit of 40°C was selected based on the results that the core temperatures in mice of 41.5 ± 0.1°C for 2 hours could resulted in apoptosis. However, it was not yet proven whether 40°C has a long-term effect on brain function. It is essential to assess intraoperative and postoperative neurobehavioral outcomes.

Unfortunately, the currentmanuscript could not give the readers more valuable clinical significance and evidence-based conclusions. 

I am sorry that we cannot be more positive on this occasion, but hope that you appreciate the reasons for this decision.

Yours sincerely,

JianJun Yang, M.D., Ph.D.

Academic Editor

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: No

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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: The authors aimed to investigate the effect of prewarming on the isoflurane-induced hypothermia in the rat. It was demonstrated that prewarming confers a protective effect against hypothermia during volatile anesthesia. The animal experiment seems to have been adequately performed. However, it is not clear what is the novel finding of this study.

1. Figures 1 and 2 seem to show the same data. How was the data in Figure 2 obtained? The authors should explain why Figure 2, in addition to Figure 1, is necessary in this paper.

2. Figure 3 is obtained from Figure 1. It is not clear why Figure 3 is necessary in this paper.

3. Effectiveness of prewarming to maintain core temperature during anesthesia has been already reported (lines 371-376). The present study shows the effect of prewarming in more detail, but novelty compared with the previous report is not clear. The author should more clearly explain novelty of this research.

4. Differences among core, rectal and fur temperature are as expected (Figures 4-6). What is the novel finding of this data?

5. It is not clear why the behavioral analyses were necessary and what was suggested by the findings of the behavioral analyses.

Reviewer #2: PONE-D-19-18070

In this preclinical study, the Authors evaluated the prewarming animals before induction of general anesthesia would delay the onset of hypothermia. A secondary objective was to compare the accuracy of different temperature measurement sites to core temperature (telemetric capsules implanted in the abdomen).

This prospective, crossover study (n = 17 adult male and female SD rats) compared three treatment groups: PW1% (pre-warming to increase core temperature 1% over baseline), PW40 (pre-warming to increase core temperature to 40°C) and NW (no warming).

The PW1% group was completed first to ensure tolerance of pre-warming.

Treatment order was then randomized and alternated after a washout period. Once target temperature was achieved, anesthesia was induced and maintained with isoflurane in oxygen without further external temperature support.

Pre-warming was effective at delaying the onset of hypothermia, with a significant difference between PW1% (11.2 minutes) and PW40 (14.7 minutes, p = 0.0044 (95%CI -12 to -2.2), PW40 and NW (6.0 minutes, p = 0.003 (95%CI 1.8 to 8.7) and PW1% and PW40 (p = 0.004, 95%CI -12 to -2.2).

The rate of heat loss in the pre-warmed groups exceed that of the NW group: PW1% versus NW (p = 0.005, 95%CI 0.004 to 0.027), PW40 versus NW (p < 0.0001, 95%CI 0.014 to 0.036) and PW1% versus PW40 (p = 0.07, 95%CI -0.021 to 0.00066).

The Authors concluded that, pre-warming alone confers a protective effect against hypothermia during volatile anesthesia; however, longer duration procedures would require additional heating support.

Comments

The study confirms in various animal subset an information already proven in humons.

Not having a sample size calculation, it is not clear the strength of reported results and derived conclusions

I would suggest to summarize the overall meaning of reported results in the first sentence of the Discussion section.

Discussion should be shortened (by 10 to 15% or more) and focused on clinical implication of the present study.

Please edit the Reference section according the journal requirements

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Reviewer #1: No

Reviewer #2: No

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For journal use only: PONEDEC3

PONE-D-19-18070R1

Pre-warming before general anesthesia with isoflurane delays the onset of hypothermia in rats

PLOS ONE

Dear Dr Pang,

Thank you for submitting your manuscript to PLOS ONE. Following your appeal to the initial decision to reject, your manuscript has now been assessed by two independent editors, and has been reviewed by an additional peer reviewer. As you will see, the third peer reviewer is generally positive, but has made some suggestions for how to improve the ms prior to final publication. 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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Christopher James Johnson, Ph.D.

Academic Editors

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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 #3: (No Response)

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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 #3: Yes

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

Reviewer #3: 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 #3: 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 #3: No

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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 #3: This is a useful study, addressing an issue that is of importance when anaesthetising both human and veterinary subjects. It is unfortunate that little emphasis is given to the important implications for research animal anaesthesia - hypothermia has the potential to influence numerous animal models, the effects may last well beyond the period of anaesthesia, and hypothermia occurs commonly when anaesthetising rodents. Although this effects is more common in mice, it is also relevant in rats, and in any event the effects noted in rats are of relevance to mice.

I have one specific comment:

Redistribution of warm blood from the core to the periphery is the primary

24 mechanism in the development of hypothermia and begins following induction of

25 anesthesia.

This is correct when the anaesthetic agent produces peripheral vasodilation, but the most widely used agent for rodents, the combination of ketamin and xylazine, produces a peripheral vasoconstriction. Perhaps it might be better to say that “when using inhalational anaesthetic agents, ….

There are a small number of typographical errors that could be corrected with further proof-reading of the manuscript.

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Reviewer #3: Yes: Paul Flecknell

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Pre-warming before general anesthesia with isoflurane delays the onset of hypothermia in rats

PONE-D-19-18070R2

Dear Dr. Pang,

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.

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Academic Editor

PLOS ONE

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