PONE-D-23-05624Severe fluctuation in mean perfusion pressure is associated with increased risk of in-hospital mortality in critically ill patients with central venous pressure monitoring: a retrospective observational studyPLOS ONE

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Additional Editor Comments:

The reviewers had mixed reactions to the manuscript but I am prepared to see a revised version. Please be sure to address the reviewer concerns in detail.

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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: Yes

Reviewer #3: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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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

Reviewer #3: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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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: Thank you for the opportunity to review the manuscript, entitled “Severe fluctuation in mean perfusion pressure is associated with increased risk of in-hospital mortality in critically ill patients with central venous pressure monitoring: a retrospective observational study” It is well written and important points are clearly presented. I have the following questions and comments to the authors.

1) It seems that the authors focused on MPP-CV as a primary exposure, but there were many sensitivity analyses that may distract readers. For example, MPP-VIM was equally reported as if it is a primary exposure. All sensitivity and subgroup analyses should be concisely summarized in the sensitivity and subgroup analysis section of the results. Can the authors choose a few important sensitivity and subgroup analyses?

2) Can the authors clarify how MPP was obtained by showing an equation? Some readers may not be familiar with it.

3) The patient characteristics were not clear. The e-ICU data includes heterogenous patients. How many patients were elective admission? How many patients underwent cardiac and non-cardiac surgery? Can the authors adjust for them in the regression analysis?

4) Line 151: Was TWA-MPP adjusted? Why?

5) Line 177: This would not be an external validation. When it comes to external validation, a newly developed prediction score is going to be tested in a different dataset. If the authors can obtain the same information from MIMIC-III, two databases can be combined into one dataset.

6) In this study, looking at ICU mortality would be less important.

7) Line 161: Why daytime and nighttime MPP-CV was measured? Please clarify.

Reviewer #2: The present manuscript is an interesting study in which the authors use a large, multicenter eICU database (with external validation database) to analyze whether the coefficient of variation (CV) of mean perfusion pressure (MPP) (MPP-CV) over 24hrs within first 72hrs of ICU stay correlated with in-hospital mortality. They determined the median MPP-CV for the 2 databases. They also found that patients with high MPP-CV (especially >19%) had higher OR of in hospital mortality. They used a variety of secondary and subgroup analyses to confirm the robustness of their primary finding. They concluded that targeting fewer MPP swings in patients (~20% of average MPP) could be target for therpies. Overall, the topic is important, the manuscript is well-written, data analysis methods overall appear solid, and the findings are significant. Please see comments below for issues that should be addressed.

General comments:

1. Why were patients with CKD5 excluded? No justification is given. The authors should justify exclusions.

2. For exclusions, what does “extreme MPP were excluded” mean? The authors need to specify.

3. What were variables in multivariable model and how were they chosen?

4. Why did the authors pick MPP-CV < or > 12% as a cutoff? Justification is not given in methods though presumably due to median of MPP-CV of 12.3% in whole dataset?

5. Were any analyses pre-specified? This should be indicated in methods.

6. Why did the authors not include hypertension or baseline blood pressure in the model? This seemingly could be a major confounder as patients with hypertension would likely have wider swings in blood pressure. They do account for this in subgroup analysis, but curious why it was not included in the original model? Is this what anti-hypertension drug refers to in the figure legend? The authors should clarify.

7. Did the authors analyze any secondary outcomes? Presumably they have information regarding outcomes such as AKI, mechanical ventilation, etc. These would be meaningful additions.

Reviewer #3: The authors submit a manuscript describing a retrospective analysis of large database of critically ill patients having invasive monitoring. The focus was on mean-perfusion pressure variation (MAP-CVP) and mortality. The found that the average coefficient of variation the first 24 hrs of ICU admission was higher in non-survivors versus survivors. The highest decile of MPP CV was independently associated with mortality.

The topic of this paper is clinically interesting and consistent with other reports. I have a few comments.

1. It would be helpful for the readers to have an understanding of the unique aspects of the question of this study. That is, what new questions the study asks. They mention that there is knowledge that MPP variation is associated with adverse outcomes then how does this paper add to this body of knowledge? Interestingly, there are other data not references showing that fluctuations in BP in patients undergoing surgery is associated with adverse events (I believe the first author was Aronson, S). They did not address MPP to my knowledge.

2. Page 5 in the Methods section line 112: Readers may want to know how you defined extreme MPP data.

3. Page 6, lines 164-165: how did you decide to categorize high and low variability as MPP 12%?

4. An entrance criteria of having both direct blood pressure and CVP present may limit the external validity of the study when those measures are not present. That is why the readers need to know the reason for exclusion from analysis. One wonders what the added value of MPP versus MAP alone might be in the predictive modeling. While I agree with the rationale for MPP is there useful data on MAP CV alone? We do not know if the relationship found in this study is due to reduced perfusion per se versus just MAP or the factors that cause MAP variation. How do we know as an example this is not simply due to HFpEF? Those patients have high variability due to diastolic dysfunction.

5. Lines 292-293. MAP is the product of cardiac output and SVR. MPP is MAP -CVP.

6. Lines 350-351: Making as statement that MPP should be targeted as a means to improve outcome is not really warranted based on these data.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Severe fluctuation in mean perfusion pressure is associated with increased risk of in-hospital mortality in critically ill patients with central venous pressure monitoring: a retrospective observational study

PONE-D-23-05624R1

Dear Dr. Mao,

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,

Karthik Raghunathan

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Congratulations!

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 #2: 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: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: 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 #1: Yes

Reviewer #2: 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

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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 #2: The authors have adjusted language and supplied additional data. Authors have satisfactorily responded to my critiques.

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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

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