PONE-D-20-03375

Progressive active mobilization with dose control and training load in critically ill patients (PROMOB): protocol for a randomized controlled trial

PLOS ONE

Dear Dr. Queiroz,

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. Please note that the methods, mainly in terms of the intervention details to explain the progressive nature of the exercise protocol, and detailed methods that allow reproducibility. In addition, a stronger rationale should clarify why strict mobilization protocols are needed in ICU given the high variability of possible conditions in such setting. Also, a proper contextualization with previous but also current literature is needed, as the reviewers noted in the comments and recommendations the authors may see below in this email.

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We look forward to receiving your revised manuscript.

Kind regards,

Jose María Blasco, Ph.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

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 #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I will focus on methods and reporting. Level of English needs to be improved but it is not bad enough to prevent publication. The abstract is informative and balanced. Randomisation is appropriate. The description of the standard treatment and the intervention is clear.

I was confused by the description of the primary outcome: "The primary outcome will be ICU stay at 28 days after randomization or discharge from the ICU, whichever occurred earlier". If I understand this correctly, the outcome is binary, status at +28 days (discharged or not). The way it is phrased I find confusing.

There are perhaps too many secondary outcomes for such a small sample, and there is a risk that something will be statistically significant by chance. So i'd urge the researchers not to make too much of the analyses of secondary outcomes and to focus on effect sizes rather than p-values.

Power calculations are OK but hospital stay is not normally distributed. So using a normal approximation for the power calculation has its issues (e.g. see https://www.sciencedirect.com/science/article/pii/S1098301517301298). Not that it's the end of the world so I'll leave to the authors to revisit if they feel they need to. Otherwise acknowledge as a limitation (the normality assumptions). Also doesn't really match the outcome, which is binary(?), unless i completely misunderstood it. Finally, I can't see the baseline level there which is needed to put into context the size of the hypothesised effect of the intervention. If on average stay is 10 days, then this is a massive effect, for example.

Analysis plan is appropriate, but make sure methods assumptions are met, e.g. proportional hazards for Cox. Again, I'm not clear exactly what the primary outcome is and hence what is the relevant analysis. If the outcome is LOS, why not use a Poisson or negative binomial model, for example.

Another concern is that the sample is relatively small. Are the authors confident balance will be achieved on all covariates of interest or a more deterministic matching approach is needed?

Reviewer #2: The topic related to the presented protocol is relevant but not new. Authors describe their single-centre trial design to evaluate the effectiveness of progressive early mobilization process in ICU.

Recently another group from Sao Paulo-Brazil have published similar data on a progressive protocol applied to ICU-patients (see Stripari et al. Crit Care Med 2020; 48:491–497)

Authors of the present submission should be therefore quote this last evidence from literature and very well explained which is the substantial difference between protocols and, moreover, what is expected from their trial as compared with the already published evidences and results.

Reviewer #3: I thank the authors for the opportunity to review this trial protocol. The authors plan to test a progressive mobilization intervention for critically ill patients in ICU. There are several strengths of this protocol, including:

-prospectively registered

-adheres to the SPIRIT statement

-important endpoints (LOS, ICUAW, Days with mechanical ventilation, Mortality)

-plan for allocation concealment and intention to treat

-plan for blinding of assessors

However, despite these strengths, I have several concerns about the rationale and intervention that need to be addressed.

Finding the 'optimal training scheme' for ICU patients seems to be a key rationale for this trial. I find this problematic. I imagine trying to find the optimal loading protocol for patients in ICU would be extremely difficult given the range of conditions/presentations. In this setting, wouldn't tailoring mobilisation to a patients level of function be more important than trying to find the optimal dose for everyone? This might be the reason guidelines don't specify an exact loading protocol for critically ill patients in ICU.

After reading the methods, it seems the progressive active mobilisation intervention will be 'added' to usual care, which means participants in the intervention will receive a greater volume of treatment/mobilisation than participants in the usual care group. If the intervention is effective, how will the researchers determine that the improvement was due to the protocol or simply due to additional treatment time?

If I have misunderstood the protocol, how will you control for treatment time between groups?

Looking at Figure 1, I am unsure how the intervention would be sufficiently different to usual care. Wouldn't all therapists gradually increase the intensity/volume of mobilisation for patients in ICU? Whether they do it intentionally, therapists will usually start by prescribing bed exercises and gradually build up to walking and then walking up stairs. I am concerned there wont be enough contrast between the groups to show something meaningful. Again, apologies if I have misunderstood the protocol.

Other comments:

LOS is missing from aim at the end of the introduction

I am unsure biceps brachii cross-sectional area would be the most important upper limb muscle to assess. I imagine loading through the arms (e.g. during sit to stand or during mobilisation in a frame) would cause more adaptations in the triceps than biceps (due to the extension moment arm of these activities)

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Josh Zadro

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Progressive active mobilization with dose control and training load in critically ill patients (PROMOB): protocol for a randomized controlled trial

PONE-D-20-03375R1

Dear Dr. Queiroz,

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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Kind regards,

Jose María Blasco, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

Reviewer #3: 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 #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I am happy with the changes the authors have made and their responses. Perhaps more of what was discussed could have made it into the paper, but I'll leave to the authors to decide that. As long as they pay attention to the methodological issues raised, it will be fine.

Reviewer #2: Authors have satisfactorily responded to my query and concern, also they updated refs as suggested in their revised version.

Reviewer #3: I am satisfied with the authors response to my concerns. I was initially concerned about the originality of this piece of work and whether there was enough contrast between the intervention and control group. The authors have highlighted the need for trials to adequately report their exercise protocols and the challenge of testing exercise interventions when usual care involves exercise. Their response highlights an in-depth understanding of their field and the need to test clearly defined protocols. I am happy for this protocol to be published and wish the authors the best of luck with their trial.

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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 #2: No

Reviewer #3: Yes: Joshua Zadro