How much is too much? A medication use evaluation of VA ICU sedation practice during the COVID-19 pandemic

Ian C. Murphy; Kelly Bryan; Muriel Burk; Rong Jiang; Francesca Cunningham; Sarah Providence; Elizabeth Rightnour; Sarah Zavala; Kathleen Morneau; Trisha Exline; Stacey Rice; Travis Schmitt; Kelly Drumright; Jennifer Lee; BreAnna Davids; Tram Guilbeault; Brooke Klenosky; Ann-Marie Sutherland; Abbie Rosen; Lauren Ratliff; Kenneth Bukowski; Margaret A. Pisani; Andrew Franck; Mark Wong; Preston Witcher; Kathleen M. Akgün

doi:10.1371/journal.pone.0340225

Peer Review History

Original SubmissionOctober 7, 2025
28 Nov 2025 Decision Letter - Benjamin Benzon, Editor PONE-D-25-50605-->-->How Much is Too Much? A Medication Use Evaluation of VA ICU Sedation Practice During the COVID-19 Pandemic-->?> PLOS ONE Dear Dr. Akgün, 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. ============================== Thank you for sending your manuscript to PLOS One. Reviewers are two anesthesiologists with extensive experience in COVID ICU, please address their comments. I am looking forward to revised version of the manuscript. ============================== Please submit your revised manuscript by Jan 12 2026 11:59PM. 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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 Reviewer #1: Yes Reviewer #2: No ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: Although study is interesting, there are some problems with methodology and interpretation od data. This retrospective study limitation is just collecting data for 48 h sedation. It is not clear for me how this narrow time periods support your conclusion. This study is not patient centred. You did not reach estimated sample size. COVID ARSD was unique lung patology, the worst cases that would dye spontaneously breading was put on mechanical ventilation, and stiff lungs were hard to ventilate. It was necessary to give more sedation than non COVID ICU patients to achieve smooth ventilation, maybe muscle relaxation was under dosed and sedation overdosed, but still it is not clear to me was you can infer for just 2 days of ICU sedation. In the first 2 days it is hard to have prognosis (survival or death). I think conclusion is not supported by data and study design. Reviewer #2: I would like to see your opinions in discussion section what were the possible reasons for analgosedation increase in Covid patients? Was it too many difficult patients and too little doctors and nurses so they could not take care as usual? Did you calculate Horowitz index for ARDS severity? What was vaccination status in year 2? Did you put patients in prone position for better ventilation? All above are possible factors for analgosedation increase. ****** what does this mean? ). If published, this will include your full peer review and any attached files. 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NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications. https://doi.org/10.1371/journal.pone.0340225.r001
Revision 1
9 Dec 2025 Author Response please see attached response letter for improved formatting Reviewer: 1 Comments to the Author Although study is interesting, there are some problems with methodology and interpretation od data. Reviewer comment 1: This retrospective study limitation is just collecting data for 48 h sedation. Reply 1: We agree that this is a limitation. However, complete data was only available during the first 48 hours; by day 5, more than half of the patients were off of the ventilator. We included these details in figure 1 and in the text, and as additional limitations in the manuscript. Results, page 10, lines 294-295: “431 (49.5%) with complete data during the first 48 hours were included for chart review” Discussion, page 16, lines 408-410: “We also only had complete data for the first 48 hours of all included patients due to the rapid decrease in ventilator use subsequently (Figure 1), limiting our ability to comprehensively evaluate ICU medication use.” Additional table added to figure 1: Patients on ventilator by day, up to 14 days, N (%) Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 N (%) 431 (100) 431 (100) 390 (90) 291 (68) 204 (47) 156 (36) 118 (27) 91 (21) 72 (17) 53 (12) 34 (8) 20 (5) 15 (3) 7 (2) Reviewer comment 2: It is not clear for me how this narrow time periods support your conclusion. Reply 2: We merely intended to report observations of medication prescribing in a national sample. We feel our conclusions are tempered and seeking to remind providers of the importance of sedation protocols and sedation stewardship. Reviewer comment 3: This study is not patient centred. Reply 3: As a chart review study, we agree we are limited in patient-centered outcomes. We included this as another limitation in the manuscript. Discussion, page 17, lines 439-441: “Finally, our findings are only descriptive frequencies and do not include patient-centered outcomes to better understand how medication use impacted clinical experiences for patients with ARDS.” Reviewer comment 4: You did not reach estimated sample size. Reply 4: We regret that we did not reach our intended goals for chart review due to exclusion criteria. This was included as a limitation already in the manuscript. Reviewer comment 5: COVID ARSD was unique lung patology, the worst cases that would dye spontaneously breading was put on mechanical ventilation, and stiff lungs were hard to ventilate. It was necessary to give more sedation than non COVID ICU patients to achieve smooth ventilation, maybe muscle relaxation was under dosed and sedation overdosed, but still it is not clear to me was you can infer for just 2 days of ICU sedation. In the first 2 days it is hard to have prognosis (survival or death). I think conclusion is not supported by data and study design. Reply 5: Please see response to comments 1 and 2 above. We also included more context about the stiff lung physiology of COVD ARDS. Discussion, page 13, lines 372-374: “The need to achieve ventilator synchrony in the setting of exaggerated inflammatory response and complex respiratory mechanics from COVID+ ARDS likely contributed to higher sedation.” Reviewer: 2 Reviewer comment 1: I would like to see your opinions in discussion section what were the possible reasons for analgosedation increase in Covid patients? Was it too many difficult patients and too little doctors and nurses so they could not take care as usual? Reply 1: We speculated about some of these factors that contributed to higher analgosedation for COVID patients, including possible staffing shortages, but more granular assessments of staffing models. Discussion, page 13, lines 360-363: “Anecdotally, higher sedation was likely needed to support patients on the ventilator although we were unable to report ARDS severity in this work. Staffing ratios appeared to be relatively stable, although this was not specifically measured.” Reviewer comment 2: Did you calculate Horowitz index for ARDS severity? What was vaccination status in year 2? Did you put patients in prone position for better ventilation? All above are possible factors for analgosedation increase. Reply 2: We did not calculate the Horowitz index for ARDS severity. We also were unable to include information on vaccination status or prone positioning. We included these as additional limitations. Discussion, page 16, lines 421-423: “We also are unable to characterize ARDS severity or prone positioning, which would also influence sedation needs. Ongoing efforts are needed to promote guideline-concordant ICU sedation practices for patients on the ventilator.” https://doi.org/10.1371/journal.pone.0340225.r002
18 Dec 2025 Decision Letter - Benjamin Benzon, Editor How Much is Too Much? A Medication Use Evaluation of VA ICU Sedation Practice During the COVID-19 Pandemic PONE-D-25-50605R1 Dear Dr. Akgün, 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. For questions related to billing, please contact billing support . 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, Benjamin Benzon, Ph.D., M.D. Academic Editor PLOS One Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0340225.r003
Formally Accepted
Acceptance Letter - Benjamin Benzon, Editor PONE-D-25-50605R1 PLOS One Dear Dr. Akgün, 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 * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, 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. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@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. Benjamin Benzon Academic Editor PLOS One https://doi.org/10.1371/journal.pone.0340225.r004

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