Use of extracorporeal membrane oxygenation for eCPR in the emergency room in patients with refractory out-of-hospital cardiac arrest

L. Christian Napp; Carolina Sanchez Martinez; Muharrem Akin; Vera Garcheva; Christian Kühn; Johann Bauersachs; Andreas Schäfer

doi:10.1371/journal.pone.0239777

Peer Review History

Original SubmissionJuly 23, 2020
3 Aug 2020 Decision Letter - Gaetano Santulli, Editor PONE-D-20-22896 Use of extracorporeal membrane oxygenation for eCPR in the emergency room in patients with refractory out-of-hospital cardiac arrest PLOS ONE Dear Dr. Schäfer, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Sep 17 2020 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Gaetano Santulli 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. Thank you for including your ethics statement: 'The HAnnover Cooling REgistry (HACORE) is a prospective observational registry approved by the ethics committee at Hannover Medical School (#3567-2017) in accordance with the Declaration of Helsinki.' a. Please amend your current ethics statement to confirm that your named institutional review board or ethics committee specifically approved this study. b. Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”). For additional information about PLOS ONE ethical requirements for human subjects research, please refer to http://journals.plos.org/plosone/s/submission-guidelines#loc-human-subjects-research 3. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information. If you are reporting a retrospective study of medical records or archived samples, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information. 4. Thank you for stating the following in the Competing Interests section: "AS has received lecture and proctoring honoraria from Abiomed and ZOLL, LCN has received lecture honoraria from Maquet, Abbott, Zoll and Orion as well as lecture, consulting and proctoring honoraria from Abiomed. All other authors declare no conflict 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. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests 5. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. [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: It was very refreshing to read your well-written manuscript that comes to a conclusion that one probably did not hope for. A "Hail Mary" treatment option such as eCPR is extremely difficult to implement in a timely fashion and adherence to selection criteria seems next to impossible. As you astutely mentioned, statistics do not apply to individuals, which explains why, in the heat of the moment, physicians may have difficulty adhering to such rigid criteria, not to mention that some of this information may not have been immediately available when the decision was made to consider eCPR. Your conclusion about needing to shorten low-flow time in the future paves the way for future eCPR studies and implementation. Finally, your tables are excellent, and it was especially interesting to read about the individual characteristics of the survivors in Table 3. I have a few questions. Why do you suppose that 75% of the patients were male? Also, could you describe "mechanical compressions?" Do all of the ambulances in your region use Lucas or other devices? According to Table 3, the only survivor with a CPC score of 1 in your study did not have mechanical compressions until arriving in the ED. Also, could you please define the parameters of neuroprotective hypothermia? The remainder of my comments are purely minor typographical errors. Lines 62-63: commas after numerous and younger. Line 63: spell out "minutes." Line 64: remove comma. Line 74: comma after 10%. Line 79: comma after here. Line 80: comma after selection. Remove comma after approach. Line 114: period after CPC. Line 176:...eCPR is obviously a very... Line 179: remove comma. Line 206 does not make sense. It should read more like: "Positive outcomes from eCPR are still limited, and only a few patients finally survive until discharge." Reviewer #2: This is a nicely written paper examining clinical outcomes of e-CPR in 40 patients, showing 5 survivors with only 3 of those 5 having a good neurological outcome. I think the data are well presented and represent a large body of experience with this approach. With a growing use of ECMO this is an important topic. However the results were not so good and were consistent with previous publications. The authors point out why this is in that the ideal criteria were not applied to these patients. I think this paper could be greatly improved by adding a Table with a list of proposed criteria based on the experiences garnered from this data set. In other words who should we not put on bypass. This is a very important question in this data set is uniquely positioned to be able to suggest reasonable criteria. Perhaps the authors could do a speculative analysis of the data set that would suggest a set of criteria that might results in a survival rate of say 20%. In other words, keep the survivors, but identify a set of criteria that would reduce the non-survivor numbers to the point where the survival rate was 20% (or whatever % the authors feel would make eCPR a reasonable option from a chance of survival standpoint as well as cost. Also they should consider adding cost data. ****** 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: Yes: Gayle Galletta, MD Reviewer #2: Yes:** T. Sloane Guy, MD [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.0239777.r001
Revision 1
11 Aug 2020 Author Response Response to Editor Manuscript PONE-D-20-22896 We would like to thank the Editor for his/her constructive criticism and valuable input. We hope that the changes made to the manuscript and the responses detailed below, satisfactorily address the concerns raised. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The manuscript has been formatted according to the recommendations given prior to any responses to the reviewers. 2. Thank you for including your ethics statement: 'The HAnnover Cooling REgistry (HACORE) is a prospective observational registry approved by the ethics committee at Hannover Medical School (#3567-2017) in accordance with the Declaration of Helsinki.' a. Please amend your current ethics statement to confirm that your named institutional review board or ethics committee specifically approved this study. b. Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”). The ethics statement has been amended as requested in the manuscript (lines 79-80) and the online submission form. 3. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information. If you are reporting a retrospective study of medical records or archived samples, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information. Written informed consent was obtained from legal guardians during the unconscious period and re-consented by survivors after gaining consciousness. Anonymized data were entered into the database. This statement is now included in the Methods section (lines 79-82) and the online submission from. 4. Thank you for stating the following in the Competing Interests section: "AS has received lecture and proctoring honoraria from Abiomed and ZOLL, LCN has received lecture honoraria from Maquet, Abbott, Zoll and Orion as well as lecture, consulting and proctoring honoraria from Abiomed. All other authors declare no conflict 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.” The statement has been included in the “conflict of interest” section on page 18 as requested. 5. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. Regarding data availability there is a legal restriction as the smaller patient sample includes potentially identifying patient information and specific dates. Contact information for the ethics committee is: Ethikkommission@mh-hannover.de. This has been included in the revised cover letter. Response to Reviewer #1 Manuscript PONE-D-20-22896 We would like to thank the reviewer for his/her constructive criticism and valuable input. We hope that the changes made to the manuscript and the responses detailed below, satisfactorily address the concerns raised. It was very refreshing to read your well-written manuscript that comes to a conclusion that one probably did not hope for. A "Hail Mary" treatment option such as eCPR is extremely difficult to implement in a timely fashion and adherence to selection criteria seems next to impossible. As you astutely mentioned, statistics do not apply to individuals, which explains why, in the heat of the moment, physicians may have difficulty adhering to such rigid criteria, not to mention that some of this information may not have been immediately available when the decision was made to consider eCPR. Your conclusion about needing to shorten low-flow time in the future paves the way for future eCPR studies and implementation. Finally, your tables are excellent, and it was especially interesting to read about the individual characteristics of the survivors in Table 3. We thank the reviewer for this positive recognition of our work. I have a few questions. Why do you suppose that 75% of the patients were male? The majority of eCPR patients without obvious non-cardiac cause of arrest such as drowning had critical coronary stenosis suggestive for acute myocardial infarction. In a recent AMI-registry at our institution of almost 300 AMI patients, 77% were male. Therefore, considering AMI as the major cause for cardiac arrest in the eCPR population as well, a ratio about 75% male patients would not be too surprising. A statement regarding this has been added to the results section (lines 130-133). Also, could you describe "mechanical compressions?" Do all of the ambulances in your region use Lucas or other devices? According to Table 3, the only survivor with a CPC score of 1 in your study did not have mechanical compressions until arriving in the ED. In order to prevent insufficient circulation during transport, we recommended the use of mechanical compression devices. In Germany, a rendezvous system consisting of a paramedic-staffed ambulance and an emergency physician-staffed response car or rescue helicopter are dispatched for cardiac arrest patients. In our city, all physician-staffed response cars and the rescue helicopters are equipped with the LUCAS device. The one patient mentioned by the reviewer was brought to our cardiac arrest centre by an anesthesiologist from our hospital, who was on call on a non-LUCAS-equipped response car outside the city boundaries. Also, could you please define the parameters of neuroprotective hypothermia? As suggested by the reviewer, we have added a short description of mode of cooling, target temperature, duration of hypothermia, rewarming, and maintained normothermia to the methods section (lines 108-113). The remainder of my comments are purely minor typographical errors. Lines 62-63: commas after numerous and younger. Line 63: spell out "minutes." Line 64: remove comma. Line 74: comma after 10%. Line 79: comma after here. Line 80: comma after selection. Remove comma after approach. Line 114: period after CPC. Line 176:...eCPR is obviously a very... Line 179: remove comma. We thank the reviewer for pointing out the typographical errors which have all been corrected in the revised version of the manuscript. Line 206 does not make sense. It should read more like: "Positive outcomes from eCPR are still limited, and only a few patients finally survive until discharge." We thank the reviewer for this helpful suggestion which has been adopted (lines 234-235). Response to Reviewer #2 Manuscript PONE-D-20-22896 We would like to thank the reviewer for his/her constructive criticism and valuable input. We hope that the changes made to the manuscript and the responses detailed below, satisfactorily address the concerns raised. This is a nicely written paper examining clinical outcomes of e-CPR in 40 patients, showing 5 survivors with only 3 of those 5 having a good neurological outcome. I think the data are well presented and represent a large body of experience with this approach. With a growing use of ECMO this is an important topic. However the results were not so good and were consistent with previous publications. The authors point out why this is in that the ideal criteria were not applied to these patients. We thank the reviewer for this positive recognition of our work. I think this paper could be greatly improved by adding a Table with a list of proposed criteria based on the experiences garnered from this data set. In other words who should we not put on bypass. This is a very important question in this data set is uniquely positioned to be able to suggest reasonable criteria. Perhaps the authors could do a speculative analysis of the data set that would suggest a set of criteria that might results in a survival rate of say 20%. In other words, keep the survivors, but identify a set of criteria that would reduce the non-survivor numbers to the point where the survival rate was 20% (or whatever % the authors feel would make eCPR a reasonable option from a chance of survival standpoint as well as cost. The reviewer’s point is very interesting. With all limitations that apply to such an approach, age >60 years, pulseless electrical activity and absence of bystander CPR could be used in our cohort to enrich the treated population towards a survival rate of 22%. We have added that hypothetical calculation as well as critical statement on influence of cost to the discussion section (lines 216-226). Also they should consider adding cost data. While cost data are certainly an interesting aspect, they differ enormously between countries and different health care systems. In some European countries the hospital has to pay for the use of ECMO, in some countries only excess costs are reimbursed, and in others the hospitals gain revenue by using extracorporeal devices. As appealing as this point is, we, therefore, restrained from adding dedicated cost data. Attachments Attachment Submitted filename: 20200803_Revision 1_eCPR.docx https://doi.org/10.1371/journal.pone.0239777.r002
14 Sep 2020 Decision Letter - Gaetano Santulli, Editor Use of extracorporeal membrane oxygenation for eCPR in the emergency room in patients with refractory out-of-hospital cardiac arrest PONE-D-20-22896R1 Dear Dr. Schäfer, 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, Gaetano Santulli, 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 ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know ****** 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 ****** 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 ****** 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: (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: Yes:** Gayle Galletta, MD https://doi.org/10.1371/journal.pone.0239777.r003
Formally Accepted
17 Sep 2020 Acceptance Letter - Gaetano Santulli, Editor PONE-D-20-22896R1 Use of extracorporeal membrane oxygenation for eCPR in the emergency room in patients with refractory out-of-hospital cardiac arrest Dear Dr. Schäfer: 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 Prof. Gaetano Santulli Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0239777.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 .