Biological evaluation of a mechanical ventilator that operates by controlling an automated manual resuscitator. A descriptive study in swine

Maryanne Melanie Gonzales Carazas; Cesar Miguel Gavidia; Roberto Davila Fernandez; Juan Alberto Vargas Zuñiga; Alberto Crespo Paiva; William Bocanegra; Joan Calderon; Evelyn Sanchez; Rosa Perales; Brandon Zeña; Juan Fernando Calcina Isique; Jaime Reategui; Benjamin Castañeda; Fanny L. Casado

doi:10.1371/journal.pone.0264774

Peer Review History

Original SubmissionSeptember 17, 2021
23 Nov 2021 Decision Letter - Simone Savastano, Editor PONE-D-21-30195Biological evaluation of a mechanical ventilator that operates by controlling an automated manual resuscitator. A descriptive study in swinePLOS ONE Dear Dr. Fanny Lys Casado, 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: Thank you very much for having submitted this paper for consideration. This paper is of potential interest however it needs to be revised according to the reviewers' comments. ============================== Please submit your revised manuscript by Jan 07 2022 11:59PM. 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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: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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 ****** 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: 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: Dear editor Dear Authors This is a descriptive preclinical study describing the physiological effect of a portable, low-cost mechanical ventilator (Masi) on a swine model; since the demand of ventilators increased dramatically worldwide during the recent pandemic, the potential of this device in terms of ease of production is of the utmost interest. The authors investigate the effects of six hours of mechanical ventilation on eight healthy pigs in terms of variation of biological parameters: • Gas exchange and pulmonary function • Acid-base disturbances • Lactate and HCO3- concentration • Cardiac output and heart rate • Hemoglobin The protocol then included histological analysis of lung, kidney, liver, brain and heart of the subjects, failing to demonstrate any major organ damage and in particular any hypoxic lesions relatable to the mechanical ventilation.The researchers concluded that Masi preserves patient physiological parameters within normal ranges during acute exposure (6 hours), avoiding barotrauma. The study has several advantages, such as the reliable animal model (swine) and the absence of evident macroscopic and microscopic organ damage secondary to mechanical ventilation with Masi, as well as the absence of any major organ dysfunction. It is interesting to note that the values of pulmonary compliance of the pigs as listed by the authors in TABLE 2 (between 37 and 44 ml/cmH20) is inferior to the normal human values of 54 [44-64] ml/cmH20 but similar to the value reported in human patients suffering from ARDS - 39 [32-50] mL/cm H2O (1), which are the patients who one would expect would need most often a mechanical ventilator. Considering this, the safety in terms of barotrauma showed by the ventilator is of even greater significance. At the end of the study period every animal was able, when ventilation was stopped, to perform spontaneous breathing supported by PSV, a strong indicator of the ability to breath autonomously previous to the endotracheal tube removal in patients under mechanical ventilation. There are however some issues: Major Issue • The first and most important limitation of the study is the short term of the follow up during mechanical ventilation (six hours). Since the aim of this animal study is to validate the ventilator, one could argue that the duration of mechanical ventilation in ARDS or Sars-CoV-2 pneumonia with respiratory failure is seldom limited to a few hours, extending well beyond such as several days in many reports (2) . Minor Issues • Even though I understand that is not strictly the point of this article, a simple diagram of the mechanical ventilator itself (such as figure 1 of the article in the fifth citation, which I understand is also from your group) could help the reader to understand the item in discussion. • Linear measurements in short axis (as shown in figure S2 of the supporting information) are not the echocardiographic assessment of choice for cardiac output. It would be reasonable in terms of accuracy to present the data in terms of LVEDV, LVESV and HR instead of cardiac output (being the clinical value most likely the same). • Line 405 “Therefore, the upper distribution of ETCO2 values is consistent the absence of lung tissue damage” should be “is consistent with the absence of lung tissue damage” (1) Arnal JM, Garnero A, Saoli M, Chatburn RL. Parameters for Simulation of Adult Subjects During Mechanical Ventilation. Respir Care. 2018 Feb;63(2):158-168. doi: 10.4187/respcare.05775. Epub 2017 Oct 17. PMID: 29042486. (2) King CS, Sahjwani D, Brown AW, et al. Outcomes of mechanically ventilated patients with COVID-19 associated respiratory failure. PLoS One. 2020;15(11):e0242651. Published 2020 Nov 23. doi:10.1371/journal.pone.0242651 Nice work! Reviewer #2: The manuscript entitled “Biological evaluation of a mechanical ventilator that operates by controlling an automated manual resuscitator. A descriptive study in swine” ( Manuscript number PONE-D-21-30195) presented the characteristics of a new ventilator device. I congratulate the authors for the study, risen from the need to dispose of larger amount of mechanical ventilation during COVID- 19 pandemics; this reason makes this study relevant. However, there are several points that needs to be addressed in order to make this paper worthy of publication. The characteristic of the tested ventilator highlighted in the title (“…that operates by controlling an automated manual resuscitator”) is not considered at all into the manuscript. Introduction. In my opinion, retracing the evolution of the COVID- 19 pandemics (i.e. Specifying date of the first case in China and in Perù) is not pertaining to the aim of the study. In order to put the new mechanical ventilator production into the context of the COVID – 19 pandemics, the authors should instead provide more precise epidemiologic data (es. number of patients admitted, patients requiring mechanical ventilation). From line 76 to 79. Please provide some details about the so called “operating mechanism” of the Masi ventilator. In this context, mentioning the commercial name of other similar ventilator may be confounding and not relevant. Which is the meaning of “less complex mechanical ventilator systems”? In other words, please brefly describe the differences between the Masi ventilator and others, commonly used in the ICU. From line 85 to 87. Please rephrase this sentence. From line 96 to 98.The aims of the study should be precisely defined at this point, together with the primary endpoints. Methods. The experimental design should be clearer then it is. Moreover, sample size calculation should be explicated for each proposed study included in the experimental design. Line 216-217. Variables measured by echocardiography should be defined and subsequently described into the results section. The assessment “there were no alterations in the functioning of these organs that could indicate injuries related to the use of Masi mechanical ventilator” (line348-349) is a qualitative evaluation. Line 251. Pigs (at baseline) are not patients. Table 3. Reference values showed in a separated figure are unclear. ****** 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:** Alessandro Fasolino 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. Attachments Attachment Submitted filename: Manuscript number PONE-D-21-30195.docx https://doi.org/10.1371/journal.pone.0264774.r001
Revision 1
20 Jan 2022 Author Response 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. ANSWER The Manuscript has been modified into PLOS One format. 2. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. ANSWER We have included all of the raw data in the Supporting Information file. 3. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section. ANSWER The Manuscript has been modified to address this requirement. 4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. ANSWER We modified the Supporting Information files and have updated the captions and in-text citations to address this requirement. II. COMMENTS OF REVIEWER #1: This is a descriptive preclinical study describing the physiological effect of a portable, low-cost mechanical ventilator (Masi) on a swine model; since the demand of ventilators increased dramatically worldwide during the recent pandemic, the potential of this device in terms of ease of production is of the utmost interest. The authors investigate the effects of six hours of mechanical ventilation on eight healthy pigs in terms of variation of biological parameters: • Gas exchange and pulmonary function • Acid-base disturbances • Lactate and HCO3- concentration • Cardiac output and heart rate • Hemoglobin The protocol then included histological analysis of lung, kidney, liver, brain and heart of the subjects, failing to demonstrate any major organ damage and in particular any hypoxic lesions relatable to the mechanical ventilation.The researchers concluded that Masi preserves patient physiological parameters within normal ranges during acute exposure (6 hours), avoiding barotrauma. The study has several advantages, such as the reliable animal model (swine) and the absence of evident macroscopic and microscopic organ damage secondary to mechanical ventilation with Masi, as well as the absence of any major organ dysfunction. It is interesting to note that the values of pulmonary compliance of the pigs as listed by the authors in TABLE 2 (between 37 and 44 ml/cmH20) is inferior to the normal human values of 54 [44-64] ml/cmH20 but similar to the value reported in human patients suffering from ARDS - 39 [32-50] mL/cm H2O (1), which are the patients who one would expect would need most often a mechanical ventilator. Considering this, the safety in terms of barotrauma showed by the ventilator is of even greater significance. At the end of the study period every animal was able, when ventilation was stopped, to perform spontaneous breathing supported by PSV, a strong indicator of the ability to breath autonomously previous to the endotracheal tube removal in patients under mechanical ventilation. (1) Arnal JM, Garnero A, Saoli M, Chatburn RL. Parameters for Simulation of Adult Subjects During Mechanical Ventilation. Respir Care. 2018 Feb;63(2):158-168. doi: 10.4187/respcare.05775. Epub 2017 Oct 17. PMID: 29042486. There are however some issues: Major Issue • The first and most important limitation of the study is the short term of the follow up during mechanical ventilation (six hours). Since the aim of this animal study is to validate the ventilator, one could argue that the duration of mechanical ventilation in ARDS or Sars-CoV-2 pneumonia with respiratory failure is seldom limited to a few hours, extending well beyond such as several days in many reports (2). (2) King CS, Sahjwani D, Brown AW, et al. Outcomes of mechanically ventilated patients with COVID-19 associated respiratory failure. PLoS One. 2020;15(11):e0242651. Published 2020 Nov 23. doi:10.1371/journal.pone.0242651 ANSWER: We agree with the reviewer that the aim of the study is to validate the ventilator and that there are clinical scenarios that we do not address in this study. However, it needs to be qualified that this is a pre-clinical validation of a medical device. Consensual technical standards such as the ISO10993-2 Biological Evaluation of Medical Devices – Part 2: Animal Welfare Requirements define validation as the “formal process by which the reliability and relevance of a test method is established for a particular purpose”. In that sense, testing the device for six-hours in pigs is a reliable and relevant method to address questions of control of gas exchange and acute damage to internal organs. The purpose of pre-clinical validation is to provide evidence to support moving into clinical validation where questions regarding time of exposure in the context of specific diseases are currently being addressed. Therefore, we respectfully disagree that a six-hour exposure represents any limitation to this specific study since it was not designed to address how long it takes to observe detrimental effects in humans diagnosed with a particular disease because those questions are better suited to be asked in clinical studies with the proper criteria of inclusion and exclusion of participants in the context of pharmaceutical interventions to stabilize the patients or cure the disease. Minor Issues • Even though I understand that is not strictly the point of this article, a simple diagram of the mechanical ventilator itself (such as figure 1 of the article in the fifth citation, which I understand is also from your group) could help the reader to understand the item in discussion. ANSWER: We added a new figure as Figure 1 and modified the introduction to better explain the characteristics of the ventilator being studied. • Linear measurements in short axis (as shown in figure S2 of the supporting information) are not the echocardiographic assessment of choice for cardiac output. It would be reasonable in terms of accuracy to present the data in terms of LVEDV, LVESV and HR instead of cardiac output (being the clinical value most likely the same). ANSWER: We have modified S2 Figure caption to better communicate its relevance and modified S4 Table to provide all of the data recorded including LVEDV, LVESV, HR and cardiac output. • Line 405 “Therefore, the upper distribution of ETCO2 values is consistent the absence of lung tissue damage” should be “is consistent with the absence of lung tissue damage” Nice work! ANSWER: Thank you for your encouraging words. We fixed this involuntary typographical error on the Manuscript. III. COMMENTS OF REVIEWER #2: The manuscript entitled “Biological evaluation of a mechanical ventilator that operates by controlling an automated manual resuscitator. A descriptive study in swine” ( Manuscript number PONE-D-21-30195) presented the characteristics of a new ventilator device. I congratulate the authors for the study, risen from the need to dispose of larger amount of mechanical ventilation during COVID- 19 pandemics; this reason makes this study relevant. However, there are several points that needs to be addressed in order to make this paper worthy of publication. The characteristic of the tested ventilator highlighted in the title (“…that operates by controlling an automated manual resuscitator”) is not considered at all into the manuscript. ANSWER: We added a new figure as Figure 1 and modified the introduction to better explain the characteristics of the ventilator being studied. Introduction. In my opinion, retracing the evolution of the COVID- 19 pandemics (i.e. Specifying date of the first case in China and in Perù) is not pertaining to the aim of the study. In order to put the new mechanical ventilator production into the context of the COVID – 19 pandemics, the authors should instead provide more precise epidemiologic data (es. number of patients admitted, patients requiring mechanical ventilation). ANSWER: We modified the introduction to include the information requested. From line 76 to 79. Please provide some details about the so called “operating mechanism” of the Masi ventilator. In this context, mentioning the commercial name of other similar ventilator may be confounding and not relevant. Which is the meaning of “less complex mechanical ventilator systems”? In other words, please brefly describe the differences between the Masi ventilator and others, commonly used in the ICU. ANSWER: We added a new figure as Figure 1 and modified the introduction to better explain the characteristics of the ventilator being studied in the context of other ventilators found in ICU. From line 85 to 87. Please rephrase this sentence. ANSWER: We modified the introduction to address this comment. From line 96 to 98.The aims of the study should be precisely defined at this point, together with the primary endpoints. ANSWER: We modified the introduction to include the information requested. Methods. The experimental design should be clearer then it is. Moreover, sample size calculation should be explicated for each proposed study included in the experimental design. ANSWER: We modified original Figure 1 to be new Figure 2 and modified the text of Experimental design to better explain the characteristics of the ventilator being studied. Line 216-217. Variables measured by echocardiography should be defined and subsequently described into the results section. The assessment “there were no alterations in the functioning of these organs that could indicate injuries related to the use of Masi mechanical ventilator” (line348-349) is a qualitative evaluation. ANSWER: We have modified S2 Figure caption to better communicate its relevance and modified S4 Table to provide all of the data recorded that supports the qualitative evaluation provided by the veterinary cardiologist. Line 251. Pigs (at baseline) are not patients. ANSWER: We modified the text to fix this involuntary error. Table 3. Reference values showed in a separated figure are unclear. ANSWER: For clarity, Table 3 was modified to only focus on summarized data from current study. We added S2 Table to showcase the comparison between swine physiological data from Table 1 (published previously) and Table 3 (current pre-clinical study). https://doi.org/10.1371/journal.pone.0264774.r002
17 Feb 2022 Decision Letter - Simone Savastano, Editor Biological evaluation of a mechanical ventilator that operates by controlling an automated manual resuscitator. A descriptive study in swine PONE-D-21-30195R1 Dear Dr. Casado, 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, Simone Savastano Academic Editor PLOS ONE Additional Editor Comments (optional): I congratulate the Authors for having addressed properly the Reviewers' comments. There are still some typos that can be fixed in the further editing phases following the reviewers' indications. 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: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 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: All my concerns were addressed by the authors. Minor issues/typos: - I don't understand the correction in the following sentence "Atypical responses in Pig #1_2 and Pig #1_5" in line 323. Maybe it should be: "Atypical responses in Pig 2 and Pig 5"? - "Figure 54" in line 387/402/404 is probably a typo Once addressed these very minor issues the article is fit for publication. Reviewer #2: The authors have clarified several of the questions I raised in my previous review. The paper is worthy of publication. The authors only should revise the language to further improve readability. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No https://doi.org/10.1371/journal.pone.0264774.r003
Formally Accepted
23 Feb 2022 Acceptance Letter - Simone Savastano, Editor PONE-D-21-30195R1 Biological evaluation of a mechanical ventilator that operates by controlling an automated manual resuscitator. A descriptive study in swine Dear Dr. Casado: 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. Simone Savastano Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0264774.r004

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