PONE-D-20-33942

Continuous positive airway pressure to reduce the risk of early peripheral oxygen desaturation following apnoea onset in children: randomised double-blind controlled trial

PLOS ONE

Dear Dr. dos Santos Neto,

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.

Our reviewers, experts in the field, have provided valuable comments, which I share. Please consider them carefully in all points when you submit a revision of your paper.

Please submit your revised manuscript by Jan 30 2021 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Thomas Penzel

Academic Editor

PLOS ONE

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University of Pernambuco where patient data were collected and the Instituto de Medicina

Integral Prof. Fernando Figueira, in which the study was conceived. The authors are grateful to

Professor José Natal Figueroa for his essential contribution with data analysis and interpretation,

the medical residents in anaesthesiology, Raniere Nobre Fonseca and Victor Lemos Macedo, for

their valuable collaboration in performing the data collection and to the Coordenação de

Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for providing the author with a

scholarship."

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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, with a randomized double-blind parallel controlled clinical trial, to evaluate whether CPAP-ventilation and passive CPAP oxygenation would reduce the risk of a SpO2 decrease to 95% following apnea onset in children as compared to no positive airway pressure. This trial was successfully accomplished in 68 children aging 2-6 years during anesthesia, and is commendable. The timeframe evaluated was 5 minutes after the start of an apnea, and recording was every 30 seconds. They found that while in the CPAP group, patients presented a 50% probability of having reached a SpO2 of 95% within 5 minutes, in the Control group this chance increased to 94.1%. In other words, a prosperous result.

Two minor comments are:

1. Could the authors elaborate on the stability and the severity of SpO2 in the 30-second intervals within the CPAP group? Namely, this analysis (and hence result) could be related back to the limitation of the spontaneous ventilation and apnea situation during their anesthesia.

2. Could the authors discuss the applicability of this approach to children with developmental disabilities undergoing surgery.

Reviewer #2: - the primary outcome is not clearly described. At first reading, it seems to be the risk of SpO2 of 95% within a 5 minute period (indeed the sample size calculation is that for estimating a risk/proportion). However, reading the manuscript it is repeatedly referred to as hazard of the outcome, implying that the outcome is a time-to-event. The authors need to clarify this.

- the units and resolution of measurement of the outcome T1 is not clear: was it measured down to the second or was it also measured in 30 second increments?

- if the primary outcome is a risk/proportion, then the sample size calculation is not sufficiently described as it does not include the 'baseline' risk of the outcome; this should be included along with a citation to support it. It is also not clear whether the 50% risk reduction proposed is an absolute or relative reduction. However, if the outcome is time-to-event, then the sample size calculation is incorrect, because other than including the hazard of the outcome in the 'baseline' group, it must also include some determination of the expected number of events.

- for the descriptive analysis the authors should follow standard reporting for randomised trials, where the mean and SD for continuous baseline variables or counts and proportions for categorical baseline variables be presented by treatment arm without statistical tests comparing the arms.

- if the primary outcome is a risk within a defined time period (5 minutes) therefore describing it as a hazard and estimating hazard ratios comparing the treatment arms for this outcome is not appropriate. It is however appropriate for the secondary outcome T1 (and perhaps T2).

- the results for the three outcomes should be tabulated in the standard reporting format for a clinical trial i.e. including the event numbers and denominators per group, risks/hazards/rates as appropriate and their ratios, confidence intervals and p-values.

- please indicate whether the trial protocol submitted with this manuscript was published before the analysis was undertaken, as I am not able to determine that.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-20-33942R1

Continuous positive airway pressure to reduce the risk of early peripheral oxygen desaturation after onset of apnoea in children: a double-blind randomised controlled trial

PLOS ONE

Dear Dr. dos Santos Neto,

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.

As academic editor, I agree with the assessment of the reviewers and I am happy to transmit their Overall positive evaluation. Now, we ask you for carefully addressing their comments, because they can be important for improving your mansucript.

Please submit your revised manuscript by May 09 2021 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: http://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,

Thomas Penzel

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 #2: (No Response)

Reviewer #3: All comments have been addressed

Reviewer #4: (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 #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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 #2: Yes

Reviewer #3: Yes

Reviewer #4: 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 #2: Yes

Reviewer #3: Yes

Reviewer #4: 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 #2: Abstract: in the third-from-bottom line, please report the exact p-value instead of p<0.05 unless it is very small e.g. p<0.001.

Introduction: given your response to the previous round of reviews, it is not correct to say that you measured SpO2 every 30 seconds as indicated in the last paragraph of the introduction; perhaps it is just better to say that you measured time to recovery of pre-apnoea SpO2 levels. (The way this has been described in the paragraph in the methods just above 'statistical analysis' seems fine though.)

Methods:

- similar to the comment above, given your response it is misleading to say in the 'materials and methods' section that you recorded SpO2 values every 30 seconds, if you were continuously checking SpO2 to determine the actual time in seconds to recovery to pre-apnoea levels, unless you were doing this in 30-second increments, which you have indicated in the response that you were not doing.

- indicating the number of children in the first line of materials and methods is actually a non-standard reporting practice, as this is actually a result. It would have been sufficient to say 'we conducted a randomised double blind controlled parallel group trial in children undergoing surgery at...'

- the methods also need to describe the treatment received by the control group. You could add this immediately after describing the intervention, just before where you describe the recruitment in the surgical wards.

- the description of the sample size calculation is still incomplete and not reproducible. Now that it is clearer that this was a time-to-event outcome, for 80% power to detect a 50% relative reduction in hazard you would expect to observe 66 events (this is not the sample size); however your sample size calculation should further indicate what the expected proportions remaining event-free at 300 seconds, given that the sample size would be obtained by dividing the expected number of events by [1 - ((S1+S2)/2)] where S1 and S2 are the proportions in the control and intervention groups respectively that remain event-free at 300 seconds. If under standard care S1 participants remain event free at 300 seconds, then for a relative reduction in hazard of 50%, S2 = S1 x exp(0.5). S1 should have been determined based on information available before this study.

- it is unclear where the chi-squared tests, Fisher's exact test, students t-test etc referred to in the statistical methods were applied. In any case, they don't appear to be necessary at any stage of the analysis.

- what you report in the methods regarding the test for normality is actually a result; instead it would have been sufficient to indicate here that for continuous measures, the test for normality was conducted and you reported means and SDs of normally distributed variables or medians and IQRs for non-normal quantities - without alluding to the results of this test.

Results

- the key to figure 3 doesn't enable the reader to distinguish between the intervention and control group.

Reviewer #3: The authors answered all comments correctly.

I've only some minor comments:

A) Method section: The authors should specify whether children with genetic syndromes, acute and chronic cardiovascular and neurological diseases were included or excluded from the study.

B) page 11: please correct the following sentences:

-"Fig 2 shows the plots of Kaplan-Meier curves for groups CPAP and Control" with "Figure 2 shows the Kaplan-Meier curves for the CPAP and control groups"

-"between-group with between groups"

Reviewer #4: The authors present a revised manuscript on the effects of apneic CPAP after general anesthesia induction in children, concluding that the use of CPAP can prolong time to desaturation. While these results are not surprising, they do highlight that post-induction CPAP may be underutilized in pediatrics and provide a nice literature review in the discussion on pre-intubation CPAP use in pediatric and adult anesthesia.

The article is well-written and has been edited for language and grammar since the prior version, although still contains some grammatical and syntax issues and would benefit from English language editing. I have attempted to highlight some of these below but my suggestions are by no means complete.

The study is well-designed and controlled, appearing to be scientifically sound. The concerns of the prior reviewers seem to have been adequately addressed. Regarding point #9 on power analysis, as any change to the power calculation would be a posteriori I would recommend still reporting the calculations that were performed a priori. If the authors wish to include an additional a posteriori calculation based on the reviewer recommendations to demonstrate the true power of the study, I would suggest stating exactly what happened: the study population size was based on the a priori calculation, but a posteriori a second analysis was performed based on feedback that the initial assumptions required adjustment, and this analysis revealed the study was powered at X% to detect Y difference, or something to that effect.

Specific comments:

Abstract: as a result of deletions, T1 is no longer defined in the abstract, but T2 is. The T1 definition can be appended to the sentence about the primary outcome.

P7 third paragraph: by ‘cardioscopy’ do you mean electrocardiogram?

P7 third paragraph: if 60% fraction was oxygen, was the rest nitrogen gas (room air)? This should be stated.

P8 first paragraph: change ‘halt’ to ‘halted’

P11/Figure 3: why does the control group return to a non-significant difference at 240 seconds? Is this due to patients in the control group getting bag mask ventilation due to falling saturations (post T1 measurement)? If so this figure is misleading and the more appropriate analysis would be to look at only patients who had not yet reached the T1 endpoint when comparing the groups.

P13 second paragraph: change ‘define the airway’ to ‘secure the airway’

P13 last word: change overpasses to surpasses

P14 second paragraph: you state that other studies ‘[show] improvements in outcomes by the use of positive pressure’. Is there definitive evidence that outcomes are improved with CPAP? I can see reduced rates of transient hypoxia during apnea, as you have shown here, but I don’t believe there is evidence that meaningful case outcomes such as postop oxygen requirements, reintubation requirements, etc. are reduced. Thus I would recommend defining what outcomes, if any, are improved.

P14 third paragraph: change ‘being one’ to ‘one being’

P14 third paragraph: change ‘showed’ to ‘shown’

P14 fourth paragraph: change ‘hold the small airways opened’ to ‘prevent atelectasis’

P15 first paragraph: I would change the word ‘threatening’ to something else, maybe ‘the impairment of these factors may predispose patients to harm’ or delete the whole sentence

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Reviewer #2: No

Reviewer #3: No

Reviewer #4: 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.]

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PONE-D-20-33942R2

Continuous positive airway pressure to reduce the risk of early peripheral oxygen desaturation after onset of apnoea in children: a double-blind randomised controlled trial

PLOS ONE

Dear Dr. dos Santos Neto,

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.

We are happy with your revision. However some very few, but important comments remain to be answered. We look forward for a good statistical treatment of these concerns.

Please submit your revised manuscript by Aug 23 2021 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: http://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,

Thomas Penzel

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.

[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 #2: (No Response)

Reviewer #4: 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 #2: Yes

Reviewer #4: Yes

**********

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

Reviewer #2: Yes

Reviewer #4: 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 #2: Yes

Reviewer #4: 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 #2: Yes

Reviewer #4: 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 #2: The authors have responded very well to previous comments. There is still one issue that the authors need to revisit. The sample size calculation is still insufficiently described. First, I would recommend that the authors include a reference to the Schoenfeld’s procedure which they used in the original sample size calculation, and also state the parameters/assumptions that went into the calculation. In the 'revised' calculation which is included in the authors' response to previous comments, the formula is incorrectly applied, specifically where the authors divide S2 by 2 (the correct application is to first sum up S1 and S2 and then divide this sum by 2; the result of this calculation is then subtracted from 1; and finally, the result of this second part of the calculation is multiplied by the expected number of events (i.e. 66 expected events for 50% relative reduction at 80% power) to obtain the overall sample size. Also, please refer to the sample size calculation as such, and not 'study population size'.

In response to previous reviews, the authors removed mentions of chi-squared tests, Fisher's exact test, students t-test etc. Mentions of Shapiro–Wilk test should also be moved. A reference to the Benjamini–Hochberg procedure should also be included, along with a brief explanation of how it adjusts the p-value to avoid type 1 error.

Reviewer #4: (No Response)

**********

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 #2: No

Reviewer #4: 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.]

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

Continuous positive airway pressure to reduce the risk of early peripheral oxygen desaturation after onset of apnoea in children: a double-blind randomised controlled trial

PONE-D-20-33942R3

Dear Dr. dos Santos Neto,

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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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 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,

Thomas Penzel

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: