-->PONE-D-26-00828-->-->Supplementation of calcium, magnesium, phosphate, and potassium in critically ill patients: a multicenter cohort study-->-->PLOS One

Dear Dr. Yarnell,

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 submit your revised manuscript by Mar 25 2026 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,

Mohammed S. Razzaque, MBBS, PhD

Academic Editor

PLOS One

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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

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

Reviewer #1: Yes

Reviewer #2: 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: No

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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: Thank you for the opportunity to review the manuscript, entitled “Supplementation of calcium, magnesium, phosphate, and potassium in critically ill patients: a multicenter cohort study.” This manuscript addresses an important issue in critical care: hospital-level variation in electrolyte supplementation practices among critically ill patients. However, several clinical and methodological issues require clarification to improve interpretability and clinical relevance. I have the following questions and comments to the authors.

Major comments.

• The manuscript does not adequately address the underlying causes of abnormal electrolyte levels (e.g., sepsis, gastrointestinal losses, diuretic use, nutritional status, acid–base disorders). Without this context, it is difficult to interpret whether observed supplementation practices reflect appropriate responses to reversible conditions or empiric replacement. Can the authors discuss whether such factors were available in the database?

• Patients with acute or chronic renal failure were excluded, but the definitions are not sufficiently detailed.

• The manuscript references mechanical ventilation in the discussion, yet the proportion of patients receiving mechanical ventilation in the cohort is not reported. Can the authors look at the frequency of mechanical ventilation?

• The cohort likely includes a heterogeneous mix of medical and surgical ICU patients. Please look at medical vs surgical admissions, and the number of patients undergoing major surgeries, such as cardiac or abdominal surgery

• Can the authors please clarify whether admissions were elective or emergent?

• Sodium is a commonly monitored and clinically important electrolyte in ICU patients. Can the authors justify why sodium was excluded from the analysis?

• It is unclear why congestive heart failure (CHF) was not included among reported comorbidities, given its association with electrolyte abnormalities and supplementation decisions. Related to this, how the term “cardiac arrhythmia” in table 1 was identified?

• The manuscript lists “fluid and electrolyte disorders” as a comorbidity in table 1. Please clarify: 1) How this variable was defined (ICD codes?), 2) Whether it overlaps with the electrolyte abnormalities measured in this study, and 3) Whether inclusion of this variable risks circular reasoning or misclassification bias.

Reviewer #2: The manuscript provides valuable descriptive data on electrolyte supplementation practices across U.S. ICUs, but its conceptual framing is limited by a narrow focus on serum values and it is not clear how supplementation was adminstered, nor if it included dietician prescribed medical nutrition therapy. The study does not provide sufficient details of the role of physiologic mechanisms that drive electrolyte abnormalities in critical illness, nor does it acknowledge that serum concentrations are poor proxies for tissue concentrations. For example, hypophosphatemia is common in hospitalized patients due to a shift of phosphate into tissue. Notably, the omission of sodium — the most commonly administered electrolyte and a major driver of iatrogenic harm from intravenous saline — further limits the comprehensiveness of the analysis. Indeed, hyponatremia is often misdiagnosed in hypervolemic conditions in which sodium concentrations are diluted by excessive fluid retention. The complex interaction of sodium levels with hypokalemia is also important. Furthermore, the paper treats supplementation as benign and does not sufficiently focus on their potential adverse effects associated with aggressive dosages. Overall, the paper would benefit from a more physiologically grounded discussion of the well-documented pathophysiological causes related to electrolyte dysregulation and a clearer acknowledgment that supplementation practices only superficially target serum numbers rather than underlying pathophysiology. Such a grounded discussion could eventually contribute to correcting the identified inconsistencies in supplementation practices in ICUs. Finally, the authors call for randomized controlled trials, but such clinical designs make little sense without a more comprehensive understanding of the underlying causative factors that disturb electrolyte homeostasis in critically ill patients.

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Reviewer #1: No

Reviewer #2: No

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-->PONE-D-26-00828R1-->-->Supplementation of calcium, magnesium, phosphate, and potassium in critically ill patients: a multicenter cohort study-->-->PLOS One

Dear Dr. Yarnell,

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 submit your revised manuscript by May 23 2026 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 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.

As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only  the individual author can complete the verification step; PLOS staff cannot  verify ORCID iDs on behalf of authors.

We look forward to receiving your revised manuscript.

Kind regards,

Mohammed S. Razzaque, MBBS, PhD

Academic Editor

PLOS One

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

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.

Additional Editor Comments (if provided):

Please explain why sodium assessment was not included in the study and highlight it as a potential limitation.

[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 #1: (No Response)

Reviewer #2: (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 #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: 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 #1: Yes

Reviewer #2: 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: 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 #1: I appreciate the authors’ explanation for excluding sodium; however, I remain concerned that this omission limits the completeness of a descriptive study of electrolyte management in the ICU. Hyponatremia is common and clinically important in critically ill patients, and its correction—particularly in moderate to severe cases—reflects active management decisions and likely inter‑hospital variation, even if not protocolized in the same manner as other electrolytes. Inclusion of sodium would enhance the clinical relevance of the study.

Reviewer #2: Regarding sodium in Comment 11:

The authors' rationale for excluding sodium requires correction. The manuscript states:

“Sodium was not included because it is generally not supplemented based on the serum level…”

This is inaccurate. In ICU practice, serum sodium is routinely monitored and sodium is supplemented accordingly—most commonly through intravenous fluids such as normal saline. Thus, the current wording implies a misunderstanding of standard electrolyte management.

Please revise to clarify that sodium was excluded not because it is rarely supplemented, but because its supplementation is embedded within fluid management rather than ordered as a discrete electrolyte replacement, and therefore falls outside the scope of the present analysis of discretionary supplementation.

Regarding Comment 23:

The response does not fully address the broader point that electrolyte supplementation in ICU patients is influenced by interactions with other supplements, dietary factors, and concurrent medications. These interactions can generate clinical harm or interfere with medical treatments. The manuscript should note that future studies should examine these supplement interactions, as they represent a potential source of adverse effects in electrolyte management.

Regarding Comment 25:

The authors’ made no response to acknowledge a central limitation of electrolyte supplementation which often treats superficial serum fluctuations without addressing the underlying homeostatic disturbances that generate them. A brief acknowledgment of this limitation is needed along with a call for further investigations of pathophysiology mechanisms associated with electrolyte dysregulation. Clinical trials and observational studies alone cannot address the need for basic research in this area.

**********

-->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

**********

[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.]

To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

-->

Supplementation of calcium, magnesium, phosphate, and potassium in critically ill patients: a multicenter cohort study

PONE-D-26-00828R2

Dear Dr. Yarnell,

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,

Mohammed S. Razzaque, MBBS, PhD

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments: