Delirium and its association with short-term outcomes in younger and older patients with acute heart failure

Jin H. Han; Candace D. McNaughton; William B. Stubblefield; Peter S. Pang; Phillip D. Levy; Karen F. Miller; Sarah Meram; Mette Lind Cole; Cathy A. Jenkins; Hadassah H. Paz; Kelly M. Moser; Alan B. Storrow; Sean P. Collins; for the Emergency Medicine Research and Outcomes Consortium Investigators

doi:10.1371/journal.pone.0270889

Peer Review History

Original SubmissionNovember 22, 2021
22 Apr 2022 Decision Letter - Enrico Mossello, Editor PONE-D-21-37051Delirium and Its Association with Short-term Outcomes in Younger and Older Patients with Acute Heart FailurePLOS ONE Dear Dr. Han, 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. ============================== ACADEMIC EDITOR: Among points raised by reviewers the following should be especially addressed: Please describe better patient selection (“convenience sample” is not sufficient) and give an estimate of exclusion rate Describe better among-group differences of HF mortality risk (the highly significant difference are not apparent from data in table 1) Include a supplementary analysis regarding the difference between older and younger patients and briefly discuss the reason of the lack of prognostic meaning of age and the similar prevalence of delirium between groups, both unexpected Among limitations, you should include the lack of information regarding functional status (frailty and/or disability). Please consider to compute a comorbidity index to adjust for in a sensitivity analysis. Moreover “cognitive impairment” does not represent premorbid cognitive impairment, also in subjects without delirium, and likely represents a mix between premorbid cognitive impairment, subsyndromal delirium and “false positives” (low education, anxiety, etc). Please discuss. ============================== Please submit your revised manuscript by 6-JUN-2022. 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, Enrico Mossello Academic Editor PLOS ONE 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. 2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. 3. Thank you for stating the following financial disclosure: “This project was partially supported by the NCATS/NIH under award number UL1 TR000445. Drs. Han and Collins receive funding from the Geriatric, Research, Education, and Clinical Center (GRECC).” 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. 4. Thank you for stating the following in the Funding Section of your manuscript: “This work was supported by the National Center for Research Resources, Grant UL1 RR024975-01, and is now at the National Center for Advancing Translational Sciences, Grant 2 UL1 TR000445-06. Dr. Han was also supported by the National Institutes of Health (NIH) under award number R21AG06312, R56HL141567 and R01AG065249. Drs. Han and McNaughton are also supported by the Veteran Affairs Geriatric Research, Education, and Clinical Center (GRECC). The content is solely the responsibility of the authors and does not necessarily represent the official views of Vanderbilt University Medical Center, NIH, and Veterans Affairs.” We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: “This project was partially supported by the NCATS/NIH under award number UL1 TR000445. Drs. Han and Collins receive funding from the Geriatric, Research, Education, and Clinical Center (GRECC).” Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 5. One of the noted authors is a group or consortium [Emergency Medicine Research and Outcomes Consortium Investigators]. In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address. [Note: HTML markup is below. Please do not edit.] 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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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 ****** 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 ****** 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: Dr. Jin Ho Han and colleagues should be congratulated for addressing the important issue of early prognostic impact of incident delirium in patients admitted for AHF in older and younger patients. This represents a novelty indeed because delirium has rarely been assessed in younger subjects. The authors identify three main groups: delirious (bCAM positive regardless of SBT score), cognitively impaired without delirium (bCAM negative, SBT > 10) or cognitive intact (bCAM negative and SBT < 10). Nevertheless my main concerns are related to possible misclassification of Delirium/ cognitive impairment and possibly related to the way these condition were classified. The rate of delirium seems similar to other literature reports while the presence of cognitive impairment seem very high (considering an overall quite young population) with one out four patients being classified with this condition. The authors may want to comment on this and on the quite unexpected similar incidence of delirium among younger and older patients. Furthermore, I do not understand why the authors say that pre-illness cognitive impairment could be ascertained in patients without delirium. Authors should better clarify this point since a history of cognitive impairment (investigated also with family members and/or caregivers) might have increased accuracy in classifications. Other minor considerations Global cognition was measured using the Short Blessed Test (SBT), which is a 6-item assessment assessing orientation, immediate and delayed memory, and attention; it is 95% sensitive and 65% for cognitive impairment [17]. Scores range from 0 to 28, with a score of 10 or more indicating the presence of cognitive impairment. add specific after 65% Prolonged index hospital length of stay was incorporated because it is a competing risk for 30-day all-cause rehospitalizations, i.e., patients who have 5 prolonged hospitalizations are less likely to be rehospitalized within 30 days. This is not true… Data from the literature show that there is a U wave relation between hospitalization length and early readmissions: short length of stay correlates with 30-days HF-hospitalizations, while long length of stay is correlated with risk Reviewer #2: Thank you for inviting me to review this study that investigated the association of delirium with short-term adverse outcomes in patients with HF. The study investigated an important topic involving cognitive impairment that is highly prevalent and affects prognosis in patients with HF. I have a few comments as follow. 1. Were consecutive patients recruited into the study? 2. Prolonged hospital stay is likely due to greater severity of HF that may be also the cause of acute delirium. So including prolonged hospital stay may have overestimated the association of delirium with short-term outcomes in your study. Prolonged hospital stay might be associated with lower readmission because of more complete treatment of HF and management of comorbidity. Patients may be discharged with optimal fluid status. Prolonged stay may be a predictor of readmission, but not a competing risk. 3. How did the authors ensure that readmissions to other hospitals were not missed? 4. Why did the authors adjust for age as a binary variable, but not as a continuous variable? Did the authors also check for interaction with continuous age variable? 5. Did the delirium resolve when patients were discharged from hospital? 6. Delirium was only significantly associated with all-cause death, which reflects a greater level of HF severity and frailty in this group of patients. The HF mortality score presented in this study was not very informative because they looked largely similar across 3 groups of patients but had a highly significant p-value. What was the comorbidity index for your patients? ****** 6. 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.] 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. https://doi.org/10.1371/journal.pone.0270889.r001
Revision 1
4 Jun 2022 Author Response Thank you for the detailed reviews and for allowing us to revise and resubmit this manuscript. We have addressed all the suggestions/criticisms below and we hope that you find our revisions satisfactory. The details of our changes are provided in the subsequent pages; our responses are preceded by “*”. Thank you again for allowing us the opportunity to revise and resubmit this manuscript. If you have any questions, please don’t hesitate to contact me by phone (615-260-0086) or by e-mail. Please describe better patient selection ("convenience sample" is not sufficient) and give an estimate of exclusion rate. Thank you for this suggestion. We added an Enrollment Flow Diagram (Figure 1) to better characterize our exclusions. We also added the following (see underlined) to the Results on Page 7: “Of the 20,883 patients who presented with AHF in the participating EDs, 1500 patients participated in the EMROC Registry (Figure 1), and 1208 patients had an adjudicated diagnosis of AHF. Of these, 47 patients were excluded because they had had missing SBT or bCAM assessments, 38 patients were excluded because of missing covariate data, and 79 were excluded because they were lost to follow-up.” Describe better among-group differences of HF mortality risk (the highly significant difference are not apparent from data in table 1). Per your suggestion, we have added Supplemental Table 2 which stratifies patient characteristics by 30-day composite outcome status. In the Results section (Page 10), we also added the following text: “Patient characteristics stratified by 30-day composite outcome status can be seen in Supplementary Table 2. Patients who had the 30-day composite outcome were older, had higher SBT scores and mortality risk, and were more likely to be on dialysis prior to enrollment, be admitted to the hospital, and be admitted to the ICU.” Include a supplementary analysis regarding the difference between older and younger patients and briefly discuss the reason of the lack of prognostic meaning of age and the similar prevalence of delirium between groups, both unexpected Thank you for this suggestion. We have added Supplemental Table 4. Patient characteristics stratified by older (> 65 years) versus younger (<65 years) at enrollment. We also added the following paragraph to the discussion section to provided potential reasons: “Surprisingly, younger age was not protective as the proportion of AHF patients with delirium were similar between older and younger patients. Age also did not modify the association between delirium and the 30-day composite outcome. Younger patients were more likely to have an ejection fraction < 40% (Supplementary Table 4) which can increase the patient’s vulnerability to developing delirium due to brain hypoperfusion [26, 27]. Reduced ejection fraction also is a powerful predictor of all-cause mortality and may potentiate delirium’s effect on long-term outcomes [28]. Younger patients with AHF were also more likely to self-identify as Black who are at higher risk for mortality and morbidity, and higher risk for heart failure-related hospitalizations compared with their non-Black counterparts [29, 30]. This is likely driven by health disparities and negative social determinants of health. Black patients with jeart failure are more likely to have poorer access to health care and have a decreased likelihood of receiving guideline-recommended heart failure therapies [31, 32]. Black race is also associated with poorer heart failure disease self-management and decreased medication adherence [33], which can lead to AHF and subsequent hospitalizations. They are also more likely to have comorbidities such as diabetes, hypertension, and obesity which may further complicate disease self-management and medication adherence [34]. The complex interplay among age, health disparities, and social determinants of health may explain our findings and would have important implications for potential interventions aimed at improving HF outcomes in diverse patient populations.” Among limitations, you should include the lack of information regarding functional status (frailty and/or disability). Thank you for pointing this out. We added the following sentence to the limitations section: “We also did not account for pre-illness comorbidity burden, frailty or disability which may have led to additional residual confounding.” Please consider to compute a comorbidity index to adjust for in a sensitivity analysis. Our registry collected a past history of myocardial infarction, hypertension, diabetes mellitus, chronic kidney disease, dialysis, dyslipidemia, pulmonary hypertension, and ejection fraction < 40%. These were adjusted in the multivariable models since we had sufficient degrees of freedom. Unfortunately, we did not collect all the variables necessary to calculate the Charlson or Elixhauser comorbidity burden and this is a limitation. We added the following sentence to the limitations section: “While we adjusted for a past history of myocardial infarction, hypertension, diabetes mellitus, chronic kidney disease, dialysis, dyslipidemia, pulmonary hypertension, we did not capture all the comorbidities necessary to calculate the Charlson or Elixhauser comorbidity burden. We also did not account for pre-illness frailty or disability. The lack of adjustment for these covariates may have led to additional residual confounding. Moreover "cognitive impairment" does not represent premorbid cognitive impairment, also in subjects without delirium, and likely represents a mix between premorbid cognitive impairment, subsyndromal delirium and "false positives" (low education, anxiety, etc). Please discuss. In the limitations, the following sentence were added: “Even in patients without delirium, the SBT may not have accurately reflected pre-illness cognition. Some of these patients may have had subsyndromal delirium or their scores were falsely low due to anxiety or multiple distractions (i.e.,monitor alarms) commonly seen in the ED environment.” Editorial Office Comments 1. Thank you for stating the following financial disclosure: "This project was partially supported by the NCATS/NIH under award number UL1 TR000445. Drs. Han and Collins receive funding from the Geriatric, Research, Education, and Clinical Center (GRECC)." 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. * The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We have added this to the cover letter. Thank you for changing the online submission form on our Behalf. 2. One of the noted authors is a group or consortium [Emergency Medicine Research and Outcomes Consortium Investigators]. In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address. **We have added the following to the Acknowledgements: “The Emergency Medicine Research and Outcomes Consortium (EMROC) Investigators consist of Drs. Sean Collins (Vanderbilt University Medical Center); Peter Pang (Indiana University and Eskenazi Hospitals), Phillip Levy (Detroit Receiving and Sinai Grace Hospitals); and Gregory Fermann (University of Cincinnati Medical Center). Dr. Sean Collins (e-mail: sean.collins@vumc.org) leads the EMROC Investigators.” Attachments Attachment Submitted filename: Delirium HF - Response Letter 2022-06-02.docx* https://doi.org/10.1371/journal.pone.0270889.r002
20 Jun 2022 Decision Letter - Enrico Mossello, Editor Delirium and Its Association with Short-term Outcomes in Younger and Older Patients with Acute Heart Failure PONE-D-21-37051R1 Dear Dr. Han, 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, 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, Enrico Mossello Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0270889.r003
Formally Accepted
15 Jul 2022 Acceptance Letter - Enrico Mossello, Editor PONE-D-21-37051R1 Delirium and Its Association with Short-term Outcomes in Younger and Older Patients with Acute Heart Failure Dear Dr. Han: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Enrico Mossello Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0270889.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .