PONE-D-24-05704Pocket Warming of Bupivacaine with Fentanyl to Shorten Onset of Labor Epidural Analgesia: A Double-Blind Randomized Controlled Clinical TrialPLOS ONE

Dear Dr. Hu,

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Guest Editor

PLOS ONE

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"1) Medical Student Research (MDSR) Roessler Scholarship from The Ohio State University – College of Medicine: 

Winters: 

Tyler M. Balon: data collection, drafting

Justin J. Abbott: data collection

URL: https://medicine.osu.edu/research/opportunities/mdsr-resources/apply-for-medical-student-research-scholarship

2) The Foundation of Anesthesia Education and Research (FAER)'s Medical Student Anesthesia Research Fellowships

Winner: Johnny McKeown, data collection, drafting;

URL: https://www.asahq.org/faer/programs/medicalstudentfellowships/summerfellowships"

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

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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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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: A randomized controlled clinical trial was conducted which aimed to investigate if prewarming of epidural medications in providers’ pockets reduced time to analgesic onset compared to the administration of medications at room temperature. The two groups had similar time to analgesic onset and adverse event rates.

Minor revisions:

1- Line 110: Include the full details for the sample size justification. The power calculation should include: (1) the estimated outcomes in each group; (2) the α (type I) error level; (3) the statistical power (or the β (type II) error level); (4) the target sample size, (5) the statistical testing method, and (6) for continuous outcomes, the standard deviation of the measurements.

2- Line 121: If block randomization was used, state the block size.

3- Line 154: Indicate the underlying covariance structure used in the mixed effects models and the criteria for selecting it.

4- The standard statistical term for average is mean.

5- Table 1: Provide only one p-value for comparing race. The one from the overall chi-square or Fisher’s exact test.

6- Line 208: Replace the two instances of the term “stratified” because it has a specific statistical meaning in relation to the randomization process which has not been conducted in the study. Perhaps “dichotomized” is a more descriptive term.

7- Line 216: Provide the overall p-value for testing the interaction effect of group by time. If the interaction effect is significant, provide an interpretation of the results, but do not test main effects because the tests for main effects are uninteresting in light of significant interactions. If interaction effects are non-significant, drop the interaction effects from the model and test the main effects. Determining which results to present when testing interactions is often a multi-step process.

8- Line 223: For clarification, indicate that the secondary outcomes (rate of adverse events) did not differ significantly between the groups.

Reviewer #2: I would like to comment on the long period of duration and unnecessary delay.

The anesthesiologist was not blind and this may expose the trial to selection bias.

I would prefer that there was a control group with no warming.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-24-05704R1Pocket Warming of Bupivacaine with Fentanyl to Shorten Onset of Labor Epidural Analgesia: A Double-Blind Randomized Controlled Clinical TrialPLOS ONE

Dear Dr. Hu,

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.

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

ACADEMIC EDITOR: Please respond to all reviewers comments

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

Please submit your revised manuscript by Sep 06 2024 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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Ahmed Mohamed Maged, MD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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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 #3: All comments have been addressed

Reviewer #4: All comments have been addressed

Reviewer #5: All comments have been addressed

Reviewer #6: 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 #3: Yes

Reviewer #4: Partly

Reviewer #5: (No Response)

Reviewer #6: Partly

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

Reviewer #1: (No Response)

Reviewer #3: Yes

Reviewer #4: N/A

Reviewer #5: (No Response)

Reviewer #6: I Don't Know

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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 #1: (No Response)

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: (No Response)

Reviewer #6: No

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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: (No Response)

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: (No Response)

Reviewer #6: 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: (No Response)

Reviewer #3: To authors,

First of all, I want to thank authors for this interesting review and for their efforts.

Title: Well written.

Abstract: well written

Background: is well written.

Methods: Thanks to authors as methods is well written in details.

Results:

• The data is statistically analyzed and expressed well.

• Tables and figures are expressed the data well.

Discussion: well written and relevant to the results of the study.

Conclusion: expressed the finding well and well written.

Best regard

Reviewer

Reviewer #4: i acknowledge the authors efforts in conducting this long duration trial. the subject is interested and of clinical importance which was conducted to explore if pocket warming would achieve similar results as body temperature warmed medications as compared to room temperature medications, however i have the following comments:

1- first it is better to describe your results ( analgesia onset) by absence of significant difference between both groups and not describing them as similar results because there was an observed difference in favor of room temperature group. - please correct it in abstract, results and discussion.

2- regarding the study outcomes, they needs more clarification regarding their definition- time points- end time point- method of assessment. for example the onset time was mentioned to be assessed for 60 minutes which doesn't reflect the clinical practice. onset of block is usually assessed every 5min within 30 min after the block if no adequate response extra-dose will be added. the time-point (60min) for follow up of the VRS score not the onset only.

and what did authors do if the analgesia target was not achieved .. they didn't exclude such cases.

when and how the rescue epidural doses were given? and why this outcome not reported in the results!

how did you assess the patient satisfaction?

are skin temperature sensors valid to measure the syringe temperature? mention your reference

3- as regard sample size, mention the used software to calculate the sample size,

the reference of the effect size, and the reference of The minimum clinically important difference (5min)

4- as regard the statistical analysis; mention the used test of normality

how did you perform the subgroup analysis in the pocket warming group to evaluate the durations of warming as reported in results

5- in Results; in CONSORT chart, if authors performed allocation before giving the epidural, so failed procedure should be inserted in the drop-out cases that didn't receive the allocated intervention.

illustrate the method of the duration of pocket warming and patient satisfaction and how they were presented in results

please revise the attached file.

Reviewer #5: (No Response)

Reviewer #6: Thank you for giving me the opportunity to review this interesting manuscript.

This study investigated whether prewarming epidural medications in providers' pockets (to approximately 27.8°C) can shorten the onset time of labor epidural analgesia compared to room temperature medications (22.1°C). The primary outcome, median time to analgesic onset, and secondary outcomes, including incidences of adverse events such as hypotension, fever, nausea, vomiting, the number of rescue epidural boluses, and patient satisfaction rates, showed no significant difference between the groups.

It was interesting but I have some questions.

One of the most important methodological flaws of this study is the inconsistent temperature measurement of bupivacaine.

The study relied on indirect methods to estimate the temperature of the epidural solution. The temperature of the accompanying saline syringe was used to approximate the temperature of the bupivacaine solution. Direct measurement of the medication temperature immediately before administration would have provided more accurate and reliable data. This inconsistency may have influenced the study outcomes and should be addressed for greater accuracy.

Please discuss how the temperature was consistently maintained during the pocket warming and any potential variations observed.

The manuscript also does not provide detailed information specifically describing the aseptic methods used during the storage of solutions in the pocket. It is critical to ensure that proper aseptic techniques are followed to prevent contamination and infection. A detailed description of these methods should be included to strengthen the study’s validity.

It is known that higher temperatures can cause changes in the density and viscosity of bupivacaine, which in turn affects its cephalad spread compared to cerebrospinal fluid (CSF). Studies such as Anesth Analg. 2006 Jan;102(1):272-5 have shown that a decrease in the density and viscosity of bupivacaine relative to CSF can impact its spread. This manuscript should discuss how these temperature-induced changes might influence the onset time of epidural analgesia, which is not administered intrathecally. Understanding these effects can provide insights into the observed results and help refine the study design.

By addressing these points, the manuscript will provide a more comprehensive and accurate evaluation of the impact of prewarming bupivacaine on the onset time of labor epidural analgesia.

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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 #3: Yes: Alshaimaa Abdel Fattah Kamel

Reviewer #4: No

Reviewer #5: No

Reviewer #6: No

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Attachments

Attachment

Submitted filename: revision to authors.docx

Attachment

Submitted filename: PONE-D-24-05704_R1_15 JUl.pdf

Pocket Warming of Bupivacaine with Fentanyl to Shorten Onset of Labor Epidural Analgesia: A Double-Blind Randomized Controlled Clinical Trial

PONE-D-24-05704R2

Dear Dr. Hu,

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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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,

Ahmed Mohamed Maged, MD

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 #4: All comments have been addressed

Reviewer #6: (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 #4: Yes

Reviewer #6: Yes

**********

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

Reviewer #4: Yes

Reviewer #6: 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 #4: Yes

Reviewer #6: 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 #4: Yes

Reviewer #6: 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 #4: the revised version of the manuscript is much improved.

The authors have addressed all my comments for this paper and answered the technical questions I have for this method. Therefore, I have no further comments.

Reviewer #6: Thank you for addressing the response regarding the lack of references and limited data on the impact of local anesthetic temperature on epidural onset. While I acknowledge the authors’ point that there is limited direct evidence on this topic within the context of epidural analgesia, I believe it is crucial to explore and discuss this aspect further. The Braz J Anesthesiol (2021) study provides a valuable perspective by suggesting that temperature changes may influence not only the intrathecal spread of anesthetics but also their direct action on spinal nerve roots.

Previous studies have proposed hypotheses that could be relevant to the current investigation. For instance, increasing the temperature of a local anesthetic decreases its dissociation constant, which in turn increases the unionized fraction of the drug. This change enhances lipid solubility, potentially leading to greater membrane permeation and more effective nerve blockade. Furthermore, the vasoconstrictive effects of cooling, which reduce the amplitude and increase the duration and latency of action potentials, could explain why cooling might delay onset. Conversely, warming could mitigate these effects, promoting faster recovery of inactivated fibers and potentially accelerating the onset of anesthesia.

Given these considerations, I recommend that the authors refer to studies such as Rosenberg and Heavner (1980), Sviggum et al. (2015), Kamaya et al. (1983), Lee et al. (2012), and Pappone (1980) to support a more detailed hypothesis. If space constraints prevent a full discussion within the main text, these points should at least be acknowledged in the limitations section to provide a more comprehensive understanding of the study’s context and the potential physiological implications of temperature variations on local anesthetic efficacy. Addressing this could significantly strengthen the manuscript by connecting existing knowledge with the current study’s findings and offering a more nuanced interpretation of the results.

1. Rosenberg P, Heavner J. Temperature-dependent nerve-blocking action of lidocaine and halothane. Acta Anaesthesiol Scand. 1980;24:314-320.

2. Sviggum H, Yacoubian S, Liu X, et al. The effect of bupivacaine with fentanyl temperature on initiation and maintenance of labor epidural analgesia: a randomized controlled study. Int J Obstet Anesth. 2015;24:15-21.

3. Kamaya H, Hayes JJ, Ueda I. Dissociation constants of local anesthetics and their temperature dependence. Anesth Analg. 1983;62:1025-1030.

4. Lee R, Kim YM, Choi EM, et al. Effect of warmed ropivacaine solution on onset and duration of axillary block. Korean J Anesthesiol. 2012;62:52-56.

5. Pappone PA. Voltage-clamp experiments in normal and denervated mammalian skeletal muscle fibres. J Physiol. 1980;306:377-410.

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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 #4: No

Reviewer #6: Yes: Ki Tae Jung

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