PONE-D-23-36879A randomised, controlled, feasibility trial comparing vasopressor infusion administered via peripheral cannula versus central venous catheter for critically ill adults: a study protocolPLOS ONE

Dear Dr. Ramanan,

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 correct identifying number

- Please explain in the manuscript why you exclude patients who “are requiring >0.1mcg/kg/min of Noradrenaline or equivalent at the time of screening”

- How many patients are included today (1 patient per week with start in November 2022 = 52 patients at that time…)

- Please give more details about how Norepinephrine infusion will be prepared? (electrical syringe? elastomeric pump?) How changeover will be performed?

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Academic Editor

PLOS ONE

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 [• Emergency Medicine Foundation (Australasia) Queensland Program Grant ID: EMJS-411R37-2022-HOLLAND 

• The Prince Charles Hospital Foundation CKW-2022-02• The University of Queensland: Mayne Academy of Critical Care Pilot Grant].  Please state what role the funders took in the study.  If the funders had no role, please state: ""The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."" If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 3. Please provide a complete Data Availability Statement in the submission form, ensuring you include all necessary access information or a reason for why you are unable to make your data freely accessible. If your research concerns only data provided within your submission, please write "All data are in the manuscript and/or supporting information files" as your Data Availability Statement. 4. Please include the reference section of your manuscript. 5. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript. 

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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: Yes

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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: Partly

Reviewer #3: Yes

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

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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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: No

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: No

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: As far as I'm concerned, there's no major problem with the way this article has been written.

Except for two points:

- 1 It seems to me very important to add to the section "2.5 Interventions", as stated in the protocol, the criteria for waiving the delayed insertion of a CVC. Without these details, patient safety conditions do not seem to be met within the framework of this protocol.

"iii. A CVC can be inserted earlier than 12 hours if required for the following reasons:

▪ Noradrenaline-equivalent dose ≥0.2mcg/kg/min,

▪ Need for irritant medications/infusions that cannot be administered via a PIVC,

▪ Failure of drug delivery via PIVC,

▪ Complications of PIVC including extravasation of VPI, or tissue necrosis."

- 2 There is a spelling error in the "2.5 Interventions" section:

20-guage size, preferably 18-guage, it's gauge and not gauge

And finally, the conclusion seems a bit rushed to me, even though it perfectly sums up the idea of this research project.

Reviewer #2: Thanks for inviting me to review this reasibility RCT protocol on peripheral vs central vasopressors at a single institution. The manuscript is reasonably well written, however there are stylistic and language errors throughout, and even a few spelling mistakes, and I encourage the authors have a closer read of the text.

My main concern is the primary clinical outcome, which is DAOH-30. Given that both arms will be receiving vasopressors, I'm not sure that there will be a meaningful difference in this outcome, even if this study is extended to a Phase 3 trial. Both arms will have pressors titrated to effect, so would it not make sense for the primary clinical outcome to be something that will generate more clinical difference? eg safety-related complications

Furthermore, there is insufficient details regarding the safety monitoring of PIVCs, which is fundamentally the key concern with PIVC vasopressors. This needs to be protocolised, and has not been well detailed in this manuscript. Details re complication monitoring/definitions are also sparse.

Some limited minor issues:

Abstract

- RC is likely to mean to be RCT

Introduction

- citation 4 is described as a systematic reivew yet this appears to be an editorial??

- Citation 7 is also described as a SR yet this is a single institutional review (as per the title)

- 'Although administration of vasopressor infusion via a PIVC is not associated with increased morbidity it can lead to complications' - I would argue that this is contradictory - I understand what the authors presumably mean (ie infusion of vasopressors through a peripheral vein via patent non-extravasated PIVC is not associated with increased morbidity), but I would contend that administration of PIVC vasopressor is a holistic process, and the risk of extravasation should be counted as morbidity associated with vasopressor infusion. I would suggest rephrasing this sentence

Methods

- the ANZCTR registration number is wrong.

- statistical plans re early terminination by the DSMC should be detailed

- details re PIVC monitoring need to be included and standardized. What about USS insertion of PIVC? Long PIVCs? Is there a need to confirm PIVC patency via flushing etc? These are important protocol details and should be outlined. Also gauge is spelt wrong.

Reviewer #3: Your article provides a comprehensive overview of the VIPCA feasibility trial, addressing the pertinent issues surrounding vasopressor administration through peripheral intravenous catheters (PIVCs) versus central venous catheters (CVCs). The protocol is meticulously detailed, outlining the trial's design, methods, and objectives. The language is predominantly formal, which suits the scientific context but could benefit from occasional simplification for broader accessibility.

The study's significance is well articulated, emphasizing the potential impact on clinical practices and healthcare systems. The strengths and limitations are candidly discussed, with acknowledgment of the trial's small sample size limitation. Overall, the document serves its purpose of detailing the VIPCA trial while providing room for some language refinement for enhanced clarity and accessibility.

The article's strengths lie in its emphasis on the need for a randomized controlled trial (RCT) and the acknowledgment of confounding factors in retrospective analysis.

The comprehensive patient exclusion criteria are highlighted, but further clarification is needed for certain aspects. Feasibility outcomes are briefly discussed, yet a more elaborate rationale for each criterion would enhance understanding. The challenge of blinding is acknowledged, and suggestions for mitigating biases could be explored. The economic analyses section, while mentioned briefly, needs expansion to address the trial's potential impact on healthcare costs and its role in shaping the Phase-3 RCT design. Overall, refining these aspects would strengthen the article's clarity and provide a more robust foundation for the VIPCA trial.

Specific Comments from Reviewer to Authors:

Page 7 Line 139:

- Consider specifying the publication date or version of the SPIRIT statement

Page 7 141-142:

- Ensure consistency in spelling: "Metro North Hospital" or "Metro North Hospital and Health Services Office."

Page 7 147-151:

- Specify the anticipated duration of the trial.

Page 7 150:

- Clarify if Caboolture Hospital is part of Metro North Hospital and Health Services.

Page 10 204-206:

- Specify the reason for the minimum 20-gauge size for PIVCs, and why 18-gauge is preferable.

Page 10 211-221:

- Clarify whether the feasibility outcomes will be measured independently or in combination.

Page 10-11 222 – 246:

- For clinical outcomes, consider providing information on how the outcomes will be measured (e.g., instruments used for PROMs/PREMs).

Page 14 325-329:

- Specify the estimated duration of the trial.

Page 14 331-337:

- Specify the types of vasopressors considered for clarity.

Page 14-15 Lines 338-362:

- To enhance clarity, specifying the patient population that stands to benefit most from reduced CVC use would be valuable.

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Reviewer #1: Yes: Julien Le Roy

Reviewer #2: No

Reviewer #3: Yes: Joseph Varon MD

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A randomised, controlled, feasibility trial comparing vasopressor infusion administered via peripheral cannula versus central venous catheter for critically ill adults: a study protocol

PONE-D-23-36879R1

Dear Dr. Ramanan,

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,

Jean Baptiste Lascarrou

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 #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 #3: Yes

**********

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

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

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 #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 #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 #3: Thank you for addressing my queries.

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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 #3: Yes: Joseph Varon, MD, FACP, FCCP, FCCM, FRSM

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