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. 2024 Aug 8;19(8):e0308000. doi: 10.1371/journal.pone.0308000

Impact of electrolyte abnormalities and adverse outcomes in persons with eating disorders: A systematic review protocol

Amos Buh 1,*, Mekaylah Scott 1,2, Rohan Kiska 1,3, Stephen G Fung 4, Marco Solmi 1,5,6,7, Rachel Kang 1,2, Maria Salman 1,8, Kathryn Lee 1,9, Benjamin Milone 1,9, Gamal Wafy 1, Sarah Syed 1,8, Shan Dhaliwal 1,8, Maya Gibb 1, Ayub Akbari 1, Pierre A Brown 1, Gregory L Hundemer 1, Manish M Sood 1,10
Editor: Muhammad Shahzad Aslam11
PMCID: PMC11309401  PMID: 39116070

Abstract

Background

Electrolytes (sodium, potassium, calcium, magnesium, chloride, phosphate) are required in specific amounts for proper functioning of the human body. Although the body has different organ systems, such as the kidneys, that regulate electrolyte levels in the blood, electrolyte abnormalities occur frequently in people with eating disorders. The objective of this review will be to examine the association between electrolyte imbalances and adverse outcomes in people with eating disorders.

Methods

A systematic review of studies on eating and electrolyte disorders shall be conducted. Electronic searches shall be done in the Ovid MEDLINE, EMBASE, and PsycINFO databases. Selected studies shall include randomized control trials (RCTs), non-randomized controlled trials, and cross-sectional studies published in English or French. Quality appraisal of studies and a narrative synthesis of extracted data shall be conducted.

Discussion

This review will synthesize existing evidence on electrolyte abnormalities in people with eating disorders. It will identify the type of electrolyte imbalances, their impact, and outcomes in people with eating disorders. We anticipate that information that will be useful to policy makers and clinicians in designing better policies to prevent eating disorders and or manage people with eating disorders shall be elucidated in this study.

Dissemination

The final manuscript will be submitted for publication in a journal.

Review registration

This protocol has been registered with the International Prospective Register of Systematic Reviews (PROSPERO); registration number CRD42023477497.

Background

Electrolytes are electrically charged molecules which play a number of vital roles in the normal functioning of the human body [1,2]. Major electrolytes found in the human body include potassium, sodium, calcium, magnesium, phosphate, chloride and bicarbonates [3,4]. Their extracellular concentrations in the body can be measured by blood tests which help in the assessment of a patient’s clinical condition–an abnormally high or low level of electrolytes can disrupt body functions and can lead to life-threatening complications [2,3].

Evidence suggests that electrolyte imbalances (abnormally high or low levels of electrolytes falling outside the normal ranges or reference intervals) are associated with increased morbidity and mortality [5]. The causes are multifactorial and include physiological factors such as nutritional status, concurrent acid-base imbalances, pharmaceuticals, other co-morbid disorders or acute illnesses [1,5]. Besides these, refeeding syndrome (when someone who has been malnourished or starved begins feeding again) is a major causes electrolyte deficiencies [6–8]. The prevalence of electrolyte abnormalities have been reported to range between 15.0% to 44.1% [2,9,10]. The abnormalities are common among older community subjects and are mainly associated with diabetes mellitus and diuretics [9].

Nonetheless, despite advances in medicine, electrolyte abnormalities remain widespread and are also very commonly observed in persons with eating disorders [11]. Eating disorders such as bulimia nervosa and anorexia nervosa are disturbances in eating behaviors that compromises a person’s health and impairs normal functioning [12]. Eating disorders often result in electrolyte abnormalities. Furthermore, some purging behaviors leading to electrolyte imbalances includes severe restriction of food, food binges, over exercising, and even activities such as forced vomiting, fasting, taking laxatives or diuretics, and performing enemas [10,11]. Some of the most common electrolyte imbalances caused by eating disorders include hypophosphatemia, hypokalemia, hyponatremia, and metabolic acidosis and alkalosis [11,13]. In fact, extracellular hypophosphatemia is the most commonly reported electrolyte disturbance resulting from a combination of cellular uptake of phosphorus together with depletion of total body stores during starvation [14–16].

The severity and type of electrolyte abnormalities are dependent on the mode, and frequency of the behaviors of the eating disorder [17]. Some signs and symptoms of electrolyte imbalances in people with eating disorders include constipation, nausea and vomiting, fatigue, heart palpitations or arrhythmias, muscle weakness, cramps, numbness, polyuria, headache, confusion, restlessness and irritability [18]. While complications of eating disorders range from minor to fatal, every organ system can be affected with problems ranging from pancytopenia to diffuse myalgias with muscle breakdown [19]. In fact, eating disorders can impact neurological, cardiac, muscle, gastrointestinal, endocrine and renal functions [11,18,20]. However, it has been documented that electrolyte abnormalities are associated with a host of serious adverse clinical outcomes [12]. For instance, derangements in potassium, magnesium, and calcium levels predispose to cardiac arrhythmias and sudden cardiac death [21]. Derangements in sodium and phosphate levels can result in generalized weakness, cognitive impairment, and seizures [22,23]. Electrolyte disturbances can also have detrimental effects on kidney, gastrointestinal and bone health [24–26]. Nonetheless, there is little or no information on reviews that have comprehensively assessed the impact of electrolyte abnormalities and adverse outcomes resulting from people with eating disorders. The objective of this review therefore shall be to assess the association of electrolyte imbalances and adverse outcomes in people with eating disorders.

Research question

What is the association of electrolyte abnormalities and adverse outcomes in people with eating disorders?

Methods

Study design

This shall be a systematic review of studies that have assessed electrolyte abnormalities in people with eating disorders. The review shall be conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) criteria (S1 File) [27]. A PRISMA diagram (S2 File) shall be used to show how studies shall be selected for this review. The review has been registered with the International Prospective Register of Systematic Reviews (PROSPERO)–number CRD42023477497.

Inclusion criteria

Population

The review shall include studies that involved people with eating disorders irrespective of age.

Exposure

This review shall consider studies that evaluated patients with electrolyte abnormalities.

Controls

The controls will be patients having no electrolyte abnormalities.

Outcomes

This review will consider studies that shall include the following outcome measures:

  • Proportion of hospitalization, worsening eating disorder / worsening mental health condition and relapse among patients resulting from their eating behavior.

  • Proportion of people with delirium, ventricular tachycardia, QT interval prolongation, sudden cardiac arrest, refeeding syndrome, and death resulting from eating disorders related issues.

Types of studies to be included

This review shall include experimental study designs including randomized control trials (RCTs), cohort and cross-sectional studies. Only studies conducted in English or French and involving people diagnosed with eating disorders shall be included in this review.

Search strategy

This review will follow a three-step strategy to find studies conducted on eating and electrolyte disorders. Firstly, an initial search of the Ovid MEDLINE database using an analysis of text words found in the title and abstract, and the index terms used to describe the article shall be conducted. Secondly, identified keywords and index terms in the first step shall be used to search for articles in other databases. Thirdly, the reference list of selected studies from the first and second steps shall be used to look for studies not found in the databases.

The databases that shall be searched for this review will include Ovid MEDLINE, EMBASE, and PsycINFO.

The initial keywords used for the searches in the Ovid MEDLINE database included ‘Electrolyte disorder’, ‘eating disorder’, ‘dehydration’, ‘hypophosphatemia’, ‘hypokalemia’, ‘hypercalcemia’, ‘hyponatremia’, ‘metabolic acidosis’, ‘metabolic alkalosis’, ‘eating disorder hospitalisation’, ‘worsening eating disorder after hospitalisation’, ‘electrolyte disorder hospitalization’ (S3 File). These searches were conducted on March 26, 2024.

Screening and selection process

All articles found in the searched databases will be imported into the Covidence software for screening. Two reviewers shall independently screen titles and abstracts to identify potentially relevant studies. Any disagreements shall be resolved through discussion. This same procedure shall be repeated in screening the full text of studies that shall be retained after the title and abstract screening.

Assessment of methodological quality

Two independent reviewers shall assess the methodological validity of the studies that will be selected for retrieval prior to their inclusion in this review. The assessment shall be done using a standard critical appraisal tool from the Joanna Briggs Institute Meta-Analysis of Statistical Assessment and Review Instrument (JBI-MAStARI) (S4 File). Any disagreements between the two reviewers shall be settled through discussion.

Data extraction

Data shall be extracted from selected studies independently by two reviewers, using a standardized data extraction tool from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review instrument (S5 File). The extracted data will include specific details about eating and electrolyte abnormalities, study populations, study methods and outcomes significant to the review question. In the event of any missing data from a study, the corresponding author of that study shall be contacted to provide the missing data.

Data synthesis

We envision conducting both a meta-analysis and narrative synthesis if we have studies with information that can permit these analyses. The meta-analysis will be done to identify the eating disorders with a significant impact on development of electrolyte imbalances in an individual. For this analysis, we will first assess the statistical heterogeneity with I2, which indicates the percentage of the total variation across studies; where 0% - 40% indicates low heterogeneity, 30% - 60% indicates moderate heterogeneity, 50% - 90% indicates substantial heterogeneity, and 75% - 100% indicates considerable heterogeneity. If there is a substantial amount of heterogeneity (75%), then sources of heterogeneity will be examined through subgroup and sensitivity analyses. We will also use Chi‐square test to test the heterogeneity and consider P-values < 0.05 as statistically significant. We will select a fixed‐effects model for significant homogeneous studies; otherwise, we will apply a random‐effects model. We will summarize our outcomes using odds ratios (OR) and 95% confidence intervals (CI). We will consider an OR<1 to indicate a lower rate of outcome (electrolyte imbalance or abnormality) among the group of participants who had a particular eating disorder. Publication bias will be assessed by visual inspections of funnel plots and Egger’s test.

The narrative synthesis will involve a description of the eating disorders, electrolyte abnormalities and their association as extracted from selected studies. This synthesis shall be structured by describing studies according to type of eating disorders, electrolyte abnormalities and the outcome. The findings shall be presented in tables and figures where possible.

Confidence in cumulative evidence

The quality of evidence in this review will be assessed by the Grades of Recommendation, Assessment, Development and Evaluation (GRADE)[28].

Ethical considerations

No ethics clearance is required for this study as no primary data will be collected. The study will strictly adhere to the procedures outlined in this protocol in reviewing published and unpublished material on the review topic. However, in case of any amendments on this protocol, the amendments will be notified and registered. The final review manuscript will be published in a peer-reviewed journal at the end of this study.

Discussion

This review will synthesize existing evidence on electrolyte abnormalities in people with eating disorders. We acknowledge that some reviews have been conducted on this area though with notable limitations including having varying objectives and being. For instance, a 2016 review was published on the approaches to refeeding in patients with anorexia nervosa. This review, besides being dated, focused exclusively on examining refeeding approaches in patients with anorexia nervosa and included articles published between 1960 and 2015 from the PubMed, PsycINFO, Scopus and Clinical Trials databases [29]. Similar to this, a 2023 review described the different nutritional interventions for children and adolescents with avoidant/restrictive food intake disorders [30]. A 2020 review on eating disorders during gestation described implications for mother’s health, fetal outcomes, and epigenetic changes. This review included articles published between January 2000 and May 2020, but the review’s focus was solely to clarify the mechanisms underpinning the adverse pregnancy outcomes in patients with eating disorders [31]. In yet another review investigating the relationship between weight and risk of medical instability in adolescents with typical and atypical anorexia nervosa, the specific medical instability risks assessed were limited to bradycardia, hypotension, hypothermia and hypophosphatemia and articles were included only from the EMBASE, Medline and PubMed databases [32]. In 2021, a nonstandard review reported common eating disorders in children and adolescent with an overview of treatment strategies [33], and a similar review in 2023 was conducted on renal and electrolyte complications in eating disorders [11]. Finally, a recent review published in 2024, only focused on providing a prevalence estimate of self-reported disordered eating and risk factors in athletes [34]. All of these prior reviews likely missed studies not published in English and those not found in the databases they assessed. More importantly, none of the reviews assessed the association between electrolyte abnormalities and adverse outcomes in people with eating disorders.

Given the limitations of the above published reviews, our review will identify the type of electrolyte imbalances, their impact, and associated outcomes in people with eating disorders.

Strengths and limitations of this review

The major strengths of this review are that it will be a systematic review of randomized controlled trials and observational studies, and it will be the first to synthesize the evidence regarding the impact of electrolyte abnormalities on health outcomes in persons with eating disorders. Nonetheless, the main limitation of this review might be scarcity of randomized controlled trials and observational studies on impact of electrolyte abnormalities resulting from eating disorders, publication bias and methodological quality of the studies that shall be found. Also, there may be heterogeneity in eligible studies and incomplete information reported in included studies which could limit our ability to statistically assess the impact of electrolyte imbalances. However, we anticipate that the findings of this study will generate information that policy makers, clinicians, and stakeholders will find useful in designing better policies or strategies to prevent eating disorders and manage people with eating disorders or any related electrolyte abnormalities linked to eating disorders.

Supporting information

S1 File. PRISMA-P checklist.

(DOCX)

pone.0308000.s001.docx (24.1KB, docx)
S2 File. PRISMA flow diagram.

(PNG)

pone.0308000.s002.PNG (55.2KB, PNG)
S3 File. Medline search strategy.

(PDF)

pone.0308000.s003.pdf (112.3KB, pdf)
S4 File. JBI assessment and review instrument.

(PDF)

pone.0308000.s004.pdf (297.2KB, pdf)
S5 File. JBI data extraction form.

(PDF)

pone.0308000.s005.pdf (483.7KB, pdf)

Acknowledgments

We acknowledge the librarian (Marie-Cécile Domecq) who guided us in developing the searching strategies.

List of abbreviations

JBI

Joanna Briggs Institute

JBI-MASTARI

Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review instrument

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

PROSPERO

International Prospective Register of Systematic Reviews

RCT

randomized Controlled Trial

Data Availability

No datasets were generated or analysed during the current study. All relevant deidentified data from this study will be made available upon study completion.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Muhammad Shahzad Aslam

10 Jun 2024

PONE-D-24-15566Impact of electrolyte abnormalities and adverse outcomes in persons with eating disorders: a systematic review protocol

PLOS ONE

Dear Dr. Buh,

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https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. When completing the data availability statement of the submission form, you indicated that you will make your data available on acceptance. We strongly recommend all authors decide on a data sharing plan before acceptance, as the process can be lengthy and hold up publication timelines. Please note that, though access restrictions are acceptable now, your entire data will need to be made freely accessible if your manuscript is accepted for publication. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If you are unable to adhere to our open data policy, please kindly revise your statement to explain your reasoning and we will seek the editor's input on an exemption. Please be assured that, once you have provided your new statement, the assessment of your exemption will not hold up the peer review process.

Additional Editor Comments:

Please consider the following important points for enhancing the quality of your study protocol:

1. Importance of a Discussion Section:

The protocol currently lacks a discussion section. Including a discussion section is crucial as it allows the authors to interpret their findings in the context of existing literature, address potential implications of the study, and suggest directions for future research. Without this section, the readers are left without guidance on how to understand the significance and context of the study results.

2. Interpretation of Potential Outcomes:

The discussion section should include interpretations of potential outcomes. This involves hypothesizing possible results and explaining their significance. What do you expect to find, and what would these findings mean in the broader context of the field?

3. Integration with Existing Literature:

It is essential to discuss how your study fits within the existing body of literature. Compare and contrast your expected findings with previous studies and explain how your research could confirm, refute, or expand upon these studies.

4. Implications of the Study:

Elaborate on the potential implications of your study. How could your findings impact clinical practice, policy, or further research? Discuss both the theoretical and practical implications.

5. Addressing Unexpected Results:

Consider potential unexpected results if come and how they might be explained. Provide alternative hypothesis and what further research might be needed if the results are contrary to your hypotheses.

Comments on Missing Limitations Section:

1. Importance of Identifying Limitations:

The protocol does not include a limitations section. Acknowledging the limitations of your study is crucial for transparency and provides context for interpreting the results. It demonstrates a comprehensive understanding of your study design and the factors that could affect the validity and generalizability of the findings.

2. Methodological Limitations:

Detail any methodological limitations. For example, consider sample size, sampling methods, measurement tools, and potential biases. How might these factors limit the interpretation or generalizability of the results?

3. Generalizability of Findings:

Discuss any limitations related to the generalizability of your findings. For instance, if your sample is drawn from a specific population, explain how this might limit the applicability of the results to other groups.

4. Potential Confounding Factors:

Identify any potential confounding factors that could influence the results. How will you control for these, and what impact could they have if they are not adequately controlled?

5. Data Collection and Analysis Constraints:

Acknowledge any limitations related to data collection and analysis. For example, if there are potential issues with data accuracy, completeness, or the analytical methods used, these should be clearly stated.

General Recommendations:

1. Enhancing Transparency:

Including detailed discussion and limitations sections will enhance the the transparency and credibility of your study. It shows that you have thoroughly considered all aspects of your research design and are forthcoming about potential weaknesses.

2. Providing Comprehensive Insight:

These sections will provide readers with a comprehensive understanding of your study, helping them to better appreciate the significance, reliability, and applicability of your findings.

3. Strengthening the Study Protocol:

I strongly recommend adding these sections to strengthen the overall quality of your study protocol. A well-rounded protocol not only highlights the strengths of your study but also critically appraises its limitations and situates it within the larger research landscape.

I hope these comments will guide the authors to improve their study protocol by ensuring it includes thorough discussion and limitations sections, thereby enhancing the overall quality and robustness of their research.

[Note: HTML markup is below. Please do not edit.]

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?

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: 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: Yes

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: In this study, authors aimed to assess the association of electrolyte imbalances and adverse outcomes in people with eating disorders. According to their research question, they explained their study designed in the methods section. However, I have not seen statistical analysis and discussion sections in the article.

Reviewer #2: Authors should check the supplementary file 1 which seems to be filled for a different study with the headline "Effective educational interventions for the promotion of sexual and reproductive health and rights for school-age children in low and middle-income countries: A systematic review protocol".

Reviewer #3: It would be really very interesting and novel review paper. Hope to open the new avenue of research in future on the same topic. Really exciting to see as soon in published form.

Categorically explain the aim, research question, background, study and methodology of the study. Upon on review the supplementary attached documents which more clear the novelty and comprehension of the stud.

However, minor changes in background chapter required to add more evidence-based studies on biological explanation how electrolytes imbalance in individual with eating disorder cause health adverse outcomes with sign and symptoms. Categorically explain the complications in ED as outcome of the electrolytes disorders.

**********

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: Huma Naqeeb

**********

[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.

PLoS One. 2024 Aug 8;19(8):e0308000. doi: 10.1371/journal.pone.0308000.r002

Author response to Decision Letter 0

4 Jul 2024

July 04, 2024

Manuscript reference #: PONE-D-24-15566

Title: Impact of electrolyte abnormalities and adverse outcomes in persons with eating disorders: a systematic review protocol

RE: PLOS ONE Decision: Revision required [PONE-D-24-15566]

Dear Dr. Muhammad Shahzad Aslam,

We thank you, the editorial team, and the reviewers for these insightful and helpful comments and for giving us the chance to revise our manuscript. We believe the comments provided have further strengthened our manuscript and we are pleased to submit a revised version at this time. Please see below our point-by-point responses to the editorial and reviewer comments.

Sincerely,

Amos Buh, PhD, FRSPH

Corresponding Author

Response to Reviewers’ reports

Journal requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response: We confirm that the manuscript meets PLOS ONE’s style requirements and all files have been named accordingly.

2. When completing the data availability statement of the submission form, you indicated that you will make your data available on acceptance. We strongly recommend all authors decide on a data sharing plan before acceptance, as the process can be lengthy and hold up publication timelines. Please note that, though access restrictions are acceptable now, your entire data will need to be made freely accessible if your manuscript is accepted for publication. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If you are unable to adhere to our open data policy, please kindly revise your statement to explain your reasoning and we will seek the editor's input on an exemption. Please be assured that, once you have provided your new statement, the assessment of your exemption will not hold up the peer review process.

Response: Thank you for this comment. In fact, all data that will be used in this study will be secondary data extracted from published papers. As such, the data will already be publicly available. Besides this, all data used in the study will be published together with the manuscript as tables or figures.

Additional Editor Comments:

Please consider the following important points for enhancing the quality of your study protocol:

1. Importance of a Discussion Section:

The protocol currently lacks a discussion section. Including a discussion section is crucial as it allows the authors to interpret their findings in the context of existing literature, address potential implications of the study, and suggest directions for future research. Without this section, the readers are left without guidance on how to understand the significance and context of the study results.

Response: We greatly appreciate this comment. A discussion section has now been added on the manuscript as requested (pages 8-9, lines 185-223): “Discussion

This review will synthesize existing evidence on electrolyte abnormalities in people with eating disorders. We acknowledge that some reviews have been conducted on this area though with notable limitations including having varying objectives and being. For instance, a 2016 review was published on the approaches to refeeding in patients with anorexia nervosa. This review, besides being dated, focused exclusively on examining refeeding approaches in patients with anorexia nervosa and included articles published between 1960 and 2015 from the PubMed, PsycINFO, Scopus and Clinical Trials databases [26]. Similar to this, a 2023 review described the different nutritional interventions for children and adolescents with avoidant/restrictive food intake disorders [27]. A 2020 review on eating disorders during gestation described implications for mother’s health, fetal outcomes, and epigenetic changes. This review included articles published between January 2000 and May 2020, but the review’s focus was solely to clarify the mechanisms underpinning the adverse pregnancy outcomes in patients with eating disorders [28]. In yet another review investigating the relationship between weight and risk of medical instability in adolescents with typical and atypical anorexia nervosa, the specific medical instability risks assessed were limited to bradycardia, hypotension, hypothermia and hypophosphatemia and articles were included only from the EMBASE, Medline and PubMed databases [29]. In 2021, a nonstandard review reported common eating disorders in children and adolescent with an overview of treatment strategies [30], and a similar review in 2023 was conducted on renal and electrolyte complications in eating disorders [11]. Finally, a recent review published in 2024, only focused on providing a prevalence estimate of self-reported disordered eating and risk factors in athletes [31]. All of these prior reviews likely missed studies not published in English and those not found in the databases they assessed. More importantly, none of the reviews assessed the association between electrolyte abnormalities and adverse outcomes in people with eating disorders.

Given the limitations of the above published reviews, our review will identify the type of electrolyte imbalances, their impact, and associated outcomes in people with eating disorders.

Strengths and limitations of this review

The major strengths of this review are that it will be a systematic review of randomized controlled trials and observational studies, and it will be the first to synthesize the evidence regarding the impact of electrolyte abnormalities on health outcomes in persons with eating disorders. Nonetheless, the main limitation of this review might be scarcity of randomized controlled trials and observational studies on impact of electrolyte abnormalities resulting from eating disorders, publication bias and methodological quality of the studies that shall be found. Also, there may be heterogeneity in eligible studies and incomplete information reported in included studies which could limit our ability to statistically assess the impact of electrolyte imbalances. However, we anticipate that the findings of this study will generate information that policy makers, clinicians, and stakeholders will find useful in designing better policies or strategies to prevent eating disorders and manage people with eating disorders or any related electrolyte abnormalities linked to eating disorders.”

2. Interpretation of Potential Outcomes:

The discussion section should include interpretations of potential outcomes. This involves hypothesizing possible results and explaining their significance. What do you expect to find, and what would these findings mean in the broader context of the field?

Response: This has been addressed in the discussion section as requested (please refer to the new text pasted above in response to Editorial comment #1).

3. Integration with Existing Literature:

It is essential to discuss how your study fits within the existing body of literature. Compare and contrast your expected findings with previous studies and explain how your research could confirm, refute, or expand upon these studies.

Response: Thank you for this suggestion; we have cited other studies on this topic in our discussion section and explained the limitations of the studies (please refer to the new text pasted above in response to Editorial comment #1).

4. Implications of the Study:

Elaborate on the potential implications of your study. How could your findings impact clinical practice, policy, or further research? Discuss both the theoretical and practical implications.

Response: This has been addressed on the discussion section as requested. Please see page 9, lines 220-223 on the Revised Manuscript with Track Changes.

5. Addressing Unexpected Results:

Consider potential unexpected results if come and how they might be explained. Provide alternative hypothesis and what further research might be needed if the results are contrary to your hypotheses.

Response: Thank you for this suggestion. We intend to adhere strictly to the inclusion criteria setout in our protocol and data will be extracted only from studies that met the criteria and were included in the study. As such, it will be very unlikely to have unexpected results except there will be studies with missing information. Even in cases of missing information, we have explained in our protocol that the corresponding authors of studies with missing information will be contacted to provide such information. In the worst-case scenario where we are unable to reach a corresponding author, the given study will be excluded following our stated criteria. Given this, the possibility of having unexpected results is rolled out in our study – we strongly anticipate that our results will reflect the data extracted only from included studies that met our inclusion criteria.

Comments on Missing Limitations Section:

1. Importance of Identifying Limitations:

The protocol does not include a limitations section. Acknowledging the limitations of your study is crucial for transparency and provides context for interpreting the results. It demonstrates a comprehensive understanding of your study design and the factors that could affect the validity and generalizability of the findings.

Response: This section has been included as requested; please refer to the new text pasted above in response to Editorial comment #1.

2. Methodological Limitations:

Detail any methodological limitations. For example, consider sample size, sampling methods, measurement tools, and potential biases. How might these factors limit the interpretation or generalizability of the results?

Response: We greatly appreciate this comment; this has been addressed in the strengths and limitation section; page 9 lines 211-223 on the Revised Manuscript with Track Changes.

3. Generalizability of Findings:

Discuss any limitations related to the generalizability of your findings. For instance, if your sample is drawn from a specific population, explain how this might limit the applicability of the results to other groups.

Response: Thank you for this suggestion; any potential limitations of our study have been discussed under the strengths and limitation section of our protocol.

4. Potential Confounding Factors:

Identify any potential confounding factors that could influence the results. How will you control for these, and what impact could they have if they are not adequately controlled?

Response: Heterogeneity in included studies and differences in study participants characteristics across included studies could potentially influence our results. However, we have explained under data synthesis that we will conduct subgroup and sensitivity analysis if there is substantial heterogeneity among included studies.

5. Data Collection and Analysis Constraints:

Acknowledge any limitations related to data collection and analysis. For example, if there are potential issues with data accuracy, completeness, or the analytical methods used, these should be clearly stated.

Response: We appreciate this suggestion. The only issue we will face with data collection and analysis is missing data from included studies. However, we have described how this will be managed under data extraction and data synthesis on the protocol.

General Recommendations:

1. Enhancing Transparency:

Including detailed discussion and limitations sections will enhance the the transparency and credibility of your study. It shows that you have thoroughly considered all aspects of your research design and are forthcoming about potential weaknesses.

Response: Thank you. As recommended, these sections have been included on the manuscript. Please refer to the new text pasted above in response to Editorial comment #1.

2. Providing Comprehensive Insight:

These sections will provide readers with a comprehensive understanding of your study, helping them to better appreciate the significance, reliability, and applicability of your findings.

Response: We appreciate this greatly and the requested sections have been included on the manuscript (please refer to the new text pasted above in response to Editorial comment #1).Thank you.

3. Strengthening the Study Protocol:

I strongly recommend adding these sections to strengthen the overall quality of your study protocol. A well-rounded protocol not only highlights the strengths of your study but also critically appraises its limitations and situates it within the larger research landscape.

Response: Thank you for this recommendation. We have added the recommended sections and we believe the manuscript has been greatly improved.

I hope these comments will guide the authors to improve their study protocol by ensuring it includes thorough discussion and limitations sections, thereby enhancing the overall quality and robustness of their research.

Response: Indeed, the comments were very constructive and have helped us improve the quality of our manuscript. We are very grateful to the editor and all reviewers; thank you.

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

Response: Thank you so much for your appraisal of our manuscript.

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

Response: We greatly appreciate your appraisal of our manuscript, thank you.

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: Yes

Reviewer #3: Yes

Response: We greatly appreciate your appraisal of our manuscript, thank you.

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

Response: Thank you.

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

PLOS ONE does not copyedit accepted

Attachment

Submitted filename: Response to Reviewers.docx

pone.0308000.s006.docx (34.5KB, docx)

Decision Letter 1

Muhammad Shahzad Aslam

9 Jul 2024

PONE-D-24-15566R1Impact of electrolyte abnormalities and adverse outcomes in persons with eating disorders: a systematic review protocolPLOS ONE

Dear Dr. Buh,

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.

Authors should check the supplementary file 1 which seems to be filled for a different study with the headline "Effective educational interventions for the promotion of sexual and reproductive health and rights for school-age children in low and middle-income countries: A systematic review protocol".

It would be really very interesting and novel review paper. Hope to open the new avenue of research in future on the same topic. Really exciting to see as soon in published form.

Categorically explain the aim, research question, background, study and methodology of the study. Upon on review the supplementary attached documents which more clear the novelty and comprehension of the stud.

However, minor changes in background chapter required to add more evidence-based studies on biological explanation how electrolytes imbalance in individual with eating disorder cause health adverse outcomes with sign and symptoms. Categorically explain the complications in ED as outcome of the electrolytes disorders.

Please submit your revised manuscript by Aug 23 2024 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: 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.

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-D

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.]

[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.

PLoS One. 2024 Aug 8;19(8):e0308000. doi: 10.1371/journal.pone.0308000.r004

Author response to Decision Letter 1

14 Jul 2024

July 13, 2024

Manuscript reference #: PONE-D-24-15566R1

Title: Impact of electrolyte abnormalities and adverse outcomes in persons with eating disorders: a systematic review protocol

RE: PLOS ONE Decision: Revision required [PONE-D-24-15566R1] - [EMID:4c1da07e9e1ed7f8]

Dear Dr. Muhammad Shahzad Aslam,

We are very grateful for the comments and for the opportunity to revise our manuscript further. We believe we have addressed all comments and are happy to submit a revised version of the manuscript. Please see below a point-by-point response to the comments.

Sincerely,

Amos Buh, PhD, FRSPH

Corresponding Author

Response to Reviewers’ reports

Authors should check the supplementary file 1 which seems to be filled for a different study with the headline "Effective educational interventions for the promotion of sexual and reproductive health and rights for school-age children in low and middle-income countries: A systematic review protocol".

Response: We greatly appreciate this observation. We made an error with the headline while filling this file; the error has been corrected and the headline now reads “Impact of electrolyte abnormalities and adverse outcomes in persons with eating disorders: a systematic review protocol”. Thank you.

It would be really very interesting and novel review paper. Hope to open the new avenue of research in future on the same topic. Really exciting to see as soon in published form.

Response: Thank you so much for appraising our manuscript. We hope our work on this topic will inspire future research on this same topic. Once we complete the review, we will submit the final manuscript for publication so that everyone can have access to our findings.

Categorically explain the aim, research question, background, study and methodology of the study. Upon on review the supplementary attached documents which more clear the novelty and comprehension of the stud.

Response: We are deeply grateful to you for taking a keen look on our manuscript and appreciating its clarity from the aim through the research question, background and study methods to the supplementary documents. Thank you.

However, minor changes in background chapter required to add more evidence-based studies on biological explanation how electrolytes imbalance in individual with eating disorder cause health adverse outcomes with sign and symptoms. Categorically explain the complications in ED as outcome of the electrolytes disorders.

Response: Thank you for this suggestion. We have expanded our background section (particularly the last paragraph of the background) to include additional text regarding the existing literature on how electrolyte disorders may lead to adverse health outcomes (pages 3-4, lines 77-93): “The severity and type of electrolyte abnormalities are dependent on the mode, and frequency of the behaviors of the eating disorder [17]. Some signs and symptoms of electrolyte imbalances in people with eating disorders include constipation, nausea and vomiting, fatigue, heart palpitations or arrhythmias, muscle weakness, cramps, numbness, polyuria, headache, confusion, restlessness and irritability [18]. While complications of eating disorders range from minor to fatal, every organ system can be affected with problems ranging from pancytopenia to diffuse myalgias with muscle breakdown [19]. In fact, eating disorders can impact neurological, cardiac, muscle, gastrointestinal, endocrine and renal functions [11, 18, 20]. However, it has been documented that electrolyte abnormalities are associated with a host of serious adverse clinical outcomes [12]. For instance, derangements in potassium, magnesium, and calcium levels predispose to cardiac arrhythmias and sudden cardiac death [18]. Derangements in sodium and phosphate levels can result in generalized weakness, cognitive impairment, and seizures [19, 20]. Electrolyte disturbances can also have detrimental effects on kidney, gastrointestinal and bone health [21 - 23]. Nonetheless, there is little or no information on reviews that have comprehensively assessed the impact of electrolyte abnormalities and adverse outcomes resulting from people with eating disorders.”

Attachment

Submitted filename: Response to Reviewers.docx

pone.0308000.s007.docx (18.7KB, docx)

Decision Letter 2

Muhammad Shahzad Aslam

16 Jul 2024

Impact of electrolyte abnormalities and adverse outcomes in persons with eating disorders: a systematic review protocol

PONE-D-24-15566R2

Dear Dr. Buh,

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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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,

Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Muhammad Shahzad Aslam

29 Jul 2024

PONE-D-24-15566R2

PLOS ONE

Dear Dr. Buh,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 File. PRISMA-P checklist.

    (DOCX)

    pone.0308000.s001.docx (24.1KB, docx)
    S2 File. PRISMA flow diagram.

    (PNG)

    pone.0308000.s002.PNG (55.2KB, PNG)
    S3 File. Medline search strategy.

    (PDF)

    pone.0308000.s003.pdf (112.3KB, pdf)
    S4 File. JBI assessment and review instrument.

    (PDF)

    pone.0308000.s004.pdf (297.2KB, pdf)
    S5 File. JBI data extraction form.

    (PDF)

    pone.0308000.s005.pdf (483.7KB, pdf)
    Attachment

    Submitted filename: Response to Reviewers.docx

    pone.0308000.s006.docx (34.5KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    pone.0308000.s007.docx (18.7KB, docx)

    Data Availability Statement

    No datasets were generated or analysed during the current study. All relevant deidentified data from this study will be made available upon study completion.

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