Closed-loop oxygen control for critically ill patients––A systematic review and meta-analysis

Caroline Gomes Mól; Aléxia Gabriela da Silva Vieira; Bianca Maria Schneider Pereira Garcia; Emanuel dos Santos Pereira; Raquel Afonso Caserta Eid; Marcus J. Schultz; Ana Carolina Pereira Nunes Pinto; Ricardo Kenji Nawa

doi:10.1371/journal.pone.0304745

Peer Review History

Original SubmissionFebruary 5, 2024
19 Mar 2024 Decision Letter - Vijay Hadda, Editor PONE-D-24-04130Closed-loop oxygen control for critically ill patients––A systematic review and meta-analysisPLOS ONE Dear Dr. Mól, 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: The manuscript addresses an important issue pertinent to management of patients needing oxygen therapy; hence, may be an useful publication. However, the manuscript need major revision. Please see the comments below and also address issues raised by reviewers. The language need thorough check for grammar and syntax. Also, it would be better if main results can be presented as main text, instead of supplementary. Please submit your revised manuscript by May 03 2024 11:59PM. 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The other authors declare no conflicts of interest.” Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. [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 Reviewer #3: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: No ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: 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 Reviewer #3: No ****** 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: The meta analysis has been thoroughly conducted but there are various issues which need consideration 1 Most studies have a very short duration of intervention ranging for only few hours which will make it difficult to generalise the results for patients requiring oxygen for prolonged duration 2 Exclusion criterion in various studies can be included 3 Hyperoxeia is equally detrimental specially in patients with Type 2 respiratory failure patients. What were the causes of hyperoxia in closed loop systems should be briefly discussed 4 Subgroup analysis based on duration of intervention should be done as there are various studies having intervention for more than 24 hours. 5 Separate analysis for studies with post surgical patients and patients with medical conditions requiring supplemental oxygen should be considered Reviewer #2: The aim of your study was to evaluate whether closed-loop oxygen control systems are effective, efficient and safe. Despite heterogeneity of studies it was seen that Closed-loop oxygen titration are effective in reducing costs, oxygen consumption and healthcare workload. Are they safe - No; as they resulted in longer patient times with hyperoxemia Are they efficient -No; as time for weaning from supplemental oxygen's not shown to reduce with these systems and they had no effects on ventilator associated adverse events, length of stay, and mortality. Please include the same clearly in conclusions. Reviewer #3: The authors have made a substantial effort to collate the literature and come to a reasonable conclusion. However, this meta analysis does not have a funnel plot to look at the publication bias. There is considerable heterogeneity(I2=80.1%) and lacks a sensitivity analysis. ****** 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: Yes: Prof Manu Chopra Reviewer #3: 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.0304745.r001
Revision 1
19 Apr 2024 Author Response Dear prof. Vijay Hadda, dear editor, We sincerely appreciate the opportunity to submit the revised version of our manuscript entitled ‘Closed-loop Oxygen Control for Critically Ill Patients: A Systematic Review and Meta-analysis’. Your comments and those of the respected reviewers were very helpful for revising the work, we have meticulously implemented changes to enhance the quality and clarity of our manuscript. Below, we provide a detailed point-by-point response to the reviewer’s comments. We look forward to your response, and also the responses from the reviewers if they get a second chance to review our work. Kindest regards, and on behalf of all coauthors, Caroline Gomes Mól ACADEMIC EDITOR: 1. The language need thorough check for grammar and syntax. Thank you for your comment. We have carefully reviewed both the manuscript and supporting information, conducting a thorough check for grammar and syntax. 2. Also, it would be better if main results can be presented as main text, instead of supplementary. Thank you for your comment. As suggested, we have transferred certain topics and figures from the supplementary material to the main text, as outlined below: ● [Page 9; line 10] S1 Appendix. Overall risk of bias for each planned outcome. ● [Page 9; line 13; Figure 2; ‘5. [PLoS One - Major Revision] Fig 2 Rob RCT’] S1 Fig. Risk of bias of RCT included studies. ● [Page 9; line 24; Figure 3; ‘6. [PLoS One - Major Revision] Fig 3 Rob RCT crossover’] S2 Fig. Risk of bias of crossover included studies. ● [Page 11; line 3] S3 Appendix. Summary of studies not included in the quantitative analyses. ● [Page 12; line 15; ‘7. [PLoS One - Major Revision] Fig 5’] S10 Fig. Forest plot of healthcare professionals' workload. Reviewer 1 1. Most studies have a very short duration of intervention ranging for only few hours which will make it difficult to generalize the results for patients requiring oxygen for prolonged duration. Thank you for your comment. This is a very valid and important comment. We added this limitation to the limitations section of the Discussion of the revised version of the manuscript, as follows: ● [Page 16; line 13] ‘It is important to emphasize that most studies in this meta-analysis featured brief intervention periods, ranging from only a few hours to 24 hours. This limitation diminishes the generalizability of the results to patients necessitating prolonged oxygen therapy, typically those in the most critical condition.’ 2. Exclusion criterion in various studies can be included. We appreciate your suggestions. Exclusion criteria of studies are now provided in table 1 as follows: 3. Hyperoxemia is equally detrimental especially in patients with Type 2 respiratory failure patients. What were the causes of hyperoxemia in closed-loop systems should be briefly discussed. Thank you for your comment and question. The percentage of time with hyperoxemia ranged from less than 1% to 35% in the closed-loop group and less than 1% to 31% in the manual titration group, and this was found to be not statistically different. Of note, in most of the studies, the duration of hyperoxemia was short. In the one study with a high percentage of time with hyperoxemia (Arnal, 2018), utilization of INTELLiVENT–ASV resulted in 35% of time with hyperoxemia versus 31.33% with manual titration. We added the following to the revised version of the manuscript: ● [Page 13; line 15] ‘However, it may not effectively reduce the occurrence of hyperoxemia, particularly in mechanical ventilation systems, or when high oxygen targets are being used. For instance, one trial [36] showed a high incidence of hyperoxemia with automatic oxygen control; however, this incidence was also high in the control group (35% vs. 33%).’ 4. Subgroup analysis based on duration of intervention should be done as there are various studies having intervention for more than 24 hours. Thank you for this valuable suggestion. See also our response to your comment 5, below. According to this suggestion, and also your suggestion in comment 5, we conducted subgroup analyses considering the duration of the intervention, and type of ICU admission, focusing on the primary endpoint of our study. We added the findings as a post hoc analysis to the supplement, and added the following to the revised version of the manuscript: ● [Page 8; line 21] ‘In addition, we conducted two posthoc analyses, one comparing the percentage of time in the SpO2 target for subgroups according to duration of the intervention, and one in subgroups according to the reason for admission, i.e., medical or surgical.’ ● [Page 10; line 11] ‘In 7 studies [37,40,44,46–49], closed-loop oxygen titration devices increased the percentage of time in the predefined SpO2 target with substantial heterogeneity, not completely explained by the planned and post hoc subgroup analysis (Fig 4, S2 Fig, S3 Fig and S11 Table).’ ● [Supporting information page 5] ‘S2 Fig. Forest plot of subgroup analysis of duration of intervention for the percentage of time spent in the SpO2 target.’ ● [Supporting information page 6] ‘S3 Fig. Forest plot of subgroup analysis of patient’s condition (medical or post-surgical) for the percentage of time spent in the SpO2.' 5. Separate analysis for studies with post-surgical patients and patients with medical conditions requiring supplemental oxygen should be considered. See our reply to your comment 4, above. Reviewer 2 1. The aim of your study was to evaluate whether closed-loop oxygen control systems are effective, efficient and safe. Despite heterogeneity of studies it was seen that Closed-loop oxygen titration are effective in reducing costs, oxygen consumption and healthcare workload. Are they safe - No; as they resulted in longer patient times with hyperoxemia. Are they efficient - No; as time for weaning from supplemental oxygen's not shown to reduce with these systems and they had no effects on ventilator associated adverse events, length of stay, and mortality. Please include the same clearly in conclusions. Thank you for your comments and suggestions. We agree that there remains a substantial gap in our understanding of the safety and efficacy of closed-loop oxygen systems in reducing mortality rates and shortening hospital stays. We revised the conclusion to better address these concerns raised, as follows: ● [Page 17; line 6]‘In summary, while closed-loop oxygen titration systems probably increase the percentage of time spent within desired SpO2 ranges and reduce healthcare workload and costs, their safety remains uncertain. Adverse events are likely underreported in existing studies. Moreover, the extent to which these systems enhance efficiency, such as by reducing the duration of oxygen weaning, and even more importantly, by affecting length of stay and mortality rates, remains unclear. This uncertainty primarily stems from the limited duration of the intervention in the scarce, and small existing studies. Future research should focus on evaluating effectiveness, safety, and efficacy over longer periods, and prioritize patient-centered endpoints.’ Reviewer 3 1. This meta-analysis does not have a funnel plot to look at the publication bias. There is considerable heterogeneity (I2=80.1%) and lacks a sensitivity analysis. Thank you for your comment regarding the 'funnel plot' and sensitivity analysis. We appreciate and agree with your suggestion. We have incorporated sensitivity analysis for the main outcomes, as follows: ● [Page 10; line 14] ‘The sensitivity analysis for the percentage of time in the SpO2 target, included only trials with a low risk of bias (S4 Fig.) and showed similar estimates of the intervention and inconsistency. There's no clinically important difference in effect estimates between the meta-analysis encompassing all studies and the one focusing solely on studies with a low risk of bias, any inconsistency is likely to be insignificant [55].’ [Supporting information page 7] S4 Fig. Sensitivity analyses for the percentage of time spent in the SpO2 target [Page 12; line 15] ‘In the sensitivity analyses excluding trials with some concerns according to the risk of bias assessment (S8 Fig), we observed a slight increase in the heterogeneity (I² = 83%) maintaining the direction of the effect of interventions (MD -4.94, 95% CI -9.43 to -0.46).’ [Supporting information page 13] S8 Fig. Sensitivity analyses for healthcare professional’s workload We fully agree that the absence of a Funnel Plot analysis is a limitation of our systematic review. Despite the inclusion of only seven studies in the meta-analysis, we also performed the funnel plot for the percentage of time in the SpO2 target (see the figure below). However, the test for publication bias is severely underpowered for this outcome, and visual inspection of a funnel plot with few studies can be highly misleading. Thus, this result should be interpreted with caution. We have incorporated this information into the results and discussion section, as follows: ● [Page 10; line 19] ‘Despite the observed asymmetry in the funnel plot (S5 Fig.), we cannot definitively attribute it to publication bias due to the limited number of studies included in this outcome.’ ● [Page 16; line 16] ‘Second, despite our considerable efforts to mitigate publication bias, we were unable to reliably assess it through the funnel plot due to the limited number of available studies.’ [Supporting information page 8] S5. Fig. Funnel plot for the percentage of time spent in the SpO2 target. Your advice aligns with the suggestions made by other reviewers above, where subgroup analyses have been proposed with the aim of exploring how effect varies across different groups. (please refer to our response to comments 4 and 5 by reviewer '1'). Attachments Attachment Submitted filename: 0. [PLoS One - Major Revision] Rebuttal letter.docx https://doi.org/10.1371/journal.pone.0304745.r002
17 May 2024 Decision Letter - Vijay Hadda, Editor Closed-loop oxygen control for critically ill patients––A systematic review and meta-analysis PONE-D-24-04130R1 Dear Dr. Mól, 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, Vijay Hadda, MD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: (No Response) ****** 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: (No Response) ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The changes recommended have been included in the revision The article is acceptable for publication Reviewer #2: (No Response) ****** 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: Yes: Manu Chopra ******** https://doi.org/10.1371/journal.pone.0304745.r003
Formally Accepted
3 Jun 2024 Acceptance Letter - Vijay Hadda, Editor PONE-D-24-04130R1 PLOS ONE Dear Dr. Mól, 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 If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks 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. 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. Vijay Hadda Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0304745.r004

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